Medicalstudyzone.com Table of contents Adenoviridae 1 Aerobic rods 3 Bacillus anthracis 3 Bacillus cereus 5 C diphtheriae 6 Listeria monocytogenes 8 Anaerobic rods 9 Clostridium botulinum 9 Clostridium difficle 11 Clostridium perfringens 13 Clostridium tetani 15 Arenaviridae 18 Lymphocytic choriomeningitis 18 Bunyaviruses 20 Hantavirus 21 Calcaviruses 23 Norvovirus 23 Central Nervous System infections 25 Acanthamoeba 26 Naegleria floweri 27 Toxoplasma gondii 28 Haemophilus ducreyi 45 Haemophilus influenza 47 Pasteurella multocida 49 Comma-shaped rods 51 Campylobacter jejuni 51 Helicobacter pylori 53 Vibrio cholerae 55 Coronaviruses 57 Coronavirus (sars) 58 Cutaneous fungal infections 59 Malassezia 59 Diplococci: aerobic 62 Moraxella catarrhalis 63 Neisseria gonorrhoeae 64 Neisseria meningitidis 66 Ecotparasites 68 Pediculosis corporis, capitis and pubis (lice) 68 Sarcoptes scabiei (scabies) 70 Enterococcus 73 Enterococcus 73 Cestodes(tapeworms) 31 Diphyllobothrium latum 32 Echinococcus granulosis 33 Filaments 75 Actinomyces israelii 76 Nocardia 78 Chlamydia 35 Chlamydia species (pneumonia) 35 Chlamydia trachomatis 36 Filoviruses 81 Ebola virus 81 Coccobacilli: aerobes 38 Bordetella pertussis 38 Francisella tularensis 40 Coccobacilli: facultative anaerobes 42 Brucella 42 Flaviviruses 84 Dengue virus 85 West nile virus 86 Yellow fever virus 88 Zika virus 89 Gastrointestinal infections 92 Cryptosporidium 93 AfraTafreeh.com exclusive Table of contents Entamoeba histolytica (amoebiasis) 95 Giardia lamblia 96 General infections 98 Abscesses 98 Sepsis 100 Gram variable 102 Gardnerella vaginallis 102 Hematologic infections 104 Babesia 105 Plasmodium species (malaria) 107 Hepadnaviridae 110 Hepatitis b virus 110 Hepatitis d virus 114 Herpesviruses 115 Cytomegalovirus 115 Epstein-barr virus (ebv) 116 Herpes simplex virus 117 Human herpesvirus 6 (roseola) 119 Human herpesvirus 8 (kaposi’s sarcoma) 120 Varicella zoster virus 122 Leishmania 125 Mycoplasma 127 Mycoplasma pneumonia 127 Nematodes (roundworms) 129 Ancylostoma duodenale & necator americanus 130 Angiostrongylus (eosinophilic meningitis) 132 Anisakis 133 Ascaris lumbricoides 134 Enterobius vermicularis (pinworm) 137 Guinea worm (dracunculiasis) 138 Loa loa (eye worm) 139 Onchocerca volvulus (river blindness) 140 Strongyloides stercoralis 142 Toxocara canis (visceral larva migrans) 144 Trichinella spiralis 145 Trichuris trichiura (whipworm) 147 Wuchereria bancrofti (lymphatic filariasis) 148 Non tuberculous mycobacterium 151 Mycobacterium leprae 151 Opportunisitc fungal infections 153 Aspergillus fumigatus 153 Candida 156 Cryptococcus neoformans 158 Mucormycosis 160 Pneumocystis jirovecii 162 Sporothrix schenckii 163 Orthomyxoviruses 165 Influenza virus 166 Papillomavirus 168 Human papillomavirus 168 Paramyxoviruses 171 Human parainfluenza viruses (hpiv) 171 Measles virus 172 Mumps virus 174 Respiratory syncytial virus (rsv) 176 Parvovirus 177 Picornaviruses 180 Coxsackievirus 181 Hepatitis a virus 182 Poliomyelitis 183 Table of contents Rhinovirus 185 Polyomavirus 187 Bk virus (hemorrhagic cystitis) 187 JC virus (PML) 188 Poxviridae 190 Molluscum contagiosum 190 Reoviruses 192 Rotavirus 192 Retroviruses 194 Human immunodeficiency virus 194 Human T-lymphotropic virus 202 Rhabdoviruses 204 Rabies virus 204 Rickettsial diseases 207 Anaplasma 208 Coxiella burnetti (q fever) 210 Ehrlichia 211 Rickettsia rickettsii 213 Rickettsia typhi 215 Rods 216 Bacteroides fragillis 216 Bartonella henselae 217 Enterobacter 219 Escherichia coli 220 Klebsiella pneuomniae 222 Legionella pneumophilia 223 Nontyphoidal salmonella 224 Proteus mirabilis 225 Pseudomonas aeruginosa 226 Serratia marcescens 228 Shigella 229 Yersinia marcescens 230 Spirochetes 233 Borrelia burgdorferi (lyme disease) 233 Borrelia species (relapsing fever) 235 Leptospira 237 Treponema pallidum (syphilis) 238 Staphylococcus 241 Staphylococcus aureus 241 Staphylococcus epidermidis 243 Staphylococcus saprophyticus 244 Streptococcus 245 Streptococcus agalactiae (group b strep) 245 Streptococcus pneumoniae 246 Streptococcus pyogenes (group a strep) 248 Streptococcus viridans 249 Systemic mycoses 251 Blastomyces spp. 251 Coccidioides spp. 253 Histoplasma capsulatum 255 Paracoccidioides brasiliensis 256 Togavirus 258 Eastern equine encephalitis virus (eeev) 258 Rubella virus 259 Western equine encephalitis virus (wee) 261 Trematodes (flatworms) 263 Clonorchis sinesis 264 Paragonimus westermani 265 Schistosomes 266 AfraTafreeh.com exclusive Table of contents Trichomona 269 Trichomonas vaginalis 269 Trypanosoma 271 Trypanosoma brucei 271 Trypanosoma cruzi 273 Tuberculosis 276 Mycobacterium tuberculosis 276 NOTES NOTES ADENOVIRIDAE ADENOVIRUS osms.it/adenovirus PATHOLOGY & CAUSES ▪ Seven subgroups, 52 serotypes ▪ Directly invades human epithelial cells (several organs) → multiple cytopathic effects, usually within 2–7 days postinfection ▪ Responsible for variety of upper, lower respiratory tract; gastrointestinal; genitourinary infections ▪ Common clinical syndromes ▫ Upper respiratory disease, pharyngoconjunctival fever, coryza, pneumonia, gastroenteritis, hepatitis, hemorrhagic cystitis, interstitial nephritis, epidemic keratoconjunctivitis Genetic material ▪ Double-stranded DNA virus Taxonomy ▪ Adenoviridae family Morphology ▪ Non-enveloped icosahedral nucleocapsid ▪ Unique ▫ Fiber-like projections (hemagglutinins) protrude from capsid’s 12 vertices Transmission ▪ Aerosol droplets ▪ Fecal-oral route ▪ Neonates ▫ Infected cervical secretion exposure ▪ Solid organ transplant ▪ Fomite contact ▫ Survives on environmental surfaces for long periods; inactivated by heat, formaldehyde, bleach RISK FACTORS ▪ Close living space (e.g. military barracks, daycare centers) ▪ Summer camps (especially with swimming pools/lakes) ▪ Healthcare facilities ▪ Immunocompromised status (especially cell-mediated immunity deficiency) COMPLICATIONS ▪ Secondary bacterial infection; meningoencephalitis; myocarditis; disseminated intravascular coagulation; myositis, rhabdomyolysis; hypogammaglobulinemia ▪ Disseminated adenovirus infection ▫ Affects multiple organs, immunocompromised individuals especially; high mortality rate SIGNS & SYMPTOMS ▪ Varies with clinical syndrome ▪ Upper respiratory ▫ Sore throat, nasal congestion, rhinorrhea, dry cough, hoarseness, inflamed tonsils, cervical lymphadenopathy; wheezes/rhonchi on auscultation 1 Chapter 54 Adenoviridae ▪ Ocular ▫ Conjunctivitis, preauricular, lymphadenopathy ▪ Gastrointestinal ▫ Nausea, vomiting, diarrhea ▪ Systemic ▫ Fever, malaise, headache, myalgia DIAGNOSIS ▪ History, physical examination ▫ Characteristic findings ▫ Diagnostic test choice based on clinical presentation DIAGNOSTIC IMAGING Chest X-ray ▪ May show diffuse bilateral pulmonary mononuclear cell infiltration, hyaline membranes, necrosis LAB RESULTS Microbe identification ▪ Viral culture (e.g. nasopharyngeal swabs, blood, urine, sputum) ▪ Viral assay (e.g. adenovirus-specific enzyme immunoassay (EIA)/ immunofluorescence assay) ▪ Nucleotide amplification test (NAT) ▪ Polymerase chain reaction (PCR) Serology ▪ Antigen/complement fixation assays ▪ Hemagglutination inhibition/neutralizing antibodies ▪ Restriction endonuclease (RE) analysis Tissue biopsy ▪ Eosinophilic inclusions (early stage) ▪ Basophilic inclusion surrounded by clear intranuclear inclusion Electron microscopy ▪ Icosahedral virions forming intranuclear paracrystalline aggregates TREATMENT ▪ Usually self-limiting disease MEDICATIONS Pharmacotherapy ▪ Immunocompromised/severe infection individuals ▫ Antivirals, immunoglobulin (IVIG) Prevention ▪ Infection control measures ▪ Live oral enteric-coated vaccine used for military recruits only 2 NOTES NOTES AEROBIC RODS MICROBE OVERVIEW ▪ Gram-positive, rod-shaped, aerobes/ facultative anaerobes BACILLUS ANTHRACIS (ANTHRAX) osms.it/bacillus-anthracis PATHOLOGY & CAUSES ▪ Etiologic agent of anthrax; nonmotile, nonhemolytic; potential biological weapon ▪ Endospore-forming (centrally located) ▫ Highly adaptable to extreme environmental conditions ▪ Surrounded by protein capsule (composed of poly-D-gamma-glutamic acid) ▫ Prevents phagocytosis ▪ Transmission (4 Is) ▫ Ingestion ▫ Inhalation ▫ skin Invasion ▫ direct Injection ▪ Anthrax toxin composed of three proteins ▫ Protective antigen (PA): essential for binding, entry to cell ▫ Lethal factor (LF): alteration of signaling pathways → cell death; ↑ 3 Chapter 55 Aerobic Rods proinflammatory cytokines production → inflammation ▫ Edema factor (EF): ↑ cyclic adenosine monophosphate (cAMP) → disordered water, electrolyte balance → edema RISK FACTORS ▪ Occupational ▫ People who work with animals/ animal products (e.g. veterinarians, livestock producers, butchers); possible bioterrorism (e.g. military personnel); laboratory professionals ▪ Injecting drug users (e.g. heroin contaminated with anthrax spores) COMPLICATIONS ▪ Hemorrhagic meningitis, mediastinitis; pleural effusion; pneumonia; shock SIGNS & SYMPTOMS ▪ Respiratory infection ▫ Prodromal phase: flu-like symptoms (e.g. fever, malaise, myalgia), hemoptysis, dyspnea, nausea, chest pain ▫ Fulminant phase: severe dyspnea, hypoxemia, cyanosis, shock, coma ▪ Gastrointestinal (GI) infection ▫ Severe abdominal pain; nausea; vomiting; ascites; ulcerations → GI hemorrhage ▪ Cutaneous infection ▫ Painless, pruritic papule → enlarges, forms central black-colored necrotic ulceration → black eschar ▫ Surrounding edema ▫ Regional lymphadenopathy, lymphadenitis Figure 55.1 A lesion on the neck caused by Bacillus anthracis. DIAGNOSIS LAB RESULTS ▪ Identify microbe ▫ Gram stain, culture, direct fluorescent antibody (DFA), polymerase chain reaction (PCR) OTHER DIAGNOSTICS ▪ History, physical examination TREATMENT MEDICATIONS ▪ Antibiotics OTHER INTERVENTIONS ▪ Vaccine (people at high risk of exposure, post-exposure prophylaxis) 4 AfraTafreeh.com exclusive BACILLUS CEREUS (FOOD POISONING) osms.it/bacillus-cereus PATHOLOGY & CAUSES ▪ Common foodborne pathogen; also associated with contaminated medical equipment (e.g. ventilators, dialysis machines), opportunistic infections ▪ Endospore-forming (centrally located) ▫ Highly adaptable to extreme environmental conditions ▪ Motile, catalase positive, beta-hemolytic ▪ Can be transient component of GI microflora Pathogenesis of food poisoning ▪ Production of enterotoxins ▫ Diarrheal toxin (thermolabile) → ↑ cAMP → disordered function of ion pumps → ↑ efflux of ions, water from infected enterocytes → diarrhea ▫ Emetic toxin, cereulide (thermostable) → ↑ afferent vagus nerve stimulation → nausea, vomiting ▪ Two types of food poisoning ▫ Diarrheal syndrome (meat, vegetables, sauces) → toxicoinfection → ingestion of bacteria, production of toxins in digestive tract ▫ Emetic syndrome (rice) → alimentary intoxication → direct ingestion of toxin SIGNS & SYMPTOMS ▪ Abdominal cramps, diarrhea, nausea, vomiting DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ Stool/contaminated food sample Gram stain Culture (blood agar) PCR TREATMENT OTHER INTERVENTIONS ▪ Intravenous (IV) fluid, electrolyte replacement RISK FACTORS ▪ Consumption of improperly cooked food 5 Chapter 55 Aerobic Rods CORYNEBACTERIUM DIPHTHERIAE (DIPHTHERIA) osms.it/corynebacterium-diphtheriae PATHOLOGY & CAUSES ▪ Infectious agent of diphtheria ▪ Rods with widening at polar regions forming club-like shape ▪ Characteristic “Chinese-letter” arrangement ▪ Nonmotile, non-spore-forming ▪ Stain ▫ Albert’s/Ponder’s; metachromatic granules (e.g. Babes–Ernst, volutin) ▪ Culture ▫ Löffler's medium ▪ Differentiation ▫ Hoyle’s tellurite agar ▪ Types of infection ▫ Respiratory (pharyngeal), cutaneous RISK FACTORS ▪ Absent/incomplete immunization ▪ Immunocompromised individuals ▪ Citizens, migrants, returning travellers from endemic areas (e.g. African, Asian, South American countries) COMPLICATIONS ▪ Myocarditis, nerve damage (e.g. demyelinating polyneuropathy, paralysis), renal failure, suffocation (due to pseudomembrane aspiration) Pathophysiology ▪ Diphtheria toxin → composed of two subunits ▫ A: active, catalytic ▫ B: binding; composed of R (receptor), T (translocation) domains ▪ Bacteria binds to host cell using R domain → endocytosis → acidification inside endosome → T domain transfers to endosomal membrane → translocation of A subunit to cytosol ▪ Subunit A inactivates elongation factor EF2 → inhibition of protein synthesis → cell death ▪ Toxin expression regulated by level of iron ▫ ↑ Fe → ↓ production of toxin ▫ ↓ Fe → ↑ production of toxin Figure 55.2 A pharyngeal pseudomembrane in a child with diphtheria. 6 SIGNS & SYMPTOMS ▪ Respiratory infection ▫ Sore throat; malaise; low-grade fever; dysphagia; thick, grey, isolated necrotic tissue → pseudomembrane; massive swelling of tonsils, cervical lymph nodes → “bull neck”; stridor ▪ Cutaneous infection ▫ Lesions, pain, rash, tenderness, erythema, ulceration DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ Gram stain Culture Elek test (differentiation of toxigenic strains) PCR OTHER DIAGNOSTICS ▪ History, physical examination Figure 55.3 An ulcerating skin lesion on the leg caused by cutaneous diphtheria. TREATMENT MEDICATIONS ▪ Diphtheria antitoxin ▪ Antibiotic OTHER INTERVENTIONS ▪ Prophylaxis ▫ Young children: diphtheria-tetanusacellular pertussis (DTaP) vaccine ▫ Adolescents/adults: tetanus-diphtheria (Td)/tetanus-diphtheria-pertussis (Tdap) vaccine 7 Chapter 55 Aerobic Rods LISTERIA MONOCYTOGENES osms.it/listeria-monocytogenes PATHOLOGY & CAUSES ▪ Facultative intracellular bacteria, anaerobe; beta-hemolytic ▪ Capable of growing at refrigeration temperatures (0–4°C/32–39.2°F) ▪ Motile ▫ ≤ 30°C/32°F (flagella); body temperature (comet tail structures, polymerized host cells actin) ▪ Foodborne pathogen, common cause of bacterial neonatal meningitis Pathophysiology ▪ Listeria enters host cell via zipper mechanism → bacterial protein internalin binds onto cell membrane protein cadherin → releases listeriolysin O → disruption of vacuolar membrane → invasion of cytosol → actin assembling-inducing protein → polymerisation of cytoskeleton → bacteria gains motility → rapid movement through cytosol, between cells RISK FACTORS ▪ Mild febrile gastroenteritis ▫ Immunocompetent individuals, ingestion of contaminated food (e.g. raw meat, unpasteurized dairy, seafood) ▪ Cutaneous infection ▫ Direct inoculation of skin (e.g. veterinarians, farmers handling infected animals) ▪ Invasive listeriosis ▫ Immunocompromised individuals, age (neonates, elderly), pregnancy COMPLICATIONS ▪ Immunodeficient, elderly individuals ▫ Sepsis, meningitis, encephalitis, pneumonia, corneal ulcer ▪ Pregnant individuals ▫ Neonatal meningitis, granulomatosis infantiseptica, miscarriage, stillbirth, premature delivery with chorioamnionitis SIGNS & SYMPTOMS ▪ Previously healthy individuals ▫ Fever, headache, diarrhea, vomiting, nausea, pustular skin lesions ▪ Individuals with weakened immune system ▫ Stiff neck, confusion, convulsions, loss of balance, cranial nerve palsies ▪ Pregnant individuals ▫ Nonspecific flu-like illness ▪ Newborns ▫ Low birth weight, irritability, fever, poor feeding, circulatory/respiratory insufficiency, pyogranulomatous lesions DIAGNOSIS LAB RESULTS ▪ Culture ▫ Blood, cerebrospinal fluid (CSF); cervix, amniotic fluid in pregnant individuals; meconium, gastric aspirate, infected tissues (e.g. skin granulomatous lesions) in newborns OTHER DIAGNOSTICS ▪ History, physical examination TREATMENT MEDICATIONS ▪ Antibiotics (e.g. ampicillin, penicillin G, gentamicin) 8 NOTES NOTES ANAEROBIC RODS MICROBE OVERVIEW ▪ Rod-shaped (bacilli) bacteria, grampositive, strict anaerobes CLOSTRIDIUM BOTULINUM (BOTULISM) osms.it/clostridium-botulinum PATHOLOGY & CAUSES ▪ Ubiquitous presence (esp. soil, water); spore-forming; catalase negative, superoxide dismutase positive, subterminal endospore ▪ Fermentation ▫ Carbohydrates ▪ Obligate anaerobe, can tolerate small amounts of oxygen due to superoxide dismutase ▪ Potential bioterrorism weapon ▪ Absorption of toxin into bloodstream → spreads to nervous system → binds to presynaptic receptors → endocytosis → cleavage of SNAP-25 protein → lack of acetylcholine with impaired transduction Virulence factors ▪ Seven distinct types of neurotoxins (A–G) ▫ Type A: most potent 9 Chapter 56 Anaerobic Rods ▪ Heat-resistant ▫ Toxins enduring temperature of 100ºC/212°F for several hours ▪ H-antigen from flagelle Culture ▪ Chopped meat, glucose, starch medium for isolation; egg yolk agar incubation in anaerobic conditions Disease ▪ Causes disease characterized by muscle weakness, nervous system impairment ▪ Infant botulism ▫ Spores ingestion → germination in gastrointestinal (GI) tract → toxin produced in vivo ▪ Foodborne ▫ Ingestion of botulinum toxincontaminated food ▫ Average incubation period is 12–36 hours ▪ Wound botulism ▫ Wound infection with spores → toxin produced in vivo ▫ Average incubation period is 10 days ▪ Adult intestinal toxemia botulism ▫ Colonization of intestines with toxins production ▪ Iatrogenic botulism ▫ Complication of therapeutic use of botulinum neurotoxins ▪ Enteric infectious botulism ▫ C. botulinum colonizes adult GI tract RISK FACTORS ▪ Infant botulism ▫ Honey consumption in first year of life; ingestion of dust/soil containing C. botulinum spores ▪ Foodborne botulism ▫ Home-canned, improperly preserved food; smoked fish ▪ Wound botulism ▫ IV/subcutaneous drug usage; crush injuries ▪ Enteric infectious botulism ▫ Achlorhydria/other GI diseases → colonization COMPLICATIONS ▪ Sudden infant death syndrome (SIDS), seizures, ileus, death SIGNS & SYMPTOMS ▪ General symptoms precede muscle weakness ▫ Abdominal pain, nausea, vomiting, lack of fever (wound botulism only type with fever) ▪ Cranial nerve impairment ▫ Dilated pupil, ptosis; double vision (due to disconjugate eye movement); ophthalmoplegia; dry mouth, difficulty swallowing; loss of facial expressions ▪ Progressive symmetrical muscle weakness descending from head ▫ Hypotonia, hyporeflexia; floppiness in infants ▫ Respiratory muscles: breathing difficulties ▪ Hyperactivation of autonomic system ▫ ↓ salivation, lacrimation, orthostatic hypotension, obstipation, urine retention DIAGNOSIS LAB RESULTS ▪ Toxin detection/bacteria isolation Enzyme-linked immunosorbent assay (ELISA), mass spectroscopy, polymerase chain reaction (PCR) ▪ Isolation of C. botulinum from feces, vomitus, food OTHER DIAGNOSTICS ▪ History, physical examination Electromyogram (EMG) ▪ Short-lasting motor unit potentials with small amplitude 10 TREATMENT MEDICATIONS ▪ IV botulinum immunoglobulin/heptavalent botulinum antitoxin ▫ Manage infection ▪ Antibiotics ▫ Manage secondary infection ▪ Cholinesterase inhibitors OTHER INTERVENTIONS ▪ Manage infection ▫ Debridement, irrigation of wound ▫ Colon cleansing (enema, cathartics) ▪ Nasogastric tube (feeding), Foley catheter (urinary retention), intubation/mechanical ventilation Prevention ▪ Pentavalent-botulinum-toxoid (PBT) vaccine ▫ Five dose vaccination with booster dose once per year CLOSTRIDIUM DIFFICILE (PSEUDOMEMBRANOUS COLITIS) osms.it/clostridium-difficile PATHOLOGY & CAUSES ▪ Ubiquitously present, can be part of “normal” flora; subterminal endospore; motile ▪ Intestinal microbiota disturbance → infection, colonization of gut → produces A, B toxins → binds to receptors on intestinal wall → internalization → fusion with lysosome → toxins exit endosome → damage of cytoskeleton → cell apoptosis → inflammatory response with accumulation of inflammatory cells, fibrin, dead cells → formation of membrane-like structure (pseudomembrane) Virulence factors ▪ Enterotoxin A (TcdA), cytotoxin B (TcdB), H-antigen from flagelle Culture ▪ Agar with cycloserine, cefoxitin, fructose ▪ C. difficile-associated colitis combined with formation of pseudomembranous plaques Transmission ▪ Fecal-oral route by ingestion of spores RISK FACTORS ▪ Antibiotic exposure ▫ Disturbance of intestinal microbiota ▪ Previous hospitalization ▫ ↑ risk for infection ▪ Children with neutropenia ▫ More prone to common bacterial infections requiring antibiotics → disturbance of intestinal microbiota ▪ Gastric acid suppression, > 65 years, comorbidities COMPLICATIONS ▪ Multiple relapses, dehydration (due to excessive diarrhea) GI complications ▪ Toxic megacolon (due to inflammation damaging muscularis propria, underlying neurons); ileus; colon perforation; intussusception; pneumatosis; ascites; sepsis Extraintestinal complications ▪ Splenic abscess; osteomyelitis 11 Chapter 56 Anaerobic Rods SIGNS & SYMPTOMS ▪ Watery diarrhea (most common) with mucus/blood ▪ Abdominal distension, cramps ▪ Malaise ▪ Fever DIAGNOSIS DIAGNOSTIC IMAGING Sigmoidoscopy/colonoscopy ▪ Visualization of plaques LAB RESULTS SURGERY ▪ Colectomy ▫ In persons with acute abdomen, refractory colitis, fulminant colitis OTHER INTERVENTIONS ▪ End previous antibiotic use ▪ Second relapse: pulse therapy ▪ Recurrent: biological therapies ▫ Fecal microbiota transplant: transplantation of microbiota from healthy individual ▪ Electrolytes, fluids replacement; appropriate nutrition ▪ Prevention of hospital-acquired infection ▫ Infection control protocol, antibiotic stewardship WBCs ▪ ↑ white blood cells Stool analysis ▪ Presence of blood/mucus ▪ Stool culture ▪ Enzyme immunoassay test ▫ Detection of glutamate dehydrogenase antigen ▪ Toxin detection ▫ Enzyme immunoassay, real-time PCR ▪ Cell culture cytotoxicity assay ▪ Biomarkers ▫ Differentiation between colonization, actual disease; ↑ fecal cytokines, CXCL5, phosphorylated p38 Figure 56.1 The gross pathological appearance of the colonic mucosa in psuedomembranous colitis. TREATMENT MEDICATIONS ▪ Mild disease: oral metronidazole ▪ Severe disease: oral vancomycin ▪ Complications: combination of oral vancomycin, IV metronidazole ▪ Second relapse: oral vancomycin tapered ▪ Recurrent: probiotics 12 CLOSTRIDIUM PERFRINGENS osms.it/clostridium-perfringens PATHOLOGY & CAUSES ▪ Ubiquitous in nature, also part of human microbiota; subterminal endospore; nonmotile Virulence factors ▪ Divided into subtypes A–E ▪ Produces 12 toxins ▪ Alpha ▫ Enzyme lecithinase splits lecithin → ↑ vascular permeability → cell destruction ▫ Responsible for gas gangrene, hemolysis ▪ Beta ▫ Formation of selective pores → ↑ permeability with cell destruction ▫ Responsible for enteritis necroticans; deactivated by trypsin ▪ Epsilon ▫ Pores form on cells → destruction ▪ Iota ▫ AB toxin: enzyme (A), binding (B) domain ▫ Destruction of cells through affection of cytoskeleton Culture ▪ Growth on tryptose sulfite cycloserine agar Clostridial gas gangrene ▪ Saprophytic anaerobic bacteria → clostridial gas gangrene due to tissue infection/food poisoning through ingestion ▪ Disease characterized by necrosis, gangrene due to infection of skin, deep tissues ▪ Bacteria produces gas → characteristic crepitation sound during palpitation ▪ Divided into ▫ Traumatic: wound → spore inoculation → bacteria growth in appropriate anaerobic conditions → production of toxins → destruction of fibroblasts, blood cells, muscle cells → necrosis of muscles, subcutaneous fat with blood vessels thrombosis ▫ Postoperative: after interventions on intestinal system ▫ Spontaneous: due to immune system weakness/intestinal diseases Food poisoning ▪ Begins 6–24 hours after ingestion ▪ Infection of food with spores → food standing temperature 30–50ºC/86–122°F → development of vegetative form → ingestion of infected food → toxin production → ↓ glucose absorption, ↑ water, sodium, chloride secretion → damage of intestinal epithelium Enteritis necroticans ▪ Inflammation of jejunum, ileum; type of food poisoning in persons who lack trypsin RISK FACTORS ▪ Gas gangrene: begins 1–4 days after infection ▫ Traumatic: injury during war/natural disaster; car crash ▫ Postoperative: GI/biliary surgery; septic abortion ▫ Spontaneous: colorectal adenocarcinoma; neutropenic states (e.g. AIDS, chemotherapy); intestinal diseases ▪ Food poisoning: improper food-handling ▪ Enteritis necroticans: improper nutrition (e.g. too many sweet potatoes); trypsin inhibitors → ascariasis COMPLICATIONS ▪ Disseminated intravascular coagulation; hemodynamic shock, hypotension, renal failure; systemic hemolysis; peritonitis; sepsis; death 13 Chapter 56 Anaerobic Rods DIAGNOSIS SIGNS & SYMPTOMS Gas gangrene ▪ Two types ▫ Cellulitis: infection of necrotic skin; crepitation sounds ▫ Clostridial myonecrosis: infection, destruction of muscles, adjacent tissue ▪ Paleness, serosanguineous exudate, pain, swelling, tenderness at injury site → color changes to bronze → purple bullae with green/black discoloration due to necrosis ▪ Characteristic sweet odor ▪ ↑ heart rate with low-grade fever Food poisoning ▪ If only toxins ingested ▫ Asymptomatic/diarrhea ▪ If vegetative form ingested ▫ Watery diarrhea without blood/mucus; abdominal cramps, last > 24 hours Enteritis necroticans ▪ Abdominal cramps; diarrhea; vomiting; meteorism (excessive gas production in intestines); blood in stool; fever DIAGNOSTIC IMAGING X-ray ▪ Gas gangrene: detection of gas in softtissue ▪ Enteritis necroticans: small bowel dilatation with presence of gas LAB RESULTS ▪ Gas gangrene: molecular methods for detection of alpha toxins; ELISA, PCR ▪ Food poisoning: detection of toxins in feces; PCR Biopsy ▪ Gas gangrene: necrosis of myocytes, connective tissue with small number of neutrophils OTHER DIAGNOSTICS ▪ Gas gangrene: physical examination; characteristic discoloration, odor, crepitation sound TREATMENT MEDICATIONS ▪ Gas gangrene: antimicrobial therapy (combination of penicillin G, clindamycin) ▪ Enteritis necroticans: penicillin G/ metronidazole; destruction of bacteria SURGERY Figure 56.2 An individual with gas gangrene of the right leg. The causative agent is Clostridium perfringens. ▪ Gas gangrene: removal of dead tissue; hyperbaric oxygen (augments neutrophil, ↓ clostridial exotoxin, spore production); amputation ▪ Enteritis necroticans: resection of necrotic intestinal parts OTHER INTERVENTIONS ▪ Food poisoning: oral/IV rehydration 14 AfraTafreeh.com exclusive CLOSTRIDIUM TETANI (TETANUS) osms.it/clostridium-tetani PATHOLOGY & CAUSES ▪ Ubiquitously present in soil; resistant to chemical/heat disinfection; terminally present endospore; motile ▪ Anaerobic rod causes nervous system disorder (i.e. tetanus) ▪ Injury → infection with spores → development of vegetative form in appropriate anaerobic conditions → production of exotoxins (tetanospasmin) → blood/lymphatic transmission → spread to neurons through neuromuscular junction → retrograde transport to spinal cord → endocytosis into inhibitory Renshaw cell interneurons → exotoxins protease activity cleaves SNARE proteins → block of glycine, gamma-aminobutyric acid (GABA) neurotransmitter-filled vesicles release at neuromuscular junction → overactivation of muscles → muscle spasms Virulence factors ▪ Two toxins: tetanolysin (relatively unknown function); tetanospasmin (responsible for clinical presentation of tetanus) ▪ H-antigen from flagelle Culture ▪ Oxygen-reduced blood agar with anaerobic incubation TYPES ▪ Four types of tetanus ▫ Generalized: affects whole musculature, from head downwards ▫ Localized: affects only area near injury ▫ Cephalic: cranial nerves affected due to head/neck injury ▫ Neonatal: tetanus occurring in neonates via infection of umbilical stump RISK FACTORS ▪ Deep puncture wounds with/without splinters, crush injuries, middle ear infections, frostbites, burns ▪ IV/subcutaneous drug abuse ▪ Infected diabetic wounds ▪ Septic abortion ▪ Umbilical stump infection via contaminated instruments, hands, cultural practices (e.g. application of cow dung, ghee) ▪ Lack of vaccination/immunization COMPLICATIONS ▪ Cardiac arrest ▫ Due to ↑ catecholamine levels, brainstem damage ▪ Palsies of phrenic, laryngeal nerves due to toxic effect ▪ Respiratory muscles ▫ Apnea ▪ Vertebral fractures/intramuscular bleeding (due to opisthotonus) SIGNS & SYMPTOMS Generalized ▪ Masseter muscle spasm → trismus/“lockjaw” → severe generalized muscle contractions ▫ Risus sardonicus: characteristic sarcastic-like facial expression due to facial muscles contraction ▫ Opisthotonus: arched back due to contraction of back muscles ▪ Abdominal respiratory muscles, diaphragm: breathing arrest Localized ▪ Weakness, pain of muscles/extremites in proximity of injury ▪ Stiffness of affected muscles occurring in following days, lasting up to few months ▪ May progress into generalized form 15 Chapter 56 Anaerobic Rods Cephalic ▪ Palsy of facial nerve ▪ Difficulty swallowing ▪ Weakness of extraocular muscles Neonatal ▪ Sucking difficulty in first days of life ▪ Generalization, opisthotonus may occur Sympathetic overactivity ▪ ↑ heart rate, arrhythmias ▪ Agitation, diaphoresis ▪ ↑/↓ blood pressure ▪ Fever ▫ Due to overactivity/superinfection TREATMENT MEDICATIONS ▪ Human tetanus immunoglobulin (TIG)/ intravenous immunoglobulins (IVIG) ▫ Neutralization of toxin ▪ Antibiotics ▫ Penicillin, cephalosporins, tetracyclines, metronidazole, vancomycin ▪ Benzodiazepines ▫ Muscle relaxation, sedation ▪ Muscle relaxants ▫ Pancuronium/vecuronium ▪ Labetalol ▫ Autonomic hyperactivity management OTHER INTERVENTIONS Figure 56.3 This body posture is known as opisthotonus and is caused by the Clostridium tetani toxin. ▪ Active immunization with tetanus/ diphtheria toxoid (Td) ▪ Respiratory support if needed ▪ Prevention ▫ Primary: vaccination at two months of life, with booster doses at 4, 6, 12–18 months, 4–6, 11–12 years (booster doses every ten years later); passive immunization in immunocompromised ▫ Secondary: vaccination, antitoxin after injury ▫ Tertiary: vaccination, antitoxin after tetanus presentation DIAGNOSIS OTHER DIAGNOSTICS ▪ History, physical investigation ▪ Spatula test ▫ Touching oropharynx with spatula causes reflex biting due to masseter spasm EMG ▪ Loss/shortening of silent interval between action potentials with continuous discharge from motor units 16 17 NOTES NOTES ARENAVIRIDAE MICROBE OVERVIEW Taxonomy ▪ Zoonotic virus family ▫ Associated with hemorrhagic fevers, meningoencephalitis ▪ Comprises > 20 viruses ▪ Groups ▫ Old World viruses (e.g. lymphocytic choriomeningitis virus, Lassa, Lujo) ▫ New World viruses (e.g. Junin, Machupo) Morphology ▪ Single-stranded RNA virus ▪ Ribosomes produce sand-like granular appearance under electron microscopy ▫ Latin: arena = sand ▪ Shape varies: pleomorphic–spherical ▪ Enveloped in lipid membrane with glycoprotein spikes ▫ Lipids in membrane → inactivation susceptibility by organic solvents/ detergents ▫ Also inactivated by temperatures > 55°C/131°F, ↑ ↓ pH, UV light, gamma irradiation Transmission ▪ Reservoir ▫ Rodents shed virus in urine, feces, saliva, nasal secretion ▪ Transmission ▫ Ingestion, direct contact, aerosolizedparticle inhalation → entry into cell by GP1 glycoprotein attachment to cellular receptors → systemic dissemination LYMPHOCYTIC CHORIOMENINGITIS VIRUS (LCMV) osms.it/LCMV PATHOLOGY & CAUSES ▪ Arenavirus ▫ Causes febrile illness with central nervous system (CNS) involvement, congenital infection ▪ Reservoir ▫ Mice (M. musculus/M. domesticus); occasional human disease outbreak related to pet hamster/guinea pig ▪ Transmission ▫ Ingestion, aerosolized-particle inhalation, transplacentally (infected mother → fetus) ▪ Post-transmission → 7–14 days incubation → replication in lungs → hematogenous dissemination → strong neurotropism (infects meninges, choroid plexus, ventricular ependyma) RISK FACTORS ▪ Infected rodent contact; dwelling/working in rodent habitats ▪ ↑ risk in substandard housing (e.g. mobile homes, inner-city housing), barns/ 18 outbuildings ▪ Peak incidence: autumn, winter COMPLICATIONS ▪ Encephalitis, aseptic meningitis ▪ Transplacental infection: spontaneous abortion, neonatal neurologic deficits, chorioretinitis, seizures, periventricular calcifications, hydrocephalus, microcephaly ▪ Rarely: orchitis, parotitis, myocarditis SIGNS & SYMPTOMS ▪ May be asymptomatic/mild flu-like symptoms ▪ Prodrome: headache (retro-orbital), nausea, vomiting ▪ Meningitis: fever, rigors, malaise, myalgia, arthralgia anorexia, photophobia ▪ Encephalitis: focal seizures, cranial nerve palsies, papilledema DIAGNOSIS LAB RESULTS ▪ Cerebrospinal fluid (CSF) ▫ ↑ lymphocytes, ↑ protein, ↓ glucose, negative Gram stain Microbe identification ▪ Viral culture, polymerase chain reaction (PCR) Serology ▪ ↑ antibody titer (IgM, IgG) TREATMENT OTHER INTERVENTIONS Prevention ▪ Rodent control 19 NOTES NOTES BUNYAVIRUSES MICROBE OVERVIEW ▪ Bunyaviruses: RNA virus order ▪ AKA Bunyavirales Genetic material ▪ Negative-sense, single-stranded RNA ▪ Tripartite genome ▫ Large (L) segment (encodes RNApolymerase); medium (M) segment (encodes surface glycoproteins); small (S) segment (encodes nucleocapsid proteins) Morphology ▪ Enveloped (outer lipid membrane) ▪ Spherical ▪ Size: 90–100nm Replication ▪ Host cytoplasm replication Transmission ▪ Vector-borne, person-to-person, contact with reservoir (species-dependent) ▪ Reservoirs: arthropods, mammals (especially rodents Figure 58.1 Families of the Bunyavirus order and associated clinical syndromes. 20 HANTAVIRUS osms.it/hantavirus PATHOLOGY & CAUSES ▪ Single-stranded RNA virus genus → causes severe renal/pulmonary disease ▪ AKA Orthohantavirus ▪ Hantaviridae family ▪ Reservoir ▫ Rodents (mice, voles, shrews, rats) ▪ Incubation period ▫ 9–33 days ▪ Tissue tropism ▫ Lymphoid organ, heart, lung, kidney vascular endothelium ▪ Hantavirus inhalation → lung phagocytosis → transport to lymph nodes → hantavirus enters epithelial cells using beta-3 integrins → ↑ vascular permeability → dissemination ▪ Immune response ▫ CD4+/CD8+ cytotoxic T cells, dendritic cells ▪ High-prevalence regions ▫ China, Russia, Europe Associated clinical syndromes ▪ Hemorrhagic fever + renal syndrome (“Old World” AKA Asia, Europe) ▪ ↑ vascular permeability → ↓ blood pressure → kidney endothelial dysfunction ▪ Hantavirus cardiopulmonary/pulmonary syndrome (“New World” AKA North, South America) ▪ ↑ vascular permeability → non-cardiogenic pulmonary edema CAUSES ▪ Rodents (urine/feces/saliva particle inhalation); person-to-person (rare) RISK FACTORS ▪ ▪ ▪ ▪ Rural indoor spaces (e.g. barns) Wild rodent exposure Smoking → Puumala virus infection risk ↑ risk among biological males COMPLICATIONS ▪ Cardiogenic shock, pulmonary edema, arrhythmia, renal insufficiency, acute kidney injury (AKI), coagulopathy, disseminated intravascular dissemination (DIC), hemorrhage; high mortality rate 21 Chapter 58 Bunyaviruses SIGNS & SYMPTOMS Urinalysis ▪ Renal syndrome: proteinuria, hematuria Pulmonary syndrome ▪ Systemic ▫ Fever, chills, myalgia, headaches, weakness ▪ Nausea, vomiting, diarrhea, abdominal pain, cough, oliguria ▪ Sometimes conjunctivitis, flushing, petechiae Tissue biopsy ▪ Kidneys: edema, perirenal hemorrhage, tubular destruction ▪ Lungs: edema, mononuclear cell infiltrates, tracheal/pleural fluid, hyaline deposits ▪ Lymphoid organs: mononuclear cell infiltrates Hemorrhagic fever + renal syndrome ▪ Fever, hypotension, malaise, headache, diffuse hemorrhage (e.g. petechiae, melena, ecchymoses), abdominal/loin pain, nausea/ vomiting, oliguria TREATMENT DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Lungs: bilateral pulmonary infiltrates, pleural effusion Abdominal ultrasound ▪ Kidneys: ↑ size, perirenal fluid LAB RESULTS MEDICATIONS ▪ Renal syndrome antivirals ▫ Nucleoside analogue OTHER INTERVENTIONS ▪ ICU monitoring, mechanical ventilation ▪ Severe cases ▫ Extracorporeal membrane oxygenation (ECMO), dialysis, platelet transfusion Prevention ▪ Potential rodent nesting site removal (e.g. debris, garbage) ▪ Closed spaces ventilation ▪ Avoid rodent contact ▪ Reverse-transcriptase polymerase chain reaction (RT-PCR) Tests ▪ Diagnostic triad: thrombocytopenia, ↑ immunoblasts (> 10%), left-shifted granulocytic series ▪ ↑ lactate dehydrogenase (LDH), serum lactate ▪ ↑ liver enzymes ▪ ↑ C-reactive protein ▪ Severe ▫ ↑ hemoglobin, hematocrit; ↓ albumin; altered coagulation tests ▪ Renal syndrome ▫ ↑ serum creatinine, ↓ glomerular filtration rate (GFR) Serologic tests ▪ IgM/IgG detection through ELISA, strip immunoblot, Western blot, immunofluorescence 22 NOTES NOTES CALICVIRUSES MICROBE OVERVIEW Genetic material ▪ Single-stranded RNA viruses Morphology ▪ Small, icosahedral, non-enveloped Taxonomy ▪ Genera: Norovirus, Sapovirus, Lagovirus, Nebovirus, Vesivirus Transmission ▪ Ingestion → small intestine → villi infection → malabsorption → osmotic diarrhea NOROVIRUS osms.it/norovirus PATHOLOGY & CAUSES ▪ Virus known as viral gastroenteritis agent ▫ AKA Norwalk virus ▪ Classified into seven genogroups ▫ I, II, IV → cause human disease Transmission ▪ Fecal-oral ▫ Infected individual: virus in stool < four weeks ▫ Immunocompetent individual: peak concentration 2–5 days post-infection ▪ Direct person-to-person ▪ Contaminated food, water, fomite ▫ Contaminated water in leafy vegetables, oysters, raspberries ▫ Prepared food → contaminated at point of service (e.g. salads, sandwiches) ▪ Droplet spread from vomitus Pathogenesis ▪ Ingestion → small intestine villi infection → disruption of epithelium, anion transport system → malabsorption of D-xylose, fat → osmotic diarrhea Small intestine histopathology ▪ Villous shortening, epithelial vacuolization, crypt hypertrophy, microvilli brush border loss, intercellular space widening, lymphocytic proliferation of lamina propria RISK FACTORS ▪ Blood group antigens ▫ Viral binding preference for A, B antigens genogroup-determinant ▪ Close-quarter residence (e.g. nursing homes, cruise ships) COMPLICATIONS ▪ Severe dehydration, malnutrition, persistent disease (immunosuppressed individuals) SIGNS & SYMPTOMS ▪ 12–48 hour incubation period ▪ Acute onset vomiting ▫ Nonbloody, nonbilious ▪ Watery diarrhea ▫ Nonbloody ▪ Fever, abdominal pain, myalgia, malaise 23 Chapter 59 Calicviruses DIAGNOSIS ▪ History ▫ Pathogen contact, contaminated food source LAB RESULTS ▪ Reverse transcriptase polymerase chain reaction (RT-PCR) ▫ Stool OTHER INTERVENTIONS ▪ Fluid maintenance, repletion ▫ From oral intake → IV fluids ▪ Electrolyte balance Prevention ▪ Hand hygiene ▪ Environmental fecal contact decontamination ▪ Limited pathogen contact TREATMENT ▪ No cure MEDICATIONS ▪ Antimotility agents ▪ Antiemetics ▫ Reserved for individuals unable to take oral hydration 24 AfraTafreeh.com exclusive NOTES NOTES CENTRAL NERVOUS SYSTEM INFECTIONS MICROBE OVERVIEW PATHOLOGY & CAUSES ▪ Rare infections of central nervous system (CNS) by ameba, parasites RISK FACTORS ▪ Immunosuppression (Acanthamoeba, Toxoplasmosis gondii), immersion in infested water (Naegleria fowleri) SIGNS & SYMPTOMS ▪ Fever, headache, seizures, focal neurological signs, mental status change DIAGNOSIS LAB RESULTS ▪ Presence of infectious agent via microscopy, culture, polymerase chain reaction (PCR), presence of specific antibodies Granulomatous amebic encephalitis ▫ Brain biopsy: trophozoites in perivascular space and thick walled cysts, PCR/DNA probes may show Acanthamoeba Primary amoebic meningoencephalitis ▪ Lumbar puncture ▫ CSF microscopy: motile amebae/ fluorescent antibody staining ▫ CSF PCR: Naegleria fowleri DNA ▫ CSF culture: Naegleria fowleri can be grown on nonnutrient agar coated with Escherichia coli Toxoplasmosis ▪ PCR (blood, CSF): Toxoplasma gondii DNA (inactive cysts may evade detection) ▪ Antibody titres ▫ IgG: evidence of current/previous infection ▫ IgM: occur in weeks after initial infection ▫ Antibody avidity testing: affinity for antigen increases with duration of infection ▪ Sabin–Feldman dye test: high titers → acute infection ▪ Tissue biopsy: tachyzoites in tissues/ smears TREATMENT MEDICATIONS ▪ Antifungal, antiparasitic agents 25 ACANTHAMOEBA osmosis.org/learn/acanthamoeba PATHOLOGY & CAUSES Genus of amebae ▪ Single-celled eukaryotes ▪ Environmentally ubiquitous organisms ▫ Acanthamoeba spp. isolated from soil, air, fresh water, sewage, seawater, chlorinated swimming pools, domestic tap water, bottled water, hospitals, airconditioning units, contact lens cases ▪ Life stages ▫ Metabolically active trophozoite ▫ Dormant stress resistant cyst ▪ Generally free living bacterivores, can cause human infection (acanthamebiasis) Granulomatous amoebic encephalitis ▪ Infection associated with immunosuppression (e.g. diabetes, HIV/AIDS, hematological malignancy, malnutrition, hepatic cirrhosis, chronic renal failure, systemic lupus, chemotherapy) ▪ Parasite enters body through cuts in skin/ inhalation → hematogenous spread to CNS → invasion of connective tissue → inflammatory response → neuronal damage Endosymbiosis, secondary infection ▪ Several human pathogens infect, replicate within Acanthamoeba ▫ Legionella pneumophila, Pseudomonas aeruginosa, some strains of E. coli, Staphylococcus aureus ▪ Replication inside Acanthamoeba → enhanced growth in human macrophages, increased antibiotic resistance → more virulent, fulminant infections SIGNS & SYMPTOMS confusion), sepsis → progressive worsening over weeks/months → death DIAGNOSIS DIAGNOSTIC IMAGING Brain CT/MRI ▪ Meningeal exudate, pseudotumoral lesions, multiple space-occupying lesions with ring enhancement LAB RESULTS Lumbar puncture ▪ Often contraindicated due to risk of herniation associated with mass lesions ▪ Analytical findings generally nonspecific ▫ Intermediate elevations in white blood cell count, elevated protein, decreased glucose levels ▪ Giemsa staining, microscopy ▫ Trophozoites Tissue biopsy ▪ Brain biopsy ▫ Trophozoites in perivascular space, thick-walled cysts on light microscopy; PCR/DNA probes may reveal Acanthamoeba ▫ Immunocompetent host: granulomatous lesions ▫ Severely immunosuppressed host: insufficient CD+ve T-cells to mount granulomatous response → perivascular cuffing with amoebae in necrotic tissue ▪ If other organs involved (e.g. skin, conjunctiva, lungs) ▫ Trophozoites ▪ Fever, headache, seizures, focal neurological signs (e.g. cranial nerve palsies), mental status change (e.g. 26 Chapter 64 Central Nervous System Infections TREATMENT MEDICATIONS ▪ Current treatment regimes uncertain (based on in vitro studies, case reports) ▫ Antifungal, antiparasitic agents in combination ▫ Empiric antifungal regime: miltefosine, fluconazole, pentamidine isethionate +/- trimethoprim-sulfamethoxazole, metronidazole, macrolide antibiotic SURGERY ▪ Single cerebral lesions ▫ Surgical resection NAEGLERIA FOWLERI (PRIMARY AMEBIC MENINGOENCEPHALITIS) osmosis.org/learn/naegleria_fowleri PATHOLOGY & CAUSES ▪ Thermophilic, free-living ameba, found in bodies of warm (stagnant), freshwater TYPES ▪ Life cycle, three forms 1. Cyst ▫ Immotile, dormant, survival phase ▫ Smooth, single-layered cell wall with single nucleus, naturally resistant to environmental factors ▫ Formation of cysts induced by unfavorable conditions such as food shortage, overcrowding, desiccation, accumulation of waste products, cold temperatures (< 10° celsius) 2.Trophozoite (ameboid) ▫ Feeding, reproductive, infective phase ▫ Transformation into trophozoites occurs around 25° celsius ▫ Reproduction occurs via binary fission (single cell divides into two offspring), optimal temperature 42° celsius 3.Biflagellate (two flagella) ▫ Mobile, infective phase ▫ Pear-shaped body with two flagella ▫ Flagellate phase occurs when ameba encounters change in fluid ionic concentration → allows movement to suitable environment ▪ In human tissues Naegleria fowleri exists as ameboid trophozoite; flagellate form may be found in CSF/during initial nasal insufflation Primary amoebic meningoencephalitis ▪ AKA naegleriasis ▪ Rare infection, fatality rate > 95% ▪ Mechanism of entry ▫ Insufflated into sinuses during waterbased activities → attaches to olfactory epithelium → follows olfactory axon through cribiform plate → migration to olfactory bulbs → spread throughout brain → diffuse meningoencephalitis ▪ In tissues, Naegleria fowleri feeds via two mechanisms; feeding on neurological tissue → necrosis, bleeding ▫ Phagocytosis of red, white blood cells ▫ Piecemeal consumption of astrocytes, neurons via amoebostome (actin-rich sucking apparatus extended from cell surface) 27 SIGNS & SYMPTOMS ▪ Symptoms appear 1–9 days after nasal exposure → death likely follows within two weeks ▪ Change in sensation of taste, smell; headache, fever, nausea, stiff neck, seizures, coma DIAGNOSIS DIAGNOSTIC IMAGING Brain imaging ▪ Initially unchanged ▫ Reveals associated complications Leptomeningeal enhancement, diffuse subarachnoid hemorrhage, oedema, hydrocephalus, multiple cerebral infarcts LAB RESULTS ▪ Lumbar puncture ▫ CSF microscopy: motile amebae/ fluorescent antibody staining ▫ CSF PCR: Naegleria fowleri DNA ▫ CSF culture: Naegleria fowleri can be grown on nonnutrient agar coated with E. coli → drop of CSF of infected individual added, incubated at 37° celsius; clearing of E. coli in thin tracks indicative of trophozoite feeding → likely infection TREATMENT MEDICATIONS: ▪ Amphotericin B +/- fluconazole ▪ Miltefosine TOXOPLASMA GONDII (TOXOPLASMOSIS) osmosis.org/learn/toxoplasma_gondii PATHOLOGY & CAUSES ▪ Obligate intracellular parasite capable of infecting nearly all warm-blooded animals ▫ Only definitive hosts: biological family Felidae (e.g. house cats) ▪ 30–50% of global population exposed, may be chronically infected Life cycle ▪ Sexual reproduction ▫ Consumes infected animal meal (e.g. mouse) → parasite survives transit through stomach → infects small intestinal epithelial cells → parasites undergo sexual development, reproduction → millions of thick-walled, zygote-containing, oocytes produced ▪ Felid shedding ▫ Infected epithelial cells rupture → release oocytes into intestinal lumen → shedding in feces → spread via soil, water, food ▫ Oocysts highly resilient; can survive, remain infective for months in cold, dry climates ▪ Infection of intermediate host ▫ Ingestion of oocysts by warm blooded animals (e.g. humans) → oocyst wall dissolved by proteolytic enzymes in stomach, small intestine → frees sporozoites from within oocyst → parasites invade intestinal epithelium, surrounding cells → differentiation into tachyzoites (motile, quickly-multiplying phase) ▪ Asexual reproduction in intermediate host ▫ Tachyzoites replicated inside specialized vacuoles until host cell dies, ruptures → release, hematogenous spread of tachyzoites to all tissues 28 Chapter 64 Central Nervous System Infections ▪ Formation of tissue cysts ▫ Host immune response → tachyzoite conversion → bradyzoites (semidormant, slowly dividing stage) → inside host cells known as tissue cysts → can form in any organ; predominantly brain, eyes, striated muscle (including cardiac muscle) ▫ Consumption of tissue cysts in meat from infected animal ▫ Primary means of infection (e.g. pork, lamb) ▫ Tissue cysts maintained in host tissue for remainder of life via periodic cyst rupture, re-encysting RISK FACTORS ▪ Consumption of raw/undercooked meat; ingestion of contaminated water, soil/ vegetables; previous blood transfusion/ organ transplant; transplacental transmission COMPLICATIONS ▪ Toxoplasmic chorioretinitis ▫ AKA ocular toxoplasmosis ▫ Common cause of posterior segment infection ▫ Majority of cases acquired; also strongly associated with congenital infection SIGNS & SYMPTOMS ▪ Initial infection (immunocompetent host) ▫ Mild flu-like symptoms (e.g. swollen lymph nodes, headache, fever, fatigue, muscle aches, pains) ▪ Congenital infection ▫ Chorioretinitis (unilateral decrease in visual acuity), hydrocephalus, seizures, lymphadenopathy, hepatosplenomegaly ▪ Chronic/latent infection ▫ Asymptomatic in healthy hosts ▪ Immunocompromised host ▫ Active infection (toxoplasmosis) ▫ Headache, confusion, poor coordination, seizures, cough, dyspnea ▫ Reactivation of latent infection: worsening of immunosuppression due to progression of underlying disease (e.g. HIV/AIDS, iatrogenic immunosuppression) → loss of immune balance → progression to active infection DIAGNOSIS DIAGNOSTIC IMAGING CT scan with contrast ▪ Multiple 1–3 cm hypodense regions with nodular/ring enhancement predominantly in basal ganglia, corticomedullary junction T2 weighted MRI ▪ Iso/hyper-intense lesions surrounded by perilesional edema Fundoscopy ▪ Toxoplasmic chorioretinitis ▫ Unifocal area of acute-onset inflammation adjacent to old chorioretinal scar Figure 8.1 A histological section of the cerebrum demonstrating cerebral toxoplasmosis. There are bradyzoites present and a mixed inflammatory infiltrate which includes eosinophils. LAB RESULTS PCR (blood, CSF) ▪ Toxoplasma gondii DNA (inactive cysts may evade detection) Antibody titres ▪ IgG (persist for life) 29 ▫ Evidence of current/previous infection ▪ IgM (acute infection) ▫ Occur in weeks after initial infection, remain detectable for months ▫ Antibody avidity testing may clarify nature of infection; early toxoplasmaspecific IgG has low affinity for toxoplasma antigen; affinity increases with duration of infection ▪ Sabin–Feldman dye test ▫ Requires specialised laboratories (live Toxoplasma gondii required); high titers → acute infection ▫ Patient serum treated with Toxoplasma trophozoites + complement, incubated → methylene blue added (membrane stain) → if anti-toxoplasma antibodies present, complement facilitates lysis of parasite membrane → no staining of lysed membrane ▫ No antibodies in serum → intact membranes → membrane stained blue under microscopy ▪ Tissue (brain/lymph node/muscle) biopsy ▫ Tachyzoites (acute infection) may be demonstrated in tissues/smears TREATMENT MEDICATIONS ▪ Prevention ▫ Trimethoprim/sulfamethoxazole ▪ Acute infection ▫ Antimalarials: pyrimethamine ▫ Antibiotics: sulfadiazine with pyrimethamine, clindamycin, spiramycin ▪ Latent infection ▫ Cysts not sufficiently penetrated by traditional therapy ▫ Atovaquone (antimalarial) +/clindamycin (lincomycin antibiotic) ▪ Toxoplasmic chorioretinitis ▫ Sight-threatening lesions ▫ Triple therapy: pyrimethamine, sulfadiazine, folinic acid ▫ Mono-antibiotic therapy: trimethoprimsulfamethoxazole, clindamycin, spiramycin Figure 8.2 An MRI scan of the head in the axial plane demonstrating cerebral toxoplasmosis. There are numerous peripherally enhancing nodules in the basal ganglia. 30 NOTES NOTES CESTODES (TAPEWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Human gastrointestinal tract parasites; AKA tapeworms ▫ Adult tapeworms live in intestines ▫ Larvae live in different tissue (brain, liver, eye, etc.) ▪ Tripartite body ▫ Head/scolex (contain suckers, hooks/ attachment organs) ▫ Thin neck ▫ Trunk (made of numerous proglottids) ▪ Hermaphroditic ▫ Each proglottid has male, female organs ▪ Transmission ▫ Egg/larvae-contaminated water/food ingestion RISK FACTORS ▪ ▪ ▪ ▪ ▪ Poor hygiene Low socioeconomic status Raw/undercooked fish/meat Livestock exposure Living/travelling in endemic areas SIGNS & SYMPTOMS ▪ Tapeworm species-dependent ▪ Can be asymptomatic, abdominal pain. nausea/vomiting, weight loss DIAGNOSIS DIAGNOSTIC IMAGING MRI, CT scan, ultrasound ▪ Cyst presence LAB RESULTS ▪ Microscopy ▫ Identify eggs/proglottids in stool ▪ Complete blood count (CBC), serology TREATMENT ▪ Tapeworm species-dependent MEDICATIONS ▪ Anthelmintics COMPLICATIONS ▪ ▪ ▪ ▪ Cysticercosis (Taenia) Cyst rupture Intestinal obstruction Malabsorption → vitamin B12 deficiency → megaloblastic anemia 31 Chapter 61 Cestodes (Tapeworms) DIPHYLLOBOTHRIUM LATUM osms.it/diphyllobothrium-latum PATHOLOGY & CAUSES ▪ AKA fish tapeworm ▪ Longest human-infecting tapeworm (4–15m/13–49ft) ▪ Causes diphyllobothriasis in humans ▪ Proglottids ▫ Width > length ▪ Competes for vitamin B12 → vitamin B12 deficiency CAUSES ▪ Raw/undercooked fish → larvae ingestion COMPLICATIONS ▪ Tapeworms → mechanical intestinal obstruction ▪ Malabsorption → weight loss ▪ Vitamin B12 deficiency → megaloblastic anemia SIGNS & SYMPTOMS ▪ Vitamin B12 deficiency ▫ Impaired oxygen delivery: fatigue, activity intolerance, pallor, compensatory mechanisms (↑ heart rate, bounding pulse) ▫ Neuronal demyelination: numbness, tingling, weakness ▪ Weight loss ▪ Abdominal pain DIAGNOSIS LAB RESULTS ▪ Megaloblastic anemia; e.g. increased mean corpuscular volume (MCV) ▪ Microscopy ▫ Identify eggs/proglottids in stool ▪ ↓ serum vitamin B12 TREATMENT MEDICATIONS ▪ Anthelmintics 32 ECHINOCOCCUS GRANULOSUS (HYDATID DISEASE) osms.it/echinococcus-granulosus PATHOLOGY & CAUSES ▪ Parasitic infection caused by E. granulosus ▫ AKA echinococcosis ▪ Produce protoscoleces ▫ Juvenile scolex invaginated in cysts ▫ Tapeworm maturation in definitive host’s intestine ▪ Humans (incidental hosts); herbivores (intermediate hosts); canids (definitive hosts) CAUSES ▪ Viable parasite egg-containing food consumption RISK FACTORS ▪ Parasite/egg-contaminated food/water ingestion ▪ Close contact with infected animals Figure 61.2 The gross pathology of hydatid cysts excised from the lung. Figure 61.1 A scolex of the organism Echinococcus granulosus, the causative agent of hydatid disease. COMPLICATIONS ▪ Arise as cysts migrate, grow in size, rupture ▫ Liver: eosinophilia, pruritus, jaundice, urticaria, liver abscess, anaphylaxis ▫ Peritoneal cavity: peritonitis, pancreatitis ▫ Pleural space: abscess formation → pneumothorax/pleural effusion ▫ Bronchial tree: respiratory distress, hemoptysis ▫ Heart: cardiomegaly/pericardial effusion ▫ Kidney: glomerulonephritis ▪ Large cyst compression effect ▫ Heart: large cyst in liver → compression of right heart ▫ Cerebral/spinal cord (CNS): neurological deficits ▫ Liver/biliary tree cysts: obstructive jaundice/cholangitis; venous drainage obstruction → portal hypertension → Budd–Chiari syndrome (abdominal pain, ascites, hepatomegaly) 33 Chapter 61 Cestodes (Tapeworms) SIGNS & SYMPTOMS ▪ Initially asymptomatic ▪ Depend on affected organs ▫ Liver: right upper quadrant pain, hepatomegaly, nausea, vomiting ▫ Lungs: cough, chest pain, dyspnea, hemoptysis ▪ Other organs (rarely affected) ▫ Heart: jugular venous distention, dyspnea ▫ Musculoskeletal: diffuse pain, pathologic fractures ▫ Kidney: hematuria, flank pain ▫ CNS: headache, motor deficit, seizure, coma ▪ Puncture-aspiration-injection-reaspiration (PAIR) ▫ Ultrasound/CT scan-guided cyst puncture ▫ Aspirate cystic fluid ▫ Inject scolicidal solution ▫ Reaspirate cystic solution ▫ Repeat procedure until aspirate clears ▫ Fill cyst with isotonic saline DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/MRI/CT scan ▪ Cyst presence LAB RESULTS ▪ Enzyme-linked immunosorbent assay (ELISA) ▫ Echinococcal antigen detection in cystic fluid ▪ Indirect hemagglutination ▫ Echinococcal antigen detection ▪ Immunodiffusion/immunoelectrophoresis ▫ Echinococcal-specific antibody detection ▪ Biopsy/cyst aspiration Figure 61.3 A CT scan of the abdomen in the axial plane demonstrating a large hepatic hydatid cyst. The numerous daughter cysts are faintly visible. TREATMENT MEDICATIONS ▪ Albendazole/ mebendazole ▫ Uncomplicated cases Figure 61.4 A histological section through a hydatid cyst wall showing a typical laminated structure. SURGERY ▪ Complicated cases ▫ Rupture, vital structure compression, cysts with diameter > 10cm/3.94in 34 NOTES NOTES CHLAMYDIA MICROBE OVERVIEW ▪ Gram-negative, obligate intracellular bacteria ▪ AKA “energy parasites”; rely on host cell for adenosine triphosphate (ATP) synthesis ▪ Primarily infects epithelium, mucous membranes Morphology ▪ Coccoid; cell walls don’t contain peptidoglycan Replication ▪ Intracellular life cycle: infectious stage (spore-like elementary body) attaches to host cell via endocytosis → reorganizes within cellular vacuole into reticulate body (vegetative form) → reproduces, forms multiple reticulate bodies → forms elementary bodies → released from host cell → continues infectious process CHLAMYDIA SPECIES (PNEUMONIA) osms.it/chlamydia-species PATHOLOGY & CAUSES ▪ Species of chlamydia; primarily causes community-acquired pneumonia ▪ Transmitted via respiratory secretions ▪ Can also infect endothelial cells → atherosclerosis RISK FACTORS ▪ ↑ risk with age COMPLICATIONS ▪ Otitis media, sinusitis, parapneumonic effusions, pericarditis 35 Chapter 62 Chlamydia SIGNS & SYMPTOMS ▪ Gradual onset ▪ General malaise, myalgia, fever, chills, pharyngitis, hoarseness, sinusitis, cough ▪ Extra-respiratory manifestations: meningoencephalitis, reactive arthritis, myocarditis DIAGNOSIS LAB RESULTS ▪ Microbial identification: serology, polymerase chain reaction (PCR), nasopharyngeal swab culture, direct antigen testing ▪ Complete blood count (CBC): normal white blood cell count OTHER DIAGNOSTICS ▪ History, physical examination: lung sounds (e.g. crackles, wheezing) DIAGNOSTIC IMAGING Chest X-ray ▪ Unilateral patchy infiltrates TREATMENT MEDICATIONS ▪ Antibiotics CHLAMYDIA TRACHOMATIS osms.it/chlamydia-trachomatis PATHOLOGY & CAUSES ▪ Species of chlamydia; primarily affects eyes, urogenital tract ▪ Different serovars cause diverse disease states ▫ A, B, Ba, C: trachoma ▫ D–K: urogenital infection, conjunctivitis ▫ L1, L2, L2a, L2b, L3: lymphogranuloma venereum RISK FACTORS ▪ Risky sexual practices (e.g. multiple sex partners, unprotected sex) ▪ Impaired mucous membrane barrier (e.g. cervical friability) ▪ History of sexually transmitted disease ▪ Exposure during birth COMPLICATIONS ▪ Ocular: ophthalmia neonatorum (conjunctivitis), blindness ▪ Genitourinary: pelvic inflammatory disease (PID), PID-associated ectopic pregnancy, infertility, proctitis, cervicitis, urethritis ▪ Chlamydial pneumonia, bronchitis, perihepatitis (Fitz-Hugh–Curtis syndrome); ↑ risk of acquiring/transmitting HIV due to genital inflammation SIGNS & SYMPTOMS Trachoma ▪ Chronic, granulomatous inflammation of eye → corneal ulceration, scaring, pannus formation → blindness Adult conjunctivitis ▪ Inclusion (purulent erythematous injection of epithelial surface) conjunctivitis, mucopurulent discharge → keratitis Urogenital infections ▪ Individuals who are biologically female ▫ May be asymptomatic ▫ Bartholinitis, cervicitis (mucopurulent endocervical discharge), endometritis, salpingitis, urethritis (dysuria, pyuria) ▫ PID: uterine/adnexal tenderness ▫ Perihepatitis: right upper quadrant (RUQ) pain 36 ▪ Individuals who are biologically male ▫ Urethritis: dysuria, watery/mucoid discharge Neonatal conjunctivitis ▪ Eyelid swelling, watery/purulent discharge, red, thickened conjunctiva (chemosis) ▪ Conjunctival scarring, corneal vascularization ▪ ↑ risk of developing C. trachomatis pneumonia Infant pneumonia ▪ Diffuse, interstitial disease; rhinitis, staccato cough Figure 62.1 Purulent discharge from the cervix of an individual with chlamydia infection. Lymphogranuloma venereum (LGV) ▪ Anorectal disease: anorectal pain, tenesmus (feeling of incomplete bowel evacuation), rectal bleeding/discharge, constipation ▪ Painless ulcer → inflammation of lymph nodes (preauricular, submandibular, cervical) → progression to systemic symptoms ▪ Population at highest risk: individuals who are biologically male who have same-sex intercourse (MSM) DIAGNOSIS LAB RESULTS ▪ Microbial identification: nucleic acid amplification test (NAAT) Figure 62.2 A cervical smear from an individual infected with Chlamydia trachomatis. There are numerous organisms contained within intracellular vacuoles. OTHER DIAGNOSTICS ▪ Clinical presentation, history TREATMENT MEDICATIONS ▪ Antibiotics ▪ Sexual partners should also be treated 37 Chapter 2 Acyanotic Defects NOTES COCCOBACILLI: AEROBES MICROBE OVERVIEW ▪ Intermediate shape between cocci (spherical bacteria), bacilli (rod-shaped bacteria) ▪ Gram-negative, obligate aerobe, nonmotile, non-spore forming BORDETELLA PERTUSSIS (PERTUSSIS/WHOOPING COUGH) osms.it/bordetella-pertussis PATHOLOGY & CAUSES ▪ Infectious agent, causes pertussis ▪ Strict human pathogen ▪ Tropism to respiratory epithelium Pathophysiology ▪ Bacteria enters upper respiratory tract, releases toxins ▪ Filamentous hemagglutinin, pertactin, agglutinogen ▫ Anchors to epithelial cells ▪ Tracheal cytotoxin ▫ Paralysis of respiratory cilia → ↑ accumulation of mucus in airways → violent cough reflex ▪ Pertussis toxin ▫ Stimulates T cells to divide, blocks them from leaving blood, migrating into tissues → lymphocytosis ▫ ↑ sensitivity of respiratory tissues to histamine → ↑ vascular permeability → fluid leaks into airway tissues → airway edema → dyspnea 38 ▪ Adenylate cyclase toxin ▫ ↑ conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP) within phagocytes → disbalance in cellular signaling mechanism → phagocytes unable to correctly respond to infection, undergo apoptosis Stages of infection ▪ Catarrhal: follows incubation period (approx. one week); lasts two weeks, very contagious ▪ Paroxysmal: 1–6 weeks ▪ Convalescent: 2–3 weeks RISK FACTORS ▪ Infants too young to have completed immunization ▪ Unimmunized individuals ▪ Debilitation of immune system COMPLICATIONS ▪ Apparent life-threatening event (ALTE) ▫ Young infants; gasping, cyanosis, apnea ▪ Hypoxia ▫ Seizures, encephalopathy, death ▪ Pneumonia, pneumothorax SIGNS & SYMPTOMS DIAGNOSIS LAB RESULTS ▪ Nasopharyngeal swab culture (Bordet– Gengou agar) ▫ Detects microbe; mercury drop colonies ▪ Polymerase chain reaction (PCR) ▫ Detects microbe ▪ Serology ▫ Detects microbe; antibody levels ▪ Complete blood count (CBC) ▫ Leukocytosis (esp. young infants) OTHER DIAGNOSTICS ▪ History, physical examination ▫ Sudden, dramatic coughing attacks; lung sounds (e.g. whooping) TREATMENT MEDICATIONS ▪ Prophylactic ▫ Diphtheria, tetanus, acellular pertussis (DTaP) vaccine ▪ Macrolide antibiotics OTHER INTERVENTIONS ▪ Compulsory isolation of infected individual ▪ Catarrhal: nasal congestion; mild cough; sneezing; low-grade fever; red, watery eyes (similar to common cold) ▪ Paroxysmal: high-pitched whooping during inhalation; uncontrollable coughing fits → vomiting, fainting, rib fracture, petechiae in face, subconjunctival hemorrhages, hernias ▪ Convalescent stage: coughing improvement; decreased paroxysm, whooping; healing of airways 39 Chapter 63 Coccobacilli: Aerobes FRANCISELLA TULARENSIS (TULAREMIA) osms.it/francisella-tularensis PATHOLOGY & CAUSES ▪ Infectious agent that causes zoonosis tularemia ▪ Facultative, gram-negative intracellular bacteria ▪ Highly infectious, virulent; potential bioterrorism agent Transmission ▪ Direct contact with infected animals (e.g. inoculation of mucous membranes via contaminated hands/infected material) ▪ Ingestion of contaminated water/meat ▪ Airborne spread via contaminated materials (e.g. dust, hay, grass, lab specimens) ▪ Insect vectors ▫ Ticks, mosquitoes, horse flies, fleas, lice Pathophysiology ▪ Francisella tularensis enters body → phagocytosed by macrophages → impairs phagosome-lysosome fusion, rapidly proliferates within macrophage → infected macrophage undergoes apoptosis → bacteria released, infection spread COMPLICATIONS ▪ Lymph node suppuration, sepsis, renal failure, rhabdomyolysis, hepatitis, pneumonia SIGNS & SYMPTOMS ▪ Fever, chills, malaise, lethargy, anorexia, chest/muscle soreness ▪ Ulceroglandular: papulo-ulcerative lesion at point of contact with animal/vector; lymphadenopathy ▪ Glandular: lymphadenopathy (no skin lesions) ▪ Oculoglandular: pain/irritation of eye; periorbital edema/erythema; increased tearing; photophobia; regional adenopathy ▪ Oropharyngeal: sore throat; cervical lymph node enlargement; pharyngitis; tonsillitis ▪ Pneumonic: dry cough; breathing difficulties; substernal chest pain ▪ Typhoidal: very high fever; abdominal pain; diarrhea; vomiting; diffuse abdominal tenderness TYPES ▪ Forms of tularemia: ulceroglandular (75%), glandular, oculoglandular, oropharyngeal, pneumonic, typhoidal RISK FACTORS ▪ Work-related ▫ Lab workers, farmers, veterinarians, gardeners, hunters, butchers ▪ Skin exposure to vectors (esp. in summer) Figure 63.1 An ulcer on the skin of an individual with tularemia. 40 DIAGNOSIS LAB RESULTS ▪ Culture ▫ Buffered charcoal yeast extract (BCYE) agar ▪ PCR, direct fluorescent antibody (DFA) test ▫ Detects microbe ▪ Serology ▫ IgM, IgG antibodies appear after 2 weeks TREATMENT MEDICATIONS ▪ Antibiotics (e.g. streptomycin, gentamicin, doxycycline) OTHER DIAGNOSTICS ▪ History, physical examination 41 Chapter 2 Acyanotic Defects NOTES COCCOBACILLI: FACULTATIVE ANAEROBES MICROBE OVERVIEW ▪ Intermediate shape between cocci (spherical bacteria), bacilli (rod-shaped bacteria) ▪ Gram-negative, facultative anaerobes, nonmotile, nonspore-forming BRUCELLA osms.it/brucella PATHOLOGY & CAUSES ▪ Characteristics ▫ Zoonotic infection ▫ Urease, catalase positive ▫ Facultatively intracellular ▫ Sensitive to heat, ionizing radiation, disinfectants, pasteurization ▪ Virulence factors ▫ Lipopolysaccharide (LPS): promotes cell entry, evasion, intracellular killing ▫ Type IV secretion system (key virulence factor): injection of effector molecules into host cell → modifies endoplasmic reticulum, enables replication ▪ Culture ▫ Isolation specimen: blood, bone marrow, body fluids, tissues ▫ Media: biphasic (solid, liquid) RuizCastaneda blood culture/modern automated blood culture systems (faster, more effective) ▫ Raised, convex colonies with smooth, shiny surface ▪ Causative agent of brucellosis ▪ Most common zoonotic infection to cause disease in humans Transmission ▪ Contact with infected animals (e.g. sheep, cattle, goats, pigs, etc) ▫ Entry of bacteria through skin lesions, conjunctival inoculation, inhalation of contaminated aerosol ▪ Ingestion of contaminated animal products (e.g. unpasteurized milk, cheese; undercooked meat) ▫ Remains viable up to two days in milk at 8°C/46.4°F, three weeks in frozen meat, three months in goat cheese Pathogenesis ▫ Inoculation of bacteria → ingestion by polymorphonuclears, macrophages → passage to local lymph nodes → bacteria replicates intracellularly → some bacteria avoid intracellular killing by different strategies (e.g. inducing phagocyte apoptosis, inhibiting phagocyte-lysosome fusion) → chronic infection TYPES Acute infection ▪ Localized infection (30% of cases), can affect any organ 42 ▫ Skeletal (most common): arthritis, spondylitis, sacroiliitis, osteomyelitis ▫ Pulmonary: bronchitis, interstitial pneumonitis, lobar pneumonia, pulmonary nodules, pleural effusion, empyema, abscesses ▫ Cardiac: endocarditis, myocarditis, pericarditis, endarteritis ▫ Alimentary: cholecystitis, ileitis, colitis, pancreatitis ▫ Reticuloendothelial: reactive hepatitis, granulomas, acute hepatitis with focal necrosis (B. melitensis), formation of noncaseating sarcoidosis-like granulomas (B. abortus), suppurative abscess formation (B. suis) in liver ▫ Genitourinary: orchitis, epididymitis ▫ Hematological: anemia, leukopenia, thrombocytopenia, pancytopenia, disseminated intravascular coagulation ▫ Neurologic: meningitis, encephalitis, myelitis, radiculitis, neuritis, mycotic aneurysms, brain abscess ▫ Ocular: uveitis, keratoconjunctivitis, corneal ulcers, iridocyclitis, nummular keratitis, choroiditis, optic neuritis, papilledema, endophthalmitis ▫ Dermatologic: nonspecific skin eruptions, ulcerations, petechiae, purpura, granumanifestationslomatous vasculitis, abscesses Chronic infection ▪ Symptoms persist one year after diagnosis; localized infection, relapse RISK FACTORS ▪ Occupational exposure ▫ Lab health care workers, farmers, slaughterhouse workers, veterinarians COMPLICATIONS ▪ Infection during pregnancy → intrauterine infection, premature delivery, spontaneous abortion, miscarriage ▪ Endocarditis damage, destroy heart valves ▪ Leading cause of death by brucellosis ▪ Skeletal ▫ May cause long-term damage, bone/ joint malformations ▪ Neurologic ▫ May lead to permanent brain damage ▪ Ocular ▫ Visual impairment 43 Chapter 64 Coccobacilli: Facultative Anaerobes SIGNS & SYMPTOMS ▪ Range from asymptomatic to severe illness ▪ Onset of symptoms can be acute/insidious ▪ Incubation ▫ 1–4 weeks to several months ▪ Acute generalized infection ▫ Acute undulating fever (key sign), arthralgia, myalgia, fatigue, headache, night sweats, malaise, weight loss ▫ Hepatomegaly, splenomegaly, lymphadenopathy ▫ Foul-smelling perspiration (characteristic sign) ▪ Localized infection ▫ Symptoms depend on organ/organ system affected DIAGNOSIS LAB RESULTS ▪ Rising titers of specific antibodies ▫ Initial rise in IgM class titers, followed in several weeks by predominance of IgG antibodies; both decrease over time with treatment ▪ Anemia, thrombocytopenia Microbe identification ▪ Positive bodily fluids/tissue culture ▪ Serum agglutination, enzyme-linked immunosorbent assay (ELISA) ▪ Polymerase chain reaction (PCR) ▪ Lysis-centrifugation technique OTHER DIAGNOSTICS ▪ History of travel, food consumption, occupation TREATMENT MEDICATIONS ▪ Six-week course of doxycycline plus streptomycin/gentamicin/doxycycline plus rifampin ▪ In children < eight years old ▫ Trimethoprim-sulfamethoxazole (TMPSMX) plus rifampin SURGERY ▪ Surgical interventions sometimes necessary for osteoarticular manifestations (e.g. pyogenic joint effusions), hepatosplenic granulomas/abscesses, cardiac complications (e.g. valve replacement surgery) OTHER INTERVENTIONS ▪ Prophylaxis ▫ Biosafety level 3 in laboratories recommended while handling Brucella cultures ▫ No vaccines for humans; live attenuated vaccines containing strains of B. abortus, B. melitensis used for animals 44 AfraTafreeh.com exclusive HAEMOPHILUS DUCREYI osms.it/haemophilus-ducreyi PATHOLOGY & CAUSES ▪ Virulence factors ▫ Lipooligosaccharide ▫ Pili: provides attachment of bacteria ▫ Soluble cytolethal distending toxin, cytotoxic hemolysin, hemoglobinbinding protein, copper-zinc superoxide dismutase, filamentous hemagglutininlike protein, zinc-binding periplasmic protein ▪ Culture ▫ Isolation specimen: genital ulcer swab, lymph node aspirate ▫ Media: enriched growth medium contains factor X (hemin), serum incubated at 33–35ºC/91.4–95°F with CO2; small, heterogenous, gray/ translucent colonies ▪ Causative agent of sexually transmitted genital ulcer called chancroid (AKA ulcus molle), associated inguinal lymphadenopathy ▪ Some strains causes cutaneous ulcers in children in South Pacific, parts of equatorial Africa Transmission ▪ Sexual intercourse (genital ulcers) ▪ Nonsexual transmission (cutaneous ulcers) Pathogenesis ▪ Incubation ▫ 4–10 days ▪ Inoculation through epidermal microabrasions → attachment of bacteria to extracellular matrix in skin via pili, lipooligosaccharide → attachment to cells via specific heat shock protein (GroEL) → cytotoxin release, epithelial injury → formation of erythematous papule → evolves into pustule → pustule ruptures, forms ulcer RISK FACTORS ▪ Uncircumcised individuals, poverty, multiple sexual partners COMPLICATIONS ▪ Increases risk for HIV contraction SIGNS & SYMPTOMS ▪ Single/multiple painful genital ulcers on erythematous base, 1–2cm/0.39–0.79in diameter with sharply demarcated borders; base of ulcer covered with purulent exudate, bleeds easily when scraped ▪ Predilection sites ▫ Prepuce, coronal sulcus, glans penis in individuals who are biologically male ▫ Labia, vaginal introitus, perianal area in individuals who are biologically female ▪ Individuals who are biologically female ▫ Dysuria, dyspareunia, vaginal discharge, rectal bleeding, painful defecation ▪ Inguinal lymphadenopathy in approx. 50% of cases (more common in individuals who are biologically male) ▫ Painful fluctuant buboes (swollen lymph nodes); if untreated, may spontaneously rupture, form draining sinus, releases pus 45 Chapter 64 Coccobacilli: Facultative Anaerobes DIAGNOSIS LAB RESULTS Microbe identification ▪ Diagnosis of confirmed chancroid ▫ Culture (not widely available) ▪ Nucleic acid amplification tests ▫ Not available outside of clinical research purposes ▪ Polymerase chain reaction (PCR) multiplex ▫ Detection of bacterial DNA ▪ Histologic characteristics of chancroid OTHER DIAGNOSTICS ▪ Diagnostic criteria for probable chancroid ▫ ≥ one painful genital ulcers ▫ No evidence of Treponema pallidum infection (by darkfield microscopy/ serologic testing) ▫ No evidence of Herpes simplex virus (HSV) infection ▫ Appearance of genital ulcers, regional lymphadenopathy ▪ Purulent exudate in superficial epidermis with perivascular, interstitial mononuclear infiltrate in dermis Figure 64.1 An ulcer on the glans penis of a male with chancroid. The ulcer is typically painful, unlike the ulcer of primary syphilis. TREATMENT MEDICATIONS ▪ Single-dose therapy with azithromycin/ ceftriaxone ▪ Alternative ▫ Multiple-dose therapy with ciprofloxacin/erythromycin OTHER INTERVENTIONS ▪ Fluctuant lymphadenopathy ▫ Needle aspiration, drainage to prevent spontaneous rupture 46 HAEMOPHILUS INFLUENZAE osms.it/haemophilus-influenzae PATHOLOGY & CAUSES ▪ Haemophilus: blood loving ▪ Characteristics ▫ Catalase, oxidase positive ▪ Virulence factors ▫ Polysaccharide capsule: prevents phagocytosis; causes ciliostasis, evades mucociliary clearance of bacteria; classified into six serotypes based on capsular antigens (A, B, C, D, E, F); some strains unencapsulated (AKA nontypable); most clinical isolates Haemophilus influenzae type B (Hib)/ nontypable ▫ IgA1 protease, adherence factors, antigenic variation, biofilm formation ▪ Gram stain of exudate shows bacteria arranged in chains (“school of fish”) ▪ Culture ▫ Isolation specimen: cerebrospinal fluid (CSF), urine, serum, synovial fluid ▫ Media: chocolate agar/Fildes medium (hemolyzed erythrocytes) with factor X (hemin), V (nicotinamide adenine dinucleotide) supplementation in aerobic, only factor X supplementation in anaerobic environment ▫ Convex, smooth, grey/transparent colonies ▪ Gram-negative coccobacillus → meningitis, respiratory tract infections ▪ Nontypeable strains colonize nasopharynx of 40–80% children, adults ▪ Hib colonizes 3–5% children TYPES Hib ▪ Epiglottitis in older children, adults ▪ Cellulitis (most common in young children) ▪ Pneumonia ▫ Sometimes with meningitis, epiglottitis ▪ Meningitis, septic arthritis, osteomyelitis Nontypable ▪ Less invasive due to lack of capsule; causes mild localized respiratory tract disease in children, adults ▪ More severe in immunocompromised/ predisposed individuals ▫ Otitis media, sinusitis, purulent conjunctivitis, bacterial pneumonia in children (in low-income countries), neonatal bacteremia ▫ Community-acquired pneumonia in adults with underlying lung disease ▫ Exacerbation of chronic obstructive pulmonary disease (COPD) ▫ Meningitis in individuals with predisposition/conditions causing leakage of CSF fluid (e.g. sinusitis, otitis media, head trauma) Transmission ▪ Direct contact with respiratory tract secretions/airborne respiratory droplets Pathogenesis ▪ Inoculation → passage through upper respiratory tract → adherence to respiratory epithelium, LPS inhibits mucociliary clearance → colonization spreads throughout respiratory tract → sinuses, otitis, pneumonia ▪ IgA1 protease, antigenic variation, paracytosis, biofilm formation → perseverance of bacteria RISK FACTORS ▪ Viral infection, sickle-cell disease, asplenia, HIV infection, malignancies, congenital deficiencies of complement components COMPLICATIONS ▪ Nontypable in neonates, immunocompromised individuals → septicemia, meningitis, septic arthritis ▪ Hib meningitis → subdural effusion/ empyema; ischemic/hemorrhagic cortical 47 Chapter 64 Coccobacilli: Facultative Anaerobes infarction; cerebritis (nonviral parenchymal infection of brain); ventriculitis; intracerebral abscess; hydrocephalus; neurologic sequelae (e.g. permanent sensorineural hearing loss, seizures, intellectual disability) ▪ Hib pneumonia can spread to pericardium → purulent pericarditis SIGNS & SYMPTOMS Hib ▪ Meningitis ▫ Fever, lethargy, irritability, vomiting, altered mental status ▫ Fulminant course → rapid neurologic deterioration, respiratory arrest ▫ Positive Kernig’s sign: inability to straighten leg when hip flexed to 90º ▫ Positive Brudzinski’s sign: flexing of neck by examiner → flexing of hips, knees ▪ Epiglottitis ▫ Fever, sore throat, difficulty speaking, dyspnea → severe stridor, dysphagia, pooling of secretions, drooling ▫ “Tripod” posture: individual takes sitting position with trunk leaning forward, neck hyperextended, chin thrust forward to get more air through obstructed airway ▪ Cellulitis ▫ Fever; warm, tender area of erythema/ violaceous discoloration on cheek/ periorbital area ▪ Septic arthritis ▫ Fever, pain, swelling, tenderness, decreased mobility of affected joint Nontypeable ▪ Otitis media ▫ Fever, ear pain, irritability, sleep disturbance, otorrhea ▫ Red bulging tympanic membrane with decreased mobility upon pneumatic otoscopy examination ▫ Often conjoined with conjunctivitis ▪ Sinusitis ▫ Fever, persistent purulent nasal discharge or cough > 10 days ▫ Tenderness over involved paranasal sinuses DIAGNOSIS DIAGNOSTIC IMAGING Laryngoscopy ▪ Red, swollen epiglottis; aryepiglottic folds ▪ Examine with caution; possible laryngeal spasm X-ray ▪ Thumb sign on epiglottis (radiographic corollary of omega sign) LAB RESULTS Microbe identification ▪ Positive Gram stain, bacterial culture of CSF, synovial fluid, epiglottis, pleural, pericardial, other sterile fluids ▪ Latex agglutination, enzyme immunoassay, coagglutination ▫ Type B capsular antigen detection in CSF, serum, urine ▪ Definitive diagnosis ▫ Culture of fluid obtained by sinus aspiration, tympanocentesis, tracheal/ lung aspiration, bronchoscopy, bronchoalveolar lavage Figure 64.2 An X-ray image of the chest demonstrating diffuse airway shadows in an individual with bronchopneumonia. H. influenzae is a causative organism of bronchopneumonia. 48 TREATMENT MEDICATIONS Prevention ▪ Conjugate Hib vaccines ▫ Routine vaccination of infants of two months ▪ Rifampin chemoprophylaxis ▫ Individuals in close contact with infected; incompletely vaccinated individuals in households with infants/ children < four years old Hib with meningitis ▪ Third generation cephalosporins ▫ Adults: ceftriaxone ▫ Children: ceftriaxone plus dexamethasone (decreases immune response to released LPS upon bacterial death, lowers chance for destruction of neurons, neurologic sequelae) ▪ Epiglottitis (life-threatening condition; prompt treatment paramount) ▫ Ceftriaxone Nontypable ▪ Amoxicillin/clavulanate, broad-spectrum cephalosporins, macrolides (azithromycin/ clarithromycin), fluoroquinolones SURGERY ▪ Epiglottitis ▫ Placement of artificial airway PASTEURELLA MULTOCIDA osms.it/pasteurella-multocida PATHOLOGY & CAUSES ▪ Characteristics ▫ Zoonotic infection (e.g. birds, cats, dogs, rabbits, cattle, pigs); oxidase, catalase, nitrate reduction positive ▪ Virulence factors ▫ Polysaccharide capsule: prevents phagocytosis; divided into serogroups based on capsular antigens (A, B, C, D, E) ▫ Lipopolysaccharide: endotoxin ▫ Sialidases, hyaluronidase, surface adhesins, iron acquisition proteins, pasteurella multocida toxin (PMT) ▪ Culture ▫ Isolation specimen: respiratory tract samples, CSF ▫ Media: sheep blood, chocolate, HS, Mueller–Hinton agar at 37ºC/98.6F; opaque/gray colonies 1–2mm in diameter ▪ Medically important subspecies ▫ P. multocida subsp multocida, P. multocida subsp septica, P. multocida subsp gallicida Transmission ▪ Most commonly cat/dog bites, scratches, licks TYPES ▪ Soft tissue infections ▫ Cellulitis at site of inoculation (most common) → abscess, necrotizing soft tissue infections, septic arthritis, osteomyelitis ▪ Respiratory infections ▫ Due to underlying chronic pulmonary disease; glossitis, pharyngitis, sinusitis, otitis media, epiglottitis, tracheobronchitis, pneumonia, empyema, lung abscess ▪ Invasive infection (immunocompromised, infants) ▫ Bacteremia, meningitis, intra-abdominal infections (peritonitis, appendicitis), endocarditis, septic arthritis, ocular infection 49 Chapter 64 Coccobacilli: Facultative Anaerobes Pathogenesis ▪ Inoculation → attachment of bacteria to ECM, cells soft tissue → PMT secretion → tissue inflammation within 24 hours COMPLICATIONS ▪ Sepsis, septic shock SIGNS & SYMPTOMS ▪ Soft tissue infections ▫ Wound inflammation, cellulitis with purulent drainage; regional lymphadenopathy ▪ Respiratory tract infections ▫ Fever, malaise, dyspnea, pleuritic chest pain ▪ Sepsis ▫ Purpura fulminans (rash rapidly progresses from petechiae, purpura to gangrene/limb amputation) ▪ Respiratory infection ▫ Wheezing, rhonchi, dullness DIAGNOSIS LAB RESULTS Microbe identification ▪ Culture, PCR, serological testing OTHER DIAGNOSTICS ▪ History of animal contact ▫ Cat bites pose higher risk for developing osteomyelitis, septic arthritis TREATMENT MEDICATIONS ▪ ▪ ▪ ▪ Penicillins Tetracyclines Cephalosporins Quinolones 50 NOTES NOTES COMMA–SHAPED RODS MICROBE OVERVIEW ▪ Gram-negative, facultative anaerobes, motile, non-spore forming CAMPYLOBACTER JEJUNI osms.it/campylobacter-jejuni PATHOLOGY & CAUSES Characteristics ▪ Zoonotic disease ▫ Reservoir in wild, domestic mammals, birds (esp. poultry) ▪ Oxidase +; invasive; microaerophilic; sensitive to heat, desiccation, acidity, irradiation, disinfectants Virulence factors ▪ Fimbriae-like filaments ▫ Promote attachment to intestinal epithelial cells ▪ Possesses single, unsheathed flagellum in one end (monotrichous)/two flagella each at both ends (amphitrichous) ▫ Provide motility, chemotaxis (mucin is chemoattractant → tropism for ileum, colon, rectum) ▪ Surface proteins (eg, PEB1, CadF) promote colonization, invasion of intestinal epithelial cells ▪ Lipopolysaccharide (LPS) ▫ Plays role in adherence, evasion of host immune response (undergoes antigenic variation) 51 Chapter 65 Comma-shaped Rods Culture ▪ Isolation specimen: stool, food ▪ Media: blood/charcoal agar with microaerophilic atmosphere (5–10% O2, 3–5% CO2), thermophilic environment (optimal 42°C/107.6°F) ▪ C. jejuni: one of most common bacterial causes of gastroenteritis with acute diarrhea Transmission ▪ Fecal-oral, contaminated water Pathogenesis ▪ Incubation period 1–7 days; tropism for distal ileum, colon, rectum ▪ Inoculation of bacteria → passage through upper GI tract → colonization, adherence to surface epithelium of distal ileum, colon → non-inflammatory secretory diarrhea (exact mechanism unknown) ▪ Invasion of intestinal epithelium, proliferation → release of cytolethal distending toxin → cell damage, inflammatory response → dysentery with fecal leukocytes ▪ Rare: translocates into lamina propria, spreads to mesenteric lymph nodes (mesenteric adenitis) → extraintestinal infections (e.g. meningitis, cholecystitis, UTI) ▫ Occurs mostly in immunocompromised RISK FACTORS ▪ Consumption of undercooked meat/ unpasteurized milk ▪ Underlying conditions/medications that reduce/buffer gastric acidity (e.g. proton pump inhibitors) ▪ Individuals with HIV/AIDS COMPLICATIONS ▪ Toxic megacolon, massive bleeding, colonic perforation ▪ Reactive arthritis ▪ Associated with Guillain–Barré syndrome ▫ Sialic acid contained bacterial core oligosaccharide can resemble gangliosides → cross-activation of autoreactive T/B cells (molecular mimicry) SIGNS & SYMPTOMS ▪ Vary in severity depending upon inoculum concentrations; range from asymptomatic carriage to systemic illness ▫ Most episodes mild, self-limiting (up to one week); rarely persists up to several weeks ▪ Fever, myalgia, malaise, headache (early symptoms, 1–2 days); severe periumbilical abdominal pain, cramping, secretory, inflammatory diarrhea, vomiting ▫ Abdominal pain may mimic acute appendicitis ▫ Secretory diarrhea: more common in children ▫ Inflammatory diarrhea: tenesmus, bloody stools, fecal leukocytes DIAGNOSIS LAB RESULTS ▪ Stool culture ▪ Rapid diagnosis with carbolfuchsin stain/ phase-contrast/dark-field microscopic examination of fresh stool specimen in case of acute manifestation ▪ PCR-based methods, enzyme immunoassays (EIAs) directly from stool OTHER DIAGNOSTICS ▪ Clinical manifestations ▪ Histology ▫ Acute mucosal inflammation with edema, cellular infiltration of lamina propria, crypt abscess formation TREATMENT MEDICATIONS ▪ Antibiotics for severe cases, immunocompromised individuals ▫ Erythromycin/azithromycin OTHER INTERVENTIONS ▪ Replacement of fluids, electrolytes 52 HELICOBACTER PYLORI osms.it/helicobacter-pylori PATHOLOGY & CAUSES Characteristics ▪ Urease +, catalase +, oxidase +; noninvasive ▪ Microaerophilic ▫ Requires oxygen, lower concentrations than present in atmosphere Virulence factors ▪ Possesses 2–7 unipolar sheathed flagella (H-antigen) ▫ Provide motility, chemotaxis (sense pH, move bacteria towards beneficial environment) ▪ Lipopolysaccharide (LPS) ▫ Promotes adherence, causes inflammation ▪ Coccoid form ▫ More resistant form; occurs as adaptation to hostile environment outside human body ▪ Urease ▫ Important for survival, colonization ▪ Mucolytic enzymes ▫ Allow passage through mucus layer to gastric epithelium ▪ Adhesive proteins (Hop proteins) ▪ Vacuolating cytotoxin A (VacA) ▫ Damages epithelial cells; disrupts tight junctions, causes apoptosis ▪ Cytotoxin associated gene CagA (CagA) ▫ Triggers inflammation ▪ Type IV secretion system ▫ Pili-like structure for injection of effectors (e.g. CagA) ▪ Proteases, lipases ▪ Biofilm formation Culture ▪ Isolation specimen: vomitus, diarrheal stools ▪ Media: blood agar/selective Skirrow’s media incubated at 37ºC/98.6°F in 5% oxygen; small, uniformly sized, translucent bacterial colonies ▪ H. pylori: causative agent of most common chronic infection in humans; common cause of duodenal, gastric ulcers, chronic gastritis Transmission ▪ Unknown; fecal/oral, oral/oral transmission suggested ▪ Reservoir ▫ Human (majority of cases); found in primates in captivity, domestic cats, sheep ▪ Also found in municipal water in endemic areas of infection with polymerase chain reaction (PCR) techniques Pathogenesis ▪ Bacterial urease hydrolyzes gastric luminal urea to form ammonia → ↑ gastric pH → formation of protective layer around bacteria → survival in hostile gastric environment ▪ ↑ pH → mucin liquefies → H. pylori passes through mucous layer to surface epithelium via bacterial flagella, mucolytic enzymes → attaches to specific gastric epithelial cell receptors via surface adhesins (Hop proteins) → release of proteases (VacA, CagA) + host immune response → inflammation, tissue injury ▪ Disruption of mucous layer → susceptibility to acid peptic damage ▪ Chronic inflammation, tissue injury together with acid peptic damage → chronic gastritis, peptic ulcers (10–20% risk) RISK FACTORS ▪ ▪ ▪ ▪ ▪ Low socioeconomic status Increased housing density Lack of running water Genetic susceptibility Swimming in pools, rivers, streams 53 Chapter 65 Comma-shaped Rods COMPLICATIONS ▪ Gastric carcinoma (1–2% risk): chronic gastritis → atrophic gastritis, intestinal metaplasia, carcinoma ▫ Chronic inflammation, ↑ TNF, ↑ IL-6, ↑ bacterial proteases → excessive tissue damage, cell mutation → intestinal metaplasia → carcinoma ▪ Gastric mucosa-associated lymphomas due to persistent immune stimulation of gastric lymphoid tissue ▫ Omeprazole/pantoprazole + clarithromycin, amoxicillin: in case of penicillin sensitivity, replace amoxicillin with metronidazole SIGNS & SYMPTOMS ▪ Majority of cases asymptomatic ▪ Acute infection ▫ Upper abdominal pain, nausea, loss of appetite ▪ Chronic infection ▫ Chronic gastritis: upper abdominal pain, nausea, bloating, vomiting/melena (black stool) ▫ Peptic ulcers: stomach pain/ache; occurs with empty stomach, between meals, early morning Figure 65.1 Helicobacter organisms in a gastric pit. DIAGNOSIS LAB RESULTS ▪ Blood antibody test ▪ Stool antigen test ▪ Carbon urea breath test ▫ Individual ingests 14C- or 13C-labelled urea, which bacterium metabolizes, yielding labelled carbon dioxide detectable in breath ▪ Urine enzyme-linked immunosorbent assay (ELISA) test TREATMENT MEDICATIONS ▪ One-week “triple therapy”: antacid/acidreducing drugs (H2-receptor antagonists/ proton pump inhibitors) + two antibiotics ▫ Bismuth salicylate + metronidazole + tetracycline ▫ Ranitidine bismuth citrate + tetracycline + clarithromycin/metronidazole 54 VIBRIO CHOLERAE (CHOLERA) osms.it/vibrio-cholerae PATHOLOGY & CAUSES Characteristics ▪ Oxidase +; non-invasive; halophilic; genome consists of two circular chromosomes; sensitive to acid, drying ▪ Reservoir: aquatic environments (saltwater, brackish) ▪ Fermentation: glucose, sucrose Virulence factors ▪ Cholera toxin ▫ Only toxigenic strains; responsible for pathogenesis of massive, watery diarrhea; coded by filamentous bacteriophage (CTXΦ) ▪ Other toxins that increase mucosal permeability ▫ Zona occludens toxin (ZOT), accessory cholera enterotoxin (ACE), WO7 toxin 17 ▪ Lipopolysaccharide (LPS) ▫ > 200 serogroups; O1, O139 associated with cholera epidemics ▪ Motility ▫ Single polar flagellum (H-antigen) ▪ Toxin-coregulated pilus (TCP) ▫ Present only in toxigenic strains; promotes adherence, aggregation of bacteria; coded by genes in Vibrio pathogenicity island (VPI) ▪ Mucinase ▫ Digests mucous layer of gastrointestinal (GI) tract Culture ▪ Isolation specimen: stool, rectal swab ▪ Media: thiosulfate citrate bile salts sucrose (TCBS) agar/taurocholate tellurite gelatin agar (TTGA); large, yellow colonies (2–4mm diameter) with opaque centers, translucent edges ▪ V. cholerae: diverse species; pathogenic, toxin-producing (toxigenic) variants cause cholera ▪ Cholera characterized by profound secretory diarrhea → rapid, life-threatening dehydration ▪ Transmitted by fecal-oral route/ contaminated food or water Pathogenesis ▪ Inoculation → passage through upper GI tract → rapid movement of bacteria through mucous via flagellum → colonization of small intestine via TCP → releases cholera toxin ▪ Cholera toxin (AB protein toxin) → B subunit binds to GM1 ganglioside on intestinal epithelial cell, allows entry of A subunit → activates G-protein regulated adenylyl cyclase → ↑ intracellular cyclic adenosine monophosphate (AMP) → secretion of chloride, sodium; inhibition of sodium chloride absorption → massive fluid secretion; loss of sodium, chloride, bicarbonate, potassium TYPES Pathogenic (toxin-producing), nonpathogenic Serological classification: O antigen differences ▪ Serogroup O1 is subdivided into two serotypes (Inaba, Ogawa), two biotypes ▫ El Tor: cause of current global pandemic of cholera ▫ Classical: cause of previous V. cholerae pandemics; now thought extinct ▪ Serogroup O139 ▪ Non-O1/O139 RISK FACTORS ▪ Travel to endemic/epidemic areas ▪ Inadequate access to clean water 55 Chapter 65 Comma-shaped Rods ▪ Shellfish consumption in areas with sporadic cholera ▪ People with blood group O at higher risk for severe cholera (mechanism unknown) COMPLICATIONS ▪ If untreated ▫ Dehydration, hypovolemic shock in 4–12 hours, death in 18 hours to several days ▪ Renal failure secondary to hypovolemia ▪ Electrolyte imbalances ▫ Hypokalemia, metabolic acidosis ▪ Pneumonia (esp. in children) due to aspiration of vomit SIGNS & SYMPTOMS ▪ Incubation period is 28–48 hours ▪ Asymptomatic to severe depending upon strain, inoculum concentration (≥ 108 → severe form) ▪ Abrupt onset of profound watery diarrhea (grey, cloudy, flecked with mucus; “ricewater stool”); painless, without tenesmus; loss of 1 liter of fluid per hour in severe cases ▪ Moderate to severe vomiting, borborygmus, abdominal discomfort ▪ Dehydration ▫ Thirst, dry mucous membranes, decreased skin turgor, sunken eyes, hypotension, weak/absent radial pulse, tachycardia, tachypnea, hoarse voice, oliguria ▪ Altered mental status ▫ Somnolence, restlessness, lethargy ▫ Culture on TCBS agar ▫ Dark field microscopy/dipstick test of stool specimen for rapid confirmation in non-endemic areas (detectable in stool for 1–2 weeks without antimicrobial therapy) TREATMENT MEDICATIONS ▪ Oral antibiotic treatment reduces duration, severity of disease ▫ Doxycycline for adults ▫ Azithromycin for children, pregnant individuals OTHER INTERVENTIONS ▪ Prophylaxis ▫ WC-rBS (Dukoral) vaccine: monovalent inactivated oral cholera vaccine containing killed whole cells of V. cholerae O1, additional recombinant cholera toxin B subunit ▫ BivWC (Shanchol) vaccine: bivalent inactivated oral vaccine containing killed whole cells of V. cholerae O1, O139 ▫ CVD 103-HgR/Vaxchora vaccine: attenuated oral vaccine derived from serogroup O1 classical Inaba strain ▪ Rapid, aggressive volume replacement (oral/intravenous fluids) ▪ Adequate nutrition to prevent malnutrition ▪ Correction of electrolyte imbalances ▪ Zinc supplementation reduces duration, severity of disease DIAGNOSIS LAB RESULTS ▪ Hypoglycemia/hyperglycemia ▪ Hypercalcemia, hypermagnesemia, hyperphosphatemia ▪ ↑ hematocrit due to volume depletion OTHER DIAGNOSTICS ▪ Clinical presentation ▪ Microbiologic diagnosis 56 NOTES NOTES CORONAVIRUSES MICROBE OVERVIEW ▪ Causes respiratory infections ▪ OC43, NL63: most common strains of human coronaviruses (HCoV) ▪ Associated clinical syndromes: common cold, pneumonia, bronchitis, Middle East respiratory syndrome (MERS-CoV), severe acute respiratory syndrome (SARS-CoV) Genetic material ▪ Positive-stranded RNA viruses Taxonomy ▪ Corona: crown; named after spiked appearance in electron microscopy ▪ Genera: alpha, beta (human pathogens), gamma, delta Morphology ▪ Helical capsid; enveloped (outer lipid membrane) ▪ Structural proteins ▫ Small envelope protein (E) → viral assembly ▫ Hemagglutinin esterase protein (HE) → binds to cell membrane (beta coronaviruses only) ▫ Membrane protein (M) → viral assembly ▫ Nucleocapsid protein (N) → forms nucleocapsid ▫ Spike protein (S) → binds, fuses with host cell membrane 57 Chapter 66 Coronaviruses CORONAVIRUS (SARS) osms.it/coronavirus-SARS PATHOLOGY & CAUSES ▪ Causes severe respiratory syndrome (SARS) ▪ B-beta coronavirus: viral pulmonary disease ▪ Viral inoculation of respiratory tract mucosa → cell damage → release of cytokines (interferon-gamma, IL-1, IL-6, IL-12) → inflammation, ↑ secretions ▪ Incubation period: 2–7 days CAUSES ▪ Direct contact, airborne droplets, fomites RISK FACTORS ▪ Immunosuppression, healthcare-related occupation, comorbid conditions COMPLICATIONS ▪ Acute respiratory distress syndrome, multiorgan failure SIGNS & SYMPTOMS ▪ Prodrome: fever, malaise, headaches, myalgia, chills ▪ Non-productive cough, dyspnea, chest pain ▪ Diarrhea, rhinorrhea, sore throat ▪ Interstitial pulmonary infiltrates LAB RESULTS Histologic pulmonary tissue observation ▪ Hyaline membranes, edema, fibroblast proliferation Reverse-transcriptase polymerase chain reaction (RT-PCR) ▪ Nasopharyngeal, oropharyngeal, stool, serum samples Serologic tests ▪ Enzyme-linked immunosorbent assays (ELISA) ▪ Fluorescence antigen detection assays Lab tests ▪ Lymphopenia, thrombocytopenia, ↑ lactate dehydrogenase (LDH), ↑ alanine aminotransferase (ALT) TREATMENT OTHER INTERVENTIONS ▪ Mechanical ventilation in respiratory failure Prevention ▪ Hand washing ▪ Proper disposal of infected materials (e.g. used tissues) ▪ Mask use within healthcare environment DIAGNOSIS ▪ Center for Disease Control and Prevention (CDC) ▫ No alternative diagnosis after 72 hours of clinical evaluation ▫ Individual at risk DIAGNOSTIC IMAGING Chest X-ray 58 NOTES NOTES CUTANEOUS FUNGAL INFECTIONS GENERALLY, WHAT ARE THEY? DIAGNOSIS PATHOLOGY & CAUSES ▪ Noninvasive fungal infections of skin and its annexes ▫ Limited to stratum corneum ▫ Caused by human skin’s commensal flora LAB RESULTS ▪ Microscopic observation OTHER DIAGNOSTICS ▪ Clinical findings upon examination SIGNS & SYMPTOMS ▪ Skin pigmentation changes ▪ Characteristic lesions: macule, patch, scale, plaque ▪ Occasional pruritus TREATMENT MEDICATIONS ▪ Antifungal MALASSEZIA (TINEA VERSICOLOR & SEBORRHOEIC DERMATITIS) osms.it/malassezia PATHOLOGY & CAUSES ▪ Genus of yeast-like fungi ▪ Cause cutaneous infections ▪ Cutaneous commensal flora, mostly lipiddependent (thrive on human sebum), saprophytic (nutrients obtained from dead, organic matter), dimorphic (yeast, hyphal/ mycelial forms) TYPES Tinea versicolor ▪ Superficial cutaneous mycosis ▪ AKA pityriasis versicolor ▪ Most common causes: M. globosa, M. furfur, M. sympodialis ▪ Fungus produces azelaic acid → tyrosinase activity (activated by sunlight) → skin pigmentation changes → hypopigmented/ hyperpigmented macules, patches, plaques 59 Chapter 67 Cutaneous Fungal Infections Seborrheic dermatitis ▪ Chronic, inflammatory dermatitis ▫ Tends to flare, relapse ▫ Likely caused by Malassezia spp. ▪ Fungus produces acids, enzymes, oxygen radicals → cell damage → inflammatory response → erythema, greasy, yellowish scaling (range from mild, flaky to coarse, thick lesions) RISK FACTORS Tinea versicolor ▪ Most common ▫ Adolescents/young adults ▪ Excessive heat, humidity, perspiration, sunlight ▪ Immunosuppression Figure 67.1 Tinea versicolor on the abdomen. Seborrheic dermatitis ▪ Biphasic occurrence ▫ Infants (cradle cap), adolescents/adults ▪ Biologically-male > biologically-female individuals ▪ Comorbidities ▫ HIV/AIDS, Parkinson’s disease SIGNS & SYMPTOMS Tinea versicolor ▪ Characteristic skin changes ▫ Usually located on abundant sebaceous gland areas (torso, proximal extremities, face, neck) ▪ Light brown in light-skinned individuals; dark brown to gray-black in dark-skinned individuals ▪ Mild erythema, pruritus, scaling ▪ Lesions fail to tan with sun exposure Seborrheic dermatitis ▪ Characteristic skin changes ▫ Usually located on trunk (“petaloid pattern”), scalp (dandruff), eyebrows, eyelids, nasolabial folds, external auditory meatus, anogenital area ▪ Pruritus, erythema, blepharitis ▪ Tends to flare during stress, cold weather ▪ Infants: adherent yellowish scales primarily on vertex of scalp Figure 67.2 Seborrhoeic dermatitis affecting the nasolabial folds. DIAGNOSIS LAB RESULTS Tinea versicolor ▪ KOH preparation: microscopic observation → “spaghetti and meatballs” ▫ Spaghetti: hyphae ▫ Meatballs: yeast 60 OTHER DIAGNOSTICS Tinea versicolor ▪ Wood’s lamp examination: yellow to yellow-green fluorescence Seborrheic dermatitis ▪ Clinical findings upon examination Seborrheic dermatitis ▪ No known cure ▪ Chronic topical agent treatment: antifungal medications, corticosteroids, calcineurin inhibitors ▫ Other topical agents: selenium sulfide, zinc pyrithione, salicylic acid or coal tar (keratolytics) ▪ Oral antifungal agents if non-responsive TREATMENT MEDICATIONS Tinea versicolor ▪ Topical agents: antifungal medications, selenium sulfide, zinc pyrithione ▪ Oral antifungal medications if nonresponsive 61 Chapter 2 Acyanotic Defects NOTES DIPLOCOCCI: AEROBIC MICROBE OVERVIEW ▪ Spherical-shaped bacteria (cocci), appear in pairs as joined cells (diplo) ▪ Gram-negative, aerobes/facultative anaerobes, non-motile, non-spore forming TYPES Moraxella catarrhalis ▪ Oxidase +, nitrate reduction + (characteristic) ▪ Part of normal respiratory flora, causes opportunistic infections ▪ Virulence factors ▫ Beta-lactamase production → penicillin resistant ▫ DNase production ▪ Culture ▫ Isolation specimen: respiratory secretions, sputum ▫ Media: blood, chocolate agar (round, opaque colonies that turn pink after 48 hours; positive “hockey puck sign”: able to slide colonies across agar with wooden stick without disruption) Neisseria gonorrhoeae ▪ Facultatively intracellular ▪ Oxidase +, catalase + ▪ Fermentation ▫ Glucose; differentiation from N. meningitidis ▪ Virulence factors ▫ LOS/endotoxin: triggers inflammation; undergoes antigenic variation ▫ IgA1 protease: cleaves IgA antibodies; aids in evasion of humoral immune response ▫ Type IV pili: promote adhesion of bacteria to epithelium; undergo phase, antigenic variation ▫ Porins (PorA, PorB): allow movement of ions, nutrients into bacteria, promote invasion into cells ▫ Opa, Opc: promote adhesion, invasion; undergo phase, antigenic variation ▪ Culture ▫ Isolation specimen: urine, vaginal/ endocervical swab, urethral swab; pharyngeal, rectal swab ▫ Media: Thayer–Martin VCN, chocolate agar Neisseria meningitidis ▪ Facultatively intracellular ▪ Oxidase +, catalase + ▪ Fermentation ▫ Maltose, glucose ▪ Present as normal non-pathogenic flora of nasopharynx in 10% of adults ▪ Virulence factors ▫ Capsule: prevents phagocytosis; N. meningitidis subdivided into 13 serogroups based on capsular polysaccharides; A, B, C, W135, Y account for most disease cases ▫ Lipooligosaccharide (LOS)/endotoxin: released in blebs/vesicle-like structures → sepsis, vascular necrosis, hemorrhage into surrounding tissue; levels of LOS closely correlate with prognosis ▫ IgA1 protease: cleaves IgA antibodies; aids in evasion of humoral immune response ▫ Pili: promote adherence of bacteria to nasopharyngeal epithelium; undergo phase, antigenic variation → protect against host immune response, vaccines ▫ Opacity proteins (Opa, Opc): promote adhesion, invasion 62 ▫ Factor H binding protein: downregulates alternative complement pathway ▪ Culture ▫ Isolation specimen: blood, cerebrospinal fluid (CSF), petechial scrapings ▫ Media: Thayer–Martin vancomycin, colistin, nystatin (VCN), chocolate agar MORAXELLA CATARRHALIS osms.it/moraxella-catarrhalis PATHOLOGY & CAUSES ▪ Gram-negative diplococcus → respiratory tract infections, otitis media ▪ Infections caused by M. catarrhalis ▫ Respiratory tract infections (bronchitis, rhinosinusitis, laryngitis, bronchopneumonia, communityacquired bacterial pneumonia) ▫ Otitis media in children < three years of age ▫ Exacerbations of chronic obstructive pulmonary disease (COPD) RISK FACTORS ▪ Immunocompromised individuals ▪ Individuals with chronic respiratory disease (e.g. COPD, emphysema) ▪ Children < two years of age, elderly COMPLICATIONS ▪ Rare: bacteremia, septicemia, urethritis, septic arthritis SIGNS & SYMPTOMS ▪ Acute bacterial rhinosinusitis: fever, nasal obstruction, purulent nasal discharge, facial pain, headache ▪ Otitis media: fever, ear pain, bulging tympanic membrane ▪ Exacerbations of COPD: increased cough, sputum production/change in color, dyspnea 63 Chapter 68 Diplococci: Aerobic DIAGNOSIS OTHER DIAGNOSTICS ▪ Clinical presentation ▫ Sufficient for diagnosis ▪ Microbiologic diagnosis TREATMENT MEDICATIONS ▪ ▪ ▪ ▪ Amoxicillin-clavulanate Trimethoprim-sulfamethoxazole Third-/second-generation cephalosporins Macrolides (e.g. azithromycin, clarithromycin) NEISSERIA GONORRHOEAE osms.it/neisseria-gonorrhoeae PATHOLOGY & CAUSES ▪ Gram-negative diplococcus → gonococcal disease (gonorrhea, disseminated gonococcemia, gonococcal ophthalmia neonatorum) ▪ Portal of entry ▫ Unprotected sex (vaginal, oral, anal): bacteria attaches, invades genitourinary, rectal, oral epithelium via Opa, Opc, pili → gonorrhea ▫ Rare: invades bloodstream → disseminated gonococcemia, septic arthritis ▫ Perinatal transmission: birth canal of infected mother → gonococcal ophthalmia neonatorum TYPES ▪ Gonorrhea ▫ Urethritis, cervicitis, proctitis, pharyngitis ▪ Disseminated gonococcemia ▫ Result of spread, intravascular multiplication of N. gonorrhoeae; joints, skin (dermatitis-arthritis syndrome) ▪ Gonococcal ophthalmia neonatorum ▫ Causes gonococcal conjunctivitis RISK FACTORS ▪ Unprotected sex ▫ Individuals with multiple sexual partners, sex between individuals who are biologically male (MSM), recent new sexual partner ▪ Low educational, socioeconomic levels ▪ Substance abuse ▪ History of gonorrhea COMPLICATIONS Gonorrhea ▪ Epididymitis, prostatitis, penile lymphangitis, urethral strictures in individuals who are biologically male; cervical gonorrhea → pelvic inflammatory disease → infertility in individuals who are biologically female Gonococcal ophthalmia neonatorum ▪ Corneal scarring/perforation, blindness SIGNS & SYMPTOMS Gonorrhea ▪ Some individuals who are biologically male, most individuals who are biologically female (50–80%) asymptomatic ▪ Urethritis: dysuria, urinary urgency, purulent foul-smelling urethral discharge ▪ Cervicitis: lower abdominal discomfort, dyspareunia (pain during sexual intercourse), vaginal pruritus, purulent foulsmelling vaginal discharge 64 AfraTafreeh.com exclusive ▪ Proctitis: anal pruritus, tenesmus, rectal fullness, constipation, purulent anorectal discharge, bleeding ▪ Pharyngitis: sore throat, swollen lymph nodes Disseminated gonococcemia ▪ Fever, chills, generalized malaise ▪ Polyarthralgia (multiple joint pain) ▪ Tenosynovitis (tendon inflammation) ▪ Pustular/vesiculopustular lesions on skin Gonococcal ophthalmia neonatorum ▪ Purulent conjunctival discharge ▪ Swollen eyelids ▪ Conjunctival hyperemia, chemosis DIAGNOSIS LAB RESULTS Blood tests ▪ ≥ two white blood cells in urethral secretions ▪ ≥ 10 white blood cells on microscopic examination of first void urine ▪ Disseminated gonococcemia ▫ Positive blood culture ▫ Synovial fluid leukocyte count: increased values (50,000 cells/microL) Gram stain ▪ Polymorphonuclear leukocytes with intracellular gram-negative diplococci Nucleic acid amplification testing (NAAT) ▪ For initial diagnosis TREATMENT MEDICATIONS Figure 68.1 A neonate with gonococcal ophthalmia neonatorum. ▪ Uncomplicated gonorrhea ▫ Intramuscular injections of ceftriaxone + azithromycin/doxycycline (in case of gonococcal resistance to cephalosporins, potential chlamydia regardless of chlamydial coinfection status) OTHER INTERVENTIONS ▪ Prophylaxis ▫ No vaccines ▫ Extensive antigenic variations of bacterial components (pili, LOS, opa proteins) prevents development of immunological memory Figure 68.2 Creamy discharge emanating from the external urethral meatus is typical of genital gonorrhea infection. 65 Chapter 68 Diplococci: Aerobic NEISSERIA MENINGITIDIS osms.it/neisseria-meningitidis PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Gram-negative diplococcus → meningococcal disease (meningitis, meningococcemia) ▪ Portal of entry ▫ Inhalation of respiratory droplets → bacteria attaches to respiratory epithelium via Opa, Opc, pili → nasopharynx colonization → usually resolves asymptomatically (carriers) ▫ Invades bloodstream → meningococcal disease (rare) Meningococcemia ▪ Petechial rash caused by destruction of blood vessels, hemorrhage due to endotoxin release; fever, chills; joint, muscle pain RISK FACTORS Meningitis ▪ Infants ▫ Early nonspecific: irritability, vomiting, inactivity, poor feeding, temperature instability ▫ Late specific: bulging anterior fontanelle, seizures ▪ Children, adolescents, adults ▫ Early nonspecific: sudden onset of fever, headache, nausea, vomiting, myalgia ▫ Late specific: altered mental status, lethargy, neck stiffness (nuchal rigidity), photophobia ▫ First specific symptoms of sepsis: abnormal skin color (pallor/mottling) which can evolve from nonspecific rash to petechial to hemorrhagic over several hours; cold hands, feet; leg pain ▪ Signs upon physical examination ▫ Positive Kernig’s sign: inability to straighten leg when hip flexed to 90º ▫ Positive Brudzinski’s sign: flexing of neck by examiner → flexing of hips, knees COMPLICATIONS Fulminant meningococcemia ▪ Abrupt onset ▪ Rapid enlargement of petechiae/ ecchymoses ▪ Hypotension, tachycardia due to vascular collapse, shock TYPES ▪ Meningococcemia ▫ Result of intravascular multiplication of N.meningitidis; can occur alone/in conjunction with meningitis ▪ Meningitis ▫ Most common; occurs upon spreading of bacteria to meninges during meningococcemia; usually affects children, adolescents ▪ Fulminant meningococcemia ▫ AKA Waterhouse–Friderichsen syndrome; most severe form of meningococcal sepsis; massive bilateral hemorrhage into adrenal glands ▪ Infants 6–24 months (due to immature immune system, inability to vaccinate) ▪ Living in close quarters (military barracks, dormitories) ▪ Adrenal insufficiency; disseminated intravascular coagulation (DIC); purpura fulminans (cutaneous hemorrhage, necrosis due to vascular thrombosis, DIC); acute respiratory distress syndrome (ARDS); coma, death 66 DIAGNOSIS LAB RESULTS ▪ Fulminant meningococcemia ▫ Adrenal insufficiency signs: ↓ blood glucose, ↑ K+, ↓ Na+, adrenocorticotropic hormone (ACTH) stimulation test (low response) ▫ Thrombocytopenia due to DIC ▫ Metabolic acidosis ▪ Meningococcemia and meningitis ▫ Blood culture and CSF analysis OTHER DIAGNOSTICS ▪ Physical examination ▫ Characteristic findings of meningitis TREATMENT MEDICATIONS Prophylaxis ▪ Quadrivalent immunization with purified capsular polysaccharides from serogroups A, C, Y, W135 (group B not available) Figure 68.3 A petechial rash can be seen in the late stages of meningococcal septicemia. Meningococcal disease ▪ Antibiotics ▫ Third-generation cephalosporins (e.g. cefotaxime, ceftriaxone)/penicillin G ▪ Chloramphenicol ▫ In case of beta-lactam antibiotics hypersensitivity ▪ Chemoprophylaxis of individuals in close contact with the infected ▫ Rifampin of ciprofloxacin ▪ Hydrocortisone ▫ For adrenal insufficiency SURGERY ▪ Plastic surgery, skin grafting, amputation to treat tissue necrosis Figure 68.4 The brain of an individual at post mortem following death from bacterial meningitis. Nesseiria meningitidis is the most common causative organism amongst adolescents and young adults. 67 NOTES NOTES ECTOPARASITES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Ectoparasites: arthropods that live on outside of host, extract nutrients at host’s expense ▫ Uncommon: viable parasites transferred without direct host contact RISK FACTORS DIAGNOSIS OTHER DIAGNOSTICS History ▪ Including close contacts/living quarters Physical examination ▪ Dermatologic examination ▪ Commonly poor hygiene, close living quarters TREATMENT MEDICATIONS COMPLICATIONS ▪ Predicated on individual’s immune status, housing situation ▪ Topical neurotoxins, topical/oral parasidal drugs OTHER INTERVENTIONS SIGNS & SYMPTOMS ▪ Pruritus, bite marks, visible body parasites ▪ Proper hygiene, household measures, isolation (if necessary) PEDICULOSIS CORPORIS, CAPITIS, AND PUBIS (LICE) osms.it/lice PATHOLOGY & CAUSES ▪ Infestation of easily transmissible sucking lice species ▫ Commonly in hairy bodily areas, characterized by local pruritus ▪ Sucking lice infection ▫ (Phylum) arthropoda → (class) insecta → (order) phthiraptera → (suborder) anoplura → (family) pediculidae/ pthiridae PATHOLOGY ▪ Lice live human hair → suck blood for nutrients ▫ Bite → saliva injection → anticoagulation effect, ↑ histamine release → maculae cerulea (blue/copperhued bite marks); pruritus 68 ▪ Lice require humans for nutritional source (parasites) ▫ Most climates allow mature louse 24 hours of viable life away from human source Transmission ▪ Physical contact ▫ Ideal location: slow-moving, parallel hair fibers ▫ Louse on one hair fiber → transfer to another individual’s hair → lay nits (eggs) on hair 1–2mm off of scalp → nymphs hatch within one week → mature over one week → female lice lay eggs for one month ▪ Fomites TYPES ▪ Pediculus humanus capitis → head louse ▫ Can survive 24–48 hours without blood meal/separated from host ▪ Pediculus humanus humanus → body louse ▫ Larger than head louse; can survive < 72 hours without blood meal ▪ Phthirus pubis → pubic louse ▫ AKA crab louse; can spread to body RISK FACTORS ▪ School-aged children ▪ Homeless population ▪ Refugee population (if living in close quarters) COMPLICATIONS ▪ Co-infections (also carried by louse) ▫ Bartonella quintana → endocarditis ▫ Epidemic typhus ▫ Louse-borne relapsing fever ▫ Trench fever ▪ Adolescents with pubic lice → ↑ gonorrhea/ chlamydial infection risk ▪ Pruritus → skin excoriation → secondary infection ▫ Commonly staphylococcal infection SIGNS & SYMPTOMS ▪ Site pruritis (head, body, pubis) DIAGNOSIS OTHER DIAGNOSTICS Dermatologic examination ▪ Examination of hair follicles, clothing seams ▪ Nits: more visible than nymphs/lice; most visible (white) after louse released from egg; does not dislodge easily from hair follicle ▪ Body louse → widespread dermatitis ▪ Often linear excoriations ▪ Maculae ceruleae → may have punctal hemorrhages → recent bites ▪ Hyperpigmentation/lichenification → older bites Lymph node examination ▪ Capitis infection → posterior lymphadenopathy TREATMENT MEDICATIONS Topical benzyl alcohol ▪ Mechanism of action → louse asphyxiation ▫ Difficult for resistance to develop Neurotoxic agents ▪ Resistance develops with ▫ Pyrethrin: botanically-derived neurotoxin ▫ Permethrin: Na+ channel blocker → paralysis → death ▫ Malathion: organophosphate cholinesterase inhibitor OTHER INTERVENTIONS Hair shaving ▪ Eradicate current infection Mechanical removal ▪ Wet combing → tedious, poor compliance ▫ Pre-treatment: vinegar/formic acid → flattened hair cuticle → better combing efficiency (does not dissolve/loosen nits) Prevention ▪ Proper hygiene 69 Chapter 69 Ectoparasites ▪ Household ▫ Housemates: examination ▫ Bedmates: prophylactic treatment ▫ Household cleaning: washing > 54°C/130°F; unwashable material → place in sealed plastic bag for two weeks ▪ School ▫ No nit policy (infected children stay home), education, screening during outbreaks SARCOPTES SCABIEI (SCABIES) osms.it/sarcoptes-scabiei PATHOLOGY & CAUSES ▪ Sarcoptes scabiei mite infection ▫ Elicits strong immune response ▫ Nocturnal pruritus Mite infection ▪ (Phylum) mite → (class) arachnida → (subclass) acari → (order) astigmata → (family) sarcoptidae ▫ Usually obligate human parasite → vars hominis ▫ Sometimes animal mange mites can infest PATHOLOGY Mite transfer ▪ Direct skin-to-skin contact for 15–20 minutes ▪ Average infested individual carries 5–12 mites ▫ Crusted scabies individuals: > 1000 mites can be shed (transmission through objects more likely) Type IV hypersensitivity reaction ▪ House dust mite cross reactivity ▪ Infestation → ↑ IL-6, vascular epithelial growth factor (VEGF) →TH1-cell activation → IL-2 release → lymphocyte proliferation, differentiation RISK FACTORS ▪ Overcrowding (including long-term care facilities, prisons), poor hygiene/nutrition, homelessness, dementia, sexual contact COMPLICATIONS ▪ Infestation → secondary staphylococcal infection ▫ Low-income countries (mostly) ▫ Impetigo → chronic kidney disease ▫ Ecthyma, paronychia, furunculosis Crusted scabies ▪ AKA Norwegian scabies ▪ Infection commonly scalp, hands, feet → diffuse spread over entire body ▪ Occurs in compromised cellular immunity setting ▫ Acquired immunodeficiency syndrome (AIDS) ▫ Human lymphocytic virus type 1 (HTLV1) ▫ Leprosy ▫ Lymphoma ▫ Long-term topical corticosteroid use ▪ Risk factors: age, Down syndrome ▪ Complications: fissional lesions develop → bacterial entryway → infection ▫ Sepsis, poststreptococcal glomerulonephritis 70 SIGNS & SYMPTOMS Classic scabies ▪ Intense, intractable, generalized pruritus ▪ Nodules, pustules at most intense pruritus sites ▪ Common areas → intertriginous spaces ▫ Anterior axillary folds, webs of fingers, volar aspect of hand/wrist, beltline, penis, areolar region (biologically-female individuals) Dermatologic examination ▪ Serpiginous keratotic lines (1–4mm) → burrow marks ▫ Often with vesicle on end (housing mite) Nodular scabies ▪ Hypersensitivity reactions → large, persistent, intensely pruritic 5–6mm nodules ▫ Commonly groin, buttock, axillary folds Crusted scabies ▪ Poorly defined, erythematous patches → scale ▫ Untreated → entire integumental spread → warty appearance (especially over bony prominences); lesions crust, fissure develop → malodorous; nail involvement → thickened, dystrophic, discolored DIAGNOSIS LAB RESULTS Microscopy ▪ Confirmatory scraping: fluorescein stain → highlights fecal material, ova fragments ▫ Epithelial milieu (eosinophils, lymphocytes, histiocytes) ▫ Crusted scabies: mate capture more likely due to disease burden Polymerase chain reaction assays ▪ S. scabiei DNA polymerase OTHER DIAGNOSTICS History ▪ Close contact commonly present with concurrent symptoms ▪ Infected individual contact history (may be many weeks prior) Figure 69.1 A high-magnification photograph of a single mite burrow in the skin of an individual with scabies. The mite is at the end of the burrow at the top right of the image. TREATMENT MEDICATIONS Classic scabies ▪ Permethrin (5%) → synthetic neurotoxin → Na+ channel blocker → paralysis → death ▪ Precipitated sulfur (6%, 10%) in petroleum ▪ Benzyl benzoate (10%, 25%) ▫ Adverse reactions: allergic dermatitis ▫ Contraindications: pregnancy/lactation (neurotoxicity); children < two years old ▪ Oral ivermectin ▫ One dose (200mcg/kg) repeated in 7–10 days Nodular scabies ▪ Topical steroids ▪ Intralesional steroid injection Crusted scabies ▪ Topical, systemic treatment required ▪ Oral ivermectin, topical permethrin (5%)/ benzyl benzoate (5%) ▫ Two week oral regimen, topical therapy 71 Chapter 69 Ectoparasites persisting after that twice weekly until cure ▫ Treatment cure → active lesion resolution, nocturnal pruritus absence for one week OTHER INTERVENTIONS ▪ Isolation for infected ▪ Nail clipping ▫ +/- brushing with scabicidal agent ▪ Thorough personal, household material laundering Prevention ▪ Monosulfiram soap in communities with ↑ ↑ incidence 72 NOTES NOTES ENTEROCOCCUS ENTEROCOCCUS osms.it/enterococcus PATHOLOGY & CAUSES ▪ Gram-positive spherical-shaped bacteria (cocci) ▪ Grow in pairs (diplococci)/short chains ▪ Non-spore forming ▪ Optimal growing conditions: 45ºC/113°F, can withstand up to 60ºC/140°F ▫ Facultatively anaerobic bacteria ▫ 6.5% NaCl, bile-containing media ▪ Characteristics ▫ Catalase negative, pyrrolidonyl arylamidase (PYR) positive ▫ Variable hemolytic activity on blood agar plates; most commonly gamma hemolytic ▪ Common human pathogens: E. faecalis, E. faecium ▪ Important cause of hospital-acquired infections, esp. infective endocarditis, urinary tract infections (UTIs), infections of prosthetic devices (e.g. venus/urinary catheters) ▫ Surface carbohydrates → adherence to cardiac valves → fibrinogen synthesis → valve vegetations → infective endocarditis ▫ Adherence to renal epithelial cells → UTI ▪ Less common associations ▫ Wound, bloodstream, biliary tract, pelvic infections; intraabdominal abscesses RISK FACTORS ▪ Indwelling medical devices (e.g. central venous, urinary catheterization) ▪ Cardiovascular abnormalities ▪ Prolonged hospitalization, mechanical ventilation ▪ Prior antibiotic use, immunodeficiency COMPLICATIONS ▪ Bacteremia ▫ Immunocompromised individuals SIGNS & SYMPTOMS ▪ UTIs ▫ Cystitis, pyelonephritis; dysuria, frequency, urgency, suprapubic/flank tenderness ▪ Infective endocarditis ▫ Subacute onset of fever, malaise, peripheral signs (e.g. Janeway lesions, Osler’s nodes), cardiac murmurs (usually left-sided), splenomegaly ▪ Infection of prosthetic devices, wounds ▫ Erythema, swelling, tenderness, warmth DIAGNOSIS DIAGNOSTIC IMAGING Transthoracic echocardiography; abdominal CT scan; ultrasound ▪ Identify organ involvement LAB RESULTS ▪ Cultures from infected sites (e.g. blood, urine) ▪ Susceptibility testing ▫ Detect antibiotic resistance 73 Chapter 70 Enterococcus ▪ Complete blood count (CBC) ▫ ↑ polymorphonuclear cells ▪ Urinalysis ▫ UTI → pyuria, proteinuria, hematuria TREATMENT MEDICATIONS Antimicrobial therapy ▪ Localized infections ▫ Ampicillin/beta lactamase inhibitors (clavulanate/sulbactam) ▫ Alternative: nitrofurantoin ▪ Serious infections with bacteremia, meningitis, endocarditis ▫ Penicillin/ampicillin + aminoglycoside ▫ Alternative: vancomycin, aminoglycoside ▪ Vancomycin-resistant enterococcal (VRE) infection ▫ Linezolid/daptomycin SURGERY ▪ Drain abscess ▪ Valve replacement OTHER INTERVENTIONS ▪ Remove venous/urinary catheters 74 NOTES NOTES FILAMENTS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Gram ⊕ slender bacteria with ⊕ branches (atypical lung disease organisms, capable of affecting any body organ ▪ Atypical organisms → indolent disease → insidious growth → severe disease RISK FACTORS ▪ Immunodeficiency ▪ Corticosteroid use → iatrogenic immunosuppression SIGNS & SYMPTOMS ▪ Cough, dyspnea ▫ Indolent course ▫ Common in fever’s absence ▪ Other symptoms ▫ Dependent on organ systems affected by organism LAB RESULTS ▪ Tissue biopsy → histological OTHER DIAGNOSTICS Physical examination ▪ Pulmonary examination ▫ Auscultation: rhonchi (crackles), ↓ breath sounds ▫ Palpation: ↓ tactile fremitus ▫ Percussive dullness TREATMENT MEDICATIONS ▪ Antibiotics SURGERY ▪ Resection ▫ Medication non-responsive ▫ Large infections → significant dysfunction DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Localized alveolar infiltrate ▫ Homogeneous, non-segmental, cavitary appearance 75 Chapter 71 Filaments ACTINOMYCES ISRAELII osms.it/actinomyces-israelii PATHOLOGY & CAUSES Microbe characteristics ▪ ⊕ Gram stain ▪ Shape ▫ Filamentous, non-spore-forming, pleomorphic bacilli ▪ Metabolism ▫ Catalase negative, anaerobic/ microanaerobic bacilli ▪ Types ▫ 21 species found in humans ▫ Actinomyces israelii most common ▪ Locations ▫ Normal mouth (by two years old), gastrointestinal (GI) tract, female genitourinary tract flora PATHOLOGY Thoracic ▪ Pulmonary → pneumonia ▫ Oropharyngeal content aspiration → bacterial alveoli seeding → immune response, bacterial growth → pneumonia Abdominal & pelvic ▪ Gastrointestinal → appendicitis ▫ Preceding colonic mucosa perforation → unrecognized → months–year course → symptomatic infection ▪ Pelvic → female genitourinary infections ▫ Complicated abortions, infected intrauterine devices (IUDs), endometritis, tubo-ovarian abscess (TOA) RISK FACTORS ▪ Chronic granulomatous disease Cervicofacial ▪ Chronic tonsillitis, dental decay, periodontal disease, mastoiditis, otitis media ▪ Uncommon infection source ▪ Mucosal membrane violated → indolent, invasive disease ▫ Commonly co-occurs with another pathogen → micro-O2 Actinomyces environment ▫ Can burrow through soft tissue, bone → small abscesses, drainage tracts ▫ Abscesses: yellow sulfur-containing granules in granulomatous reactive material setting (bacteria found in microfilament tangles, surrounded by neutrophils) COMPLICATIONS TYPES Thoracic ▪ Pneumonitis Cervicofacial ▪ Osteomyelitis of mandible/maxilla ▫ Resident flora in periodontal pockets, carious teeth, dental plaque, tonsillar crypts Abdominal & pelvic ▪ Gastrointestinal ▫ Peritoneal, hepatic, pelvic infectious spread Thoracic ▪ Aspiration history Cervicofacial ▪ Deep neck tissue infection → retropharyngeal space → mediastinitis ▪ Meningitis → if sinus tracts to posterior neck, spinal cord 76 SIGNS & SYMPTOMS Cervicofacial ▪ Lumpy jaw ▫ Usually in fever’s/other infectious signs’ absence ▪ Progression → oral mucosa, trismus sinus tract draining Thoracic ▪ Fever, cough > three day duration ▪ Auscultation ▫ Rhonchi ▫ ↓ breath sounds ▪ Palpation ▫ ↓ tactile fremitus ▪ Percussive dullness Abdominal & pelvic ▪ Gastrointestinal → appendicitis ▫ Asymptomatic colonic mucosa (micro) perforation → months–years prodrome → symptomatic appendicitis ▫ Nonspecific prodrome: chronic fever, weight loss, diarrhea, constipation, night sweats ▫ Appendicitis: nausea, vomiting, anorexia ▪ Pelvic → female genitourinary infections ▫ Painful abdominal, cervical examination ▫ Purulent vaginal discharge CT scan ▪ Abdominal, pelvic ▫ Disrupted tissue planes Colonoscopy ▪ Abdominal, pelvic ▫ Normal/thickened mucosal appearance, colitis, ulceration, nodular lesion, buttonlike appendiceal orifice elevation Bedside ultrasound ▪ Abdominal, pelvic ▫ TOA evaluation LAB RESULTS ▪ Cervicofacial ▫ Monoclonal antibody staining ▫ Polymerase chain reaction (PCR) of 16S rRNA Cultures (needle aspiration) ▪ Cervicofacial ▫ Histology: granulation tissues with neutrophils, foamy macrophages, lymphocytes, plasma cells (with surrounding fibrosis) ▪ Abdominal, pelvic ▫ Histology: granulation tissue surrounding oval, eosinophilic zones DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Thoracic ▫ Localized alveolar infiltrate: homogeneous; non-segmental, cavitary appearance; can extend past fissure lines → into chest wall Barium enema ▪ Abdominal, pelvic ▫ Luminal narrowing, fistualization, extrinsic compression Figure 71.1 Sulphur granules formed by Actinomyces organisms. 77 Chapter 71 Filaments OTHER DIAGNOSTICS History ▪ Thoracic ▫ May have community-acquired pneumonia diagnosis, treatment (without relief within 3–5 days) Physical examination ▪ Cervicofacial ▫ Lymphatic examination ▪ Thoracic ▫ Pulmonary examination TREATMENT MEDICATIONS ▪ Antibiotics ▫ Prolonged (weeks–months) penicillin V (oral)/penicillin G (intravenous) ▫ Amoxicillin (alternative) SURGERY ▪ Necrotic disease/especially large abscess formation cases NOCARDIA osms.it/nocardia PATHOLOGY & CAUSES ▪ Microbe characteristics ▪ ⊕ Gram stain ▪ Shape ▫ Filamentous, branch-forming, bacillus ▫ Branches → beaded appearance (delicate nature of stain → cocci/bacilli fragmentation) ▪ Metabolism ▫ Aerobic, catalase ⊕, urease ⊕ ▪ Types ▫ > 80 species ▫ Around 30 disease-causing in humans ▪ Locations ▫ Saprophyte (organic pathogen) → found in soil, house dust, water (fresh/salt), bathing pools PATHOLOGY ▪ Direct tissue inoculation ▫ Saprophyte → aerosolization common (↑ ↑ pulmonary infections) ▫ Soil/water contamination (contaminated food → GI disease, skin trauma → cutaneous disease, eye trauma → ocular disease) ▪ Facultative intracellular organism → requires innate host defense mechanisms ▫ Inhalation entry: deficient/ineffective mucociliary clearance, host response → bronchopulmonary disease ▫ Skin trauma entry: deficient keratinized skin barrier → local subcutaneous infection; deficient keratinized cornea → ocular infection ▪ Rapid filamentous growth → ↓ phagocytic clearing ▫ Phagocytosed → ↓ lysosomal destruction (phagocyte-lysosome fusion inhibition; catalase, dismutase production → ↓ reactive oxygen species → pathogen survival) TYPES Pneumonia ▪ Nocardia asteroides (common pathogen) ▪ > 2⁄3 of total disease ▪ Progression ▫ Empyema, pericardial effusion Primary cutaneous infections ▪ Nocardia brasiliensis (common pathogen) ▪ Cellulitis, ulcers, pyoderma, myocetma 78 ▪ Progression ▫ Abscess/nodular development, lymphangitis RISK FACTORS ▪ ↓ mucociliary clearance ▫ Cystic fibrosis, asthma, bronchiectasis ▪ Immunosuppression ▫ Iatrogenic (most commonly corticosteroid use); lymphoreticular malignancy; chronic obstructive pulmonary disease; chronic granulomatous disease; dysgammaglobulinemia; HIV infection; bone marrow, organ transplant COMPLICATIONS ▪ Organ dissemination ▫ Pulmonary infection → hematogenous spread (commonly) ▫ Most common: central nervous system (meningitis, cerebral abscess) ▪ Pulmonary ▫ Empyema, pericardial effusion ▪ Cutaneous ▫ Lymphangitis ▪ Ocular ▫ Endophthalmitis (ocular infection) SIGNS & SYMPTOMS Pneumonia ▪ Acute, subacute, chronic suppurative course ▫ Symptoms may also relapse/remit ▪ Cough, dyspnea common ▫ Anorexia, weight-loss (uncommon) ▫ Hemoptysis (cavitary disease) ▪ Rhonchi (crackles) ▪ ↓ breath sounds, tactile fremitus, +/egophony Local cutaneous infection ▪ Local erythema, warmth, +/- ulceration, nodular growth Neurologic infection ▪ Meningismus, fever, rigors, seizure DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary ▫ Homogeneous, non-segmental, cavitary alveolar infiltrate Brain MRI ▪ Neurologic ▫ ↑ T1 imaging intensity → ↑ enhancement (gadolinium) LAB RESULTS ▪ Tissue biopsy: histology (acid fast stain) ▫ Gram ⊕, branching, beaded filamentous growth TREATMENT MEDICATIONS Antibiotic monotherapy ▪ Mild/moderate disease ▪ 3–6 months treatment duration ▪ Sulfonamides → trimethoprimsulfamethoxazole (TMP-SMX) ▪ Linezolid ▫ Nocardia 100% sensitive ▫ Limited treatment duration (2–3 weeks) → ineffective monotherapy for complete therapy duration Antibiotic multi-agent therapy ▪ Severe disease ▪ Up to 6–12 months treatment duration ▪ Agents ▫ TMP-SMX + amikacin/carbapenem/ linezolid ▪ Commonly for progressive disease in immunosuppressed individuals/pulmonary, disseminated disease Prevention & vaccine ▪ Daily, full-strength TMP-SMX → secondary prophylaxis ▪ P. jirovecii TMP-SMX prophylaxis (3x/week) → ineffective 79 Chapter 71 Filaments SURGERY ▪ Indicated for ▫ Antibiotic-resistant, large cutaneous/ cerebral abscess (craniotomy/aspiration effective) ▫ Empyemas, large fluid collections ▫ Pulmonary nocardiosis → pericarditis (fatal if not performed) 80 NOTES NOTES FILOVIRUSES MICROBE OVERVIEW Genetic material ▪ Single-stranded negative-sense RNA virus family; causes viral hemorrhagic fever Taxonomy ▪ Genera: Ebolavirus, Marburgvirus, Cuevavirus Morphology ▪ Enveloped virions; filamentous, nonsegmented morphology Replication ▪ Transcription, replication mediated by virus-encoded polymerase in infected cell cytoplasm ▫ Transcription: negative-sense RNA genome transcribed into monocistronic, polyadenylated RNA species using host cell ribosomes, tRNA etc. → translated into seven proteins ▫ Replication: positive-sense antigenome serves as template for negative-sense genomes Transmission ▪ Zoonotic infection ▫ Natural host: unknown (bats, especially fruit bats considered infection source) ▫ Intermediate host: Often nonhuman primates (gorillas, chimpanzees) Structural proteins ▪ Viral RNA encodes seven structural proteins ▫ Nucleoprotein ▫ Polymerase cofactor (VP35) ▫ Viral proteins VP40, VP24 ▫ Glycoprotein: projecting spikes from lipid bilayer (attachment to host cell receptors) ▫ Transcription activator ▫ RNA-dependent RNA polymerase EBOLA VIRUS osms.it/ebola-virus PATHOLOGY & CAUSES ▪ Ebola virus: causative agent of severe, often fatal hemorrhagic fever ▪ Species: Zaire, Sudan, Tai Forest, Bundibugyo, Reston ▪ Transmission ▫ Animal-human: direct infected-animal tissue, body-fluid contact; butchering, consuming undercooked meat ▫ Human-human: direct tissue, body fluid contact with ill/deceased ▫ Potential transmission: contaminated surface/object contact PATHOLOGY ▪ Inoculation → incubation: 6–12 days average (ranges 2–21 days) ▫ Host cell attachment, virus endocytosis → nucleocapsid release in cytoplasm → 81 Chapter 72 Filoviruses ▪ ▪ ▪ ▪ replication → nucleocapsid formation → viral shedding, cell necrosis Initially macrophages, dendritic cells infected → sentinel lymph node spread → bloodstream → many cell types infected (endothelial cells, fibroblasts, hepatocytes, epithelial cells, adrenal-gland cells) with lymphocyte/neuron exception ▫ Although uninfected, inflammatory mediators; support signal loss from dendritic cells → “bystander” apoptosis of lymphocytes Multifocal necrosis in various tissues (e.g. liver, spleen) Systemic inflammatory syndrome: proinflammatory mediator, cytokine release from infected macrophages, dendritic cells, necrotic cell breakdown products, etc. → vasodilation, ↑ vascular permeability → vascular leakage, shock, multiorgan failure Dendritic cell dysfunction, “bystander” lymphocyte apoptosis → impaired adaptive immunity ▪ Spontaneous abortion, vaginal bleeding in infected pregnant individuals (100% third trimester maternal, fetal mortality) ▪ Fatality ranges ▫ 40% to 80–90% (depending upon species) RISK FACTORS ▪ Healthcare workers without appropriate protective equipment, adequate training ▪ Inadequate infected waste product, corpse handling ▪ Sexual intercourse with person recovering from Ebola in previous three months ▪ Travel to endemic/Ebola epidemic areas ▪ Wild animal contact (mostly nonhuman primates) COMPLICATIONS ▪ Gastrointestinal dysfunction ▫ Fluid loss, hypotension, acute kidney injury, shock ▪ Neurologic ▫ Meningoencephalitis, meningitis ▪ Coagulopathy ▫ Infected macrophages produce tissue factor (TF), stimulate extrinsic coagulation pathway → disseminated intravascular coagulation (DIC) ▪ Respiratory failure ▪ Coinfection/superinfection ▪ Impaired adaptive immunity → bacterial sepsis Figure 72.1 A scanning electron micrograph of an ebola virus demonstrating the typical filamentous structure seen in its class, Filoviridae. SIGNS & SYMPTOMS Initial nonspecific symptoms ▪ Fever, chills, fatigue, headache, appetite loss, malaise, sore throat, myalgias, lumbosacral pain Dermatological ▪ Diffuse erythematous; nonpruritic maculopapular/morbilliform rash, especially on torso/face Gastrointestinal ▪ Watery diarrhea (up to 10L/2.2gal); nausea; vomiting; epigastric, abdominal pain; abdominal tenderness 82 Hemorrhage ▪ Commonly hematochezia, followed by hematemesis, melena, metrorrhagia, purpura, petechiae, ecchymoses, mucosal bleeding, venipuncture site bleeding ▫ Often occur later in disease course; not all infected individuals develop significant bleeding; host susceptibilitydependent (genetically determined viral immune response difference), different species’ pathogenicity Neurologic ▪ Meningoencephalitis symptoms (altered level of consciousness, hyperreflexia, myopathy, stiff neck, gait instability, seizure) Ocular ▪ Conjunctival injection, uveitis symptoms (blurred vision, photophobia, blindness) Respiratory ▪ Tachypnea, dyspnea Convalescent period ▪ Can persist > two years often followed by symptoms such as arthralgia, blurred vision, retro-orbital pain, hearing loss, alopecia, difficulty swallowing, insomnia ▪ Infectious virus/viral RNA can persist in body fluid (semen, breast milk, urine, cerebrospinal fluid, aqueous humor) < nine months after not detectable in blood → variable transmission risk DIAGNOSIS ▪ Diagnostic criteria ▫ Clinical manifestation ▫ Travel to endemic/Ebola epidemic areas (within three weeks prior to disease onset) ▫ Infected individual contact during acute disease ▪ Laboratory findings ▫ Leukopenia; thrombocytopenia; ↑ ↓ hematocrit; ↑ aspartate aminotransferase (AST), alanine aminotransferase (ALT) ▫ Prolonged prothrombin (PT), partial thromboplastin time (PTT) ▫ Proteinuria, ↑ blood urea nitrogen, ↑ creatinine ▫ Hyponatremia, hypocalcemia, hyperkalemia TREATMENT ▪ No cure ▪ Infected individual isolation; placement in negative airflow room advised MEDICATIONS ▪ Complications treatment ▫ Coinfection/superinfection: empiric antimicrobial therapy with broad spectrum antibiotics ▫ Shock: intravenous fluids, vasoconstrictors ▫ Fever reduction: antipyretic agents OTHER INTERVENTIONS ▪ Complications treatment ▫ Fluid, electrolyte loss correction ▫ Acute kidney injury: renal replacement therapy (dialysis) ▫ Respiratory failure: supplemental oxygen therapy, mechanical ventilation (if necessary, barotrauma risk) ▪ Prevention ▫ Ervebo: FDA-approved vaccine ▫ Proven highly effective, safe during trial conducted in Guinea (2015) LAB RESULTS ▪ Reverse-transcription polymerase chain reaction (RT-PCR) ▫ Detectable Ebola virus in blood samples within three days after symptom onset ▪ Rapid chromatographic immunoassay (ReEBOV) 83 NOTES NOTES FLAVIVIRUSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Single-stranded, ⊕-sense, enveloped RNA viruses ▪ AKA arboviruses ▪ > 40 types identified Replication ▪ Cell surface attachment → cytoplasm entry → viral protein translation → viral RNA genome replication → virion formation (encapsidation) → cellular release Transmission ▪ Primarily transmitted via arthropod bites RISK FACTORS ▪ Recent endemic area travel/residence ▪ Poor insect repellant use ▪ Improper skin coverage (e.g. long sleeve clothing) SIGNS & SYMPTOMS ▪ Mainly asymptomatic ▪ Others commonly have acute-onset flu-like symptoms ▪ Serious complications/sequelae commonly characterized by neurologic disease (e.g. seizure, encephalopathy) ▫ Fever, nausea/vomiting DIAGNOSIS LAB RESULTS ▪ Serology ▪ Time-dependent on infection course, immune response ▪ Reverse transcription polymerase chain reaction (RT-PCR) for viral antigens OTHER DIAGNOSTICS ▪ Endemic area travel/residence ▪ Presence of mosquito bite(s) TREATMENT ▪ No cure MEDICATIONS ▪ Variable vaccine availability ▫ Untenable mainly due to antigenic mutations, multiple genotypes OTHER INTERVENTIONS ▪ Fluid, electrolyte balance 84 AfraTafreeh.com exclusive DENGUE VIRUS osms.it/dengue-virus PATHOLOGY & CAUSES ▪ Viral disease, mosquito transmission ▫ Characterized by febrile illness ▫ AKA break-bone fever ▪ Four serotypes ▫ DENV-1 through DENV-4 ▫ IgG response to specific type → lifetime immunity ▫ Limited, transient cross-protectivity across viral types ▪ Vector ▫ Primarily Aedes aegypti and A. albopictus Pathogenesis ▪ Aedes mosquito bite → dengue virus skin introduction → local infection, response → dissemination → viremia (2–6 days later) → circulating leukocyte infection (especially) monocytes → viral replication, release → fever RISK FACTORS ▪ Endemic area residence ▪ Recent travel COMPLICATIONS Severe dengue ▪ AKA dengue hemorrhagic fever ▪ Viremia → local hemorrhage → systemic hemorrhage → hemodynamic collapse → shock ▫ Dengue shock syndrome (rare complication—DENV-2 confers highest risk) ▪ Direct bone marrow infection → hematopoietic stem cell infection → ↓ megakaryocyte differentiation (among all other cell lines) → ↓ platelets formed ▫ ↓ Circulating lifetime: virus-antibody complex → circulating platelet adherence → complement destruction ▪ ▪ ▪ ▪ of virus-antibody complex → adherent platelet destruction Capillary leak ▫ Direct effect: viral endothelial cell infection → cellular dysfunction → tight junction widening → capillary leak ▫ Indirect: virus-infected monocytes, dendritic cells, mast cells → TNFalpha, IFN-gamma, IL-2, IL-8, vascular endothelial growth factor release, complement activation → ↑ capillary permeability Molecular mimicry ▫ Viral E protein antibody response → plasminogen cross-reaction → inefficient coagulation cascade → hemorrhage Liver failure ▫ Direct viral infection → Kupffer cells, hepatocytes → apoptosis → hepatocellular necrosis, Councilman bodies ▫ Sever disease → shock → liver hypoperfusion → hepatocellular injury, death Central nervous system (CNS) involvement ▫ Rare, direct viral infection of brain parenchyma SIGNS & SYMPTOMS ▪ High-grade fever (> 38.5°C/101.3°F) ▪ Generalized pain ▫ Abdominal pain/tenderness, headache, joint pain, muscle pain, eye/retro-orbital pain ▪ Nausea/vomiting ▪ Mucosal bleeding ▪ Rash Severe symptoms and signs ▪ Severe bleeding ▪ Fluid accumulation → respiratory distress ▫ Ascites, pleural effusion 85 Chapter 73 Flaviviruses ▪ Neurologic impairment ▫ Lethargy, seizure, encephalopathy DIAGNOSIS LAB RESULTS ▪ Leukopenia ▪ Thrombocytopenia ▪ ↑ Hematocrit TREATMENT MEDICATIONS ▪ No antiviral therapy available ▪ Fever control ▫ Antipyretics OTHER INTERVENTIONS Antibody testing ▪ Antigen assay ▫ ⊕ < five days of infection ▪ IgM ▫ ⊕ ≧ three days of infection ▪ IgG ▫ ⊕≧ seven days of infection ▫ May be ⊕ due to prior infection OTHER DIAGNOSTICS Positive tourniquet test ▪ Blood pressure cuff insufflation → maintain pressure midway between systolic, diastolic → hold for five minutes → deflate → observe for petechiae ▫ Positive test:10+ petechiae in 2.5cm/1in ▪ Maintain adequate intravascular volume ▪ Shock ▫ Crystalloid fluid resuscitation ▪ Bleeding ▫ Platelet transfusion if severe thrombocytopenia and/or active, uncontrolled bleeding Prevention ▪ Mosquito control ▫ ↓ Standing water breeding sites ▫ Copepod use (organisms feed on mosquito larvae) ▫ Insecticides ▪ Personal protective measures ▫ Repellant use ▫ Permethrin-treated clothing (Na+ channel blockade → neurotoxicity → paralysis → death; low toxicity in humans) WEST NILE VIRUS osms.it/west-nile-virus PATHOLOGY & CAUSES ▪ Virus causing mosquito-borne, self-limited disease ▫ Characterized by flu-like symptoms ▫ Potential for severe neurologic sequelae ▪ Vector ▫ Culex mosquito Pathogenesis ▪ Culex mosquito bite → viral replication in skin’s dendritic cells → lymph node migration → further replication → enters bloodstream → visceral organ dissemination ▫ Complication arise when virus enters bloodstream → crosses blood-brain barrier Transmission ▪ Infected bird (amplifying host) → prolonged viremia → Culex mosquito blood meal → human/other vertebrate bite → blood meal, virus-laden saliva injected→ virus transmission ▪ Viral-load organ/blood donation ▪ Transplacental infection 86 RISK FACTORS ▪ Elderly ▪ Immunosuppressed individuals ▪ Malignancy (especially hematologic malignancies) ▪ Chemokine receptor CCR5 deficiency ▫ Chemokine involved in viral infection immune response (especially brain parenchyma) COMPLICATIONS ▪ Neurological ▫ Meningitis, encephalitis, tremor, flaccid paralysis, Guillain–Barré syndrome ▪ Ocular ▫ Chorioretinitis, uveitis, optic neuritis ▪ Cardiac ▫ Myocarditis, cardiac arrhythmias ▪ Muscular ▫ Myositis, rhabdomyolysis ▪ Other ▫ Pancreatitis, orchitis, hepatitis, central diabetes insipidus SIGNS & SYMPTOMS ▪ Abrupt-onset fever, headache, myalgias ▫ Usual presentation is self-limited (AKA West Nile Fever) ▪ Abdominal pain, anorexia, nausea/vomiting, diarrhea, maculopapular rash Neurologic complications ▪ Motor ▫ Tremor, flaccid paralysis (Guillain-Barré complications) ▪ Meningoencephalitis ▫ Meningismus, altered mental status DIAGNOSIS DIAGNOSTIC IMAGING Nerve action potentials ▪ Normal sensory conduction velocity ▪ Abnormally ↓motor neuron velocity, potentials LAB RESULTS ▪ Reverse transcription polymerase chain reaction (RT-PCR) ▪ Viral cultures ▪ Cerebrospinal fluid ▫ Severe cases ▫ If present in CSF → neuroinvasive disease likely ▫ Neutrophilic pleocytosis (<500 cells/ microL) → lymphocytic predominance as disease progresses ▫ ↑ Protein (<150mg/dl) ▪ Serology ▫ Enzyme-linked immunosorbent assay (MAC-ELISA) for IgM detection → positive 4-10 days after viremia detection OTHER DIAGNOSTICS ▪ Integument examination ▫ Maculopapular rash ▪ Neurological ▫ Meningismus (in severe cases) Electroencephalography (EEG) ▪ Generalized, continuous slowing prominent in frontal/temporal regions TREATMENT ▪ No cure OTHER INTERVENTIONS Prevention ▪ Personal protection measures ▪ Mosquito control programs ▪ Blood donor screening MRI ▪ Neurologic sequelae → ↑ signal in T2 imaging 87 Chapter 73 Flaviviruses YELLOW FEVER VIRUS osms.it/yellow-fever-virus PATHOLOGY & CAUSES ▪ Virus that causes mosquito-borne illness in endemic, tropical areas (Africa, South America) ▫ Characterized by hemorrhagic fever, coagulopathy, shock (most severe cases) ▪ Seven major genotypes, conserved in each specific endemic region ▫ Only one serotype that has remained antigenically conserved ▪ Vector ▫ Aedes, Haemagogus mosquitoes Pathogenesis ▪ Female Haemagogus mosquito bite → viral transmission → skin dendritic cells infected→ lymphatic spread → monocyte/ macrophages, histiocytes in lymph node → replication → lymphatic, hematogenous spread throughout body ▫ 3–6 day incubation period until symptoms appear Transmission ▪ Infected monkey → Haemagogus mosquito bite → human bite → blood meal, viral transmission ▪ During epidemics/urban spread ▫ Aedes mosquito feeds on infected humans → infected Aedes mosquito → feeds on another human → viral transmission COMPLICATIONS ▪ Hepatic injury → viral hepatitis ▫ Councilman bodies (hepatocytes characterized by eosinophilic degeneration with condensed nuclear chromatin) present on histology ▫ Jaundice results ▫ Severe disease → ↓ vitamin ▪ ▪ ▪ ▪ ▪ K-dependent coagulation factors → hemorrhagic diathesis Shock ▫ Due to cytokine dysregulation ▫ ↑ IL-1, IL-6, TNF-alpha, IFN-10 Renal failure ▫ Hypotension/hepatorenal syndrome → eosinophilic degeneration, renal parenchyma fatty change Hemorrhage Secondary bacterial infection Myocardial infection Neurological ▪ Delirium, convulsions, coma SIGNS & SYMPTOMS ▪ Infection period (3–4 days) ▫ Acute-onset headache, fevers, chills, myalgia ▫ Photophobia, restlessness, anorexia, vomiting ▪ Remission period (up to 48 hours) ▫ Afebrile ▫ No other symptoms Severe yellow fever ▪ Intoxication period (3–6 days after infection onset) ▪ Nausea/vomiting, fever, oliguria → anuria, epigastric tenderness, jaundice ▪ Hemorrhage ▫ Coffee-ground emesis, melena, hematuria, petechiae, ecchymoses ▪ Myocardial injury ▫ Cardiac enlargement, conduction abnormalities ▪ Neurological dysfunction ▫ Altered mental status, convulsions, delirium 88 OTHER DIAGNOSTICS DIAGNOSIS LAB RESULTS ▪ Renal dysfunction ▫ Azotemia, proteinuria, creatinine (3–-8x normal value) ▪ PCR ▫ Viral genome ▪ CSF analysis ▫ ↑ opening pressure, ↑ protein, ⊝ cells Serology ▪ Enzyme-linked immunosorbent assay (ELISA) ▫ IgM antibodies ▪ Reverse-transcriptase loop-mediated isothermal amplification (RT-LAMP) ▫ Field test for quick diagnostics ▫ Easy-to-read visual test, good sensitivity ECG ▪ Cardiac conduction abnormalities ▪ ST-T abnormalities TREATMENT OTHER INTERVENTIONS ▪ Fluid management, resuscitation ▪ Bleeding diathesis reversal ▫ Fresh frozen plasma ▪ Adequate nutrition Prevention ▪ Live attenuated vaccine ▫ Recommended for individuals > nine months old residing in/traveling to endemic areas ▫ Contraindication in children < six months old ▪ Passive maternal immunization ▫ Safest immunoglobulin transfer ZIKA VIRUS osms.it/zika-virus PATHOLOGY & CAUSES ▪ Mosquito-borne virus ▫ Characterized by mild disease in infected individuals, serious neurologic sequelae in developing fetus ▪ Vector ▫ Aedes aegypti/albopictus mosquitoes Pathogenesis ▪ Aedes mosquito bite → dendritic cell infection, replication → bloodstream → dissemination ▪ Maternal infection → placental injury → fetus infection → neuronal progenitor cell infection → neuronal cell death Transmission ▪ Human-to-human close contact ▫ E.g. sexual contact ▫ Possible transmission via other bodily secretions (e.g. tears, sweat) in individuals with very high viral loads ▪ Blood transfusion ▪ Organ transplantation ▪ Maternal-fetal spread COMPLICATIONS ▪ Microcephaly in developing newborns ▪ Greatest risk for sequelae estimated to occur with first, second trimester infection ▫ Serious neurological, intellectual deficits ▫ Seizures ▫ Vision, hearing problems ▪ Neurological sequelae ▫ Guillain–Barré syndrome ▫ Myelitis 89 Chapter 73 Flaviviruses ▫ Meningoencephalitis SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ Mild fever Maculopapular rash Nonpurulent conjunctivitis Joint, muscle pain DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Pregnant individuals ▫ Microcephaly, growth retardation evaluation LAB RESULTS ▪ RT-PCR ▫ If < 14 days from symptoms onset ▫ Confirmatory testing with plaque reduction neutralization test (PRNT) ▫ PRNT: measure of antibodies that neutralize virus-specific antigens Serology ▪ IgM against Zika virus ▫ If > 14 days from onset of symptoms TREATMENT ▪ No cure MEDICATIONS ▪ Antipyretics OTHER INTERVENTIONS Mother ▪ Rest ▪ Fluid management, resuscitation Newborn ▪ Nutritional support ▪ Physical therapy ▪ Specialty referral (especially neurology) Prevention ▪ No vaccine available ▪ Personal protective measures in endemic areas ▪ Consultation with physician prior to travel for pregnant individuals ▪ Safe sexual practice ▫ Biologically-male individuals wait at least six months after endemic-area travel for unprotected sex ▫ Biologically-female individuals wait at least eight weeks after endemic-area travel for unprotected sex ▪ Blood donation ▫ Do not donate for at least six months after endemic-area travel 90 91 NOTES NOTES GASTROINTESTINAL INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Gastrointestinal tract (GIT) inflammation caused by virus, bacteria, other parasites ▪ GIT mucosa inflammation → ulceration → epithelial disruption → edema, bleeding → fluid, electrolyte loss (diarrhea) → dehydration, electrolyte imbalance, anemia (bloody diarrhea) ▪ Mainly fecal-oral transmission RISK FACTORS ▪ Living/traveling to endemic areas, youth, immunosuppression (e.g. corticosteroid treatment, HIV co-infection), malnutrition, poor hygiene DIAGNOSIS ▪ Pathogen-dependent LAB RESULTS ▪ Stool culture TREATMENT ▪ Rehydration ▪ Antimicrobial therapy (pathogendependent) SIGNS & SYMPTOMS ▪ Fever, diarrhea, abdominal pain (cramps) ▪ Dehydration ▫ Sunken eyes, dry mouth, decreased urination, dark yellow urine (deep amber—severe), dry skin, syncope 92 CRYPTOSPORIDIUM osms.it/cryptosporidium PATHOLOGY & CAUSES ▪ Cryptosporidiosis: diarrheal disease caused by Cryptosporidium (intestinal intracellular protozoan parasite) ▪ Life-cycle can be completed in one host ▫ Immunocompetent hosts: self-limited diarrhea ▫ Immunocompromised hosts: lifethreatening complications CAUSES ▪ Cryptosporidium oocysts (infective form) transmitted via fecal → oral route ▫ Infected individual/animal feces contaminates food; drinking, swimming water → fecally-contaminated food/ water ingestion ▪ Parasites → intestinal epithelial inflammation → villi structure distortion → ↓ absorption, ↑ secretion → watery diarrhea ▫ Sclerosing cholangitis/acalculous cholecystitis, respiratory cryptosporidiosis, pancreatitis RISK FACTORS ▪ Endemic-area exposure (tropical countries, Kuwait), immune deficiencies, poor hygiene ▪ Interpersonal transmission: sexual partners, daycare centers, household members COMPLICATIONS DIAGNOSIS LAB RESULTS Microscopic oocyte identification ▪ Stool; bile secretion, affected GIT aspirates; affected GIT tissue biopsy; respiratory secretion Polymerase chain reaction (PCR) ▪ More sensitive, specific ▪ Differentiates between Cryptosporidium genotypes Monoclonal antibodies and enzyme immunoassays (EIA) ▪ Monoclonal antibody test against oocyst wall ▪ More sensitive, specific than light microscope TREATMENT MEDICATIONS ▪ Immunocompetent host: antidiarrheal, antimicrobial agents ▪ Immunocompromised host: antiretroviral therapy (HIV-infected individuals), antimicrobial agents, azithromycin (severe diarrhea) OTHER INTERVENTIONS ▪ Immunocompetent host: oral/IV fluid/ electrolyte-loss replacement ▪ Dehydration, fluid and electrolyte imbalance SIGNS & SYMPTOMS ▪ Host’s immune status-dependant 93 Chapter 74 Gastrointestinal Infections Figure 74.1 Cryptosporidium organisms lining the crypt epithelium in an infected individual. 94 ENTAMOEBA HISTOLYTICA (AMOEBIASIS) osms.it/entamoeba-histolytica PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Amebiasis ▫ Caused by Entamoeba histolytica (anaerobic parasitic protozoan) ▪ Trophozoites bind to intestinal epithelial cells in colon, release lytic enzymes (e.g. cysteine proteinases) → epithelial cell lysis → trophozoites lyse inflamed/attracted immune cells → immune cell’s lytic enzymes ↑ release ▫ Intestinal mucosa ulcers → colitis → bowel necrosis → perforation → sepsis ▫ Tissue destruction → mucosa blood vessel injury, malabsorption, ↑ intestinal secretion → bloody diarrhea, amebic dysentery ▫ Blood vessel injury → trophozoites in blood stream → extraintestinal amebiasis (liver, pulmonary, cardiac, brain) ▪ Mostly asymptomatic; bloody diarrhea, mucus in stool (severe dysentery); abdominal pain; fever; weight loss; right upper-quadrant pain, jaundice (liver); cough (pulmonary); dehydration RISK FACTORS ▪ Endemic-area exposure (Africa, Southern Asia, Central America) ▪ Intimate partner transmission possible ▪ Youth ▪ Malnutrition ▪ Immunodeficiency (e.g. malignancy, corticosteroid treatment, HIV) ▪ Poor hygiene COMPLICATIONS ▪ Amebic liver abscess rupture ▫ Pericarditis, peritonitis ▪ Toxic megacolon ▪ Cerebral amebiasis → brain abscess → ↑ intracranial pressure ▪ Cutaneous amebiasis ▪ Dehydration DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Liver CT scan, MRI, ultrasound ▪ Cystic intrahepatic cavity detection LAB RESULTS Microscopic identification ▪ Cysts/trophozoites in stool/pus (e.g. liver abscess) Antigen detection ▪ Enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, immunofluorescence PCR ▪ Entamoeba DNA detection Serology ▪ Entamoeba antibodies detection Sigmoidoscopy/colonoscopy ▪ Histological examination biopsies 95 Chapter 74 Gastrointestinal Infections TREATMENT MEDICATIONS ▪ Antibacterial agents ▫ Invasive amoebic colitis ▪ Luminal agents ▫ Intraluminal cysts, trophozoites ▪ Metronidazole ▫ Amebic liver abscess ≤ 10cm/3.94in ▪ Broad-spectrum antibiotics ▫ Suspected perforation, bacterial superinfection SURGERY ▪ ▪ ▪ ▪ ▪ Figure 74.2 Trophozoites of Entamoeba histolytica in a colonic biopsy. The trophozoites have ingested red blood cells. Massive GIT bleeding Amebic liver abscess > 10 cm/3.94 in Ruptured amebic liver abscess Perforated amebic colitis Toxic megacolon OTHER INTERVENTIONS ▪ Rehydration GIARDIA LAMBLIA osms.it/giardia-lamblia PATHOLOGY & CAUSES ▪ Giardiasis ▫ Diarrheal disease caused by Giardia intestinalis/Giardia duodenalis (flagellated protozoan parasite, colonizes small intestine) ▪ Pathogenesis not well understood ▪ Infection causes microvilli shortening → intestinal malabsorption, hypersecretion → diarrhea CAUSES ▪ Contaminated/untreated water ingestion ▪ Contaminated food (uncommon) RISK FACTORS ▪ Endemic-area exposure (tropical countries), immunosuppression, comorbidities (e.g. cystic fibrosis), poor sanitation COMPLICATIONS ▪ Weight loss; dehydration; zinc, disaccharidase deficiency; malabsorption syndrome (adult); growth delay (children) 96 SIGNS & SYMPTOMS ▪ Usually asymptomatic Acute giardiasis ▪ 7–14 days after infection exposure ▪ Diarrhea, malaise, abdominal pain, flatulence, nausea/vomiting, malodorous stool, steatorrhea, fever (uncommon) Chronic giardiasis ▪ > 18 days after infection exposure ▪ Loose stools (not typical diarrhea), profound weight loss (occasionally), abdominal pain, borborygmus (moving gas/fluid → GIT gurgling sound), flatulence, burping, malaise, fatigue, depression Figure 74.3 Giardia lamblia in a cytology specimen. DIAGNOSIS LAB RESULTS Antigen detection assays ▪ Trophozoite antigen (stool) detection Nucleic acid amplification assays (NAAT) ▪ Giardia DNA detection Stool microscopy ▪ Giardia cyst detection Figure 74.4 A duodenal biopsy demonstrating giardia organisms in the duodenal crypt. TREATMENT MEDICATIONS ▪ Antimicrobial therapy ▫ Paromomycin (pregnant/lactating individuals) 97 NOTES NOTES GENERAL INFECTIONS GENERALLY, WHAT ARE THEY? TREATMENT PATHOLOGY & CAUSES ▪ Localized, systemic disorders caused by microbial infections SIGNS & SYMPTOMS MEDICATIONS ▪ Antimicrobials OTHER INTERVENTIONS ▪ Drainage ▪ See individual conditions DIAGNOSIS ▪ See individual conditions ABSCESSES osms.it/abscesses PATHOLOGY & CAUSES ▪ Localized, circumscribed pus collection surrounded by inflamed tissue ▪ May develop in any body region ▫ Superficial (e.g. skin, soft tissue) ▫ Internal (e.g. lung, liver, brain) ▪ Caused by pyogenic bacteria (e.g. S. aureus, S. pyogenes, S. epidermidis, P. aeruginosa) ▪ Bacterial invasion → local inflammatory response ▫ Suppuration (pus production) ▫ Necrosis, liquefaction ▫ Cellular debris accumulation ▪ Loculation, walling off of abscess by adjacent, healthy cells RISK FACTORS ▪ ▪ ▪ ▪ ▪ Trauma Foreign body presence (e.g. body piercing) Intravenous (IV) drug use Dermatological conditions (e.g. cellulitis) Anatomical involvement-related risks ▫ Examples: ascending infection → pelvic abscess, hematologic spread → central nervous system (CNS) abscess, local spread → liver abscess COMPLICATIONS ▪ Spread to other tissue ▪ Fistula formation ▪ Sepsis 98 SIGNS & SYMPTOMS ▪ Localized warmth, erythema, swelling, tenderness/pain, induration ▪ Fluctuant mass DIAGNOSIS ▪ History, physical examination: characteristic findings DIAGNOSTIC IMAGING CT scan ▪ Central decreased attenuation area with circumferential enhancement ring MRI ▪ T1: central hypointense area ▪ T2: hyperintense ▪ T1, T2: rim is iso- to hypointense Ultrasound ▪ Internal abscess ▫ Homogeneous fluid collection appears as hypoechoic region within tissue ▫ Edema: cobblestone appearance—thin hyperechoic (dark gray) bands, anechoic (black) fluid Figure 75.1 The clinical appearance of a pilonidal abscess. LAB RESULTS ▪ Ultrasound-guided needle aspiration ▫ Specimen collection, culture TREATMENT MEDICATIONS ▪ Antimicrobials OTHER INTERVENTIONS ▪ Incision, drainage Figure 75.2 A CT scan of the brain in the coronal plane demonstrating a cerebral abscess of the left frontal lobe. The abscess shows typical ring enhancement. 99 Chapter 75 General Infections SEPSIS osms.it/sepsis PATHOLOGY & CAUSES ▪ Serious, life-threatening, systemic infection reaction ▫ Microbial host barrier breach (skin, mucous membranes) → provokes host dysregulated immune response → proinflammatory mediator release (e.g. TNF-α, interleukins) → detrimental physiological effects, tissue damage ▫ Endothelial damage, dysfunction; ↑ vascular permeability; microvascular dysfunction; coagulopathies RISK FACTORS ▪ Bacteremia (most common) Gram-positive organisms ▪ Hospital/intensive care unit (ICU) admission → nosocomial infection ▪ Immune system deficiency ▫ E.g. HIV/AIDS, hematologic malignancy, immunosuppressant medication ▪ Recent surgery/hospitalization → altered microbiome ▪ Indwelling medical device presence ▫ E.g. urinary catheter, venous access device ▪ Bimodal age distribution ▫ Infants, adults ≥ 65 ▪ Community-acquired pneumonia ▪ Chronic disease ▫ E.g. diabetes, heart failure (HF), chronic obstructive pulmonary disease (COPD) ▪ Genetic factors ▪ Respiratory failure ▪ Disseminated intravascular coagulation (DIC) ▪ Metabolic acidosis ▪ Stress ulcer ▪ Treatment complications ▫ E.g. ventilator-associated pneumonia, venous thrombosis ▪ Death SIGNS & SYMPTOMS General presentation ▪ Fever; tachypnea; tachycardia; hypotension; hypoxemia; ↓ urine output; ↓ PaO2; edema; ileus, ↓ bowel sounds ▪ Altered mental status ▫ Malaise, agitation, lethargy, stupor ▪ Signs of shock ▫ E.g. cool skin, cyanosis, ↑ capillary refill, mottling Quick Sequential Organ Failure Assessment (qSOFA) ▪ Score ≥ 2 → ↑ mortality risk ▪ See table COMPLICATIONS ▪ Severe sepsis → septic shock ▫ Sepsis-induced vasodilation, hypotension ▫ Unresponsive to fluid resuscitation ▪ Multiple organ dysfunction syndrome (MODS) 100 DIAGNOSIS ▪ History, clinical presentation, physical examination LAB RESULTS Blood studies ▪ ↑ white blood cell (WBC) count, left shift ▪ ↑ C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) ▪ Indications of organ hypoperfusion, injury, dysfunction ▫ ↑ lactate, ↓ platelets (may precede DIC), ↑ glucose, ↑ creatinine, ↑ bilirubin ▪ Coagulation studies ▫ ↑ international normalized ratio (INR), activated partial thromboplastin time (aPTT) ▪ Blood cultures ▫ Identify pathogen TREATMENT SURGERY ▪ Source control ▫ E.g. infected device removal, abscess drainage) OTHER INTERVENTIONS Hemodynamic support ▪ Invasive monitoring Respiratory support ▪ Supplementary oxygen; mechanical ventilation Infection prevention ▪ Infection control practices ▫ ↓ hospital-acquired infections (ventilator-associated pneumonia, catheter-associated bloodstream infections) Complication prevention ▪ Deep-vein thrombosis prophylaxis ▪ Glycemic control MEDICATIONS ▪ Antimicrobials ▫ Initial broad-spectrum antibiotics until pathogen identified ▪ Hemodynamic support ▫ Fluid resuscitation ▫ Vasopressors ▪ Infection prevention ▫ Vaccinations for at risk individuals (influenza, pneumonia) ▪ Complication prevention ▫ Proton pump inhibitor 101 NOTES NOTES GRAM VARIABLE GARDNERELLA VAGINALIS (BACTERIAL VAGINOSIS) osms.it/gardnerella-vaginalis PATHOLOGY & CAUSES DIAGNOSIS ▪ Facultative, anaerobic, gram-variable coccobacilli ▪ Microscopically ▫ Very thin gram-positive cell wall appears gram-positive/negative ▪ Non-spore forming, non-motile ▪ Causative agent for bacterial vaginosis (BV) ▫ Disruption of vaginal microbiome ▪ Most common vaginal infection in individuals who are biologically female, age 15–44 LAB RESULTS RISK FACTORS OTHER DIAGNOSTICS ▪ Multiple sex partners, douching, smoking COMPLICATIONS ▪ ↑ risk of contracting HIV, other STDs ▪ Acute cervicitis, endometritis, postabortal infection ▪ During pregnancy ▫ Premature birth, low birthweight SIGNS & SYMPTOMS ▪ Malodorous (fishy), thin white/gray vaginal discharge ▪ Vaginal pain, itching, burning ▪ Burning with urination ▪ Gram-stain smear of vaginal discharge; using criteria (e.g. Nugent, Hay/Ison) ▪ Affirm VP III ▫ Commercial automated DNA probe assay detects G. vaginalis ▪ OSOM BVBlue test ▫ Chromogenic identifies presence of elevated sialidase enzyme produced by G. vaginalis, other bacteria (e.g. Bacteroides, Prevotella, Mobiluncus) ▪ Requires three of the following Amsel criteria ▫ Characteristic vaginal discharge ▫ pH > 4.5 ▫ Clue cells visible on saline wet mount (vaginal epithelial cells covered with bacteria) ▫ Positive whiff-amine test (combine vaginal discharge sample with 10% KOH → fishy odor) TREATMENT MEDICATIONS ▪ Antibiotics: metronidazole 102 103 NOTES NOTES HEMATOLOGIC INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES Taxonomy ▪ Apicomplexan phylum protozoa → infectious hematological diseases Replication/multiplication ▪ Arthropod transmission Transmission ▪ Multiple life cycle stages (host-, vectordependent) DIAGNOSIS LAB RESULTS ▪ Blood smear: best intra-erythrocyte location diagnosis TREATMENT ▪ See individual infections SIGNS & SYMPTOMS ▪ See individual infections 104 BABESIA osms.it/babesia PATHOLOGY & CAUSES RISK FACTORS ▪ Malaria-like parasitic infection ▫ Ixodes tick transmission ▪ Phylum Apicomplexa (same as Plasmodium, Toxoplasmosis) ▪ Common species ▫ Babesia microti most predominant (northeast, upper midwest United States) ▫ B. duncani (Western United States) ▫ B. divergens (Europe) ▪ Endemic area resident ▪ Endemic area travel, especially May– September ▪ Blood transfusion (last six months) ▪ Age > 50 ▪ Biologically male ▪ Asplenia ▪ Decreased immunity (malignancy, HIV/ AIDS infection, immunosuppressive drugs) ▪ Coinfection with Borrelia and/or Anaplasma ▪ Premature birth CAUSES COMPLICATIONS ▪ Ixodes scapularis tick: only recognized vector ▫ Same tick transmits Borrelia burgdorferi (→ Lyme disease; concurrently infects ⅔ babesiosis-infected individuals) and Anaplasma phagocytophilum (→ human granulocytic anaplasmosis; concurrently infects ⅓ babesiosis-infected individuals) ▫ Contaminated blood transfusion → rare human-to-human transmission ▪ Life cycle ▫ Two hosts: white-footed mouse, Ixodes tick (definitive) ▫ Blood meal → Babesia-infected tick sporozoites into mouse host → sporozoites directly invade mature mouse erythrocytes → sporogony (asexual reproduction; budding) → in blood, some parasites differentiate into male, female gametes → gametes unite → sporogonic cycle → sporozoites → tick bites human → 1–4 week incubation → sporozoites enter erythrocytes → sporogony ▪ Sporogony ▫ Asynchronous with host → no massive hemolysis (versus malaria) ▪ Tick’s nymph stage is most infectious ▪ ↑ occurence in anemic/parasitemic individuals ▫ Congestive heart failure ▫ Noncardiac pulmonary edema ▫ Acute respiratory distress syndrome ▫ Splenic infarct ▫ Splenic rupture ▫ Septic shock ▫ Myocardial infarction ▫ Disseminated intravascular coagulation ▫ Death SIGNS & SYMPTOMS ▪ Mostly asymptomatic, may persist undiagnosed months/years ▪ Blood-stage parasite multiplication → clinical manifestation ▪ Non-specific flu-like symptoms (misdiagnosis common) ▫ Fatigue (gradual onset) ▫ Fever, chills, sweats ▫ Headache, myalgia, arthralgia ▫ Anorexia, nausea ▫ Cough 105 Chapter 77 Hematologic Infections ▪ Severe manifestations include malaria-like illness (fever, fatigue, malaise) + hemolytic anemia manifestation ▪ B. microti case-fatality rate is 5% ▪ B. divergens infections case-fatality rate is 42% ▫ Disseminated intravascular coagulation, bleeding diathesis ▫ Acute renal failure ▫ Cardiopulmonary complications (e.g. hypotension, poor perfusion, pulmonary edema) OTHER INTERVENTIONS ▪ Severe disease (parasitemia > 4%) ▫ Antimicrobial + exchange transfusion Prevention ▪ Personal: avoid endemic areas; long pants, shirts minimize exposed skin ▪ Tick repellant on skin (e.g. DEET) ▪ Post-exposure tick checks ▪ No antibiotic prophylaxis DIAGNOSIS LAB RESULTS Blood smear ▪ Wright/Giemsa staining ▫ Thin: rapid, ↓ microscopy experience required ▫ Thick: ↑ accurate, ↑ microscopy experience required ▫ Pathognomic tetrad “Maltese cross” visible in erythrocyte Laboratory ▪ Thrombocytopenia ▪ Reticulocytosis ▪ ↓ Hematocrit ▪ ↓ Hemoglobin ▪ ↑ Lactate dehydrogenase ▪ ↓ Haptoglobin ▪ ↑ Liver function tests ▪ ↑ Creatinine Polymerase chain reaction (PCR) ▪ Speciation (useful for low-level parasitemia) Serology ▪ Immunofluorescent antibody testing; species specific TREATMENT ▪ Asymptomatic: no treatment MEDICATIONS ▪ Symptomatic disease: azithromycin + atovaquone 106 PLASMODIUM SPECIES (MALARIA) osms.it/malaria PATHOLOGY & CAUSES ▪ Anopheles mosquito vector → parasitic hematologic infection ▪ Four major malarial parasite species ▫ Plasmodium falciparum: most lethal, most drug-resistant (sub-Saharan Africa) ▫ P. vivax: widest geographic distribution, relapsing species ▫ P. ovale: relapsing species (western areas of sub-Saharan Africa) ▫ P. malariae: AKA ‘benign’ malaria (mild course) ▪ P. knowlesi: normally infects macaques, recent cause of human malaria cases ▪ Erythrocytic life cycle stage ▫ In erythrocytes → parasites can undergo asexual schizogony/ sexual differentiation (necessary for transmission) → gametocytes ▪ Asexual schizogony ▫ Trophozoites (parasite name once inside erythrocyte) digest host cell hemoglobin (amino acids, energy source) → schizont → undergoes mitosis → differentiates into merozoites → erythrocyte rupture → merozoite bloodstream release → fever, malarial symptoms CAUSES ▪ Exoerythrocytic (sporogonic; blood) life cycle stage ▫ Blood-stage gametocytes in other host (e.g. human) → female Anopheles mosquito blood meal → mosquito multiplication, growth cycle → 10–18 day incubation → sporozoites in mosquito salivary gland → human bite → sporozoite inoculation → hematogenous translocation to liver → rapid hepatic parenchymal cell invasion → parasites undergo exoerythrocytic schizogony (asexual multiplication) → development, multiplication → 7–14 day incubation → merozoite development → invade erythrocytes → symptomatic stage develops → P. ovale, P. vivax can differentiate into quiescent stage → hypnozoite → can re-enter into schizogony → reemerge to invade erythrocytes ▫ Blood stage → malaria symptoms ▫ Mosquito vector does not have parasite presence Figure 77.1 A peripheral blood film taken from an individual with Plasmodium malariae infection. There is a mature schizont, composed of 6-12 merozoites, contained within a red blood cell. ▪ P. malariae ▫ Low-level persistence possible for decades without diagnosis, treatment ▪ P. vivax ▫ Prefers erythrocytes with Duffy blood group antigen (rare in persons from West and Central Africa); prefers reticulocytes but will also invade mature erythrocytes ▪ Others preferentially invade mature erythrocytes 107 Chapter 77 Hematologic Infections ▪ P. falciparum ▫ Develop ‘knobs’ on infected erythrocytes in late trophozoite stage → parasitized erythrocytes adhere to capillary endothelium → various organ sequestration (notably brain) → cerebral malaria ▪ Most malaria deaths ▫ Children < five years old in hightransmission areas COMPLICATIONS Coma Seizure Severe anemia Acute renal failure ▫ Acute tubular necrosis secondary to hypoperfusion, hypovolemia ▪ Acute respiratory distress syndrome ▪ Shock ▪ Septicemia ▪ ▪ ▪ ▪ SIGNS & SYMPTOMS RISK FACTORS ▪ Poor rural populations in endemic areas ▪ Proximity to standing water ▫ Larvae breeding site (e.g. agriculture, irrigation ditches) ▪ Travel in endemic areas ▪ Blood transfusion (last six months) ▪ Lack of insect repellant, chemoprophylaxis, personal protective measures (long pants, shirts, mosquito nets) ▪ Duffy blood group antigen-positive individuals Protective factors ▪ P. falciparum protection: sickle cell trait (heterozygotes) ▪ P. vivax: Duffy blood group antigennegative individuals ▪ Febrile paroxysm (hallmark feature) ▫ 10–12 hours of intense rigors, chills → high fever, profuse diaphoresis ▫ Febrile seizure potential ▪ Non-specific complaints ▫ Headache, malaise, myalgia, arthralgia ▪ Abdominal pain, diarrhea, vomiting ▪ Possibly remarkably asymptomatic between episodes ▪ P. falciparum cerebral effects ▫ Significant morbidity, mortality (delirium, confusion, seizures → declining mental status → coma → death) ▪ Parasitemia, cytokine disturbance → hypotension, metabolic acidosis, hypoglycemia ▪ Anemia (high parasitemia → more pronounced) ▪ Sequestration, red blood cell destruction by spleen → hypersplenism DIAGNOSIS LAB RESULTS Giemsa stain blood smear ▪ Thin: rapid, ↓ microscopy experience required ▪ Thick: ↑ accurate, ↑ microscopy experience required ▪ P. falciparum: red blood cells contain multiple parasites, ring forms, lack of schizonts ▪ Banana-shaped gametocyte form 108 Rapid diagnostic test ▪ 15–20 minute results ▪ Histidine-rich protein 2: detects P. falciparum PCR ▪ Supportive laboratory results (nondiagnostic) ▫ Normocytic hemolytic anemia ▫ Thrombocytopenia TREATMENT MEDICATIONS ▪ Severe malaria ▫ Quinidine + doxycycline/tetracycline/ clindamycin/artesunate (test for G6PD deficiency) ▪ Uncomplicated malaria ▫ Chloroquine-sensitive strain: chloroquine phosphate/ hydroxychloroquine (blocks Plasmodium heme polymerase) ▫ Chloroquine-resistant strain: atovaquone-proguanil, mefloquine, artesunate, quinine-based regimens ▪ P. ovale, P. vivax: + primaquine for hypnozoite (test for G6PD deficiency) OTHER INTERVENTIONS Figure 77.2 A histological section of the placenta from an individual infected with malaria. The numerous black dots within the red blood cells are malaria organisms. Prevention ▪ Chemoprophylaxis ▪ Avoid outdoors (dusk/dawn) ▪ Reduce exposed skin (long pants, shirts) ▪ Bed netting/mosquito nets ▪ Insect repellent (DEET 30–50%) 109 NOTES NOTES HEPADNAVIRIDAE MICROBE OVERVIEW ▪ Hepadnaviridae: family of DNA viruses, causes liver disease ▪ Produces DNA polymerase with reverse transcriptase, RNAse activity Replication/multiplication ▪ Reverse transcription (RNA intermediate) Structure ▪ Enveloped ▪ Icosahedral capsid ▪ Partially double stranded, partially single stranded circular DNA COMPLICATIONS ▪ Chronic hepatitis, acute liver failure (fulminant hepatitis), liver cirrhosis, hepatocellular carcinoma (HCC) HEPATITIS B VIRUS osms.it/hepatitis-b-virus PATHOLOGY & CAUSES ▪ Hepatitis B virus (HBV) ▫ DNA virus: can cause acute/chronic liver disease ▫ Member of Hepadnaviridae family (only human pathogenic species) ▪ Target: hepatocytes, zone I (periportal area) ▪ Incubation period: six weeks to six months Antigens ▪ Hepatitis B surface antigen (HBsAg/ Australia antigen) ▫ Key infection marker ▪ Hepatitis B core antigen (HBcAg) ▫ Not detectable in serum; found in liver with acute/chronic hepatitis B ▪ Hepatitis B e antigen (HBeAg) ▫ Secreted by infected cells; indicates active infection, replication Transmission ▪ Perinatal (childbirth), parenteral (e.g. IV drug use, blood transfusions), sexual ▪ HBV survives ≥ seven days in environment Highest prevalence ▪ Parts of sub-Saharan Africa, mainly due to perinatal transmission ▪ Lower prevalence areas have greater association with parenteral, sexual transmission TYPES Acute hepatitis ▪ Liver inflammation for < six months) ▪ HBV penetrates hepatocytes → CD8+ T-lymphocyte activation → cytotoxic killing → hepatocyte apoptosis → liver damage, inflammation ▪ Phases ▫ Early, window (antigens undetectable), recovery 110 ▪ Acute liver failure progression: < 1% ▪ Chronic hepatitis progression (in adults): < 5% ▪ Acute liver failure ▫ Acute liver injury (severe hepatocyte necrosis), hepatic encephalopathy, coagulopathy ▫ Excessive immune response → massive hepatocyte lysis ▫ Preexisting liver disease absence ▫ Associated with HBV genotype D Chronic hepatitis ▪ HBsAg persistent for > six months ▪ Pathogenesis ▫ HBV penetrates hepatocytes → insufficient CD8+ T-lymphocyte activation → “immune tolerance” → HBV persistence ▪ Progression to HCC ▫ HBV integrates to host DNA → oncogene activation → oncogenesis ▪ Chronicity depends highly on age at time of infection ▫ Younger age, ↑ chronicity risk ▫ Immunosuppressed, elderly people also more susceptible ▪ Phases ▫ Immune tolerant: no liver inflammation/ fibrosis ▫ Immune active: liver damage, inflammation, possible fibrosis ▫ Immune inactive: ↓ inflammation ▫ Reactivation: liver damage, inflammation, possible fibrosis ▫ “Recovery”: occult HBV, HBsAg negative; still infected, disease inactive (best prognosis) RISK FACTORS ▪ IV drug use ▪ Healthcare workers ▫ Frequent contact with blades, needles, body fluids ▪ High-risk sexual behavior ▪ Anal intercourse ▪ Previous HIV/hepatitis C infection COMPLICATIONS ▪ HCC, fulminant hepatitis, liver cirrhosis Hepatic encephalopathy ▪ Excessive nitrogen load, electrolyte disturbances → altered neurologic functions in individuals with severe liver disease Hepatorenal syndrome ▪ Portal hypertension → splanchnic vasodilation → ↓ effective circulatory volume → ↑ renin-angiotensin-aldosterone system → renal vasoconstriction → hepatorenal syndrome (liver dysfunction → kidney failure) Bleeding diathesis ▪ Hypocoagulability → ↑ hemorrhage risk SIGNS & SYMPTOMS Acute hepatitis ▪ Can be anicteric (not accompanied by jaundice) with non-specific symptoms (e.g. fever, malaise, nausea, vomiting) ▪ Some progress to icteric hepatitis with hepatomegaly, right upper-quadrant pain, jaundice (30%), dark-colored urine (due to conjugated hyperbilirubinemia), pale stool Chronic hepatitis ▪ Mostly asymptomatic/non-specific symptoms until late disease stages ▪ Exacerbations may present as acute hepatitis ▪ Jaundice, ascites, splenomegaly, encephalopathy (e.g. personality changes, ↓ level of consciousness, intellectual impairment, asterixis) may present ▪ Extrahepatic manifestations (occasionally) ▫ Fever, rash, arthralgia, arthritis, glomerulonephritis DIAGNOSIS LAB RESULTS ▪ HBV DNA detection ▫ Polymerase chain reaction (PCR), in-situ hybridization, Southern hybridization 111 Chapter 78 Hepadnaviridae Laboratory testing ▪ ↑ alanine aminotransferase (ALT), aspartate aminotransferase (AST) ▫ ALT > AST ▫ Usually ALT in acute hepatitis > 1000 U/L (may be ↓ in chronic hepatitis) ▫ ALT levels take longer than AST to return to normal ▪ ↑ ALT for > six months indicates chronicity ▪ ↑ alpha-fetoprotein (AFP) in HCC ▪ Liver fibrosis ▫ ↓ leukocytes, platelets ▫ AST/ALT > 1 (normal ≈ 0,8) ▫ ↑ total bilirubin ▫ ↓ serum albumin ▫ Delayed prothrombin time, ↑ international normalized ratio (INR) Serologic marker detection through enzyme immunoassay ▪ Hepatitis B surface antigen (HBsAg) ▫ Indicates infection (acute/chronic) ▪ Hepatitis B surface antibodies (Anti-HBs) ▫ Provides HBV infection immunity appears after vaccination/resolved acute hepatitis ▪ IgM antibodies against hepatitis B core antigen (IgM anti-HBc) ▫ Acute infection/chronic hepatitis reactivation phase ▪ IgG antibodies against hepatitis B core antigen (IgG anti-HBc) ▫ Non-specific antibody; may be ↑ during acute, resolved, chronic hepatitis ▪ Hepatitis B e antigen ▫ Active replication, high infectivity ▪ Hepatitis B e antibodies ▫ Low replication, infectivity Liver biopsy ▪ Acute hepatitis ▫ Mononuclear infiltrate ▫ Pericentral inflammation, necrosis ▫ Eosinophilic hepatocytes ▪ Chronic hepatitis ▫ Fibrosis ▫ Nodule formation ▫ Mononuclear portal infiltrate ▫ Some hepatocytes have uniformly dull cytoplasm due to endoplasmic reticulum swelling (“ground glass” hepatocytes) 112 Figure 78.1 Ground glass hepatocytes seen in the liver of an individual with hepatitis B infection. TREATMENT MEDICATIONS ▪ Antiviral monotherapy ▫ Severe acute hepatitis, pre-existing liver disease, concomitant hepatitis C/D infection, immunocompromised, elderly Acute hepatitis ▪ Post-exposure prophylaxis ▫ HBV vaccine and immunoglobulin Prevention ▪ HBV vaccine ▪ Recombinant type most commonly used ▫ HBsAg inserted in yeast cells ▪ HBsAg → development of anti-HBsAg → HBV infection immunity ▪ Intramuscular administration ▪ Three doses for coverage (very effective) ▪ Administration regime: 0, 1–2 months, 6–12 months ▫ Infant immunization: first dose at birth ▫ Does not require booster dose (longterm protection) SURGERY ▪ Acute liver failure ▫ Consider liver transplantation OTHER INTERVENTIONS ▪ Acute liver failure ▫ Fluid resuscitation, early nutritional support, antiviral therapy (nucleoside/ nucleotide analogues) Acute hepatitis ▪ Supportive treatment (e.g. fluid therapy, nutrition) Chronic hepatitis ▪ Combination therapy (e.g. lamivudine, interferon) 113 Chapter 78 Hepadnaviridae HEPATITIS D VIRUS osms.it/hepatitis-d-virus PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Hepatitis D virus (HDV/delta virus): incomplete RNA virus; contributes to acute liver failure development, chronic hepatitis exacerbation in people coinfected/ previously infected with HBV ▪ HDV not member of Hepadnaviridae family ▪ HDV infection inhibits HBV replication due to HBV, HDAg interaction during viral replication ▫ Coinfected individuals: HDV predominant ▫ ↑ inflammatory response (compared to HBV alone) ▫ Poor response to existing HBV treatment ▪ Incubation period ▫ 6–24 weeks Coinfection ▪ Biphasic course with acute hepatitis symptoms Structure ▪ Outer envelope made of HBsAg, inner HDV RNA, delta antigen (HDAg) LAB RESULTS Transmission ▪ Parenteral, sexual, perinatal (very rare) Satellite virus ▪ Can only infect if host also infected with HBV ▫ Coinfection: simultaneous infection ▫ Superinfection: HDV infection after established HBV infection; more severe RISK FACTORS ▪ IV drug use, high-risk sexual behavior, HBV presence Acute liver failure ▪ Systemic symptoms ▫ E.g. fever, malaise, nausea, vomiting) ▫ Hepatomegaly, right upper quadrant pain; sometimes jaundice, dark colored urine, pale stool ▪ Hepatic encephalopathy ▫ Personality changes, ↓ level of consciousness, intellectual impairment, asterixis DIAGNOSIS ▪ Serologic marker detection ▫ IgM/IgG anti-HDV ▪ PCR assays ▫ HDV RNA detection TREATMENT MEDICATIONS ▪ Pegylated interferon alpha ▪ Prevention ▫ HBV vaccine SURGERY ▪ Consider liver transplantation for chronic hepatitis D, acute liver failure 114 AfraTafreeh.com exclusive NOTES NOTES HERPESVIRUSES MICROBE OVERVIEW ▪ Large family of DNA viruses Species known to infect humans ▪ Herpes simplex virus (HSV) ▫ HSV-1, HSV-2 ▪ Varicella-zoster virus (VZV) ▪ Epstein-Barr virus (EBV) ▪ Human cytomegalovirus ▪ Human herpesvirus 6 (roseola) ▪ Human herpesvirus 8 (Kaposi’s sarcoma) Genetic material ▪ Double-stranded, linear DNA genome encoding 84 proteins Morphology ▪ Icosahedral capsid; enveloped virus Life cycle ▪ Obligate intracellular parasites ▪ Can perpetuate in latent phase ▪ Expression of lytic genes → lytic phase→ host cell death → shedding CYTOMEGALOVIRUS osms.it/cytomegalovirus PATHOLOGY & CAUSES ▪ Primary infection of immunocompetent individuals usually asymptomatic; lifelong latency ▪ Infects mononuclear leukocytes, endothelial cells CAUSES ▪ Person-to-person transmission ▫ Kissing; intimate, sexual contact ▪ Vertical transmission ▫ Congenital infection ▪ Blood products/transfusion ▪ Organ/stem cell transplant RISK FACTORS COMPLICATIONS ▪ Congenital CMV infection ▫ Cognitive, sensorineural deficits SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Fever, malaise, sore throat, splenomegaly ▪ Individuals with AIDS ▫ Retinitis, colitis, encephalitis, pneumonitis ▪ Individuals with congenital CMV infection ▫ Positive CMV-IgG (if pregnant); intrauterine fetal growth restriction (IUGR), hydrocephalus, microcephaly, intracranial calcification, poly/ oligohydramnios, hepatosplenomegaly ▪ Immunocompromised ▫ HIV/AIDS; organ transplant; medications (e.g. steroids, chemotherapy) 115 Chapter 79 Herpesviruses DIAGNOSIS LAB RESULTS ▫ Highly active antiretroviral therapy (HAART) ▫ CMV immunoglobulin G (CMV-IGIV) ▪ Complete blood count ▫ Atypical lymphocytosis, anemia, leukopenia, thrombocytopenia ▪ ↑ serum creatinine, AST, ALT ▪ Serology tests ▫ ↑ CMV-IgM titre; acute infection ▫ ↑ CMV-IgG titre; past infection TREATMENT ▪ Usually self-limiting MEDICATIONS ▪ At-risk individuals ▫ Antiviral prophylaxis; IV ganciclovir; oral valganciclovir Figure 79.1 A colonic biopsy taken from an individual with CMV colitis. The large nuclei that give the virus its name can be clearly seen. EPSTEIN–BARR VIRUS (INFECTIOUS MONONUCLEOSIS) osms.it/epstein-barr_virus PATHOLOGY & CAUSES ▪ EBV (human herpesvirus 4) ▪ Causes Infectious mononucleosis (glandular fever) ▪ Infection in children ▫ Asymptomatic/mild flu-like symptoms ▪ Infection in adolescents, young adults ▫ Fever, sore throat, enlarged lymph nodes ▪ Lytic, latent life cycle ▫ Lytic in oropharyngeal B cells; latent in lymphocytes CAUSES ▪ Transmitted through saliva (“kissing” disease), sexual transmission RISK FACTORS ▪ Multiple sexual partners COMPLICATIONS ▪ Splenic rupture ▪ EBV infection associated with Hodgkin’s, Burkitt’s lymphoma ▪ Neurologic syndromes (2–4 weeks after initial symptoms) ▫ Guillain-Barré syndrome, cranial nerve palsies (e.g. facial nerve palsy); meningoencephalitis (e.g. aseptic meningitis), transverse myelitis, peripheral neuritis, optic neuritis ▪ EBV can affect, manifest in any organ system ▫ Hepatitis, pneumonia, myocarditis, pancreatitis, acute renal failure, gastric pseudolymphoma 116 ▪ Classic triad ▫ Fever; cervical/generalized lymphadenopathy; tonsillar pharyngitis (exudative/non-exudative) ▪ Malaise, hepatosplenomegaly, rash, jaundice, myalgia morphology (large, irregular nuclei) ▪ ↑ hepatic transaminase (50% of infected individuals) ▪ Monospot test ▫ Positive heterophile antibodies (IgM) ▪ Identification of EBV ▫ EBV-specific antibodies, real-time PCR, EBV DNA detection DIAGNOSIS TREATMENT SIGNS & SYMPTOMS MEDICATIONS LAB RESULTS ▪ Complete blood count (CBC) ▫ Lymphocytosis (50%) with atypical ▪ Antipyretics, analgesics ▫ Avoid aspirin; may lead to Reye’s syndrome ▪ Corticosteroid for upper airway obstruction (e.g. prednisolone) ▪ Intravenous immunoglobulin (IVIG) for thrombocytopenia Figure 79.2 Atypical lymphocytes with bizarre nuclear forms in a peripheral blood film from an individual infected with infectious mononucleosis. HERPES SIMPLEX VIRUS osms.it/herpes-simplex-virus PATHOLOGY & CAUSES ▪ HSV-1, HSV-2 ▫ Members of herpesviridae family ▪ Causes oral, genital, ocular ulcers ▪ Portal of entry ▫ Mucosal surfaces/skin breaks; vertical transmission during pregnancy/ childbirth ▪ Primary infection often symptomatic; replicates in epidermis of skin → travels down nerve endings, axon→ sensory ganglia ▪ Periodic reactivation, subsequent episodes ▫ Virus becomes active in ganglia → transported via axon to skin → replicates in epidermis → sheds → new sores ▫ Often asymptomatic shedding; may feel tingling, burning sensation 117 Chapter 79 Herpesviruses TYPES ▪ Infection types ▫ Primary: first infections; seronegative; symptoms more extensive, systemic; greater viral shedding loads ▫ Non-primary: previously infected individuals; serum antibody, humoral immunity (e.g. genital HSV-2 infection in adulthood after oral mucosa HSV-1 infection in childhood) ▫ Recurrent: previously infected individuals; reactivation episodes (e.g. genital HSV-2 infection in adulthood after genital HSV-2 infection in adolescence) ▪ Herpes labialis (AKA oral herpes) ▫ HSV-1 infection of oral mucosa, lips ▪ Genital herpes ▫ HSV-2, HSV-1 infection of genital area ▫ Healing takes 2–4 weeks SIGNS & SYMPTOMS ▪ Herpes labialis ▫ Painful ulcers around mouth; high fever; sore throat; pharyngeal oedema; myalgia, cervical lymphadenopathy ▫ Recurrent infection: pain, burning, tingling, vesicle formation ▪ Genital herpes ▫ Genital ulceration, vesicles: vulva, cervix, vagina, penis shaft/glans, perineum, buttocks ▫ Genital pain, dysuria, fever, neuralgia ▫ Constipation, rectal pain, tenesmus, proctitis CAUSES ▪ Portal of entry ▫ Mucosal surfaces/skin breaks; vertical transmission during pregnancy/ childbirth ▪ Spread person to person; sexual transmission RISK FACTORS ▪ Genital herpes ▫ Contact with infected individual (producing, shedding virus) ▫ Immunosuppression (e.g. medications, HIV/AIDS) ▫ High-risk sexual behavior (e.g multiple sexual partners, unprotected intercourse, first sexual activity at early age) COMPLICATIONS ▪ Neonatal HSV infection, meningitis, encephalitis, acute retinal necrosis, uveitis, keratitis, esophagitis Figure 79.3 Blisters on the lips caused by infection with herpes simplex virus. DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ Viral culture HSV polymerase chain reaction (PCR) Direct fluorescent antibody (DFA) test Serological HSV-1/HSV-2 specific IgG assay 118 TREATMENT MEDICATIONS Herpes labialis ▪ Antivirals (e.g. oral aciclovir, valaciclovir, famciclovir) ▪ Topical antivirals Genital herpes ▪ Antivirals (e.g. oral aciclovir, valaciclovir, famciclovir) ▪ Pregnant: antiviral prophylaxis OTHER INTERVENTIONS Genital herpes ▪ Pregnant: possible cesarean delivery Figure 79.4 Blisters on the dorsum of the penis of an individual infected with genital herpes simplex. HUMAN HERPESVIRUS 6 (ROSEOLA) osms.it/human-herpesvirus-6 PATHOLOGY & CAUSES ▪ Causes roseola (infantum) ▪ Common cause of fever, followed by rash in early childhood, associated with febrile seizures ▪ Incubation period ▫ 1–2 weeks CAUSES ▪ Asymptomatic contacts ▫ Person-to-person spread by respiratory secretions ▪ Trophic for CD4+ T lymphocytes ▪ Following acute infection, remains latent in various tissues RISK FACTORS ▪ More common in young children (six months–two years) ▪ Immunosuppressed ▫ Bone marrow/organ transplant ▫ Reactivation of latent virus COMPLICATIONS ▪ Afebrile seizures ▪ Associated with chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus 119 Chapter 79 Herpesviruses SIGNS & SYMPTOMS ▪ 3–5 days of high fever; peak in early evening ▪ Exanthem; morbilliform rash appears with defervescence; 3–5mm pink/red macules, papules along trunk, extremities ▪ Diarrhea, tympanic membrane inflammation, upper respiratory symptoms ▪ Nagayama’s spots: enanthem of red papules on soft palate, uvula ▪ Rare ▫ Seizures, periorbital oedema, bulging anterior fontanelle, cervical/occipital/ postauricular lymphadenopathy TREATMENT ▪ Usually self-limiting MEDICATIONS ▪ Immunocompromised ▫ Antiviral compounds (e.g. acyclovir, ganciclovir, cidofovir, foscarnet) ▪ Oral hydration, antipyretics (e.g. paracetamol, ibuprofen) ▪ Avoid aspirin; may lead to Reye’s syndrome DIAGNOSIS LAB RESULTS ▪ Complete blood count ▫ ↓ white blood cells ▪ Detection of HHV-6B/HHV-7 ▫ Viral culture, specific IgG detection Figure 79.5 A child with roseola infantum, also known as sixth disease. The most common causative agent is human herpes virus six. HUMAN HERPESVIRUS 8 (KAPOSI'S SARCOMA) osms.it/human-herpesvirus-8 PATHOLOGY & CAUSES ▪ Causes Kaposi’s sarcoma ▫ Low-grade vasoformative neoplasm associated with human herpesvirus-8 (HHV-8) infection/Kaposi’s sarcoma herpesvirus (KSHV) infection ▪ Lesions on mucocutaneous areas; may involve lymph nodes, viscera ▪ Skin lesions ▫ Patch → plaque → ulcerating tumor nodules ▪ Morphology ▫ spindle-shape, vasoformative cells with vascular proliferation, inflammatory cells 120 ▪ Spontaneous regression may occur after HAART/immunosuppressive treatment TYPES ▪ Epidemic AIDS-associated Kaposi’s sarcoma ▫ HIV-positive individuals ▪ Classic sporadic Kaposi’s sarcoma ▫ More common in individuals who are male, older, with Mediterranean/Jewish background ▪ Iatrogenic, transplant-associated Kaposi’s sarcoma ▫ Solid organ transplant individuals ▪ African endemic Kaposi’s sarcoma ▫ More common in central Africa, unrelated to HIV RISK FACTORS ▪ More common in individuals who are biologically male, > 50 years ▪ Immunosuppression, HIV (co-infection synergistic → aggressive, widespread); drug abuse; immunosuppression therapy COMPLICATIONS ▪ Secondary skin lesion infection SIGNS & SYMPTOMS ▪ Skin lesions ▫ Multifocal; asymmetrically distributed; size, colour variation; non-pruritic; papular; nodular; plaque-, bullous-like; indurated; hyperkeratotic ▪ Oral lesions ▫ Hard palate, gingiva, dorsum of tongue ▫ Macules, papules, nodules, exophytic masses ▪ Lymphadenopathy, lymphoedema ▪ Fever, weight loss, night sweats Figure 79.6 The skin of an individual with Kaposi’s sarcoma. DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Nodular/interstitial/alveolar infiltrates; hilar/ mediastinal lymphadenopathy; nodules LAB RESULTS ▪ HIV test ▪ Positive in AIDS-associated Kaposi’s sarcoma ▪ Fecal occult blood ▫ Positive may indicate intestinal lesions OTHER DIAGNOSTICS ▪ Lesion, lymph node biopsy of vascular lesion TREATMENT MEDICATIONS ▪ Delay disease progression ▫ HAART; in HIV infected individuals, HIV suppression may shrink Kaposi’s sarcoma lesions; systemic chemotherapy ▪ Cosmetic ▫ Topical retinoids; intralesional vinblastine 121 Chapter 79 Herpesviruses SURGERY ▪ Cosmetic ▫ Surgical excision; cryotherapy; laser therapy (external beam radiation) Figure 79.7 The histological appearance of a Kaposi sarcoma. The tumor is composed of spindle cells and numerous branching vascular spaces. The occasional spindle cell contains hyaline globules. VARICELLA ZOSTER VIRUS osms.it/varicella-zoster-virus PATHOLOGY & CAUSES ▪ Double-stranded, linear DNA virus ▫ Causes chickenpox, shingles ▫ Chickenpox: generally benign, selflimited disease in immunocompetent children ▫ Shingles: painful skin rash, can occur in individuals who have recovered from primary VZV infection Primary infection (chickenpox) ▪ Transmission: airborne spread through aerosolized droplets, direct lesion contact ▪ VZV enters respiratory system → lymph node spread → targets skin, mucous membranes → small blood vessel vasculitis → epithelial cell degeneration → fluid-filled vesicles ▫ Incubation period: 14 days ▫ Most infectious: 1–2 days before rash; infectious 3–4 days, until lesions crusted ▫ After symptoms resolve, VZV dormant in nervous system; latent in trigeminal, dorsal root ganglia Figure 79.8 A child with chickenpox. 122 Secondary infection (shingles) ▪ Occurs when dormant VZV reactivates ▫ Reactivation in dorsal root, cranial nerve ganglia → travels down axons → local skin inflammation innervated by ganglion ▫ Prodromal 2–4 day tingling/localized pain before rash onset RISK FACTORS Chickenpox ▪ More common in children ▫ 1–9 years old (highest risk) ▪ Non-immunized status ▪ Immunocompromised status Shingles ▪ Primary varicella infection history ▪ More common in adults ▫ > 50 years old (highest risk) ▪ Immunocompromised status ▪ Stress SIGNS & SYMPTOMS Chickenpox ▪ Fever, headache, malaise, sore throat, tachycardia ▪ Rash characteristics ▫ Generalized pruritic, vesicular rash ▫ “Dew drop on rose petal” appearance ▫ Formation: macules → vesicles → rupture → scab ▫ Vesicles on mucous membranes (e.g. nasopharynx, conjunctiva, mouth, vulva) Shingles ▪ Erythematous, maculopapular lesions evolve into painful vesicular rash ▫ Rash follows dermatomal distribution of cranial nerve/dorsal root ganglion ▫ Thoracic, lumbar dermatomes most commonly affected COMPLICATIONS Chickenpox ▪ Secondary bacterial infection, cutaneous scarring, encephalopathy, varicella pneumonitis/pneumonia ▪ Central nervous system (CNS) complications ▫ Meningitis, encephalitis, intracranial vasculitis ▪ Congenital varicella syndrome ▫ Limb hypoplasia, paresis, microcephaly, ophthalmic lesions Shingles ▪ Ramsay Hunt syndrome ▫ VZV of geniculate ganglion affects facial nerve; hearing loss, facial weakness ▪ Postherpetic neuralgia, superinfection of skin lesions, encephalitis, Mollaret’s meningitis, zoster multiplex/sine herpete, stroke, myelitis ▪ Herpes zoster ophthalmicus (sightthreatening) Figure 79.9 Herpes zoster, or shingles, affecting the ophthalmic branch of the trigeminal nerve. 123 Chapter 79 Herpesviruses TREATMENT MEDICATIONS Chickenpox ▪ Low risk: usually self-limiting ▪ Moderate risk: oral antiviral therapy ▪ High risk: intravenous antiviral therapy; zoster-immune globulin (ZIG) Figure 79.10 Herpes zoster in a dermatomal distribution on the chest. DIAGNOSIS LAB RESULTS ▪ Microbe identification ▫ PCR: VZV DNA ▫ Viral culture: positive VZV ▫ DFA: VZV antigen Shingles ▪ Oral/intravenous antiviral therapy ▪ Analgesics ▫ E.g. paracetamol, ibuprofen; topical; opioid ▪ Calamine lotion ▪ Varicella-zoster immune globulin OTHER INTERVENTIONS ▪ Prevention ▫ Live attenuated VZV vaccine 124 NOTES NOTES LEISHMANIA MICROBE OVERVIEW ▪ Flagellated, parasitic protozoan ▪ Contains kinetoplast (form of mitochondrial DNA) ▪ Hosts: humans, canids, rodents, hyraxes Classification ▪ “Old World” ▫ Usually found in Africa, Asia, Middle East, India ▫ Includes Leishmania infantum, L. donovani, L. tropica, L. aethiopica, L. major ▪ “New World” ▫ Usually found in Central, South America; Mexico ▫ Includes L. braziliensis, L. mexicana, L. infantum (chagasi), L. amazonensis, L. panamensis, L. guyanensis Life stages ▪ Amastigote ▫ Oval; 3–6µm ▫ Intracellular, nonmotile form (no external flagella) ▫ Found in human circulatory system in mononuclear phagocytes ▪ Promastigote ▫ Spindle-shaped; 15–30µm ▫ Extracellular, motile form (long external flagellum) ▫ Found in alimentary tract of sandflies LEISHMANIA osms.it/leishmania PATHOLOGY & CAUSES ▪ Causes disease leishmaniasis ▪ Spread by female sandflies of genus Lutzomyia/Phlebotomus ▪ Human leishmaniasis characterized by ulcers (e.g. skin, oral, nasal mucosa), systemic illness ▪ Lipophosphoglycan layer helps it survive immune system TYPES Cutaneous leishmaniasis (CL) ▪ Most common ▪ Usually caused by L. major, L. tropica, L. aethiopica Mucocutaneous leishmaniasis (ML) ▪ Causes mucosal, skin ulcers ▪ Usually caused by L. braziliensis Visceral leishmaniasis (VL) ▪ AKA kala-azar ▪ Most severe, systemic involvement ▪ Usually caused by L. donovani, L. infantum ▪ If recurs post-treatment: post kala-azar leishmaniasis ▪ Resists host’s complement system, prevents natural killer cells ▪ Infected macrophages spread infection ▫ Spleen → splenomegaly ▫ Liver → Kupffer cells with increased size 125 Chapter 80 Leishmania → liver dysfunction ▫ Bone marrow → hyperplastic → ↓ hematopoiesis → pancytopenia ▫ Lymph nodes → lymphadenopathy RISK FACTORS ▫ Poverty, malnutrition, poor hygiene; deforestation, urbanization SIGNS & SYMPTOMS CL ▪ Skin ulcers resembling leprosy lesions ML ▪ Ulcers on oropharyngeal, nose mucosa ▪ Midfacial destruction: nose cartilage/septal granulation, tear; ulcers on palate, uvula, lips ▪ Hoarse voice, gingivitis, periodontitis ▪ Genital mucosal (severe cases) VL ▪ Fever, weight loss, hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, abdominal tenderness TREATMENT MEDICATIONS CL ▪ Topical paromomycin, miltefosine, pentamidine isethionate, fluconazole, ketoconazole ML ▪ Liposomal amphotericin B, miltefosine, pentamidine VL ▪ Liposomal amphotericin B, miltefosine OTHER INTERVENTIONS Prevention ▪ Nets treated with insecticide while sleeping; over doors, windows ▪ Insect repellents, insecticide-impregnated dog collars ▪ Treat infected dogs DIAGNOSIS LAB RESULTS ▪ Enzyme-linked immunosorbent assay (ELISA) ▪ Antigen-coated dipsticks ▪ Direct agglutination test Light microscope ▪ Amastigotes/Leishman-Donovan body visualization: blood, aspirates from marrow, spleen, lymph nodes, skin lesions ▫ Blood, spleen monocytes ▫ Circulating neutrophils, aspirated tissue macrophages Figure 80.1 A leishmaniasis ulcer on the leg. Polymerase chain reaction (PCR) ▪ Detects Leishmania kinetoplast DNA (most sensitive, specific) 126 NOTES NOTES MYCOPLASMA MICROBE OVERVIEW ▪ Smallest free living organisms ▪ Prokaryotic with absence of cell wall, presence of flexible cell membrane containing cholesterol ▫ Pleomorphic ▫ Not visible on Gram stain ▫ Resistant to beta lactam, glycopeptide antibiotics ▪ Limited metabolic activity → not culturable on standard culture media, require specialized medium (e.g. Eaton’s agar) with sterols, nutrients provided by natural animal protein (e.g. blood serum) ▪ Can grow under aerobic, anaerobic conditions MYCOPLASMA PNEUMONIAE osms.it/mycoplasma-pneumoniae PATHOLOGY & CAUSES ▪ Species of mycoplasma; primarily affects respiratory tract; usually causes upper respiratory tract infections; can also cause atypical pneumonia ▪ Transmitted through respiratory droplets after close contact with infected individual → attaches to respiratory epithelium with P1 surface protein → hydrogen peroxide, superoxide radicals synthesized by mycoplasma interact with endogenous toxic molecules synthesized by host cells → oxidative stress in respiratory epithelial cells ▪ Macrophages migrate to site of infection → activation and phagocytosis → initiate inflammatory response → T, B lymphocyte proliferation → antibody production, release of inflammatory cytokines → control infection/initiate immune-mediated lung injury ▪ Extrapulmonary disease (rare) ▫ Due to immune mediated injury/cross reactive antibody mechanism/direct invasion ▪ Central nervous system (CNS), joints, skin, blood, heart, liver, pancreas affected ▫ CNS is the most common extrapulmonary site; usually encephalitis ▪ Can develop cold agglutinin response (60%) ▫ Autoimmune hemolytic anemia ▫ Coombs positive ▫ Cold (active below 37°C/98.6°F) IgM antibodies against erythrocyte surface antigen due to cross reaction of antigen with mycoplasma antigens → can agglutinate/lyse erythrocytes RISK FACTORS ▪ Common in children, young adults ▪ Immunocompromised status, smoking, close community living (e.g. nursing homes, dorms) COMPLICATIONS ▪ Asthma exacerbations ▪ Respiratory failure ▪ CNS involvement 127 Chapter 81 Mycoplasma ▫ Encephalitis with high mortality rate ▪ Heart involvement ▫ Rhythm disorders, heart failure SIGNS & SYMPTOMS ▪ Can be asymptomatic ▪ Gradual onset ▫ General fatigue, myalgias, headache, low grade fever, sore throat, cough (worsening, frequent, non-productive), chills ▪ Less common ▫ Sinus/ear pain, wheezing ▪ Chest auscultation ▫ Scattered rales, wheezes, rhonchi, crackles ▪ Sinus tenderness ▪ Erythema of tympanic membrane ▪ Pharyngeal erythema ▪ Pulse-temperature dissociation: normal pulse despite fever indicative of atypical pneumonia DIAGNOSIS LAB RESULTS ▪ Molecular testing with polymerase chain reaction (PCR); most accurate ▪ Serological tests ▫ ≥ four-fold rise in IgM antibodies titers of acute, convalescent sera 2–3 weeks apart using enzyme immunoassay ▫ High titer of IgM antibodies ▫ Cold agglutinins titer ▪ Isolation with culture ▫ Limited use due to slow growth (2–3 weeks), need for specialized media DIAGNOSTIC IMAGING Chest X-ray/CT scan/high resolution CT scan ▪ Diffuse reticulonodular pattern indicative of interstitial pneumonia ▪ Areas of airspace consolidation (esp. lower lobes) ▪ Thickening of bronchovascular bundle OTHER DIAGNOSTICS ▪ Histopathology ▫ Inflammation in trachea, bronchioles, peribronchial tissues ▫ Airspaces filled with purulent exudate with polymorphonuclear cells ▪ Physical examination ▫ Vague symptoms (e.g. fatigue) indicative of atypical/“walking” pneumonia TREATMENT ▪ Most cases mild, self-limited MEDICATIONS ▪ Atypical pneumonia ▫ Macrolides (e.g, erythromycin, azithromycin); tetracyclines (e.g. doxycycline); fluoroquinolones (e.g., levofloxacin, moxifloxacin) 128 NOTES NOTES NEMATODES (ROUNDWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ AKA roundworms ▫ Microfilariae: immature worms ▫ Microfilariae: mature worms ▪ Parasites usually enter body cutaneously ▫ Produce gastrointestinal (GI), occasionally cutaneous symptoms, disease COMPLICATIONS ▪ Loffler syndrome ▫ Transient pulmonary disease during select nematode development (Necator Americanus, Strongyloides, Ascaris Lumbricoides, Toxocara, Ancylostoma duodenale) ▫ Symptoms: irritating, nonproductive cough, substernal burning discomfort, dyspnea, wheezing, fever, blood-tinged sputum production SIGNS & SYMPTOMS TREATMENT MEDICATIONS ▪ Antihelminthic therapy ▫ Nematode location-dependent Intestinal nematodes ▪ Mebendazole/albendazole ▫ Bind tubulin colchicine-sensitive sites → inhibit microtubule assembly → inhibited glucose uptake (without human effect) → organism death Systemic nematodes ▪ Diethylcarbamazine (DEC) ▫ Piperazine derivative (uncertain mechanism of action) ▪ Ivermectin ▫ Synthetic lactone → negative-charged ion influx via glutamate-sensitive chloride channels → hyperpolarizes cells → helminth cell death ▫ Not macrofilaricidal, pregnancy contraindication ▪ GI/localized tissue symptoms, organismdependent DIAGNOSIS LAB RESULTS ▪ Eosinophilia ▪ Gammaglobulinemia abnormalities (↑/↓ depending on organism) Serology ▪ IgG levels ▪ Enzyme linked immunosorbent assays (ELISA), western blot 129 Chapter 82 Nematodes (Roundworms) ANCYLOSTOMA DUODENALE & NECATOR AMERICANUS osms.it/ancylostoma-duodenale osms.it/necator-americanus PATHOLOGY & CAUSES ▪ Infectious hookworm species Adult morphology ▪ Ancylostoma duodenale ▫ Two ventral plates on buccal capsule’s anterior margin; two large teeth fused at base (male 8–11mm, female 10–13mm long) ▪ Necator americanus ▫ Two dorsal/ventral cutting plates around buccal capsule’s anterior margin, paired subdorsal/subventral teeth (male 7–9mm, female 9–11mm long) ▪ A. duodenale, Necator americanus: most common hookworm species causing helminth gastrointestinal infection ▫ Light infection (< 100 worms) ▫ Moderate infection (100–500 worms) ▫ Heavy infection (500–1000 worms) ▪ Pathophysiology ▫ Hookworm attachment, hyaluronidase release → intestinal wall degradation, capillary laceration → anticoagulant peptides, inhibits platelet function inhibitor production → bleeding facilitation → extravasated blood ingested (approx. 0.5mL daily) ▫ Moderate–heavy infections → chronic iron-deficiency anemia; protein malnutrition Infectious form ▪ Filariform larva Life cycle ▪ Infectious form maturation ▫ Female A. duodenale lays 10,000– 30,000 eggs daily ▫ Female N. americanus lays 5,000– 10,000 eggs daily ▫ Human feces egge release → soil deposition → eggs hatch (24–48 hours—favorable conditions) → rhabditiform larvae (L1) → transformation to infectious filariform larvae (L3) in 5–10 days ▪ Human stages ▫ Filariform larvae skin penetration → passage through veins to heart, lung → pulmonary alveoli penetration, ascend bronchi to pharynx → coughed up/swallowed into small intestine → maturation → intestinal wall attachment via buccal capsule ▪ Some A. duodenale larvae undergo developmental arrest in gut tissues/muscle ▫ Await more favorable environmental conditions (hypobiotic larvae) ▪ Natural life-span ▫ A. duodenale: approx. one year ▫ N. americanus: 3–5 years Transmission ▪ Contaminated soil contact → percutaneous larval penetration ▪ Oral route ▪ Transmammary route RISK FACTORS ▪ Inadequate clean-water access ▪ Poor sanitary conditions ▪ Walking barefoot (endemic areas) COMPLICATIONS ▪ Severe iron-deficiency anemia; protein malnutrition → impaired growth, cognitive 130 development (children); heart failure (adults) ▪ Pregnancy ▫ Low birth weight, maternal anemia, ↑ infant mortality SIGNS & SYMPTOMS ▪ May be asymptomatic Three phases ▪ Cutaneous phase ▫ Local pruritic dermatitis (ground itch) with papular, sometimes vesicular, focal rash at larval penetration site (usually between toes) ▪ Pulmonary phase ▫ Usually asymptomatic, may involve mild cough, pharyngeal irritation, sore throat, fever ▪ Gastrointestinal phase ▫ Midepigastric pain, appetite loss, nausea, diarrhea, vomiting ▫ A. duodenale, N. americanus eggs are morphologically indistinguishable OTHER DIAGNOSTICS ▪ History ▫ Contaminated-soil skin exposure; endemic-area travel; physical examination TREATMENT MEDICATIONS ▪ Anthelmintic treatment Heavy infection ▪ Hypoproteinemia → weight loss, anasarca, edema ▪ Anemia → fatigue, mental dullness, dyspnea, pallor ▪ Overt gastrointestinal bleeding DIAGNOSIS DIAGNOSTIC IMAGING Abdominal X-ray ▪ Intestinal worm visualization LAB RESULTS ▪ Acute infection ▫ Eosinophelia ▪ Chronic infection ▫ Anemia ▪ Kato–Katz method (thick smear) ▪ Polymerase chain reaction (PCR) test Direct microscopy ▪ Stool specimen egg visualization 131 Chapter 82 Nematodes (Roundworms) ANGIOSTRONGYLUS (EOSINOPHILIC MENINGITIS) osms.it/angiostrongylus PATHOLOGY & CAUSES ▪ Parasitic nematode ▫ Causes human GI/CNS disease ▪ Angiostrongylus cantonensis ▫ Medically important species ▫ Causes angiostrongyliasis (most common eosinophilic meningitis cause) Adult morphology ▪ Three outer protective collagen layers; contains fully-developed gastrointestinal tract, simple stomal opening Hosts ▪ Primary intermediate host: snails ▪ Paratenic hosts: fish, frogs, freshwater prawns ▫ Not needed for developmental cycle ▪ Definitive hosts: wild rodents (brown, black rat) ▪ Incidental hosts: humans Life cycle ▪ Infectious form maturation ▫ Worms lay eggs in rat pulmonary artery → spread from lung capillaries to alveoli, larvae hatch → migrate up bronchi, trachea, across epiglottis → swallowed → fecal larvae passage → soil deposition → intermediate-host ingestion ▪ Human stages ▫ Intermediate host larval ingestion (contaminated water/vegetable) → CNS tropism → migration into meningeal capillaries, brain tissue → meningoencephalitis ▪ Larvae usually fail to complete life-cycle, rarely → adult form in human host Transmission ▪ Intermediate/paratenic host ingestion (raw/undercooked snails, fish, frogs), contaminated vegetables/water Pathophysiology ▪ Post-inoculation, A. cantonensis larvae exhibit neurotropism → meninges, deeper brain tissue invasion → neural-tissue mechanical, toxic byproducts damage; antigen release → meningoencephalitis ▪ Migration to mesenteric arterioles → arteritis, thrombosis, small infarctions ▫ May cause necrotic ulcers → peritonitis, fistula formation COMPLICATIONS ▪ Long-term encephalitis → permanent nerve damage, intellectual disability, permanent brain damage, death SIGNS & SYMPTOMS ▪ Incubation period: three weeks–two months ▪ Meninges invasion: meningitis picture ▫ Severe headache, photophobia, stiff neck, fatigue, fever, hyperesthesia, vomiting, paresthesias ▪ Brain parenchyma invasion: encephalitis symptoms (brain location-dependent) ▫ Cognitive impairment, slowed reactions, neuropathic pain, ascending weakness ▫ t quadriparesis, areflexia, respiratory failure, muscle atrophy, death (rare) ▪ Eye invasion: visual impairment, pain, keratitis, retinal edema 132 DIAGNOSIS TREATMENT LAB RESULTS ▪ Self-limiting infection (usually) ▪ Cerebrospinal fluid (CSF) ▫ Eosinophilia ▫ ↓ glucose levels (severe meningoencephalitis) MEDICATIONS ▪ Analgesics, sedatives ▫ Treat headache, hyperesthesia ▪ Corticosteroids ▪ Antihelminthic therapy not advised ▪ Dying parasites, neurologic damage exacerbation → potential inflammatory response OTHER DIAGNOSTICS ▪ Endemic-area travel history ▪ Physical examination ▪ Clinical presentation OTHER INTERVENTIONS ▪ CSF drainage ▫ Reduces intracranial pressure, relieve headache ANISAKIS osms.it/anisakis PATHOLOGY & CAUSES ▪ Zoonotic roundworm ▫ Causes human gastrointestinal, extragastrointestinal disease ▫ Causative anisakiasis agent Adult morphology ▪ Anteriorly-located mouth surrounded by projections; length (2cm/0.8in) Infectious form ▪ L3 larvae Hosts ▪ Natural hosts: marine mammals ▪ Incidental hosts: humans Life cycle ▪ Infectious form maturation ▫ Eggs hatch into larvae (seawater) → larval crustacean ingestion → fish/ squid ingest crustaceans → muscular/ subdermal larval encystation (L3 larvae) → marine mammals ingest fish → excystation, maturation, nematode reproduction → fecal egg release ▪ Human stages ▫ Larval ingestion (infected fish) → larvae fail maturation, cannot complete lifecycle Transmission ▪ Raw/undercooked fish ingestion Pathophysiology ▪ Infected fish larvae ingestion → larvae burrow into intestinal wall, die → dead organism → inflammatory response → possible allergic reaction, abscess, mechanical obstruction ▪ If parasites pass into large intestine ▫ Eosinophilic granulomatous response → mimic appendicitis/Crohn’s disease RISK FACTORS ▪ Raw/undercooked seafood ingestion (common in Japan) 133 Chapter 82 Nematodes (Roundworms) COMPLICATIONS ▪ Small bowel obstruction ▪ Intestinal perforation ▪ Peritoneal cavity perforation (extraintestinal anisakiasis) ▪ Eosinophilic gastroenteritis/enterocolitis SIGNS & SYMPTOMS ▪ Gastric anisakiasis ▫ Acute epigastric pain, nausea, vomiting ▪ Intestinal anisakiasis ▫ Severe abdominal pain, abdominal distension, palpable abdominal mass, intestinal obstruction, bloody diarrhea ▪ Allergic reactions ▫ Urticaria, bronchoconstriction, angioedema, anaphylactic shock DIAGNOSIS DIAGNOSTIC IMAGING ▪ Parasite visualization ▫ Gastroscopic examination, emesis examination LAB RESULTS ▪ ↑ serum IgE TREATMENT SURGERY ▪ Parasite removal (endoscopically, surgically) ASCARIS LUMBRICOIDES osms.it/ascaris-lumbricoides PATHOLOGY & CAUSES ▪ Intestinal roundworm parasite ▫ Causative ascariasis agent ▪ Adult worm size: 15–30cm/5.9–11.8in ▫ Largest intestinal nematode Life cycle ▪ Female A. lumbricoides lays 200,000 eggs daily; begins egg-laying 9–11 weeks postinfection ▪ Infectious-form maturation ▫ Eggs passed in stool → soil deposition → eggs embryonate; infectious after 2–4 weeks; can survive < ten years (favorable conditions) ▪ Human stages ▫ Egg ingestion → larvae hatch → invade intestinal mucosa → portal circulation → systemic circulation → liver → lungs → larvae mature in alveoli (10–14 days) → ascend bronchial tree, pharynx, swallowed → larvae develop into adult form in small intestine ▪ Life-span: 10–24 months Pathophysiology ▪ Varies upon life-cycle stage ▫ Pulmonary phase (early): caused by larval migration into lungs → pneumonitis ▫ Intestinal phase: manifestations caused by adult-form presence → mechanical obstruction (degree worm-burdendependent) RISK FACTORS ▪ Egg-contaminated food/water ingestion (especially pig/chicken liver) ▪ Infected soil (children) ▪ Feco-oral route reinfection COMPLICATIONS ▪ Intestinal obstruction ▫ May → volvulus, ileocecal 134 ▪ ▪ ▪ ▪ intussusception, gangrene, intestinal perforation Children ▫ Malnutrition/malabsorption, impaired growth, cognitive development Hepatobiliary involvement ▫ Biliary colic, biliary strictures, obstructive jaundice, liver abscesses Pancreatic duct obstruction → pancreatitis Aspiration pneumonia during esophageal migration to trachea SIGNS & SYMPTOMS ▪ Often asymptomatic ▪ Pulmonary phase (Loffler syndrome): develops 4–16 days post-infection ▫ Dry cough, dyspnea, fever, wheezing, substernal discomfort, blood-tinged sputum; symptoms subside after 5–10 days ▪ Intestinal phase: develops 6–8 weeks postinfection ▫ Abdominal discomfort, anorexia, nausea, vomiting, diarrhea Barium swallow ▪ Intestinal phase ▫ Defects in filling; if worms ingest contrast, tram-track appearance demonstrated Microscopic examination ▪ Pulmonary phase ▪ Eosinophils, Charcot–Leyden crystals in sputum ▪ Intestinal phase ▪ Eggs/adult form stool visualization (KatoKatz/FLOTAC method) LAB RESULTS ▪ Pulmonary phase ▫ Peripheral eosinophilia OTHER DIAGNOSTICS ▪ Exposure/endemic-area travel history DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary phase ▫ May show migratory bilateral oval infiltrates, range from several mm– several cm ▪ Intestinal phase ▫ Adult Ascaris worm visualization, intestinal obstruction CT scan ▪ Pulmonary phase ▫ Multiple nodules, “ground-glass” attenuation ▪ Intestinal phase ▫ “Bull’s eye” appearance (worm crosssection) Figure 82.1 A barium study demonstrating ascariais. There are numerous worms in the distal part of the duodenum and the ileum. 135 Chapter 82 Nematodes (Roundworms) TREATMENT MEDICATIONS ▪ Anthelmintic treatment ▫ Only effective in intestinal phase ▫ Pregnancy: pyrantel pamoate SURGERY ▪ Complete intestinal obstruction, volvulus, intussusception, appendicitis, perforation cases OTHER INTERVENTIONS ▪ Endoscopic retrograde cholangiopancreatography (ERCP) ▫ Hepatobiliary-involvement cases Figure 82.2 Ascaris worms emerging from the two free ends of the small intestine during an operation to remove a length of ischemic bowel. Figure 82.3 Small bowel packed with Ascaris lumbricoides worms. The bowel is distended so greatly that the visceral peritoneum on the antimesenteric border is split. 136 ENTEROBIUS VERMICULARIS (PINWORM) osms.it/enterobius-vermicularis PATHOLOGY & CAUSES ▪ Small roundworm ▫ May infect human colon, rectum ▫ Causative enterobiasis agent Life cycle ▪ Female E. vermicularis lays > 10,000 eggs daily ▪ Perianal fold egg deposition → autoinfection by scratching; contaminated hand, mouth contact → eggs hatch into larvae (small intestine) → adult-form maturation (cecum, appendix) ▪ Life-span: 2–3 months Transmission ▪ Scratching perianal area (autoinfection) → hand–mouth contact ▪ Contaminated hands (person–person) ▪ Contaminated surface contact ▪ Eggs may become airborne, inhaled ▪ High worm burden → abdominal pain, nausea, vomiting DIAGNOSIS OTHER DIAGNOSTICS ▪ Pinworm paddle/Scotch tape test ▫ Adhesive clear plastic paddle pressed against perianal areas → placed onto glass slide; reveals eggs upon microscopic examination TREATMENT MEDICATIONS ▪ Anthelmintic treatment RISK FACTORS ▪ Crowded living conditions ▪ Children 5–10 years old COMPLICATIONS ▪ Persistent perianal-area scratching, skin tearing → bacterial dermatitis, folliculitis ▪ Adult worms migrate to extraintestinal sites; cause vulvovaginitis, salpingitis, oophoritis, cervical granuloma, peritoneal inflammation Figure 82.4 Pinworm found incidentally in an appendectomy specimen. SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Perianal itching (pruritus ani) occurs nocturnally 137 Chapter 82 Nematodes (Roundworms) GUINEA WORM (DRACUNCULIASIS) osms.it/guinea-worm PATHOLOGY & CAUSES ▪ Water-borne nematode disease ▫ Characterization: rash, GI illness with subcutaneous worm visualization Life cycle/transmission ▪ Infected water → human copepod ingestion → GI, subcutaneous migration, sexual reproduction → pruritus, percutaneous larval eruption upon water-immersion → copepod larval consumption → two molting processes → pathogenic larvae in copepods Pathogenesis ▪ GI symptoms ▫ Ingested copepod death in GI system → larval migration into stomach, intestinal wall → entry into abdominal, retroperitoneal space ▪ Cutaneous symptoms ▫ Larval sexual reproduction → female survival, skin migration → limb waterimmersion → eruption RISK FACTORS ▪ Rural Eastern-Africa residence/travel ▪ Cutaneous symptoms ▫ Painful papule (2–7cm/0.8–2.8in) → enlarges, ↑ pain → worm emerges through ulceration DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Calcified dead worm in subcutaneous tissue ▫ If worm does not emerge through skin OTHER DIAGNOSTICS ▪ Endemic-area travel/residence history ▪ Physical examination ▫ Systemic → cutaneous symptom development TREATMENT OTHER INTERVENTIONS ▪ Worm extraction; careful extraction protocol ▫ Multiple days (centimeters at a time); keeps worm intact, prevents local pruritic, edematous reaction COMPLICATIONS ▪ Ectopic site migration → abscess development ▫ Lung, eye, pericardium, spinal cord ▪ Broken worm → intensely painful, edematous local, subcutaneous reaction SIGNS & SYMPTOMS ▪ Systemic symptoms initially ▫ Fever, urticaria, pruritus, dizziness, nausea/vomiting, diarrhea Figure 82.5 A match stick being used to extract a guinea worm from an ulcer on the leg. 138 Prevention ▪ Community surveillance, transmission methods education ▪ Safe water precautions ▫ Nylon filters for water filtration, insecticides in drinking water courses, water source covering (prevents infected body-part immersion) ▪ Occlusive dressings applied to papules LOA LOA (EYE WORM) osms.it/loa-loa PATHOLOGY & CAUSES ▪ Vector-borne filarial nematode endemic in Africa ▫ Characterization: transient swelling episodes, subconjunctival adult worm migration ▪ AKA African eye worm ▪ Allergic reaction ▪ Subconjunctival infiltration ▫ Associated with conjunctivitis, eyelid swelling Life cycle/transmission ▪ Vector ▫ Chrysops (biting deer fly; AKA tabanid fly) ▫ Breed in rainforest canopies, lay eggs in muddy swamps; bite humans during daytime ▪ Tabanid fly human bite → filarial larvae transmission → three month maturation process → microfilarial production → bloodstream release ( ↑ release during daytime) → tabanid blood meal (infected individual) → filarial maturation in tabanid fly COMPLICATIONS ▪ Onchocerciasis co-infection ▪ Encephalitis (coincident headache, insomnia, coma may result) ▪ Cardiomyopathy (endomyocardial fibrosis) ▪ Nephropathy ▪ Arthritis ▪ Lymphadenitis ▪ Calabar swelling → entrapment neuropathy SIGNS & SYMPTOMS Allergic reactions ▪ Calabar swellings ▫ 5–20cm/2–7.9in non-erythematous lesions ▫ Transient, local subcutaneous swelling; face, extremities most common; localized pain, itching prior to swelling episodes ▫ Urticaria, pruritus, asthma Subconjunctival eye infection ▪ Commonly non-painful infiltration of eye subconjunctival area; conjunctivitis may occur (with eyelid swelling) ▪ Worm may be visible RISK FACTORS ▪ Endemic-area residence/travel ▫ Eastern, Central Africa 139 Chapter 82 Nematodes (Roundworms) DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ Hypergammaglobulinemia ↑ IgE level Worm’s presence (blood smear) Serology ▫ IgG antibodies against L. loa antigens OTHER DIAGNOSTICS ▪ History, physical examination ▫ Worm detection in subcutaneous tissue, conjunctiva ▫ Onchocerciasis co-infection contraindicated (DEC provokes severe inflammatory skin, eye response; Mazzotti reaction) ▫ Eradication may require multiple treatment rounds ▪ Albendazole ▫ Sterilizes mature worms without microfilarial activity ▪ Antihistamine/corticosteroids ▫ Limits post-treatment immune reactions (e.g. Calabar swelling) SURGERY ▪ Large worm removal TREATMENT MEDICATIONS ▪ Diethylcarbamazine (DEC) ▫ Active against L. loa microfilariae, microfilariae (adult worms) OTHER INTERVENTIONS Prevention ▪ Weekly DEC prophylaxis ▪ Only considered for long-term endemicarea exposure ONCHOCERCA VOLVULUS (RIVER BLINDNESS) osms.it/onchocerca-volvulus PATHOLOGY & CAUSES ▪ Filarial nematode transmitted by blackflies ▪ Leading preventable blindness cause in sub-Saharan Africa Life cycle/transmission ▪ Simulium blackfly human bite → larvae skin deposited → adult parasite maturation (microfilariae) → subcutaneous/deeper intramuscular tissue migration → fibrous capsule/nodule development → reproduction → microfilarial (immature worm) production, subcutaneous tissue migration → human blackfly bite → microfilarial development into infective larvae (in blackfly) Ocular onchocerciasis ▪ Common manifestation: West African savanna ▪ Commonly affects anterior eye chamber ▫ Iridocyclitis, glaucoma, uveitis ▪ Posterior chamber may also be affected ▫ Onchochorioretinits, optic atrophy ▪ Ocular involvement degree correlates with symbiotic Wolbachia bacteria quantity Onchocercal skin disease ▪ AKA Leopard/lizard/elephant skin (especially when depigmentation present); common manifestation in African forest areas ▪ Classified by chronicity ▫ Acute/chronic papular onchodermatitis 140 ▪ Lichenified onchodermatitis (AKA sowda/ black/dark); epidermal atrophy, elastic fiber breakdown may occur PATHOLOGY Subcutaneous involvement ▪ Onchocercoma ▪ Dermal O. volvulus → inflammatory response (prostaglandin E2, transforming growth factor-beta-mediated) → nodule formation (onchocercoma); nodules predominate in bony prominence areas, peak inflammatory response occurs upon subcutaneous male O. volvulus death Ocular involvement ▪ Anterior chamber disease ▫ O. volvulus infiltration → immune response, O. volvulus death → Wolbachia release → innate immune response → corneal damage ▪ Posterior chamber disease ▫ O. volvulus infiltration → immune response → cross-reactivity of O. volvulus antigen with retinal pigment epithelial protein → persistent immunologic response → inflammatory limbus, iris, choroid damage RISK FACTORS ▪ West Africa, Eastern South America travel/ residence ▫ Especially savanna, forest SIGNS & SYMPTOMS Cutaneous ▪ Pruritus ▪ Nodule development (lymphadenopathy may develop, persist depending on infection duration) ▪ Focal darkening/depigmentation ▪ Epidermal atrophy, hyperpigmentation, hyperkeratosis may be present Ocular ▪ Punctate keratitis → fluffy corneal opacities → eosinophilic infiltrate → sclerosing keratitis → corneal opacification; progressive (eventually irreversible) vision deficit DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Deep ochoceroma detection LAB RESULTS ▪ Eosinophilia ▪ Hypergammaglobulinemia ▪ PCR assay ▫ O. volvulus OTHER DIAGNOSTICS ▪ Rheumatologic/dermatologic onchocercoma evaluation Skin snips ▪ Corneoscleral punch biopsy (ocular involvement)/ disposable razor blade for epidermal sample (cutaneous disease) ▪ 2+ snips taken in areas likely to harbor highest microfilariae concentration ▪ Positive only within 9–15 months postinfection (mature microfilariae produce microfilariae) Patch test ▪ Topical DEC application → local skin reaction assessment ▪ Akin to Mazzotti reaction Fundoscopic and corneal evaluation ▪ Slit-lamp examination reveals wriggling microfilariae ▪ Individuals sit forward for two minutes prior to examination (↑ microfilarial visualization likelihood on chamber examination) TREATMENT MEDICATIONS ▪ Ivermectin, doxycycline ▫ Ivermectin: kills immature worms only, adult worm repopulate months after treatment 141 Chapter 82 Nematodes (Roundworms) ▫ Doxycycline: kills Wolbachia (symbiotic bacteria needed for O. volvulus fertility) for 24 months; block reproduction OTHER INTERVENTIONS Prevention ▪ Protective clothing, insect repellent (especially when blackflies most active— morning/evening) STRONGYLOIDES STERCORALIS osms.it/strongyloides-stercoralis PATHOLOGY & CAUSES ▪ Filarial disease endemic in tropical areas with characteristic pulmonary infection route, complications include septic shock in immunocompromised individuals ▪ Mild GI, cutaneous, pulmonary inflammation, disease ▫ Dermatitis, urticaria, duodenitis, enterocolitis, pneumonitis ▫ May persist for years Life cycle ▪ Larvae live in fecally-contaminated ground soil → enter human host through broken skin → hematologic spread → pulmonary alveolar sac infiltration, penetration → ascend tracheobronchial tree → swallowed → larval maturation in duodenum, jejunum → larval reproduction, fecal excretion ▪ Autoinfection (single-host life-cycle completion) may occur via larval perianal skin entry PATHOLOGY ▪ Larvae contaminate skin through breakage → lung migration → inflammation infiltrate → intestinal wall migration → maturation, replication → larval intestinal mucosa penetration → autoinfection RISK FACTORS ▪ Constipation, diverticula, steroid-use, ↓ bowel motility → ↑ autoinfection likelihood ▪ Hypogammaglobulinemia ▪ Anti-tumor necrosis factor receptor therapy ▪ Organ transplantation, immune suppression COMPLICATIONS ▪ Hyperinfection (uncontrolled autoinfection → high worm-burden disease) ▫ Immunocompromised individuals ▫ Hematologic parasite spread includes CNS, heart, liver, lungs, endocrine glands ▫ May manifest as septic shock SIGNS & SYMPTOMS ▪ Immunocompetent individuals ▫ Bloating, diarrhea ▪ Cutaneous ▫ Edema, petechiae, serpiginous/urticarial tracking ▪ Gastrointestinal ▫ Anorexia, nausea, vomiting, epigastric pain (duodenal ulceration cases), malabsorption (chronic enterocolitis) ▪ Pulmonary ▫ Dry cough, throat irritation, dyspnea, wheezing, hemoptysis 142 DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pulmonary disease ▫ Foci of hemorrhage, pneumonitis, pulmonary edema LAB RESULTS Organism identification ▪ Stool examination ▫ Low sensitivity due to intermittent larval release ▫ Repeat testing ↑ finding’s reliability ▪ ELISA ▫ Immunocompetent individuals TREATMENT MEDICATIONS ▪ Ivermectin ▪ Albendazole ▫ May combine with ivermectin in hyperinfection/disseminated disease states OTHER INTERVENTIONS Prevention ▪ Proper shoe wearing ▫ Prevents broken-skin exposure ▪ Serologic evaluation ▫ Solid organ transplant donors OTHER DIAGNOSTICS ▪ Endemic-area travel history Endoscopy ▪ Histopathological (biopsy-driven) diagnosis ▫ Stomach, duodenum, colon evaluation of mucosa appearance Figure 82.6 A duodenal biopsy containing an entire Strongyloides worm, likely an adult female. 143 Chapter 82 Nematodes (Roundworms) TOXOCARA CANIS (VISCERAL LARVA MIGRANS) osms.it/toxocara-canis PATHOLOGY & CAUSES ▪ Human roundworm disease: dog, cat, pig vectors characterized by cutaneous/ocular disease ▫ Dogs: toxocara canis ▫ Cats: toxocara cati ▫ Pigs: Ascaris suum Life cycle/transmission ▪ Definitive hosts: cats, dogs, pigs ▪ Accidental hosts: humans ▪ Egg-laden stool → soil contamination → definitive host ingestion → GI tract reproduction → larval gut wall penetration → pulmonary migration, penetration → ascend tracheobronchial tree → swallowed → small intestine worm maturation → reproduction, egg excretion in stool ▪ Paratenic host: non-canine, small mammals; egg ingestion → larval gut wall penetration → tissue migration → cyst formation → human paratenic host ingestion → infection Disease ▪ Ocular involvement: inflammatory granuloma of posterior pole, diffuse endophthalmitis, solitary peripheral retinal granuloma RISK FACTORS ▪ Raw liver/undercooked meat ingestion (e.g. rabbit, chicken, cattle, pork) ▪ Children ▫ Playground, sandbox use COMPLICATIONS ▪ Hepatitis ▪ Pneumonitis ▪ Cardiac ▫ Pericarditis, myocarditis ▪ CNS involvement ▫ Myelitis, meningoencephalitis, seizure, cerebral vasculitis ▪ Ocular ▫ Retinal detachment, blindness SIGNS & SYMPTOMS ▪ Visceral larva migrans ▫ Pruritic urticaria, fever, anorexia, malaise, irritability ▪ Ocular larva migrans ▫ Unilateral vision impairment, uveitis, papillitis, endophthalmitis ▪ Hepatomegaly ▪ Respiratory distress DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Bilateral peribronchial infiltrates CT scan ▪ Chest: multifocal subpleural nodules, “ground-glass” opacities, ill-defined margins ▪ Abdomen: multiple ill-defined lesions in liver parenchyma Ultrasound ▪ Abdomen: may also identify lesions LAB RESULTS ▪ Leukocytosis ▪ Hypogammaglobulinemia (↑ IgG, IgE) ▪ ELISA 144 AfraTafreeh.com exclusive ▫ IgG antibodies against Toxocara excretory/secretory antigens ▫ Does not differentiate Toxocara canis from cati OTHER DIAGNOSTICS ▪ Endemic-area travel history ▪ Physical examination TREATMENT MEDICATIONS ▪ Moderate → severe symptoms ▫ Albendazole ▪ Severe inflammatory disease (myocarditis, pneumonitis, CNS involvement) ▫ Prednisone ▪ Ocular larva migrans ▫ Corticosteroids, albendazole OTHER INTERVENTIONS Prevention ▪ Hand hygiene practice ▪ Pet feces disposal, deworming ▪ Undercooked meat (especially liver) consumption risk education TRICHINELLA SPIRALIS osms.it/trichinella-spiralis PATHOLOGY & CAUSES → female worm release larvae → striated muscle encystation ▪ Roundworm infection (prevalent worldwide) ▫ Raw/undercooked meat with encysted organism consumption ▪ Trichinella: nine species, twelve genotypes ▫ Animal intermediate host-specific ▫ T. spiralis: most common worldwide; variety of carnivorous, omnivorous animals Disease ▪ Severity correlates with multiple factors ▫ Number of ingested larvae directly correlates with ingested meat cooking temperature ▫ Trichinella species ▫ Incubation period (shorter correlates with ↑ disease severity) ▪ Gastrointestinal involvement ▫ Maturing larvae burrow in intestinal mucosa ▫ Diarrheal illness, nausea, vomiting ▪ Muscular involvement ▫ Adult worm dissemination into skeletal muscle ▫ Symptom resolution occurs with complete worm encystment ▫ Mild subclinical fatigue, post-exercise weakness persists months–years Life cycle/transmission ▪ Domestic cycle: involves pigs, rodents ▪ Sylvatic cycle: broad animal range ▫ Bear, moose, wild boar most common human infection sources ▪ Trichinella larvae/mature worm ingestion by intermediate host → GI tract maturation → larvae release, migrate from female worms to striated muscles → encyst → intermediate host consumption (inadequate cooking temperature) → larval ingestion → larvae release in stomach (upon gastric acid, pepsin exposure) → small bowel mucosa invasion → adult worm maturation RISK FACTORS ▪ Undercooked/raw meat consumption 145 Chapter 82 Nematodes (Roundworms) COMPLICATIONS ▪ Myositis, myocarditis ▫ Eosinophil-enriched inflammatory response → life-threatening arrhythmia development ▪ Encephalitis, pneumonia ▫ Direct larval parenchyma infiltration, respiratory muscle disease SIGNS & SYMPTOMS ▪ Gastrointestinal ▫ Nausea/vomiting, abdominal pain, diarrhea ▪ Muscular ▫ Most severe symptoms ▫ Pain (activity-dependent; ↑ muscle use/ strain correlates with ↑ ↑ pain) ▫ Tenderness, swelling, weakness ▪ Other ▫ High fever, periorbital edema, chemosis, visual disturbance ▫ Retinal hemorrhage on fundoscopic examination DIAGNOSIS DIAGNOSTIC IMAGING CT scan/MRI ▪ In severe neurologic-involvement cases ▪ Multifocal cerebral cortex, white matter lesions LAB RESULTS ▪ Serology ▫ ELISA, western blot, immunofluorescence assays ▫ Antibodies only detectable after 2-3 weeks of disease ▫ Eosinophilia ▫ Leukocytosis ▫ ↑ Muscle enzymes, ↑ creatinine kinase, ↑ lactate dehydrogenase ▪ Muscle biopsy ▫ Near tendinous insertion → highest yield obtained Figure 82.7 A muscle biopsy containing a Trchinella spp. larva. TREATMENT MEDICATIONS ▪ Mild disease ▫ Self-resolving ▫ Analgesia, antipyretics ▪ Systemic symptoms ▫ Antiparasitic therapy (assists larval burrowing into intestinal mucosa treatment) ▫ Corticosteroids OTHER INTERVENTIONS Prevention ▪ Postexposure prophylaxis in suspected cases ▫ Mebendazole within six days of exposure ▪ Undercooked/raw meat consumption risk education, safe cooking practices 146 TRICHURIS TRICHIURA (WHIPWORM) osms.it/trichuris-trichiura PATHOLOGY & CAUSES ▪ Human intestinal parasite (AKA whipworm) ▪ T. Trichiura causative trichuriasis agent Morphology ▪ Adult ▫ 4 cm/1.6 in in length; made of anterior whip-like esophageal portion, posterior intestine/reproductive organ portion ▪ Egg ▫ Prolate spheroids, polar plugs at each end Life cycle ▪ Female T. Trichiura lays 3000–20,000 eggs daily 60–70 days post-infection ▪ Infectious form maturation ▫ Unembryonated egg passage in stool → soil deposition → eggs embryonate, become infectious in 15–30 days ▪ Human stages ▫ Egg ingestion → eggs hatch into larvae in small intestine → larvae mature into adult worms, embed in cecum, ascending colon ▪ Life-span: 1-3 years RISK FACTORS ▪ Poor hygiene, sanitary conditions; inadequate human fecal disposal; uncooked/contaminated vegetable ingestion COMPLICATIONS ▪ Heavy infection → rectal prolapse ▫ Inflammation, edema caused by high embedded worm quantity in rectum (usually small children) ▪ Persistent blood loss → iron-deficiency anemia ▪ Children ▫ Impaired growth, cognitive development SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Heavier infection ▫ Abdominal pain, distension, diarrhea, fecal blood/mucus, nocturnal stooling, tenesmus DIAGNOSIS OTHER DIAGNOSTICS ▪ Kato–Katz thick-smear technique ▫ Eggs in stool visualization TREATMENT MEDICATIONS ▪ Antihelminthic treatment 147 Chapter 82 Nematodes (Roundworms) WUCHERERIA BANCROFTI (LYMPHATIC FILARIASIS) osms.it/wuchereria-bancrofti PATHOLOGY & CAUSES ▪ Mosquito-borne nematode infection ▫ Characterization: lymphatic, subcutaneous involvement → disfigurement, disability ▪ Mosquito species vector geographicspecific (e.g. Culex, Aedes) Life cycle/transmission ▪ Filarial larvae introduction into human skin during mosquito bloodmeal → lymphatic spread → maturation into adult worm → reproduction, microfilarial hematologic release (commonly nocturnal release) → further transmission after infected individual’s mosquito bite Disease ▪ Adenolymphangitis, tropical pulmonary eosinophilia, hydrocele, chronic lymphatic disease ▪ Chyluria ▫ Intestinal lymphatic discharge into pelvis ▫ May → nutritional deficiency (including anemia, hypoproteinemia) SIGNS & SYMPTOMS ▪ Fever, hydrocele Lymphatic disease ▪ Acute adenolymphangitis ▪ Painful lymphadenopathy, retrograde lymphangitis; self-resolving (4–7 days), may recur multiple times per year ▪ Dilation ▪ Lymphangiectasia ▪ Lymphedema ▫ Pitting edema → non-pitting edema → limb hardening ▫ Hyperpigmentation, hyperkeratosis may occur late in disease Pathogenesis ▪ Filarial antigens → TH2-type immune response → cytokine production (IL-5, IgE) ▪ Adult worm → mechanical lymphatic disruption → lymphangiectasia, lymphatic dilation ▪ Endosymbiotic bacteria Wolbachia → immune response potentiation DIAGNOSTIC IMAGING RISK FACTORS LAB RESULTS ▪ Sub-Saharan africa, Southeast Africa, India, Pacific island travel/residence COMPLICATIONS ▪ Lymphedema (AKA elephantiasis) ▫ Chronic lymphatic vessel inflammation → limb swelling DIAGNOSIS Ultrasound ▪ Lymphatic dilation, lymphangiectasia, adult worms may be visualized ▪ Circulating filarial antigen assays ▫ ELISA: Og4C3 antigen detection ▫ ↑ IgG4 levels indicate active infection ▪ Blood smear ▫ Nocturnal blood draw important to ↑ microfilariae concentration 148 OTHER DIAGNOSTICS ▪ Physical examination ▫ Wriggling adult filariae in lymphatic vessels TREATMENT MEDICATIONS ▪ DEC ▫ Contraindication: onchocerciasis, severe Loa Loa infection, pregnancy ▫ Doxycycline may be added as combination agent for direct larvicidal activity ▫ ↓ lymphedema effectiveness ▫ Proper skin care, topical antimicrobial administration (antifungal, antibacterial agents), extremity elevation, exercise may ↓ edema over time SURGERY ▪ Hydrocele complications Figure 82.8 A histological section of a lymph node which contains a filarial worm. The normal lymph node architecture has been replaced with an inflammatory infiltrate composed largely of eosinophils. OTHER INTERVENTIONS Prevention ▪ Mass drug administration programs ▪ Insecticide-treated bed nets ▪ Repellant, protective clothing in mosquitoendemic regions 149 Chapter 82 Nematodes (Roundworms) 150 NOTES NOTES NON TUBERCULOUS MYCOBACTERIUM MICROBE OVERVIEW ▪ Pleomorphic acid-fast bacillus; usually rodshaped ▪ Thick waxy coating ▪ Obligate intracellular microorganism ▪ Optimal growing conditions: cool temperatures (27–33ºC/80.6–91.4°F), aerobic environment ▪ Proliferates slowly; cannot be cultivated in vitro ▪ Appearance: red; Ziehl–Neelsen stain MYCOBACTERIUM LEPRAE osms.it/mycobacterium-leprae PATHOLOGY & CAUSES ▪ Primarily infects skin, superficial nerves, upper respiratory tract mucosa, eyes ▪ Chronic infection: leprosy; AKA Hansen’s disease ▪ Targets Schwann cells → nerve damage → sensation loss → repeated injuries, infections → gradual destruction of extremities ▪ Infiltration of skin, cutaneous nerves → hypopigmented skin lesions Ridley-Jopling classification ▪ Tuberculoid ▫ ↑ cell-mediated immunity response ▫ AKA paucibacillary (↓ mycobacteria) ▪ Lepromatous ▫ ↓ cell-mediated immunity response ▫ AKA multibacillary (↑ mycobacteria) ▪ Broad disease spectrum ▫ Borderline tuberculoid, mid-borderline, borderline lepromatous, indeterminate RISK FACTORS ▪ Close contact with infected individuals (esp. in areas of poverty), armadillos (enzootic in Dasypus novemcinctus) ▪ Older age, genetic factors, immunosuppression COMPLICATIONS ▪ Lifelong neuropathy → severe disfigurement, disability ▪ Severe ophthalmic injury → vision loss ▪ Social stigma (falsely believed contagious) SIGNS & SYMPTOMS ▪ Can be asymptomatic for years ▪ ↓ sensation ▫ Glove, stocking pattern → repeated painless injuries ▪ Hypopigmented/reddish skin lesions, heal spontaneously ▫ Tuberculoid: rare, well-demarcated ▫ Lepromatous: numerous, poorly demarcated 151 Chapter 83 Non Tuberculous Mycobacterium Nodular swelling (face, earlobes) Body hair loss (esp. eyebrows, eyelashes) Tender, thickened peripheral nerves Ocular involvement ▫ Chronic uveitis (common) ▫ Facial nerve paralysis (lagophthalmos) → corneal exposure, dry eye → corneal ulceration ▪ Late stages ▫ Claw fingers, toes ▫ Foot droop (inability to lift front of foot); peroneal nerve infiltration ▫ Nasal septum destruction → nose collapse (saddle nose) ▪ ▪ ▪ ▪ Figure 83.1 A skin lesion on the scalp of an individual with leprosy. DIAGNOSIS LAB RESULTS ▪ Skin biopsy of active lesion ▫ Mycobacteria in cutaneous nerve ▪ Polymerase chain reaction (PCR) ▫ M. leprae DNA in tissues OTHER DIAGNOSTICS ▪ Clinical examination Figure 83.2 The hands of an individual with leprosy. The distal portions of almost all the digits, aside from one, have been lost. TREATMENT MEDICATIONS ▪ Multidrug therapy to prevent resistance ▫ Tuberculoid: dapsone, rifampicin; six months ▫ Lepromatous: dapsone, rifampicin, clofazimine; 12 months OTHER INTERVENTIONS Figure 83.3 Skin changes on the chest of an individual infected with Mycobacterium leprae. ▪ Bacillus Calmette–Guérin (BCG) vaccination ▫ Administered at birth in regions with increased leprosy rates (e.g. Brazil, India, Indonesia) 152 NOTES NOTES OPPORTUNISTIC FUNGAL INFECTIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Range of infections caused by fungi; take advantage of weakened immunity (e.g. HIV/ AIDS, malignancy, immunosuppression), altered microbiota, breached integumentary barriers ▪ Present in environment worldwide → immunocompetent, healthy individuals can be exposed without resulting in disease RISK FACTORS ▪ Immunosuppression (e.g. HIV/AIDS, neutropenia, chemotherapy, hematologic malignancies, transplant recipients) SIGNS & SYMPTOMS ▪ Primary local cutaneous, pulmonary infection to dissemination to various internal organs DIAGNOSIS LAB RESULTS ▪ Direct microscopy with staining, culture, tissue biopsy, bronchoalveolar lavage (sputum sample if pulmonary in origin), polymerase chain reaction (PCR) TREATMENT MEDICATIONS ▪ Antifungals ASPERGILLUS FUMIGATUS osms.it/aspergillus-fumigatus PATHOLOGY & CAUSES ▪ Saprophytic fungi species responsible for majority of invasive, chronic aspergillosis ▪ Found in soil, compost ▪ Asexual reproduction → production of green pigmented asexual conidia (spores) → aerosolized → individuals inhale everyday → macrophages attempt to clear conidia → secondary inflammation after conidia germinate into hyphal forms → neutrophil recruitment → activation of cellular immunity to kill hyphae ▪ Histopathologically, invasive aspergillosis characterized by progression across tissue planes ▫ Hallmark: vascular invasion → infarction + tissue necrosis ▪ Characteristics of Aspergillus as successful opportunistic pathogen ▫ Ability to grow at 37ºC/98.6°F ▫ Small conidial (2.5–3 micrometers) → buoyant in air for prolonged periods of time → inhaled deeply into lung alveoli 153 Chapter 84 Opportunistic Fungal Infections ▪ Aspergillus hyphae angioinvasive ▫ Thrombose arteries → hemorrhagic infarcts → abscesses ▪ Suspect in immunocompromised individuals with respiratory distress, fever (despite broad-spectrum antibiotics) ▪ Second most common cause of invasive fungal infections in neutropenic individuals (after Candida species) ▪ Specifically affects pulmonary, sinus, central nervous system (CNS) Diseases ▪ Necrotizing otitis externa ▫ More common in advanced HIV cases ▪ Acute pulmonary aspergillosis ▫ Inhaled conidia ▫ Most common cause of death in persons with chronic granulomatous disease (CGD) ▫ Can spread locally to involve pleura, chest wall, vertebrae → dissemination to other organs Figure 84.1 Bronchial washing stained with Grocott methenamine silver stain from and individual with pulmonary aspergillosis. The hyphae are uniform, narrow and branch at acute angles. ▪ Cerebral aspergillosis ▫ Occurs in approx. 40% of individuals with invasive aspergillosis ▫ Hematogenous dissemination from extracranial focus (e.g. lung)/direct extension from sinus ▫ Most common brain abscess in stem cell transplant individuals ▪ Pulmonary aspergilloma ▫ Nonsaphrophytic (noninvasive) ▫ Colonization of pre-existing cavities (e.g. tuberculosis, sarcoidosis, bullous emphysema, bronchiectasis) ▫ Occurs in 15–25% of persons with cavitating lung disease from tuberculosis ▫ Lesion impinges on major vessel/airway → massive hemorrhage → hemoptysis ▫ “Fungus ball” ▪ Allergic bronchopulmonary aspergillosis ▫ Exposure to allergens of A. fumigatus → saprophytical growth → colonization of bronchial lumen → persistent bronchial inflammation → IgE-mediated allergic response in airways → hypersensitivity lung disease → bronchial obstruction ▫ Affects those with asthma (1–2%)/cystic fibrosis (1–15%) RISK FACTORS ▪ Decreased immunity ▫ Malignancy, chemotherapy, transplant (esp. from HLA-mismatched donor), HIV/AIDS, immunosuppressant therapy, neutropenia, prolonged high dose corticosteroid use ▪ Prior pulmonary damage/disease ▪ ↑ age ▪ History of tuberculosis, histoplasmosis, sarcoidosis, bronchiectasis ▪ Cystic fibrosis, asthma (allergic bronchopulmonary aspergillosis) COMPLICATIONS ▪ Hemorrhage → massive hemoptysis ▪ Widespread bronchiectasis + fibrosis → respiratory failure, death SIGNS & SYMPTOMS ▪ Acute pulmonary aspergillosis ▫ Unremitting fever in high-risk cases (most common), dry cough, chest pain, dyspnea (more common in persons with diffuse disease), ↑ erythrocyte sedimentation rate (ESR) 154 ▪ Invasive sinusitis ▫ Ear/facial pain, discharge, swelling; nasal septum/turbinate pallor; epistaxis; orbital swelling, headache; localized areas of frank crusting, ulceration, blackened necrotic areas ▪ Cerebral infection ▫ Headache, nausea, vomiting; altered mental status, confusion, cranial nerve palsies, hemiparesis ▪ Pulmonary aspergilloma ▫ May be asymptomatic; persistent, productive chronic cough, hemoptysis, weight loss ▪ Allergic bronchopulmonary aspergillosis ▫ Manifestations due to immune system response to A. fumigatus antigens; asthma-like symptoms (e.g. wheezing), eosinophilia ▪ Invasive aspergillosis ▫ Acute onset of fever, cough, respiratory distress, diffuse bilateral pulmonary infiltrates DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Increased sensitivity for radiological diagnosis ▪ Halo sign ▫ Neutropenic individuals (hemorrhagic nodule due to angioinvasion); rim of ground glass opacity surrounding nodule ▪ Air crescent sign ▫ Can develop from halo sign; cavitation → sloughed lung tissue encircled with rim of air MRI ▪ Target sign ▫ Nodule with lower central signal, higher contrast-enhancing signal on periphery; late stage disease ▪ For diagnosis of cerebral aspergillosis; multiple lesions in basal ganglia X-ray ▪ Unilateral infiltrates (interstitial, alveolar, mixed), cavitary lesions, multiple nondefined 1–3cm.0.39–1.18in peripheral nodules coalesce into larger masses LAB RESULTS Tissue biopsy ▪ Not utilized frequently due to invasive nature; ↑ risk of bleeding or secondary infection in immunosuppressed individuals Cultures ▪ Respiratory tract, sputum cultures commonly negative; rarely diagnosed by blood Bronchoalveolar lavage ▪ Approx. 40% diagnostic yield Serology ▪ Useful for diagnosis of aspergilloma, allergic bronchopulmonary aspergillosis in immunocompetent individual; not useful in immunocompromised Galactomannan antigen testing ▪ Enzyme immunosorbent assay recognizes side chains of galactomannan molecule ▫ Positive: invasive disease ▫ High false-positive rate in neutropenic cases Allergic bronchopulmonary aspergillosis ▪ Eosinophilia, ↑ serum IgE Figure 84.2 A tissue section containing Aspergillus hyphae and fruiting heads. 155 Chapter 84 Opportunistic Fungal Infections TREATMENT MEDICATIONS ▪ Invasive aspergillosis ▫ Voriconazole (preferred over amphotericin B)/caspofungin; azoleresistance developing ▪ Local pulmonary aspergilloma ▫ Percutaneous intracavitary instillation of antifungals ▪ Allergic bronchopulmonary aspergillosis ▫ Corticosteroids (attenuate immune system response) ▫ Antifungal therapy: itraconazole (decrease fungal burden, antigen load) ▫ Preventative long term antifungal therapy in immunocompromised individuals SURGERY ▪ Local pulmonary aspergilloma ▫ Surgical removal (e.g. lobectomy in massive hemoptysis) CANDIDA osms.it/candida PATHOLOGY & CAUSES ▪ Oval, budding yeast; forms hyphae, pseudohyphae ▪ Nonpathological colonization of humans → overgrowth leads to pathology ▪ Most common cause of invasive fungal infections in immunocompromised individuals (e.g. neutropenic cases) ▫ C. albicans species most common cause of candidiasis ▫ Increasing proportion of fungal infections caused by nonalbicans Candida species (e.g. C. tropicalis, C. parapsilosis, C. kruseim, C. glabrata) Chronic mucocutaneous candidiasis ▪ Persistent infection of mucous membranes, skin, nails ▪ More commonly affects those with defective T-cell mediated immunity Vulvovaginal candidiasis (VVC) ▪ Originates from spread from GI tract, sexual transmission ▪ Occurs in 75% of healthy individuals who are biologically female ▫ 80–90% caused by C. albicans ▫ 10–20% of those with VVC have severe, recurrent infections; usually from nonalbicans species Candida esophagitis ▪ Most common in severely immunocompromised individuals (e.g. HIV individuals) ▪ May occur in absence of thrush ▪ In individuals with AIDS, can occur simultaneously with cytomegalovirus, herpes simplex infection (HSV) Disseminated/invasive candidiasis ▪ Rare in immunocompetent individuals ▪ Development of invasive disease due to interaction between Candida species virulence factors, colonization burden, host immunological status ▪ Candidemia ▫ Isolation of Candida from blood culture ▪ Candida species exhibit tissue tropism → deep organ involvement (e.g. liver, spleen, brain, bone) in absence of prolonged candidemia 156 RISK FACTORS ▪ Antibiotic therapy, diabetes mellitus (poorly controlled), immunocompromised state (e.g. immunosuppressive therapy, neutropenia, hematologic malignancy, chemotherapy, transplant), chronic granulomatous disease, Job syndrome, impaired cell-mediated immunity, pregnancy, contraceptive use (hormonal/intravaginal, intrauterine devices) COMPLICATIONS ▪ ▪ ▪ ▪ hypertension, flank mass, pyelonephritis, acute urinary obstruction from fungal mycetoma → hydronephrosis CNS: altered mental status, characteristic symptoms of meningitis Optic: chorioretinal infections, lens abscess Hepatosplenic: right upper quadrant pain; nausea, vomiting; hepatosplenomegaly Other: endocarditis (may be from central vascular catheters), bone/joint infections ▪ Meningoencephalitis ▫ Obstructive hydrocephalus, calcifications, thrombosis ▪ Renal system ▫ Pyelonephritis ▪ Abscesses in multiple organs ▪ Sepsis, septic shock SIGNS & SYMPTOMS Mucocutaneous growth (most common) ▪ Mouth, oropharynx ▫ AKA thrush ▫ Thick, pearly white, curd-like plaques on oral mucosa ▫ Painful → dysphagia/odynophagia ▫ Otherwise unexplained → suspect HIV infection ▪ Vagina ▫ Thick, cottage-cheese-like, white vaginal discharge ▫ Painless, pruritic ▫ Dysuria possible ▪ Cutaneous candidiasis ▫ Erythematous pruritic patches + satellite lesions ▫ Individuals who are obese, diabetic ▫ Skin folds, underneath breasts ▪ GI tract ▫ May be asymptomatic ▫ Esophagus → odynophagia Disseminated/invasive candidiasis ▪ Candidemia: nonspecific (hard to distinguish from bacteremia); most commonly manifests as persistent fever despite antibiotic therapy ▪ Renal system: candiduria, rising creatinine, Figure 84.3 Oral candidiasis on the tongue of a child who had recently taken oral antibiotics. DIAGNOSIS LAB RESULTS ▪ Microscopic examination ▫ KOH preparation; visualization of hyphae, pseudohyphae, blastospores ▪ Invasive candidiasis ▫ Blood/tissue culture ▪ PCR ▪ Esophagitis ▫ Tissue biopsy (definitive) 157 Chapter 84 Opportunistic Fungal Infections OTHER DIAGNOSTICS ▪ Clinical presentation, history TREATMENT MEDICATIONS ▪ Oropharyngeal candidiasis ▫ Oral nystatin suspension; clotrimazole troches (dissolves in mouth) ▪ Candida dermatitis ▫ Topical nystatin/miconazole ▪ Vulvovaginal candidiasis ▫ Local miconazole/clotrimazole creams; oral fluconazole ▪ Invasive, systemic candidiasis ▫ Echinocandins; voriconazole, caspofungin (preferred over amphotericin/fluconazole) ▪ Individuals with HIV ▫ Prophylactic antifungals (e.g. oral nystatin, fluconazole) OTHER INTERVENTIONS ▪ Candida dermatitis ▫ Keep skin dry ▪ Invasive, systemic candidiasis ▫ Immediate removal of all central lines, catheters (Candida can develop rapid biofilms) CRYPTOCOCCUS NEOFORMANS osms.it/cryptococcus-neoformans PATHOLOGY & CAUSES ▪ Heavily encapsulated, nondimorphic, yeastlike fungus, urease positive ▪ Virulence factors ▫ Grows well in 37ºC/98.6°F environment ▫ Produces polysaccharide capsule, melanin (neurotropism) ▪ Most common cause of fungal meningitis in immunocompromised adults ▪ Found in bird droppings, soil → inhalation of airborne fungi → evident/nonevident pulmonary infection → spreads lymphohematogenously (can affect any organ) → meninges ▪ CNS infection associated with high mortality COMPLICATIONS ▪ Increased intracranial pressure → herniation → death ▪ May be due to buildup of cryptococcal polysaccharide at arachnoid villi → disruption in cerebrospinal fluid (CSF) reabsorption RISK FACTORS ▪ Impaired cell-mediated immunity, highdose corticosteroid treatment, hematologic malignancies (e.g. leukemia, lymphoma) ▪ HIV/AIDS (most common immunocompromising state): < 100 cells/ mm3 CD4+ count Figure 84.4 A histology photomicrograph of the lung. 158 SIGNS & SYMPTOMS ▪ Pulmonary manifestations ▫ Asymptomatic in 1/3 of immunocompetent individuals; fever, cough, pleuritic chest pain, dyspnea, weight loss, hemoptysis ▪ Neurologic manifestations (most common) ▫ Acute/insidious; headache, fever, vomiting, nuchal rigidity, mental status changes/seizures, cryptococcal abscesses (e.g. cryptococcomas, not common) ▪ Skin manifestations (10–15%) ▫ Result of direct hematogenous spread/ extension from bone lesion; single/ multiple pustules/papules → ulcer/ abscess ▪ Bone infection (5–10%) ▫ Pain, swelling; joint involvement; often found incidentally DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Focal/diffuse interstitial infiltrates, hilar lymphadenopathy LAB RESULTS ▪ CSF ▫ Lymphocytic pleocytosis; ↓ glucose; ↑ protein, opening pressure; results may be unchanged in individuals with AIDS ▪ Direct microscopic analysis of CSF/other body secretions ▫ India ink: capsule visualized with clear halo ▫ Mucicarmine: visualization of red inner capsule ▫ Visualize budding ▪ Culture ▫ Sabouraud glucose agar, incubation up to two weeks ▪ Cryptococcal capsular antigen (serum, CSF, urine, bronchoalveolar lavage) ▫ Most reliable nonculture-based method ▪ Latex agglutination test ▫ Detects polysaccharide capsular antigen, ↑ specificity Figure 84.5 Bronchial washings from an immunocompromised individual with pulmonary cryptococcosis. The cryptococcus spores have a characteristically thick capsule. TREATMENT MEDICATIONS ▪ Amphotericin B, flucytosine ▪ Prevention in HIV cases with CD4+ cell counts < 100 cells/mm3—fluconazole OTHER INTERVENTIONS ▪ ↑ intracranial pressure complication treatment ▫ Repeat CSF drainage (most important factor in reducing mortality) 159 Chapter 84 Opportunistic Fungal Infections MUCORMYCOSIS osms.it/mucormycosis PATHOLOGY & CAUSES ▪ Several genera of family Mucoraceae causing rapidly progressive, invasive mucormycosis in various body systems ▪ Subphylum Mucoromycotina, order Mucorales ▫ Most human infections from members of family Mucoraceae ▫ Six genera: Rhizopus, Mucor, Actinomucor, Rhizomucor, Apophysomyces ▪ Present in decomposing organic matter (e.g. spoiled food items, soil) ▪ Forms broad, aseptate hyphae branching at right angles by sexual reproduction with formation of zygospores ▪ Inhalation of spores → sinuses, lungs primary location of infection ▪ Immunocompetent host → lung macrophages ingest, kill spores → neutrophils kill hyphae ▪ Immunosuppressed individuals → macrophages fail to stop spore germination ▪ Severe neutropenia/diabetic ketoacidotic individuals → abnormal neutrophil function → increased risk of invasive infection ▪ Angioinvasive mold → results in thrombosis, infarction, necrosis of surrounding tissues Diseases ▪ Rhinocerebral mucormycosis ▫ Necrotic lesion in paranasal sinus → orbit, face, palate, brain ▫ Most common in diabetic ketoacidosis ▫ Progresses rapidly ▪ Pulmonary mucormycosis ▫ Most common in severe neutropenic individuals ▪ Gastrointestinal mucormycosis ▫ Rare, occurs in severely malnourished children ▫ Can affect all segments of GI tract (esp. stomach, small/large intestine, esophagus) ▪ Cutaneous mucormycosis ▫ Due to traumatic implantation of spores from soil (e.g. site of surgical incisions, burn wounds) ▫ Extensive necrotic infection → necrotizing cellulitis ▫ Most common in immunocompetent individuals ▪ Disseminated mucormycosis (involves CNS) ▫ Most common in severe neutropenic individuals following pulmonary infection ▫ Brain (most commonly affected), metastatic necrotic lesions can occur in any organ RISK FACTORS ▪ DM ▪ Diabetic ketoacidosis state ▫ ↑ risk for rhinocerebral mucormycosis ▪ Leukemia, neutropenia, chemotherapy ▫ ↑ risk of rhinocerebral, pulmonary, disseminated disease ▪ Severe malnutrition ▫ GI mucormycosis ▪ Deferoxamine treatment for iron overload state ▪ Recipient of bone marrow transplant ▪ Prolonged use of corticosteroids/other immunosuppressive therapies ▪ Prolonged use of broad-spectrum antibiotics ▪ IV drug use COMPLICATIONS ▪ Cavernous sinus thrombosis, cranial nerve palsies (e.g. proptosis, ptosis, dilation, fixation of pupil), vision loss, 160 brain abscess, necrosis of frontal lobes, GI tract perforation, perirenal abscess, renal infarction SIGNS & SYMPTOMS ▪ Typical course: rapid onset of necrotic lesion → fulminant course requiring aggressive therapy ▪ Rhinocerebral ▫ Black, necrotic lesion on nasal/palatine mucosa; nasal/sinus congestion, pain; epistaxis; fever; edema, induration, necrosis of perinasal, periorbital tissue ▪ Pulmonary ▫ Nonspecific, pneumonia-like; may involve pleuritic chest pain, cough, fever, hemoptysis ▪ GI ▫ Abdominal pain, bleeding (e.g. hematemesis) ▪ Cutaneous ▫ Painful edema, erythema → raised, indurated lesions with black, necrotic center ▪ Disseminated ▫ Altered mental status (e.g. lethargy, obtunded state, confused) DIAGNOSIS DIAGNOSTIC IMAGING Figure 84.6 Bronchial washings stained with Papanicolaou stain from an individual with pulmonary mucormycosis. The mucor hyphae contain no septa, are of variable width and branch at a wide angle. TREATMENT MEDICATIONS ▪ Aggressive antifungal therapy ▫ Amphotericin B SURGERY ▪ Infected necrotic tissue ▫ Extensive surgical debridement OTHER INTERVENTIONS ▪ Adjunctive therapy ▫ Hyperbaric oxygen, immune modulation, white blood cell infusion CT scan, MRI ▪ Thoracic: nodular lesions, cavitations ▪ Head: extension of infection in sinuses → affecting brain tissue LAB RESULTS ▪ Histopathological identification ▫ Distinct hyphae; broad irregularly branched with rare septations 161 Chapter 84 Opportunistic Fungal Infections PNEUMOCYSTIS JIROVECII (PNEUMOCYSTIS PNEUMONIA) osms.it/pneumocystis-jirovecii PATHOLOGY & CAUSES ▪ Opportunistic yeast-like fungi (originally classified as protozoan) responsible for pneumocystis pneumonia ▪ Formerly known as Pneumocystis carinii ▪ Airborne transmission route; human-tohuman route occurs early in life ▪ Immunocompetent individuals may act as asymptomatic reservoirs ▪ 5–7 micrometer cysts contain up to eight pleomorphic intracystic sporozoites → become excysted → form trophozoites ▪ Reside in alveoli ▪ Disease: pneumocystis pneumonia ▫ Occurs exclusively in immunocompromised individuals ▫ Remains localized in lungs ▫ Clinical manifestations due to inflammatory reaction in alveoli lumen/ septum ▫ Fatal if left untreated RISK FACTORS ▪ Defects in cell-mediated immunity, HIV/ AIDS, severe combined immunodeficiency syndrome, hematological malignancies, transplant recipients, hyper IgM syndrome SIGNS & SYMPTOMS ▪ Most infections asymptomatic in immunocompetent individuals ▪ Abrupt onset of tachypnea, fever, cough ▪ Respiratory distress DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Diffuse, bilateral ground glass opacities ▪ First appearing in perihilar area → progresses peripherally, apical regions spared LAB RESULTS ▪ Microscopic examination with silver stain ▫ Disc-shaped yeast ▪ Open lung biopsy ▪ Bronchoalveolar lavage ▪ PCR of sputum/lavage samples ▪ ↓ PaO2 (reflects severity of disease) ▪ Unchanged WBC count TREATMENT Figure 84.7 A foamy alveolar cast in a bronchial washing taken from an individual with Pneumocystis pneumonia. MEDICATIONS ▪ Trimethoprim-sulfamethoxazole ▪ Alternatives ▫ Pentamide, dapsone + trimethoprim, atovaquone 162 ▪ Prophylactic trimethoprimsulfamethoxazole/pentamide ▫ Individuals with HIV, < 200 CD4+ cells/ mm3 OTHER INTERVENTIONS ▪ Respiratory support Figure 84.8 A bronchial wash stained with Grocott’s methenamine silver highlighting Pneumocystis spores. SPOROTHRIX SCHENCKII osms.it/sporothrix-schenckii PATHOLOGY & CAUSES ▪ Chronic subcutaneous thermally dimorphic fungus → sporotrichosis ▪ Found in soil, decomposing vegetation, plant materials (e.g. moss, hay, wood, rose bushes) ▪ Found worldwide, mostly in temperate/ tropical regions (16–22ºC/60.8–71.6°F) ▪ Outside human body grows as filamentous mold; in tissue grows as small budding yeast cells Diseases ▪ Lymphocutaneous sporotrichosis ▫ Follows traumatic inoculation of skin/ subcutaneous tissue (e.g. minor insult from thorns or splinters) → incubation 1–4 weeks → papule develops at site of inoculation → ulceration of primary lesion → nonpurulent, odorless drainage → similar lesions occur along lymphatic channel proximal to primary lesion ▪ Pulmonary sporotrichosis ▫ Following inhalation of Sporothrix conidia ▫ May progress to disseminated disease ▪ Osteoarticular sporotrichosis ▫ Most commonly affected joints: knee, elbow, wrist, ankle ▫ Chronic infection with progressive decreased range of motion, pain, swelling ▪ Meningeal sporotrichosis ▫ Rare, mostly in individuals with cellular immune defects (e.g. lymphoma, AIDS) ▫ Chronic course ▪ Disseminated cutaneous sporotrichosis ▫ Rare (< 1%) ▫ Numerous small papules/vesicles → necrotic, ulcerated nodules on trunk, limbs ▫ Follows lymphatic spread RISK FACTORS ▪ Lymphocutaneous ▫ Exposure due to skin trauma (e.g. living in homes with dirt floors) ▫ Individual with outdoor preoccupation ▫ Contact with cats ▪ Pulmonary ▫ Chronic obstructive pulmonary disease (COPD) ▪ Excessive alcohol use 163 Chapter 84 Opportunistic Fungal Infections SIGNS & SYMPTOMS ▪ Lymphocutaneous sporotrichosis ▫ Primary papule → ulcerated lesion; similar lesions visualized along lymphatic channel proximally; chronic, fixed cutaneous lesion ▪ Pulmonary ▫ Fever, night sweats, weight loss, fatigue; dyspnea, cough; purulent sputum; hemoptysis ▪ Osteoarticular sporotrichosis; progressive decreased range of motion, pain, swelling in joints ▪ Meningeal sporotrichosis ▫ Chronic (weeks to months) fever, headache DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Unilateral/bilateral upper lobe cavities ▪ Variable amount of fibrosis ▪ Scattered nodular lesions LAB RESULTS ▪ Culture (most sensitive) ▫ Tissue biopsy, sputum, body fluid ▫ Sabouraud’s agar at room temperature ▫ Characteristic arrangement of conidia on hyphae ▪ Direct microscopy ▫ Typical oval/cigar-shaped cells ▫ Asteroid bodies of S. Schenckii ▪ CSF analysis ▫ Lymphocytic pleocytosis, ↑ protein, ↓ glucose OTHER DIAGNOSTICS ▪ Clinical examination, history Figure 84.10 Sporothrix fungi forming conidia. Figure 84.9 Partially healed skin lesions of sporotrichosis in a typical lymphcutaneous distribution. TREATMENT MEDICATIONS ▪ Localized: itraconazole ▪ Severe: amphotericin B 164 NOTES NOTES ORTHOMYXOVIRUSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Associated clinical syndromes: influenza (“the flu”), pneumonia ▪ RNA virus family; causes acute respiratory disease Genetic material ▪ Negative-sense, single-stranded RNA Taxonomy ▪ Genera ▫ Influenza A, Influenza B, Influenza C: infect humans ▫ Influenza D, Isavirus, Thogotovirus, Quaranjavirus ▪ Classified by surface protein ▫ Influenza A, B: hemagglutinin (H) (glycoprotein, allows progeny release); neuraminidase (N) (lectin; binds to host cell through sialic acid residues) ▫ Influenza C: hemagglutinin esterase fusion (F) (binds to host cell) Morphology ▪ Enveloped (outer lipid membrane) ▪ Spherical/filamentous ▪ Size: 50–120nm SIGNS & SYMPTOMS ▪ Fever, malaise, myalgia, sore throat, nonproductive cough DIAGNOSIS ▪ Clinical examination DIAGNOSTIC IMAGING X-ray ▪ Chest CT scan LAB RESULTS ▪ Molecular assays ▪ Viral culture TREATMENT MEDICATIONS ▪ Antiviral therapy 165 Chapter 85 Orthomyxoviruses INFLUENZA VIRUS osms.it/influenza PATHOLOGY & CAUSES ▪ Single-stranded RNA virus; causes acute respiratory disease ▪ AKA “the flu” ▪ Incubation: 1–4 days Pathogenesis ▪ Influenza virus penetrates upper respiratory tract → hemagglutinin binds to epithelial cell sialic acid residue → endocytosis → viral replication → neuraminidase releases progeny → viral infection spreads ▪ Viral shedding (progeny release) ▫ Duration: average 4–8 days ▫ Magnitude: ↑ symptoms = ↑ shedding ▪ Influenza A antigen variations → immune evasion, reinfection ▫ Antigenic shift: major changes in H/N proteins (two different influenza virus genome segments reassort) → epidemic/pandemic ▫ Antigenic drift: minor changes in H/N proteins (mutation in H/N gene) → outbreak Taxonomy ▪ Nomenclature: [type] / [original host] / [location of first identification] / [strain number] / [year of origin] ([subtype]) ▫ Host type, subtype included in influenza A viruses only ▫ E.g. H1N1 type A flu virus of duck origin, found in Alberta, Canada, 35th strain, found in 1976 → A/duck/ Alberta/35/76(H1N1) Pandemics, associated strains ▪ 1918 “Spanish flu” → H1N1 ▪ 1957 “Asian flu” → H2N2 ▪ 1968 “Hong Kong flu” → H3N2 ▪ 2009 (worldwide) → H1N1 RISK FACTORS ▪ Immunosuppression, age ≥ 65 years, age < six months, nursing/chronic care facility resident, pregnancy, chronic disease, morbid obesity COMPLICATIONS ▪ Secondary bacterial infection (e.g. pneumonia, sinusitis, otitis media, bronchiolitis), acute respiratory distress syndrome, myositis, rhabdomyolysis, myocarditis, pericarditis, encephalitis ▪ Secondary bacterial infections generally due to Streptococcus pneumoniae SIGNS & SYMPTOMS Uncomplicated influenza ▪ Systemic: fever, malaise, myalgia, headaches, weakness, dizziness ▪ Respiratory: non-productive cough, sore throat, nasal secretion ▪ Mild cervical adenopathy Complicated influenza ▪ Primary influenza pneumonia: fever, dyspnea, cyanosis ▪ Secondary bacterial pneumonia: fever, cough, purulent sputum Transmission ▪ Direct contact, airborne droplets, fomites Outbreak ▪ Abrupt ▪ Winter; year-round in tropical regions ▪ Duration: 2–3 months 166 DIAGNOSIS ▪ Clinical examination, during outbreak DIAGNOSTIC IMAGING X-ray ▪ chest CT scan ▪ Primary influenza pneumonia: bilateral reticular/reticulonodular opacities, sometimes consolidation ▪ Secondary bacterial influenza: pulmonary infiltrates LAB RESULTS ▪ Respiratory tract specimen molecular assay: reverse-transcriptase polymerase chain reaction (RT-PCR) ▪ Rapid antigen test: immunoassay ▪ Respiratory tract specimen viral culture TREATMENT MEDICATION ▪ Severe illness/risk factors → antiviral therapy ▫ Neuraminidase inhibitors; H1N1 commonly resistant ▫ M2 proton channel inhibitors; active against influenza A only ▪ Symptomatic treatment: acetaminophen, non-steroidal anti-inflammatory drugs (NSAID) ▪ Secondary bacterial infection: antibiotics OTHER INTERVENTIONS ▪ Hydration Prevention ▪ Vaccine ▫ Inactivated (intramuscular/intradermal)/ live attenuated (intranasal); trivalent/ quadrivalent (2 influenza A antigens + 1/2 influenza B antigens); annual, single-dose application (before winter); age ≥ six years ▪ Antiviral prophylaxis (high-risk individual) ▫ Neuraminidase inhibitors ▪ Infection control ▫ E.g. hand hygiene, face mask 167 NOTES NOTES PAPILLOMAVIRUS HUMAN PAPILLOMAVIRUS osms.it/human-papillomavirus PATHOLOGY & CAUSES ▪ Human papillomavirus (HPV): virus that causes cutaneous and mucosal infections, resulting in warts (verrucae) ▪ > 200 known types; > 40 transmitted through sexual contact ▪ Humans: only host Genetic material ▪ Small, double-stranded, circular DNA virus Taxonomy ▪ Papillomaviridae family Morphology ▪ Non-enveloped, capsid virus CAUSES ▪ Transmission ▫ Skin-to-skin contact via breaks in epithelium (autoinoculation causes local spread) ▫ Vaginal, anal, oral sexual intercourse ▫ Vertical transmission (congenital infection) ▪ Cutaneous HPV ▫ Infection of the basal stem cells of keratinized skin → viral genome replicates within proliferating cells → infected cell eventually reaches the upper epithelial layers → hyperkeratotic growth ▪ Mucosal HPV ▫ → infection of epithelium → integration into the host genome → flat, papular, or pedunculated growths → high-grade lesions and cancer may develop RISK FACTORS ▪ Epithelial trauma ▪ Walking barefoot ▪ Occupational ▫ Meat, poultry, and fish handlers ▪ Use of communal showers ▪ Smoking ▪ Early age of first sexual intercourse ▪ Multiple sexual partners ▪ Uncircumcised males ▪ Immunocompromised state; esp. HIV/AIDS COMPLICATIONS ▪ Some types have oncogenic potential SIGNS & SYMPTOMS ▪ Common warts: verruca vulgaris (HPV types 2, 4) ▫ Cauliflower-like raised surface located on hands, feet, elbows, knees, subungual/periungual (under, around fingernail/on cuticle; may be painful) ▫ Common in children, adolescents ▪ Plantar: verruca plantaris (HPV type 1) ▫ Located on soles of feet ▫ May induce pain when walking ▪ Flat: verruca plana (HPV types 3, 20, 28) ▫ Flat warts found on arms, face, forehead ▫ Common in children, adolescents ▪ Anogenital: condyloma acuminatum (HPV types 6, 11 low risk; 15 types have oncogenic potential; types 16 and 18 cause 90% of all genital warts) 168 ▫ Cervical cancer: types 16 and 18 70% of all cases ▫ Anal cancer: type 16 is the usual cause ▫ Other cancers; e.g. oropharyngeal, vaginal, vulvar, penile cancers usually caused by type 16 ▪ Laryngeal papillomatosis (HPV types 6, 11) ▫ Larynx, respiratory tract TREATMENT MEDICATIONS ▪ Cutaneous warts ▫ Topical salicylic acid, fluorouracil 5% ▪ Anogenital warts ▫ External warts: podofilox solution or gel, sinecatechins ointment, imiquimod cream SURGERY ▪ Anogenital warts ▫ Surgical removal OTHER INTERVENTIONS ▪ Cutaneous warts ▫ May resolve spontaneously ▫ Cryotherapy (liquid nitrogen) ▪ Anogenital warts ▫ External or internal (vaginal, cervical, intra-anal): cryotherapy, trichloroacetic acid, bichloroacetic acid Figure 86.1 A giant anal condyloma in an immunocompromised male. DIAGNOSIS LAB RESULTS ▪ Genetic testing: in situ hybridization/ polymerase chain reaction (PCR) ▫ Real-time PCR (detect HPV viral load) ▪ Immunohistochemistry: biomarker detection ▫ E6, E7 mRNA ▫ p16 cell-cycle protein ▪ Cervical lesions: cytology ▫ If positive for abnormal cells: colposcopy and biopsy Prevention ▪ HPV vaccines ▫ Gardasil (quadrivalent), Cervarix (bivalent), 9-valent ▫ Both vaccines protect against HPV 16, 18; Gardasil also protects against HPV 6, 11 ▫ Administered before primary infection occurs (9–13 years old) ▪ Cervical cancer screening ▫ Pap smear ▪ Effective barrier contraception ▫ Condoms (reduces risk; less protection compared to other STIs) ▪ Decrease number of sexual partners 169 Chapter 86 Papillomavirus Figure 86.2 The histological appearance of a condyloma. There is hyperkeratosis and parakeratosis. Numerous keratinocytes demonstrate perinuclear clearing known as koilocytosis. 170 NOTES NOTES PARAMYXOVIRUSES MICROBE OVERVIEW ▪ Paramyxoviruses: negative-sense singlestranded RNA virus family ▪ Natural hosts: humans, vertebrates, birds ▪ Replication: occurs in cytoplasm; exits by budding ▪ Transmission: air borne particles ▪ Viral structure: enveloped, linear genomes, spherical/pleomorphic ▪ Pathogenic paramyxoviruses: human parainfluenza virus (HPIV), measles, mumps, respiratory syncytial virus (RSV) HUMAN PARAINFLUENZA VIRUSES (HPIV) osms.it/human-parainfluenza-viruses PATHOLOGY & CAUSES ▪ Croup (laryngotracheobronchitis): infection usually caused by HPIV ▪ Four distinct HPIV serotypes ▫ HPIV-1: croup ▫ HPIV-2: croup; upper, lower respiratory tract illnesses ▫ HPIV-3: bronchiolitis, pneumonia ▫ HPIV-4: infrequently detected ▪ Common respiratory distress cause (children) ▪ Viral infection → infiltration of histiocytes, lymphocytes, other white blood cells → airway inflammation, edema → upperairway obstruction → ↑ breathing work, barky cough, inspiratory stridor (turbulent, noisy airflow), vocal hoarseness RISK FACTORS ▪ Age ▫ Six months to three years ▪ Biologically-male to biologically-female ratio of 1.4:1 ▪ Previous intubation ▪ Hyperactive airways ▪ Congenital airway narrowing ▪ Late autumn (peak case onset) COMPLICATIONS ▪ Respiratory failure ▪ Bacterial superinfection ▫ Pneumonia, bacterial tracheitis SIGNS & SYMPTOMS ▪ Prodrome ▫ Upper respiratory tract infection symptoms (coryza, cough, mild fever) ▪ Acute onset: “barking” cough ▪ Inspiratory stridor; biphasic stridor (severe obstruction sign) ▪ Hoarseness 171 Chapter 87 Paramyxoviruses ▪ Respiratory distress, ↑ breathing work (e.g. suprasternal, intercostal, subcostal retractions) ▪ Agitation ▪ Symptoms worse at night ▪ Asynchronous chest movement ▪ Severe: fatigue, hypoxia, hypercarbia DIAGNOSIS TREATMENT MEDICATIONS ▪ Corticosteroids; dexamethasone for antiinflammatory effects ▪ Nebulized epinephrine in moderate, severe croup; temporary airway obstruction relief OTHER INTERVENTIONS ▪ Provide comfort, avoid child’s further distress OTHER DIAGNOSTICS Westley score ▪ Severity classification ▪ Calculated on five factors ▫ Level of consciousness, cyanosis, stridor, air entry, retractions ▫ Score between 0–17 classifies case as mild, moderate, severe croup; impending respiratory failure MEASLES VIRUS osms.it/measles PATHOLOGY & CAUSES ▪ A paramyxovirus that causes measles, a highly infectious illness ▫ Fever, cough, coryza, conjunctivitis, followed by exanthem ▪ Transmitted via person-to person contact, droplets → infects upper respiratory tract epithelial cells Clinical stages (four) ▪ Incubation ▫ 6–21 days ▫ Virus infects respiratory mucosa/ conjunctiva → local replication → lymphatic tissue spread → disseminates via blood circulation → first virema (infection of endothelial, epithelial, monocyte, macrophage cells) ▫ Usually asymptomatic ▪ Prodrome ▫ 2–4 days ▫ Onset of fever, malaise, anorexia, conjunctivitis, coryza, cough ▪ Exanthem ▫ Onset 2–4 days after fever ▫ Erythematous, maculopapular, blanching rash ▫ Begins on face → trunk → extremities ▪ Recovery ▫ Cough persists 1–2 weeks ▫ Immunity thought to be lifelong RISK FACTORS ▪ ▪ ▪ ▪ ▪ Measles virus exposure Travel to measles-endemic areas No prior measles immunization Failed measles vaccine response Immunocompromised individuals: AIDS, lymphoma/other malignancy, T cellsuppressive medication 172 COMPLICATIONS ▪ Secondary infection ▪ Diarrhea (most common) ▪ Pneumonia (most common children’s death cause) ▪ Otitis media (younger individuals) ▪ Encephalitis, acute disseminated encephalomyelitis, subacute sclerosing panencephalitis ▪ Subacute sclerosing panencephalitis SIGNS & SYMPTOMS ▪ Prodrome ▫ Fever onset, malaise, anorexia, conjunctivitis, coryza, cough ▪ Koplik’s spots on buccal mucosa (1–2 days before rash onset) ▫ Red spots on erythematous buccal mucosa ▫ Measles pathognomonic ▪ Maculopapular, blanching, erythematous rash (approx. 14 days after initial infection) ▫ Head → trunk → extremities ▪ Persistent cough after resolution ▪ Modified measles ▫ Measles infection in individual with existing measles immunity ▫ Milder symptoms ▪ Atypical measles ▫ Measles virus infection in individuals immunized with killed virus vaccine ▫ Higher, prolonged fever ▫ Dry cough, pleuritic chest pain may present DIAGNOSIS ▪ Individual presenting with febrile rash, cough, coryza, conjunctivitis LAB RESULTS ▪ Measles detection; one of following ▫ Enzyme-linked immunosorbent assay (ELISA): positive measles-specific IgM serology (most common) ▫ Measles IgG antibody: ↑ (between acute, convalescent titers) ▫ Reverse transcription polymerase chain reaction (PCR): measles virus RNA detection ▫ In culture: Measles virus isolation TREATMENT MEDICATIONS ▪ Antipyretics, bacterial superinfection treatment OTHER INTERVENTIONS Figure 87.1 Koplik spots on the oral mucosa of an individual infected with the measles virus. ▪ Respiratory support, fluids ▪ Vitamin A supplementation ▫ Vitamin A deficiency plays role in delayed recovery, complications ▪ Prevention ▫ No specific antiviral therapy ▫ MMR (measles, mumps, rubella) vaccine ▫ Infection control (airborne transmission precautions for four days after rash onset) 173 Chapter 87 Paramyxoviruses Figure 87.2 The histological appearance of the lungs of an individual with measles pneumonia. There are numerous giant cells, the nuclei of which display inclusions. MUMPS VIRUS osms.it/mumps PATHOLOGY & CAUSES ▪ Causes mumps; largely preventable by vaccination ▫ Fever, headache, malaise, myalgia, anorexia; followed by parotitis ▪ Transmission ▫ Highly contagious ▫ Transmission via respiratory droplets, direct contact, contaminated fomites ▫ Viral shedding begins before symptoms onset ▪ Incubation period: 14–18 days ▪ Outbreaks: schools, military posts, camps, healthcare settings, workplaces ▪ Replication: occurs in upper respiratory tract epithelium → spread via lymphatics → viremia ▪ Lifelong post-infection immunity RISK FACTORS COMPLICATIONS ▪ Orchitis/oophoritis, meningitis, encephalitis, pancreatitis, myocardial involvement, arthritis, deafness SIGNS & SYMPTOMS ▪ Prodrome ▫ Fever, malaise, headache, myalgias, anorexia ▪ Parotitis ▫ Swelling, inflammation, tenderness of parotid gland(s) ▫ May obscure mandible angle ▫ Unilateral/bilateral ▫ Usually 48 hours after prodrome onset ▫ Commonly children 2–9 years old ▫ Stensen duct orifice: may be erythematous, enlarged ▪ Mastitis ▪ Unvaccinated status, international travel, vaccine failure, immunosuppressed individuals, healthcare workers, closecontact 174 DIAGNOSIS ▪ Diagnosis suspected in individuals with parotitis/other salivary gland swelling, orchitis/oophoritis with prodrome, mumps virus exposure LAB RESULTS ▪ In parotitis setting, diagnosis established by detection of ▫ Mump virus RNA: reverse-transcription PCR (buccal/oral swab) ▫ Serum mumps IgM (may not be detectable until 5 days after symptom onset) ▪ Full blood count ▫ Leukocytosis may be seen ▪ Lumbar puncture indicated in suspected meningitis/encephalitis Figure 87.3 Mumps virus causes parotitis, which presents as swelling at the angle of the jaw, widening the facial outline. TREATMENT ▪ No specific antiviral therapy MEDICATIONS ▪ Analgesics, antipyretics, non-steroidal inflammatory agents (orchitis/oophoritis) OTHER INTERVENTIONS ▪ Prevention ▫ Measles, mumps, rubella (MMR) vaccine ▫ Infection control (isolation with droplet precaution until parotid swelling resolved) 175 Chapter 87 Paramyxoviruses RESPIRATORY SYNCYTIAL VIRUS (RSV) osms.it/respiratory-syncytial-virus PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Most common cause of bronchiolitis: viral infection of the lower respiratory tract, blockage of small airways (bronchioles) ▫ May also be caused by rhinovirus, influenza virus ▪ Terminal bronchiolar epithelial cell viral infection → lung epithelial cell damage/ destruction → small bronchi/bronchioles inflammation → edema, mucus production, inflammation → small airways/atelectasis obstruction ▪ Commonly: children < two years old ▪ Often preceded by upper respiratory tract infection symptoms; rhinorrhea, headache, mild fever ▪ Prodrome ▫ Upper respiratory tract infection (rhinitis, fever) ▪ Cough; tachypnea; expiratory wheeze; ↑ breathing work (nasal flaring, grunting, retractions); crackles heard on auscultation; cyanosis RISK FACTORS ▪ Infants < 12 weeks old, November–May, prematurity, bronchopulmonary dysplasia/ other chronic lung disease history, tobacco smoke exposure, daycare attendance, impaired airway clearance/function (e.g. cystic fibrosis), congenital heart disease, immunodeficiency COMPLICATIONS ▪ Bacterial pneumonia, apnea, respiratory failure, dehydration, aspiration pneumonia, asthma DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ If differential diagnosis includes pneumonia OTHER DIAGNOSTICS Pulse oximetry ▪ ↓ oxygen saturation TREATMENT MEDICATIONS ▪ Oral corticosteroids: prior wheeze history OTHER INTERVENTIONS ▪ Supplemental oxygen, hydration, mechanical ventilation ▫ Respiratory symptoms peak on days 3–5, begin to resolve 176 Chapter 88 Parvoviruses Parvovirus B1 is the smallest known DNA animal virus, coming in at an itty bitty 18 to 28 nanometers in diameter. In comparison, the average size of a single human red blood cell is a whopping 7200 nanometers! While it's mostly known for causing fifth disease, or “slapped cheek syndrome,” in children, parvovirus B19 can also affect adults and it can cause serious illness in individuals with pre-existing conditions like sickle-cell anemia and HIV. Parvovirus B19 is part of the parvoviridae family. It’s a single-stranded DNA virus surrounded by an icosahedral capsid, which is a spherical protein shell made up of 20 equilateral triangular faces. And it’s “naked” because the capsid isn’t covered by a lipid membrane. Parvovirus B19 is primarily transmitted by respiratory droplets when someone coughs or sneezes. You can also catch it via an infected blood transfusion and a pregnant female can also transmit it through the placenta to her unborn child. Now, although the virus first enters cells of the respiratory tract by binding to receptors on host cells, it doesn’t replicate in them. Instead it keeps travelling through cells and into the circulatory system until it reaches bone marrow, where red blood cells are made, a process called erythropoiesis. Once there, parvovirus B19 uses receptor-mediated endocytosis to enter erythroid progenitor cells, also called proerythroblasts, the early cells that eventually become red blood cells. It then uses these cells’ DNA replication machinery in the nucleus to replicate its DNA and assemble new copies of the virus. Why not simply replicate in cells of the respiratory system? Well it turns out that Parvovirus B19 needs two things: it prefers to bind to a specific receptor, the P antigen, which is found in large numbers on proerythroblasts’ cell membrane and it needs cells that pass through the S phase of the cell cycle, which is the phase where cell DNA is replicated. Since the body is constantly producing new red blood cells, there are always proerythroblasts going through the S phase at any given time. As the virus replicates and matures, it produces a protein called non-structural protein 1 or NS1, which is toxic to human cells and causes apoptosis, or cell death. This means that erythropoiesis breaks down, and fewer new red blood cells go into circulation as a result of parvovirus B19 infection. But thankfully this is only temporary. When the cell dies, it bursts open, releasing copies of the virus into the blood, also called viremia. 177 Our immune system detects the virus and starts producing specific immunoglobulin M and immunoglobulin G antibodies to fight the infection by forming immune complexes with the parvovirus B19 antigen. For individuals with a functioning immune system, this typically happens between 10 and 14 days after first becoming infected with the virus. Parvovirus B19 is most common in young children and those who live or work with them, like parents, siblings, and daycare workers. Fetuses are at risk of parvovirus B19 if their pregnant mother has never had the virus in the past. Immunocompromised individuals are also particularly at risk of chronic parvovirus B19 infection, since their immune system cannot mount an appropriate response to the virus. The incubation period for parvovirus B19 - basically the period before viremia starts - is between 4 and 14 days, after which symptoms develop. Flu-like symptoms - like a mild fever, headache, and aching muscles - are most common during viremia. Once the immune response begins and the viremia ends, these symptoms go away and some individuals will then develop a rash and/or joint pain. The rash appears as uniform redness of the cheeks, but not the area around the mouth, giving the classic fifth disease “slapped cheek” appearance. A lace-like rash might also appear on the trunk and the limbs. Joint pain and inflammation, or arthralgia and arthritis, linked to parvovirus B19 infection usually affects the small joints of the hands, wrists, feet, and knees, and are often symmetrical, meaning that the same joints on both sides of the body will be affected. Children tend to get the rash whereas adults are more likely to develop joint pain, but it’s not exclusive to either group. There are a few complications caused by parvovirus B19 infection. The decreased red blood cell production can cause transient aplastic crisis in individuals who have underlying conditions like sickle cell anemia, hereditary spherocytosis, and thalassemia. Because they already have fewer red blood cells, the breakdown of erythropoiesis results in severe anemia, with symptoms like pale skin, fatigue, and weakness. Parvovirus B19 in a pregnant female can cause anemia in her fetus. Because there are fewer red blood cells to carry oxygen, the heart will pump a larger volume of blood to give the growing fetus all the oxygen it needs. This raises the pressure inside blood vessels and fluid can start to leak out of capillaries as a result. This can result in hydrops fetalis, or the abnormal accumulation of fluid in soft tissues. 178 Chapter 88 Parvoviruses Fetal anemia is also linked to fetal loss, particularly if the parvovirus B19 infection is in the first half of the pregnancy. The good news is that there no fetal defects associated with parvovirus B19 for those fetuses that survive the infection. Lastly, immunocompromised individuals, such as organ transplant recipients and people with HIV, can develop a serious complication from parvovirus B19 called pure red blood cell aplasia. This is a form of chronic, severe anemia where there are very few immature red blood cells in circulation in blood vessels or erythroid progenitor cells in the bone marrow. Symptoms of pure red blood cell aplasia are similar to other forms of anemia, such as lethargy and malaise. Parvovirus B19 infection is usually diagnosed by clinical examination. Blood tests looking for antibodies to the virus - specifically immunoglobulin M and immunoglobulin G - are reserved for atypical presentations of the virus and for pregnant individuals. Another option is polymerase chain reaction, or PCR, which looks for viral DNA. It’s the preferred diagnostic method of parvovirus B19 infection in immunocompromised individuals, who typically do not have high IgM or IgG levels in response to an infection. PCR can also be used on amniotic fluid to diagnose infection in a fetus. When it comes to treatment for parvovirus B19 infection, it varies based on the symptoms. Fifth disease is usually mild and gets better on its own, while a transient aplastic crisis often requires transfusion of blood products. Arthralgia and arthritis are treated with NSAIDs and usually resolve on their own. Chronic infections in immunocompromised individuals are treated with immune globulin intravenous therapy or IVIG, which involves giving antibodies - mostly immunoglobulin G - taken from donor blood plasma. Severe anemia in a fetus between 18 and 35 weeks of gestation can be treated with an intrauterine blood transfusion. Before 18 weeks, the procedure is too difficult technically. After 35 weeks, risks of the transfusion are high compared to simply delivering the baby. Finally, there is no vaccine for parvovirus B19. Preventive measures include proper hand washing with antiseptic soap and water and sanitizing surfaces that would’ve come into contact with respiratory droplets, since the virus can survive on surfaces. 179 NOTES NOTES PICORNAVIRUSES MICROBE OVERVIEW ▪ Have small, cytoplasmic, single-stranded, linear, positive-polarity RNA Taxonomy ▪ Family Picornaviridae; 35 genera (e.g. Enterovirus, Apthovirus, Cardiovirus, Rhinovirus, Hepatovirus) Morphology ▪ Non-enveloped ▪ Icosahedral capsid ▪ Diameter ▫ 27–30nm(smallest of RNA viruses) ▪ Genome length ▫ About 2500nm Transmission ▪ Hosts: humans, birds, vertebrates 180 COXSACKIEVIRUS osms.it/coxsackievirus PATHOLOGY & CAUSES SIGNS & SYMPTOMS HFMD (hand, foot and mouth disease) ▪ Clinical syndrome characterized by oral enanthem; maculopapular/vesicular rash of hands, feet ▫ Common exanthem in children and adults ▫ Most commonly caused by coxsackie A virus HFMD ▪ Mouth, throat pain ▫ Young children may refuse to eat ▪ Mild fever ▪ Lethargy ▪ Oral enanthem: on tongue, buccal mucosa ▫ Erythematous macules → vesicles with halo of erythema ▪ Exanthem: macular, maculopapular, vesicular; nonpruritic, usually not painful ▫ Involves hands (including palms), feet (including soles), buttocks, legs, arms ▫ Palmer and plantar desquamation 1–3 weeks after presentation Herpangina ▪ Benign clinical syndrome characterized by fever, papulo-vesiculo-ulcerative oral enanthem ▫ Most commonly caused by coxsackie A virus ▪ Transmission person to person via oralfecal route or respiratory aerosols → incubation for 3–5 days → virus replicates in the submucosal lymphoid tissue of pharynx or lower intestine → spread to regional lymph nodes (minor viremia) → dissemination throughout the body → major viremia RISK FACTORS ▪ Age ▫ Most common in children <10 years ▪ Season ▫ Spring, summer, autumn ▪ Poor hygiene Herpangina ▪ Acute onset with high fever; may present with febrile seizure ▪ Anorexia, emesis, irritability common in young children ▪ Malaise, headache, sore throat, dysphagia, abdominal pain ▪ Papulovesicular lesions in throat ▪ Additional findings ▫ Neck stiffness, positive Kernig sign, cervical adenitis COMPLICATIONS ▪ ▪ ▪ ▪ ▪ ▪ Reduced oral intake → dehydration Rhombencephalitis Acute flaccid paralysis Aseptic meningitis Myocarditis Pancreatitis Figure 89.1 Characteristic mouth lesions of hand, foot and mouth disease. 181 Chapter 89 Picornaviruses DIAGNOSIS LAB RESULTS ▪ Throat, stool, vesicular fluid samples for cell culture/polymerase chain reaction (PCR) TREATMENT MEDICATIONS ▪ Analgesia, fluids ▪ No specific antiviral therapy OTHER INTERVENTIONS ▪ Treat complications (e.g. neurological, cardiovascular) Prevention ▪ Infection control practices ▫ Hand hygiene; isolate hospitalized individuals; contact precautions Figure 89.2 Characteristic mouth lesions of hand, foot and mouth disease. HEPATITIS A VIRUS osms.it/hepatitis-a-virus PATHOLOGY & CAUSES ▪ Hepatitis A virus (HAV) → hepatitis A infection ▪ Reservoir ▫ Humans ▪ Transmission ▫ Oral-fecal route ▪ Infection of hepatocyte by HAV → replication hepatocyte cytoplasm→ hepatocellular damage → HAV-specific CD8+ T lymphocytes, natural killer cells destroy infected hepatocytes → host’s immune response to HAV → hepatic injury ▪ Infection usually self-limiting (does not become chronic); results in life-long immunity (IgG antibodies) RISK FACTORS ▪ Poor sanitation ▪ Limited access to clean water ▪ Travel to low resource countries COMPLICATIONS ▪ Cholestatic hepatitis: characterized by prolonged jaundice ▪ Relapsing hepatitis: symptoms relapse after acute illness ▪ Autoimmune hepatitis: chronic hepatitis, characterized by hyperglobulinemia SIGNS & SYMPTOMS ▪ Usually self-limiting; fulminant hepatic failure rare ▪ Incubation period ▫ 28 days (average) ▪ Symptoms ▫ Nausea, vomiting, anorexia, fever, malaise, abdominal pain 182 ▪ Signs ▫ Dark urine, pale stools, jaundice (peaks within two weeks of infection), pruritus, scleral icterus, hepatosplenomegaly DIAGNOSIS LAB RESULTS ▪ Elevated serum aminotransferase levels may indicate diagnosis ▪ Established diagnosis by detection of serum IgM anti-HAV antibodies ▫ Serum IgG antibodies in absence of anti-HAV IgM indicates previous infection/vaccination TREATMENT Prevention ▪ Hepatitis A vaccination ▪ Immune globulin; passive immunization indicated for ▫ Immunocompromised individuals (unable to amount immune response to HAV vaccine) ▫ < 12 months, > 40 years ▫ Individuals with chronic liver disease ▫ Allergy to hepatitis A vaccine OTHER INTERVENTIONS Prevention ▪ Infection control practices ▫ Handwashing; avoid tap water, raw foods in poorly-sanitized areas MEDICATIONS ▪ Medications known to cause liver damage should be avoided/used with caution POLIOMYELITIS (POLIO) osms.it/poliomyelitis PATHOLOGY & CAUSES ▪ Infectious disease caused by poliovirus ▪ Characterized by (rare but devastating) cases of muscle weakness, permanent paralysis ▫ Most infections remain asymptomatic ▫ Some experience minor symptoms (e.g. fever, sore throat, headache) ▫ Some may recover from muscle paralysis ▪ Natural host ▫ Humans ▪ Transmitted by fecal-oral route; less commonly via respiratory droplets ▫ Asymptomatic, infected persons may shed virus ▪ Pathogenesis ▫ Oral entry → poliovirus infects cells of mouth, nose, throat → spread to lymphatics → primary replication in tissue of gastrointestinal tract and oropharynx → primary (minor) viremia → invasion of the central nervous system → replication in motor neurons of spinal cord, brain stem, or motor cortex → destruction of motor neurons → secondary (major) viremia and paralysis RISK FACTORS ▪ Unvaccinated status ▪ Travel to countries endemic for poliovirus COMPLICATIONS ▪ Post-polio syndrome ▫ Slowly developing muscle weakness similar to initial infection ▪ Bulbar poliomyelitis 183 Chapter 89 Picornaviruses ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▫ Infection of brain stem; may lead to drooling, aspiration pneumonia, respiratory muscle paralysis Skeletal malformations due to muscle paresis, paralysis Equinus foot (club foot) Stunted growth Osteoporosis, bone fractures Urinary tract infections, kidney stones Paralytic ileusv Myocarditis, cor pulmonale Acute flaccid paralysis ▪ Complete paralysis; spinal, bulbar, bulbospinal ▪ Quadriplegia/respiratory failure ▪ Reflexes absent ▪ Sensation intact SIGNS & SYMPTOMS Minor illness/minor viremia ▪ Abortive poliomyelitis ▫ Nausea ▫ Vomiting ▫ Abdominal pain ▫ Constipation ▫ Diarrhea ▫ Sore throat ▫ Mild fever ▫ Coryza Major illness/major viremia ▪ Involvement of central nervous system (CNS) ▪ Nonparalytic aseptic meningitis ▪ Headache ▪ Neck, back, abdominal, extremity pain ▪ Fever ▪ Vomiting ▪ Lethargy ▪ Irritability Paralytic disease ▪ Varies from one muscle to muscle group ▪ Reduced tone; often asymmetric ▪ Affects proximal muscles > distal muscles ▪ Affects legs > arms ▪ Worsens over 2–3 days Figure 89.3 An individual with atrophy of the mucles of the right leg caused by polio. DIAGNOSIS ▪ Acute-onset flaccid paralysis LAB RESULTS ▪ PCR detection of poliovirus RNA from cerebrospinal fluid; cerebrospinal fluid (CSF) may also show ↑ leukocytes, ↑ protein ▪ Alternative ▫ Detection by poliovirus isolation, culture (from throat secretions); comparison of viral titers in acute, convalescent sera 184 AfraTafreeh.com exclusive TREATMENT MEDICATIONS Antiviral therapy ▪ Role remains uncertain Prevention ▪ Passive immunization: gamma globulin; reduces infected individuals’ disease severity ▪ Inactivated poliovirus vaccine ▫ Given in high-income countries ▫ Cannot revert to paralytic form ▪ Live attenuated oral poliovirus vaccine ▫ Inexpensive, easy to administer; given in countries where virus endemic ▫ Risk: attenuated virus reverting to paralysis-causing form OTHER INTERVENTIONS ▪ Physical therapy; respiratory failure → mechanical ventilation ▪ No effective treatment for restoring motor neuron function Figure 89.4 An individual with polio inside an iron lung, which provided mechanical ventilation by creating negative pressure. RHINOVIRUS osms.it/rhinovirus → host inflammatory response to virus → elaboration of inflammatory mediators, recruitment of polymorphonuclear leukocytes → symptoms → illness lasts about 1–2 weeks PATHOLOGY & CAUSES ▪ The causative agent of most common colds ▪ > 100 serotypes ▪ Most frequent human infectious disease, preferentially infecting the upper respiratory tract ▪ Usually causes mild, self-limiting disease, with increased incidence in early autumn (September–November) and in Spring (March–May) ▪ Predisposes to other infections ▫ Otitis media in children, community acquired pneumonia ▪ Potential to infect the lower respiratory tract → exacerbation of asthma, chronic bronchitis ▪ Inoculation of the nose or conjunctiva → intracellular adhesion molecule-1 (ICAM1) attachment → incubation (2–4 days) Transmission ▪ Airborne droplet nuclei/aerosols (from sneezing, coughing) ▪ Droplet transmission ▪ Direct contact (e.g. hand contact → rubbing eyes, nasal mucosa) ▪ Fomites RISK FACTORS ▪ ▪ ▪ ▪ ▪ Fatigue (insufficient sleep) Psychological stress Work in daycare/schools Smoking Underlying chronic disease 185 Chapter 89 Picornaviruses COMPLICATIONS ▪ ▪ ▪ ▪ Sinusitis Lower respiratory tract disease Asthma exacerbations Acute otitis media SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Cough Coryza Rhinorrhea (clear/purulent) Sore throat Myalgia Fatigue, malaise Headache Anorexia Fever DIAGNOSIS DIAGNOSTIC IMAGING ▪ Lower respiratory tract infection → chest radiograph OTHER DIAGNOSTICS ▪ Nasal cavity examination: swollen, erythematous nasal turbinates TREATMENT MEDICATIONS ▪ Analgesics ▫ Relieve headache, ear pain, myalgia ▫ E.g. acetaminophen, nonsteroidal antiinflammatory drugs ▪ Antihistamine/decongestant combinations ▪ Cough suppressants OTHER INTERVENTIONS ▪ Zinc supplements at initial infection may reduce duration 186 NOTES NOTES POLYOMAVIRUS MICROBE OVERVIEW ▪ Small DNA virus → central nervous system, urinary system, skin infection ▪ Poly = multiple, oma = tumor → relationship with multiple tumors ▪ Viral DNA replication, virion assembly occurs inside cell nucleus ▪ Primary infection usually asymptomatic → persistent state Taxonomy ▪ Human polyomavirus species ▫ BK virus ▫ JC polyomavirus ▫ Wu polyomavirus ▫ KI polyomavirus ▫ Merkel cell polyomavirus (MCV) ▫ Trichodysplasia spinulosa virus (TSV) Morphology ▪ Structure ▫ Double-stranded circular DNA ▫ Icosahedral capsid composed of few proteins: VP1 (cell surface binding), VP2, VP3 ▫ Nonenveloped ▪ Non-structural proteins: large, small T antigens ▫ Initiate viral DNA replication ▫ Oncogenic potential Transmission ▪ Probable transmission routes ▫ Fecal-oral, oral, respiratory RISK FACTORS ▪ Immunodeficiency BK VIRUS (HEMORRHAGIC CYSTITIS) osms.it/bk-virus PATHOLOGY & CAUSES ▪ Causes hemorrhagic cystitis ▪ BK virus in hematopoietic stem cell transplant recipients → bladder inflammation → bladder mucosa bleeding ▪ Primary infection usually asymptomatic/ mild respiratory infection → urinary tract infection → virus in bladder mucosal lining, kidneys ▪ Weak immune system → BK viral replication → cells large, round → separate from basal membrane, cell lysis CAUSES ▪ ▪ ▪ ▪ Radiation Chemotherapy Immunosuppressive drugs Urinary tract infection (e.g. BK virus, adenovirus) 187 Chapter 90 Polyomavirus TREATMENT SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ MEDICATIONS Frequent urination Dysuria Hematuria Suprapubic pain ▪ Mesna, chemotherapy co-administered ▫ ↓ hemorrhagic cystitis risk SURGERY ▪ Cystectomy (severe case) DIAGNOSIS OTHER INTERVENTIONS LAB RESULTS ▪ Polymerase chain reaction (PCR) → infection agent fragments in urine ▪ Urinalysis, cytology ▪ Cystoscopy ▪ Bladder irrigation ▫ Water/sodium chloride solution ▪ Pain management ▪ Hyperhydratation ▪ Hyperbaric oxygen, prostaglandins (↓ efficacy) JC VIRUS (PROGRESSIVE MULTIFOCAL LEUKENCEPHALOPATHY) osms.it/jc-virus PATHOLOGY & CAUSES ▪ Causes progressive multifocal leukoencephalopathy (PML) ▪ Immunocompromised individuals → JC virus → PML (rare demyelinating disease) ▪ Childhood primary asymptomatic infection → latent JC virus in lymphoid organs, kidneys ▪ Immunodeficiency → virus spreads via blood → infects brain oligodendrocytes, astrocytes → viral replication → cell lysis → myelin sheath loss ▪ Triggers ▫ Immunosuppressive drugs (e.g. Natalizumab) ▫ Immune system disorders (e.g. HIV/ AIDS) SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ Cognitive, mental dysfunction Gait, coordination problem Hemiparesis, monoparesis Double/blurred vision Seizure DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Hypodense lesions affect white matter MRI ▪ T1 image decreased signal ▪ T2 image increased signal 188 ▪ Affects subcortical, periventricular white matter (usually) ▪ Absent contrast enhancement LAB RESULTS Brain biopsy ▪ Large oligodendrocyte nuclei with inclusion bodies ▪ Myelin sheath destruction ▪ Abnormal, enlarged astrocytes ▪ Macrophages engulfing myelin ▪ Immunohistochemistry for JC proteins Cerebrospinal fluid (CSF) analysis ▪ PCR detects viral DNA ▪ ↑ white blood cell count (pleocytosis) ▪ ↑ protein level Figure 90.1 An MRI scan in the coronal place of the head of an individual with progressive mutlifocal leucoencephalopathy. TREATMENT ▪ No specific treatment; high mortality MEDICATIONS ▪ HIV-infected individuals ▫ Start/optimize antiretroviral therapy (ART) ▪ No HIV infection ▫ Stop immunosuppressive therapy ▪ Potentially beneficial drugs ▫ Interleukin-2, cytarabine, chlorpromazine, mefloquine OTHER INTERVENTIONS ▪ Natalizumab-caused PML ▫ Plasma exchange Figure 90.2 Immunohistochemical staining for JC virus protein in the brain of an individual with progressive multifocal leukoencephalopathy. The protein, stained brown, has accumulated in the oligodendrocytes. 189 Chapter 2 Acyanotic Defects NOTES POXVIRIDAE MICROBE OVERVIEW Genetic material ▪ Linear double-stranded DNA Replication ▪ In host cell cytoplasm Taxonomy ▪ Poxviridae: family of double-stranded DNA viruses Associated clinical syndromes ▪ Febrile rash illnesses: smallpox (eradicated), monkeypox ▪ Skin lesions: vesicles, pustules, papules, skin thickening Morphology ▪ Brick-shaped/ovoid ▪ Enveloped (outer lipid membrane) ▪ Size: 220–450nm MOLLUSCUM CONTAGIOSUM osms.it/molluscum-contagiosum PATHOLOGY & CAUSES ▪ Molluscum contagiosum virus (MCV): poxvirus; causes papular skin disease ▪ Four subtypes; genotype 1 causes most U.S. cases ▪ Common in children, adolescents ▪ Skin penetration → stratum spinosum replication within keratinocytes → epidermal hypertrophy → papules ▪ Incubation period: 2–6 weeks COMPLICATIONS ▪ Widespread/refractory lesions in immunosuppressed individuals CAUSES ▪ Physical contact, autoinoculation, fomites RISK FACTORS ▪ Contact sports; sexual intercourse with infected individuals; immunosuppression; atopic dermatitis Figure 91.1 The wart-like lesions caused by molluscum contagiosum infection. 190 SIGNS & SYMPTOMS ▪ Dome-shaped, shiny, umbilicated papules (2–5 mm); sometimes polypoid ▪ Lesion distribution: trunk, genitals, intertriginous areas (e.g. axilla, antecubital folds); not on palms, soles ▪ Sometimes pruritus, inflammation, swelling ▪ Molluscum dermatitis: eczematous patches/plaques around papules ▪ Eyelid lesions → keratoconjunctivitis DIAGNOSIS Figure 91.2 A histological section through a molluscum wart at low power. There is marked acanthosis and marked hyperplasia causing inversion. LAB RESULTS ▪ Histologic examination: keratinocyte eosinophilic inclusion bodies (Henderson– Paterson bodies) OTHER DIAGNOSTICS ▪ Clinical examination: dermoscopy; polylobular, amorphous structures with central umbilication, peripheral blood vessels TREATMENT ▪ Optional; lesions resolve spontaneously in 6–18 months in immunocompetent individuals MEDICATIONS Chemical disruption ▪ Topical blistering agent: cantharidin ▪ Antimitotic agent: podophyllotoxin ▪ Topical immunomodulator: imiquimod ▪ Potassium hydroxide (KOH) ▪ Keratinolytic agent: salicylic acid Antiviral treatment ▪ Cidofovir SURGERY Lesion removal ▪ Cryotherapy, curettage, laser OTHER INTERVENTIONS Figure 91.3 A histological section through a molluscum wart at high power. The stratum spinosum and granulosum contain eosinophilic inclusions, known as molluscum bodies. Prevention ▪ Avoid sharing towels/clothing ▪ Cover lesions with bandage/clothing ▪ Barrier contraception (e.g. condoms) 191 Chapter 2 Acyanotic Defects NOTES REOVIRUSES MICROBE OVERVIEW ▪ Rotavirus: most important Reovirus in clinical practice Genetic Material ▪ RNA viruses with segmented double stranded linear RNA Morphology ▪ Encapsulated (icosahedral capsid) ▪ Nonenveloped Replication/multiplication ▪ Replicates in cytoplasm ROTAVIRUS osms.it/rotavirus PATHOLOGY & CAUSES ▪ A major cause of acute diarrhea, especially in children ▫ Most important cause of severe gastroenteritis in infants, young children worldwide ▪ Short incubation period ▫ ↓ activity of brush-border enzymes (such as maltase, lactase) → malabsorption of nutrients → presence of reducing substances in stools → osmotic diarrhea ▫ Direct effects of enterotoxin nonstructural protein 4 (NSP4) on gastrointestinal mucosa (apoptosis of enterocytes) ▫ Activation of enteric nervous system → ↓ absorption of Na+, loss of K+ CAUSES ▪ Transmission by fecal-oral route (ingestion of water/food contaminated by stools) ▫ Spreads easily; minimal infective dose (10 viral particles) RISK FACTORS ▪ Age ▫ Usually affects children between 6–24 months of age ▪ Cooler months in temperate climates ▪ Hospitalization, long term care facilities, day care centers, kindergartens, college dormitories ▪ Immunodeficiency ▪ Non-immunized status COMPLICATIONS ▪ Secondary lactase deficiency ▪ Severe dehydration ▫ Shock, multisystem failure ▪ Central nervous system complications ▫ Seizures, encephalopathy ▪ Persistent gastroparesis, diarrhea ▪ Necrotizing enterocolitis ▪ Intussusception ▪ Biliary atresia ▪ Can be fatal 192 SIGNS & SYMPTOMS ▪ Average duration: 8 days ▪ Children: watery diarrhea, vomiting, fever ▪ Adults: less severe symptoms DIAGNOSIS LAB RESULTS Blood tests ▪ ↑ blood urea nitrogen (BUN) ▪ Hyperchloremic acidosis ▪ ↓ serum calcium Stool analysis ▪ Immune based assays ▫ Enzyme linked immunosorbent assay (ELISA), latex agglutination tests (best diagnostic tests); PCR, culture TREATMENT OTHER INTERVENTIONS ▪ Most cases are self-limited, do not require pharmacotherapy ▫ Antidiarrheal medications not recommended (they delay elimination of infectious agent from intestines) ▪ ↑ fluid intake; oral rehydration solutions ▪ Good nutrition ▪ If infection is severe ▫ Hospitalization for IV fluids Prevention ▪ Live attenuated vaccine is indicated routinely for all infants, except for those with history of intussusception/severe combined immunodeficiency (SCID) 193 Chapter 2 Acyanotic Defects NOTES RETROVIRUSES MICROBE OVERVIEW ▪ RNA viruses ▫ Require DNA generation, integration into host DNA → produce viral progeny ▪ Large viral family ▫ Seven genera ▪ Target cells determined by viral glycoprotein spikes on cell membrane → recognized cell surface receptors, coreceptors → viral entry → provirus creation ▫ Viral reverse transcriptase takes singlestranded viral RNA genome → creates linear, double-stranded DNA virus → provirus ▪ Provirus integration (via integrase) into host-cell DNA → viral particle production ▫ Integration stability of provirus, transmission to host-cell progeny determines retroviral infection persistence in host organism Morphology ▪ Lipid-enveloped particles 80–100nm diameter ▪ Protein core ▫ Two linear, ⊕-sense, single-stranded RNA genomes (7–11 kb) ▫ Enzymes (gene locus) needed for viral replication (protease—pol gene, p10 locus; reverse transcriptase—pol gene, p66 locus; integrase—pol gene, p32 locus) TYPES Human endogenous retroviruses ▪ Proviral DNA/partial genomic sequences integrated into host-genome ▪ Constitutes up to 8% of human DNA ▪ Vertical transmission via germline cells ▪ Translated DNA does not lead to infectious viruses; may → functional proteins Human exogenous retroviruses ▪ Passed horizontally via exposure to blood, sexual secretions, breast milk HUMAN IMMUNOFEDICIENCY VIRUS osms.it/HIV-(AIDS) PATHOLOGY & CAUSES ▪ HIV: human immunodeficiency virus ▪ Member disease of Lentivirus genus of Retroviridae family ▫ Characterized by immune cell targeting, immunodeficiency Two pathogenicity targets ▪ Immune system ▫ Mucosal HIV virion infiltration → bloodstream spread → infection of T cells, dendritic cells, macrophages → latency (may be chronic, indolent) → active replication → symptom progression/emergence → further replication→ severe 194 immunocompromise, progression to AIDS (acquired immune deficiency syndrome) ▫ HIV infection → targeting, infection of CD4+ cells (e.g. CD4+ T-lymphocytes, monocytes, macrophage) → replication, spread → ↓ CD4+ cells → immunodeficiency ▫ Co-receptor CCR5 important in early infection; persistence ▪ Central nervous system (CNS) ▫ HIV infection → macrophage/microglia infection → abnormal CNS cytokine milieu → neuronal cell death Structure ▪ 110nm diameter spherical virion ▪ Core surrounded by lipid bilayer envelope ▪ Lipid envelope ▫ External glycoprotein gp-120, anchored by gp-41 ▫ Binding sites for host-cell CD4+ receptor (co-receptors—chemokine receptors; especially CCR5, CXCR4) ▪ Core ▫ Two single-stranded RNA copies ▫ Two transfer RNA primers (host-cell origin) ▫ Multiple enzyme copies: reversetranscriptase (RT), integrase, ribonuclease H (RNAse H) ▫ Other proteins: vpr, vif, nef (important in early virion life-cycle) Genome ▪ 9kb ▪ Similar to other retroviruses (six genes—tat, rev, vpr, vpu, vif, nef) ▫ HIV-2 specific: Vpx gene (homologous to gene in simian immunodeficiency virus (SIV); not present in other lentiviruses) Life cycle ▪ Cell contact, fusion: gp-120, CD4+ receptor fusion → gp-120 conformational change → opened gp-120 recognition site → gp-120 binding to host-cell co-receptor (CCR5/CXCR4) → gp-41 conformational change → gp-41 hydrophobic domain exposed → virion lipid bilayer insertion into cell membrane → virus-host-cell membrane fusion → viral entry ▪ Viral genome replication: viral RNA transcribed by viral RT in host-cell cytoplasm → HIV provirus production (double-stranded complementary DNA transcript) → transport to nucleus → integrase insertion in cell DNA → viral DNA transcription → viral RNA, protein ▫ Host-cell activation (naive T cells) important factor in determining active vs. latent HIV replication ▫ Antigen/cytokine-mediated T cell activation → NF-KB (nuclear transcription factor) cell stress activation → ↑ NF-KB promoter-associated gene transcription (in HIV proviral DNA) → ↑ viral replication → viral RNA, protein aggregation in cytoplasm → viral protein cleavage (e.g. gag) → viral content assembly → ↑ virion production (↑↑ virion budding → cell death) ▪ Host-cell death: ↑ virion budding → ↑ host-cell plasma membrane permeability; ↑ viral replication → native protein synthesis interference → dysregulated cellular protein concentrations → cell death ▫ Non-cytopathic host-cell HIV infection: HIV infection → inflammasome pathway activation → pyroptosis (inflammatory cytokine, cellular content release) → immune cell recruitment → viral spread (likely plays large role in HIV infection spread) Transmission ▪ HIV-1, HIV-2 ▪ Three transmission modes ▫ Sexual: USA—biologically-male individuals engaging in same-sex sexual contact (MSM) particularly important transmission mode (highest disease incidence → homosexual biologicallymale individuals); global—majority of sexual transmission via heterosexual intercourse; co-existent sexuallytransmitted disease (genital ulceration especially) → ↑ transmission risk during intercourse ▫ Parenteral: non-iatrogenic, intravenous (IV) drug users (shared needles, syringes, other paraphernalia contaminated with HIV ⊕ blood); iatrogenic (hemophiliacs who received 195 Chapter 93 Retroviruses HIV-contaminated factor VII, IX concentrates; HIV-contaminated blood transfusion recipients; health personnel—e.g. needle-stick injuries) ▫ Vertical, mother-to-infant: in utero, transplacental spread; infected birth canal → delivery → neonatal infection; neonatal HIV ⊕ breast milk ingestion ▪ HIV-2 only ▫ Believed to be zoonosis resulting from SIV cross-speciation infection ▫ Endemic areas correlate with those of sooty mangabey ▫ Less transmissible than HIV-1 Disease ▪ Acute retroviral syndrome ▪ AIDS AIDS ▪ Persistent fever (> one week); fatigue; weight loss; diarrhea; generalized lymphadenopathy (LAD); serious, opportunistic infection ▪ Secondary neoplasms ▪ Neuropsychiatric disease ▫ Delirium; major depression; mania; schizophrenia; post traumatic stress disorder; substance abuse, addiction (commonly HIV infection risk factor) ▫ Dementia (AKA AIDS dementia complex): cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, cerebral toxoplasmosis, cryptococcal meningitis, CNS lymphoma TYPES ▪ Likely related to SIV ▪ Two human virus types ▫ HIV-1, HIV-2 RISK FACTORS ▪ West Africa residence (HIV-2), homosexual/ bisexual biologically-male individuals (USA), IV drug users, hemophiliacs, blood (or component) transfusion recipients, maternal HIV infection COMPLICATIONS ▪ Opportunistic infections, secondary malignancies, AIDS, neuropsychiatric disease Figure 93.1 An esophaeal biopsy composed of squamous mucosa with candida hyphae. Esophageal candidiasis is a common opportunitic infection in individual with AIDS. SIGNS & SYMPTOMS Acute retroviral syndrome ▪ Self-resolving, flu-like syndrome; sore throat; myalgias; fever; weight loss; fatigue Chronic infection ▪ Variable ▫ Asymptomatic → minor infection ▫ Oral/vaginal candidiasis, herpes zoster, mycobacterial tuberculosis (especially Sub-Saharan Africa) Figure 93.2 The histological appearance of mycobacterium avium intracellulare. There are numerous organisms within the cell cytoplasm. 196 197 Chapter 93 Retroviruses 198 DIAGNOSIS TREATMENT LAB RESULTS MEDICATIONS Serology: enzyme-linked immunoassay (ELISA) ▪ IgG, IgM, p24 antibody testing ▫ Time to positivity: 15–45 days (P24 (viral core protein) earliest positive marker) ▫ May be combined for HIV-1, HIV-2, p24 immunoassay in diagnostic, screening purposes Highly active antiretroviral therapy (HAART) ▪ Antiretroviral drug combination regimen ▫ Early initiation → ↓ morbidity, ↓ mortality, ↓ transmission risk (regardless of CD4+ count) ▪ Six distinct drug classes ▫ Combination of three drug types used for effective viral load management, combat particular drug class resistance development ▪ Protease inhibitor preferred initial agent ▫ Resistance testing results → narrow therapy ▪ Complications ▫ Immune reconstitution inflammatory syndrome ▫ ↓ in clinical state (symptom return experienced during active viremic phase), despite ↑ CD4+ levels ▫ Believed to be due to reinvigorated host response to high antigenic burden of persistent microbes, remaining viral load ▪ ⊕ Viral RNA level test (> 100,000 copies/ mL) ▫ May be used in indeterminate HIV-1/ HIV-2/ p24 immunoassay ▪ Leukopenia ▫ ↓↓ CD4+ count ▫ CD4+:CD8 ratio < 1 OTHER DIAGNOSTICS ▪ ▪ ▪ ▪ Flu-like illness Opportunistic infection Needlestick injury with HIV ⊕ individual Unprotected sex with partner of unknown/ HIV ⊕ status Pre-exposure prophylaxis ▪ Daily tenofovir use can very effectively ↓ transmission 199 Chapter 93 Retroviruses 200 OTHER INTERVENTIONS Monitoring ▪ HIV RNA testing two, four, eight weeks after ART initiation ▫ Continue testing every two weeks until levels below detection limits ▫ Drug resistance testing at 24 weeks if ↑ in RNA viral level/no ↓ in RNA levels ▪ Once viral suppression achieved → repeat testing for RNA levels 3–6 months Screening ▪ One-time for individuals 13–75 years old ▪ Pregnant individuals (even in negative prior pregnancy screening) ▪ Annual/more frequent for high-risk individuals ▫ MSM (USA) ▫ IV drug users ▫ Sex partners of HIV unknown status, HIV ⊕, bisexual, individuals who inject drugs ▪ Blood factor screening ▫ Plasma/recombinant factor hemophiliac recipients Opportunistic infection prophylaxis ▪ Determined by CD4+ count ▪ Situational avoidance advised (e.g. cat litter, Toxoplasma exposure) Pre-exposure prophylaxis ▪ Indications ▫ High-risk sexual behavior/drug use ▫ Reliable individual to adhere to daily medication regimen Saito Says Hi 201 Chapter 93 Retroviruses HUMAN T-LYMPHOTROPIC VIRUS osms.it/human_t-lymphotropic_virus PATHOLOGY & CAUSES ▪ Oncogenic retrovirus endemic to certain areas of world → T cell leukemia/lymphoma ▫ AKA HTLV-1 ▫ Genus: Deltaretrovirus ▪ Structure ▫ Enveloped, single-stranded RNA virus ▫ Only human pathogen of oncovirus subfamily ▪ Genome ▫ Contains retrovirus-consistent gag, pol, env, long terminal repeat (LTR) ▫ HTLV-1 specific: tax; encodes protein essential for viral replication; viral RNA transcription stimulation from 5’ LTR ▪ Transmission ▫ Usually via infected T cells (vs. virion particle) ▫ Breastmilk, sexual transmission, blood transfusion, tissue donation, IV drug use, zoonotic transmission (nonhuman primate source) ▪ Disease ▫ Adult T cell leukemia/lymphoma ▫ Myelopathy/tropical spastic paraparesis Targets CD4+ cells ▪ Unlike HIV life cycle, pathogenesis; largely unknown targeting, infection, replication mechanisms ▫ Tumor initiating cell appear to be CD4+ memory T cell with stem-cell-like properties ▪ Distinct from HIV ▫ HTLV-1 → proliferation of T cell population rather than killing of cells ▪ Integrated provirus → mitotic cell division → host cell replication ▫ Low replication rate ▫ Host cell DNA polymerase ensure high transcription fidelity (HTLV-1 genetically stable) Tax-specific oncogenic hallmarks ▪ Inr pro-growth signaling, cell survival ▫ Stimulates AKT (via PI3K), NF-KB, cyclin D2, ↓ CDK inhibitors → ↑ prosurvival, cell growth → polyclonal T cell expansion ▪ Inc genomic instability ▫ Interference with DNA-repair function ▫ Inhibition of cell cycle checkpoints (activated by DNA damage) RISK FACTORS ▪ Travel/residence in Japan, Caribbean basin, South America, Africa ▫ Sporadic incidence in USA COMPLICATIONS ▪ Mycosis fungoides ▫ Cutaneous T cell leukemia/lymphoma manifestation ▪ Uveitis ▪ Gastric cancer Rheumatologic, pulmonary disorders ▪ Chronic inflammatory arthropathy ▫ Shoulder, wrists, knees ▪ Sjögren syndrome ▪ Immune thrombocytopenia Infectious replication ▪ Integrated provirus re-expression → intracellular virion 202 SIGNS & SYMPTOMS Adult T cell lymphotropic leukemia/lymphoma ▪ Skin lesions ▪ Generalized lymphadenopathy ▪ Hepatosplenomegaly Myelopathy/spastic paraparesis ▪ Insidious-onset lower extremity weakness, spasticity ▪ Hyperreflexia, ankle clonus present ▪ ⊕ extensor plantar responses ▪ Lumbar pain ▪ Others ▫ Back pain ▫ Detrusor instability → nocturia, urinary frequency, incontinence ▫ Minor sensory change: paresthesias, ↓ vibrational sense DIAGNOSIS DIAGNOSTIC IMAGING ▪ Lytic bone lesions MRI ▪ Tropical spastic paraparesis ▫ Cervical/thoracic cord atrophy ▫ Spinal cord white matter disease LAB RESULTS ▪ Leukopenia ▪ Hypercalcemia ▪ Histology is variable, with characteristic circulating tumor cells ▫ Medium-sized lymphocytes with condensed chromatin, bizarre hyperlobated nuclei (AKA clover leaf/ flower cells) ▪ ELISA ▫ Antibody against HTLV-1 virus detection ▪ Western blot ▫ Confirmatory testing for ELISA ▪ Polymerase chain reaction (PCR) ▫ Available for HTLV-1 ▫ Useful with ↑↑ suspicion (ELISA negative) ▪ Flow cytometry ▫ ↑ FoxP3 expression in leukocytes (↑ regulatory T cell-indicative) ▫ Otherwise immunophenotypically mature T lymphocytes OTHER DIAGNOSTICS ▪ Travel/residence in endemic area TREATMENT ▪ No therapy proven to benefit affected individuals MEDICATIONS ▪ Corticosteroid therapy may slow disease course ▪ Antiviral therapy ▫ NRTI zidovudine, IFN-alpha proven beneficial OTHER INTERVENTIONS Prevention ▪ Endemic area-avoidance when breastfeeding ▪ Blood donor screening ▪ Safe-sex practices ▪ Discourage needle sharing 203 Chapter 2 Acyanotic Defects NOTES RHABDOVIRUSES MICROBE OVERVIEW ▪ Diseases ▫ Rabies encephalitis, vesicular diseases ▪ Genera: Lyssavirus, Vesiculovirus, Sigmavirus, Varicosavirus, Spirivivirus, etc. Genetic material ▪ Rod-shaped, single-stranded RNA virus Morphology ▪ Enveloped, bullet-shaped, with helical nucleocapsids, linear genomes Taxonomy ▪ Order: Mononegavirales ▪ Family: Rhabdoviridae Transmission ▪ Via bite (infected host’s saliva) RABIES VIRUS osms.it/rabies-virus PATHOLOGY & CAUSES ▪ Serious central nervous system (CNS) viral zoonotic infection ▪ Virus spreads via nerves (retrograde axoplasmic transport) ▪ Muscle tissue inoculation → incubation (1–3 months), local multiplication → acetylcholine receptor binding → nerve entry → travel via spinal cord axons → brain infection (found in cerebellum Purkinje cells, hippocampal neurons) → encephalitis Advanced-stage ▪ CNS → other organs (salivary glands, cornea, skin, gastrointestinal, etc.) via parasympathetic nervous system CAUSES ▪ Caused by genus Lyssavirus (multiple species, Rhabdoviridae family) Transmission ▪ Saliva in virus-infected host bite (dogs, bats, cats, raccoon, foxes, skunks, monkeys, etc.) ▪ Rabies-infected organ/tissue transplantation (rare) ▪ Aerosol transmission (e.g. bat caves) possible RISK FACTORS Animal exposure (bite risk) Travel (rabies-endemic Asian/African areas) Age < 15 years Deep bite Head wound (virus → brain transmission risk ↑ ) ▪ No post-exposure prophylaxis ▪ Occupational (laboratory, veterinarian) ▪ Recreational (spelunking → ↑ bat exposure risk) ▪ ▪ ▪ ▪ ▪ 204 COMPLICATIONS ▪ ▪ ▪ ▪ ▪ Encephalopathy Increased intracranial pressure Coma Permanent neurological deficits Often fatal SIGNS & SYMPTOMS Prodromal stage ▪ Non-specific symptoms (first week) ▫ Headache; low grade fever, chills; myalgia, weakness, fatigue; malaise, anorexia; nausea/vomiting; sore throat; photophobia (sometimes) ▪ Wound site pain/tenderness/paresthesia/ tingling/itching Encephalitic rabies ▪ AKA furious rabies ▪ Most common form ▪ Involuntary pharyngeal spasms → hydrophobia (fear of water); aerophobia ▪ Fever ▪ Muscle spasms → opisthotonus position ▪ Seizure ▪ ↑ autonomic stimulation ▫ Excess salivation; lacrimation; sweating; mydriasis; impaired temperature homeostasis; tachycardia ▪ Dysphagia ▪ Aggressiveness, agitation, hallucination, confusion ▪ Respiratory distress → coma → respiratory arrest → death Paralytic stage ▪ AKA dumb rabies ▪ Ascending flaccid paralysis ▪ Sphincter atony ▪ Hydrophobia (rare) ▪ Neck stiffness ▪ Cranial nerves palsy ▪ Fasciculations/deep tendon reflex loss ▪ Pharyngeal, diaphragm muscle paralysis → death DIAGNOSIS ▪ Clinical Presentation ▫ History of rabid animal bite, rabies infection symptoms/signs DIAGNOSTIC IMAGING CT scan ▪ Cerebral edema LAB RESULTS Reverse transcription PCR (RT-PCR) ▪ Saliva ▫ Detects rabies virus RNA Skin punch biopsy ▪ RT-PCR; immunofluorescence staining for viral antigen Cerebrospinal fluid (CSF) ▪ Indirect immunofluorescence, virus neutralization assay ▪ CSF analysis ▫ Pleocytosis, ↑ protein Serum ▪ Anti-rabies virus antibodies in serum appear after first week (if individual not immunized) OTHER DIAGNOSTICS Post mortem ▪ Brain tissue/other neural tissue examination ▫ Negri bodies, eosinophilic cytoplasmic inclusions in nerve cell cytoplasm (often) TREATMENT MEDICATIONS ▪ Antivirals ▪ Rabies vaccine ▫ Both post-, pre-exposure prophylaxis ▫ Immunocompetent people: four injections (day 0, 3, 7, 14) ▫ Immunocompromised people: fifth injection (day 28) 205 Chapter 94 Rhabdoviruses ▫ Previously immunized people: two injections (day 0, 3) ▪ Human rabies immune globulin (HRIG) ▫ Single dose (20 units/kg) injected in, around wound ▫ Remainder administered intramuscular at distant site (e.g. other deltoid) OTHER INTERVENTIONS Post-exposure prophylaxis (rapid) ▪ Wound cleaning ▫ Water/soap, povidone iodine ▪ Antibiotics/tetanus prophylaxis Figure 94.1 Multiple Negri bodies in the brain of an individual infected with the rabies virus. The negri bodies form in the Purkinje cells of the cerebellum. Management ▪ Respiratory (supplemental oxygen, mechanical ventilation), cardiovascular support (fluids) Prevention ▪ Exposed population may receive preexposure prophylaxis ▪ Domestic animal vaccination (especially dogs, cats) 206 NOTES NOTES RICKETTSIAL DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Vector-borne obligate intracellular bacteria; poor Gram staining, rod-shaped structure ▪ Common tropism for endothelial cells → variable amount of hemorrhage, edema, organ dysfunction SIGNS & SYMPTOMS ▪ Disease-specific; fairly consistent integument manifestations (e.g. rash) DIAGNOSIS LAB RESULTS ▪ Isolation of Rickettsiae ▫ Inoculation of animal/via cell culture ▪ Serology ▫ Enzyme-linked immunosorbent assay (ELISA), western blot, microimmunofluorescent antibody test (detection of bacterial-specific antigens) ▪ Immunologic detection in tissue ▫ Isolation in epithelial tissue (from integument involvement) ▫ Requires sophisticated laboratory capability (not common in endemic areas of disease) ▪ Polymerase chain reaction (PCR) ▫ Detection of rickettsial DNA OTHER DIAGNOSTICS ▪ Clinical presentation (disease-specific) TREATMENT MEDICATIONS ▪ Prompt antimicrobial therapy ▫ Doxycycline (preferred) 207 Chapter 95 Rickettsial Diseases ANAPLASMA osms.it/anaplasma PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular bacteria, endemic to wooded areas in North America → self-resolving disease, AKA human granulocytic anaplasmosis (HGA) Vector ▪ Anaplasma phagocytophilum: Ixodes tick ▫ Ixodes scapularis: also transmits Borrelia burgdorferi, Babesia spp. in eastern United States (US) ▫ Ixodes pacificus: main vector in western US ▫ Ixodes ricinus: implicated in European disease Life cycle and transmission ▪ Reservoir hosts: deer, white-footed mice (source of disease, not affected by pathogen) ▪ Vector: Ixodes tick (connects organism from reservoir to target) ▪ Human transmission Pathogenesis ▪ Tick bite → blood circulation → leukocyte infection, membrane attachment → phagocytosis → replication (in early endosome of leukocyte) → dysfunctional vacuolization, immature lysosomal micelles → microcolony (AKA morulae) development → release into extracellular space after cell lysis/exocytosis ▫ P-selectin glycoprotein (identified binding domain for A. phagocytophilum) ▫ Ligand: P-selectin glycoprotein ligand-1 (PSGL-1) required on granulocytes for internalization Disease: HGA ▪ Direct leukocyte cell death ▪ Inflammatory response → perivascular inflammatory infiltrates in multiple organ systems (without organ failure/endothelial damage) RISK FACTORS ▪ Residence in/travel to wooded areas in North America ▫ Especially during peak tick activity (e.g. spring, summer) ▪ Direct contact with slaughtered deer ▪ Occupational exposure (e.g. military) COMPLICATIONS ▪ Co-infection with Borrelia burgdorferi, Babesia spp. ▪ Respiratory insufficiency, renal failure, septic shock ▪ Neurological ▫ Demyelinating polyneuropathy, brachial plexopathy ▪ Serious, fatal opportunistic infections ▫ Herpes simplex esophagitis, invasive aspergillosis, SIGNS & SYMPTOMS ▪ Onset 1–2 weeks after identified tick bite ▪ Fever, malaise, headache ▪ Rash ▫ Typically trunk (sparing hands, feet), maculopapular (more evident in children) ▪ Gastrointestinal (GI) symptoms infrequent ▪ Neurological (rare) ▫ Mental status change, meningismus, clonus DIAGNOSIS LAB RESULTS ▪ Leukopenia ▫ Specific to disease (neutropenia) ▪ ↑ hepatic enzymes, lactate dehydrogenase 208 ▪ Serology: indirect IFA ▫ Detection of IgG/IgM antibodies of Anaplasma species ▫ If negative on acute serum testing, repeat with convalescent serum (confirms diagnosis if ↑ fourfold in IgG antibody titer) ▪ Whole blood PCR ▫ Detects epank1 primers on genogroup A. phagocytophilum ▪ Wright stain: morulae of Anaplasma in leukocyte ▫ A. phagocytophila: peripheral blood neutrophils; 25–75% (highest among morulae-producing bacteria) OTHER DIAGNOSTICS ▪ History ▫ Tick bite in endemic area TREATMENT Figure 95.1 Mites of the genus Ixodes act as vectors for many rickettsial diseases. MEDICATIONS ▪ Prompt antibacterial management ▫ Doxycycline (if pregnant, rifampin); chloramphenicol OTHER INTERVENTIONS ▪ Prevention ▫ Avoid tick habitats ▫ Careful inspection after outside activity in wooded areas (esp. in spring, summer); rapid discovery, tick removal < 24–48 hours post bite → effective prophylaxis ▫ Skin application of insect repellants ▫ Proper clothing for outside work/play (light-colored, long pants tucked into socks, long-sleeved shirts) 209 Chapter 95 Rickettsial Diseases COXIELLA BURNETII (Q FEVER) osms.it/coxiella-burnetii PATHOLOGY & CAUSES ▪ Coxiella burnetii: primarily zoonotic pathogen → febrile illness (after contact with animal amniotic fluid/placental contents) Taxonomy ▪ Order: Legionellales ▪ Family: Coxiellaceae Morphology ▪ Short, pleomorphic rod ▫ Strict intracellular bacterium Life cycle ▪ Source of human infections ▫ Farm animals (e.g. cattle, goats, sheep) ▫ Wild animals (e.g. birds, rabbits, reptiles) ▫ Arthropods (e.g. ticks) ▪ Main reservoir ▫ Ticks Transmission ▪ Inhalation of spores/bacteria ▫ Animal feces, milk, products of conception ▪ Ingestion of contaminated milk ▪ Percutaneous ▫ Crushing of ticks near skin breaks ▪ Vertical spread (transplacental) Pathogenesis ▪ Host cell ▫ Macrophage ▪ Antigenic variation (AKA phase variation) important in virulence ▫ Lipopolysaccharide capsule modifications underly antigenic variation RISK FACTORS ▪ Occupation involving animal contact (e.g. veterinarian, farmer) ▪ ↑ age ▪ Unpasteurized milk consumption COMPLICATIONS ▪ Q fever pneumonia, chronic hepatitis, osteomyelitis ▪ Infective endocarditis ▫ Pre-existing heart/valve disease predisposes to endocarditis development ▫ May have secondary, septic embolic manifestation SIGNS & SYMPTOMS ▪ Q fever (sudden onset) ▫ Fever, headache (often frontal), general malaise, cough, anorexia, myalgia ▪ Pneumonia ▫ Cough, pleural effusion ▪ Hepatitis ▫ Hepatomegaly DIAGNOSIS LAB RESULTS ▪ ↑ serum hepatic enzymes, leukopenia/ leukocytosis, thrombocytopenia ▪ Immunofluorescent antibody assays: detect IgM/IgG antibodies; differentiate between acute, chronic infection ▫ IgM: detectable 4 days after symptom onset ▫ IgG: detectable 9–14 days after symptom onset ▫ Concentration of serum samples can assist in diagnosis (esp. if vague clinical presentation) 210 ▪ PCR ▫ Blood/serum detection possible before IgM serology peak ▪ Immunohistochemistry ▪ Culture OTHER DIAGNOSTICS ▪ History ▫ Animal contact, occupation ▫ Trimethoprim-sulfamethoxazole: pregnant individuals; treat even if asymptomatic ▪ Chronic infection: prolonged therapy ▫ 18 months doxycycline, hydroxychloroquine (monitor serologic response across therapeutic intervention; biannual ophthalmic examinations required) OTHER INTERVENTIONS TREATMENT MEDICATIONS ▪ Prompt antimicrobial treatment ▫ Doxycycline: effectiveness of antibacterial agent, severity of complications warrants use despite side effects; shorter therapy for children (14 day course) ▪ Management ▫ Individuals with pre-existing valvulopathy/cardiomyopathy; echocardiogram ▪ Prevention ▫ Whole cell vaccine; recommended for individuals working with farm animals (e.g. farmers, slaughterhouse workers) EHRLICHIA osms.it/ehrlichia PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular bacteria with leukocytic tropism, associated with febrile disease with rare, serious neurologic complication ▫ AKA human monocytic ehrlichiosis (HME) ▪ Characteristics ▫ Small (0.5–1.5 micrometer) gramnegative cocci, (1.8 megabases) genome TYPES ▪ Ehrlichia ewingii ▫ Southeastern, central United States ▪ Ehrlichia chaffeensis ▫ Northeastern, midwestern United States ▪ Ehrlichia sennetsu ▫ Western Japan Vector ▪ Amblyomma americanum (AKA lone star tick) ▫ Ehrlichia ewingii, Ehrlichia chaffeensis Life cycle ▪ Tick bite → blood circulation → leukocyte infection, membrane attachment → phagocytosis → replication (in early endosome of leukocyte) → dysfunctional vacuolization, immature lysosomal micelles → microcolony (AKA morulae) development → release into extracellular space after cell lysis/exocytosis Pathogenesis ▪ Direct leukocyte cell death ▪ Inflammatory response → perivascular inflammatory infiltrates in multiple organ system without organ failure/endothelial damage Disease: Sennetsu fever 211 Chapter 95 Rickettsial Diseases RISK FACTORS ▪ Residence in/travel to western Japan ▪ Occupational exposure (e.g. military) COMPLICATIONS ▪ Co-infection with Babesia spp./B. burgdorferi ▪ Encephalitis, seizure ▫ Associated most with E. chaffeensis ▫ May result in persistent neurologic deficit (rare; seen especially in children) ▪ Heart failure, respiratory insufficiency, renal failure, shock SIGNS & SYMPTOMS ▪ Sennetsu fever ▫ Abrupt-onset fever, chills, headache, malaise, sore throat, myalgias, arthralgias ▪ Atypical rash ▫ Maculopapular with occasional petechiae; located on trunk (sparing hands, feet) ▪ Generalized lymphadenopathy ▫ Most associated with E. sennetsu; includes hepatosplenomegaly ▪ GI ▫ Associated with E. chaffeensis ▫ Anorexia, diarrhea, nausea, vomiting ▪ Leukopenia, thrombocytopenia, anemia, hyponatremia ▪ Hepatic transaminitis: most common in E. chaffeensis infection ▪ Cerebrospinal fluid (CSF) analysis: pleocytosis (mononuclear cells with morulae), ↑ protein OTHER DIAGNOSTICS ▪ History ▫ Tick bite in endemic area TREATMENT MEDICATIONS ▪ Prompt antibacterial management: poxycycline, chloramphenicol OTHER INTERVENTIONS Prevention ▪ Avoidance of tick habitats ▪ Careful inspection after outside activity (esp. in spring, summer) ▫ Rapid discovery, removal < 24–48 hours after bite → effective prophylaxis ▪ Proper skin application of insect repellants DIAGNOSIS LAB RESULTS ▪ Serology: indirect IFA ▫ Detection of IgG/IgM antibodies (Ehrlichia species) ▫ If negative on acute serum testing, repeat with convalescent serum (confirms diagnosis if fourfold increase in IgG antibody titer) ▪ Whole blood PCR: detects 16S rRNA gene ▪ Wright stain: morulae (Ehrlichia) in leukocyte ▫ E. ewingii: in peripheral blood granulocyte ▫ E. chaffeensis: in peripheral blood monocyte 212 RICKETTSIA RICKETTSII (ROCKY MOUNTAIN SPOTTED FEVER) osms.it/rickettsia-rickettsii PATHOLOGY & CAUSES ▪ Tick-borne, obligate intracellular, Gramnegative bacteria endemic to parts of North America → potentially lethal febrile disease ▪ Characteristics ▫ Weakly gram-negative, nonmotile coccobacillus; 0.7–2.0 micrometers: cannot be visualized by traditional staining methods/direct fluorescent antibody techniques ▫ Bacterial contents: ribosome; single, circular chromosome; microcapsule surrounding cell wall (may be important in pathogenicity) Vectors ▪ Dermacentor variabilis (American dog tick) ▫ Eastern, South-central US ▪ Dermacentor andersoni (Rocky Mountain wood tick) ▫ West of Mississippi River ▪ Rhipicephalus sanguineus (common brown dog tick) ▫ Southwestern US ▪ Virulence of strain depends on tick’s feeding status ▫ ↑ feeds → ↑ incubation at high temperatures → ↑ extracellular slime → ↑ virulence (AKA reactivation phenomenon) Life cycle ▪ Tick bite (requires 6–10 hours of feeding) → proliferates by binary fission ▪ Grows in nucleus, cytoplasm of host cells Pathogenesis ▪ Tropism for endothelial cells, downstream systemic effects as sequelae ▪ Endothelial cell entry: rickettsial outer membrane proteins (rOmps) interact with ▪ ▪ ▪ ▪ ▪ ▪ lipopolysaccharides, surface-exposed proteins (SEPs) for entry ▫ rOmps bind Ku70 (membrane protein) → activate Ku70 → recruit ubiquitin ligase → ubiquitination of Ku70 → act upon cAMP receptors protein kinase A, Epac (exchange protein) → rearrangement of host cell actin filaments → rickettsial endocytosis Bacterial spread: R. rickettsii express phospholipase D, tlyC → lyse phagosomal membrane → entry into cytosol → polymerization of host cell monomeric actin filaments → invagination of host cell membranes → passage into neighboring cells Further bacterial spread ▫ Filopodia (from host cell membranes) assist in intercellular movement ▫ Bloodstream, lymphatic spread assist in more distant infection sites Small blood vessel injury (not entirely elucidated) ▫ Associated with phospholipase A activity, protease activity, free radicalinduced lipid peroxidation ▫ Cell necrosis (from other infected cells) → CD8+ T-cell response → endothelial cell injury → immune, phagocytic cellular response → lymphohistiocytic vasculitis Sequelae of small vessel injury: ↑ fluid in interstitial space → exposes brain, lung parenchyma to devastating pathophysiologic consequences Ability to spread cell-to-cell without causing obvious damage ▫ Rarely accumulate in large numbers inside cells Speeds of 4.8m/min ▫ Achieves speed via rapid recruitment, polymerization of host cell actin filaments 213 Chapter 95 Rickettsial Diseases RISK FACTORS ▪ Residence in/travel to endemic areas (esp. in spring, summer) ▪ ↑ age (peak: 40–64) ▪ Individuals who are biologically male ▪ Glucose-6-phosphate dehydrogenase (G6PD) deficiency COMPLICATIONS ▪ Skin necrosis at sites of terminal arterial supply (e.g. fingers, toes, nose, ears, genitals) ▪ Interstitial pneumonitis, myocarditis, encephalitis SIGNS & SYMPTOMS ▪ Early infection ▫ Fever, headache, malaise, myalgias, arthralgias, nausea (without vomiting), edema (esp. in children) ▪ Rash development (hallmark of infection) ▫ Blanching, erythematous rash ▫ Macules (1–4mm) → petechiae ▫ Ankles, wrist → truncal spread → palms, soles rash (characteristic of late-stage disease) ▪ Confusion, conjunctival erythema, seizures, focal neurologic deficit ▪ Fundoscopic examination ▫ Retinal vein engorgement, arterial occlusion, flame hemorrhage DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Interstitial infiltrates Echocardiogram ▪ Minimal myocardial dysfunction with normal capillary wedge pressure ▪ Consistent with noncardiogenic nature of pulmonary edema (commonly present) ▪ Advanced disease ▫ Hyponatremia (sign of central nervous system involvement); transaminitis; ↑ bilirubin; azotemia (due to hypovolemia); ↑ prothrombin, partial thromboplastin times ▪ CSF ▫ Pleocytosis (monocytic, polymorphonuclear predominance possible), ↑ protein OTHER DIAGNOSTICS ▪ History ▫ Residence in/travel to endemic area; recollection of tick bite (only 30% of individuals recollect bite) TREATMENT MEDICATIONS ▪ Early treatment: prompt, empiric antimicrobial therapy with doxycycline (first-line), chloramphenicol (second-line) ▫ Even if mild symptoms (due to potential lethality of bacterial strain); recommended for pregnant individuals, children ▫ Goal: initiate < five days after symptom onset ▫ Duration: until three days after resolution of febrile illness; minimum seven days ▪ Antiemetics, antimotility agents (individuals intolerant of doxycycline) OTHER INTERVENTIONS ▪ Hemodynamic monitoring in ICU setting; respiratory support; renal replacement therapy, blood transfusions ▪ Prevention ▫ Vigilant detection, early removal of ticks, proper clothing LAB RESULTS ▪ Thrombocytopenia (worsens with progression of disease) 214 AfraTafreeh.com exclusive RICKETTSIA TYPHI (MURINE TYPHUS) osms.it/rickettsia-typhi PATHOLOGY & CAUSES ▪ Rat-borne zoonotic disease transmitted to humans via flea; flu-like illness; minority of individuals require ICU-level care ▫ AKA murine, endemic, flea-borne typhus Transmission ▪ Zoonotic reservoir: Rattus typhi ▪ Vector: Xenopsylla cheopis (AKA Oriental rat flea) Life cycle ▪ Flea feeds on infected rodent → lifetime infection → fecal bacterial shedding → human contact with flea feces through breaks in skin barrier/inhalation → human disease ▫ Further human infection occurs via body lice passed human-to-human ▪ Replicates in high titers in yolk sacs of embryonated chicken eggs Pathogenesis (not well elucidated) ▪ Perivascular infiltration with lymphocytes, macrophages, plasma, mast cells (on biopsy) ▪ Vasculitis (rare) ▫ Accompanied by mural/intimal thrombi; heart, lungs, kidneys, central nervous system (CNS) ▪ Disease ▫ Mild, flu-like illness RISK FACTORS ▪ Warmer climates, seaports, major commercial areas COMPLICATIONS ▪ Shock, sepsis, myocarditis, renal/respiratory failure, severe hemolysis (associated with G6PD deficiency) ▪ Neurological ▫ Meningitis, meningoencephalitis, facial paralysis, hearing loss, ocular abnormalities SIGNS & SYMPTOMS ▪ Fever (8–16 days after exposure), chills, headache (commonly frontal), myalgia, rash (concurrent with fever; maculopapular, less commonly petechial; spares face, palms, soles), nausea, vomiting DIAGNOSIS LAB RESULTS ▪ ↑ erythrocyte sedimentation rate (ESR) ▪ Left shifted leukocyte count (absolute neutropenia/lymphopenia possible) ▪ Abnormal hepatic enzymes ▪ Electrolytes ▫ Hyponatremia, hypokalemia, ↑ serum creatinine TREATMENT MEDICATIONS ▪ Prompt doxycycline antimicrobial therapy ▪ Ciprofloxacin (viable alternative) OTHER INTERVENTIONS Prevention ▪ Rodent, flea eradication ▪ Rat-proofing homes, food service areas ▪ Protective clothing for occupational exposure to rats 215 Chapter 2 Acyanotic Defects NOTES RODS MICROBE OVERVIEW ▪ Rod shaped bacteria (bacilli), Gramnegative, non-spore forming BACTEROIDES FRAGILIS osms.it/bacteroides-fragilis PATHOLOGY & CAUSES ▪ Flora of oral cavity, GI tract (primarily large intestine), genitourinary tract of individuals who are biologically female; responsible for variety of infections ▪ Obligately anaerobic, non-motile ▪ Beta lactamase positive → resistance to beta lactam antibiotics ▪ Fastidious → difficult to isolate ▪ Grows in 20% bile ▪ Usually involved in widespread polymicrobial anaerobic Gram-negative bacilli infections (AGNB) ▫ Intra-abdominal, skin/soft tissue, pulmonary RISK FACTORS ▪ Prior antibiotic use ▪ ↓ blood supply (e.g. trauma, malignancy, surgery, shock, vascular disease) ▪ Tissue necrosis ▪ Disruption of intestinal mucosa ▪ High risk for aspiration pneumonia (e.g. alcoholism, coma, stroke) ▪ Bronchial obstruction → lung abscesses SIGNS & SYMPTOMS ▪ Foul-smelling discharge, tissue necrosis, formation of abscesses, gas production in tissues/discharges DIAGNOSIS DIAGNOSTIC IMAGING CT scan ▪ Abscesses/presence of gas in infected site ▫ Highly suggestive of anaerobic infection LAB RESULTS ▪ Rapid enzymatic test ▪ Polymerase chain reaction (PCR) assays ▪ Direct needle aspiration 216 TREATMENT MEDICATIONS ▪ Antimicrobials ▫ Recovered anaerobes mixed with aerobic organisms; clindamycin, metronidazole, carbapenems, tigecycline, beta-lactam/beta-lactamase inhibitors, cefoxitin SURGERY ▪ Drain abscesses, relieve obstructions BARTONELLA HENSELAE osms.it/bartonella-henselae PATHOLOGY & CAUSES ▪ Zoonotic microbe; affects skin (most common), regional lymph nodes, internal organs (e.g. liver, spleen); small, pleomorphic; fastidious, slow growing; requires specific culture conditions; grows in lysis centrifugation tubes; detected with Warthin–Starry (WS)/silver stain ▪ Natural reservoir ▫ Domestic cats, usually young cats ▪ Mode of transmission ▫ Infection follows cat scratch, bite, exposure to cat feces/fleas Commonly associated diseases ▪ Cat-scratch disease (CSD) ▫ Usually affects children ▪ Bacillary angiomatosis (BA) ▫ Rare vasoproliferative disorder; usually occurs in severely immunocompromised individuals (e.g. due to HIV) COMPLICATIONS CSD ▪ Lymph nodes necrosis; can disseminate, cause life-threatening complications involving visceral organs (e.g. liver, spleen), central nervous system (CNS), eyes BA ▪ Potentially fatal if untreated SIGNS & SYMPTOMS ▪ May be asymptomatic CSD ▪ Usually develops 1–3 weeks after inoculation ▪ Regional lymphadenopathy/lymphadenitis (most common) ▫ Usually unilateral; lymph nodes drain site of inoculation; tender, swollen lymph nodes ▪ Rare ▫ Low grade fever, malaise, ↓ appetite, abdominal aches ▪ Cutaneous erythematous lesion at site of inoculation; regresses spontaneously after 1–4 weeks ▪ Visceral organs → hepatomegaly, splenomegaly ▪ Eyes → neuroretinitis, parinaud oculoglandular syndrome ▪ Central nervous system (CNS) → encephalopathy BA ▪ Usually affects skin → red papules, nodules/ subcutaneous masses DIAGNOSIS LAB RESULTS ▪ Difficult to culture; incubation takes 2–4 weeks ▪ PCR assays 217 Chapter 96 Rods Biopsy ▪ CSD: granulomatous inflammation of lymph nodes, stellate microabscesses; organisms visualized using WS/silver stain ▪ BA: biopsy of lesions; Bartonella demonstrated with WS stain Serologic test ▪ Indirect immunofluorescence antibody (IFA)/enzyme immunoassay (EIA) Nonspecific findings ▪ ↑ erythrocyte sedimentation rate (ESR), ↑ C-reactive protein (CRP) in CSD OTHER DIAGNOSTICS ▪ Clinical findings suggestive of Bartonella infection with history of contact with cat Figure 96.1 The histological appearance of an lymph node excised from an individual with cat-scratch disease. There are numerous neutrophils which form characteristic stellate, or star-shaped, microabscesses. TREATMENT MEDICATIONS CSD ▪ Usually self-limited within 2–4 months; antimicrobial therapy with azithromycin prevents life-threatening complications; alternative agents include doxycycline, rifampin BA ▪ Erythromycin, doxycycline, tetracycline Figure 96.2 The histopathological appearance of bacillary angiomatosis. There is a proliferation of small capillaries surrounded by mixed inflammatoru cells, histiocytes and bacterial colonies. 218 ENTEROBACTER osms.it/enterobacter PATHOLOGY & CAUSES ▪ Opportunistic microbe; nosocomial, various organ system infections; Enterobacteriaceae family; motile, nonfastidious; fast lactose fermenter, pink colonies on MacConkey agar (lactose containing medium); grows in aerobic, anaerobic conditions, rapidly on selective, nonselective agars; expresses fimbria; hemolysin, urease positive ▪ Commonly isolated species: E. cloacae, E. aerogenes ▪ Natural reservoir ▫ Soil, water, intestinal flora; occasionally respiratory tract ▪ Mode of transmission ▫ Endogenous: transfer from flora to adjacent sterile sites ▫ Exogenous: direct/indirect contact of mucosal surfaces with Enterobacter Commonly associated diseases ▪ Lower respiratory tract infections ▫ Tracheobronchitis, pneumonia, lung abscess, empyema ▪ Urinary tract infections (UTIs) in hospitalized individuals ▫ Cystitis, pyelonephritis, prostatitis ▪ Bloodstream infections (BSI) ▪ Skin, soft tissue infections ▫ Cellulitis, fasciitis, myositis, skin abscesses, wound infections ▪ Intra-abdominal infections ▫ Abscesses, peritonitis following intestinal perforation/surgery ▪ Uncommon ▫ Endocarditis, septic arthritis, osteomyelitis, CNS, ocular infections ▪ Prolonged hospitalization ▪ Invasive procedures (e.g. post-surgery infections) ▪ Prior antibiotic therapy ▪ Invasive devices (e.g. venous catheterization) ▪ Underlying conditions ▫ Malignancy, chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), burns ▪ Mechanical ventilation ▪ Immunosuppression COMPLICATIONS ▪ Septic shock SIGNS & SYMPTOMS ▪ Non-specific, depends upon organ system affected ▪ UTIs ▫ Frequency, urgency of urination, dysuria DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Respiratory infections Abdomen CT scan/ultrasound ▪ Abdominal infections LAB RESULTS ▪ Urinalysis for UTIs Microbe identification ▪ Gram staining, culture RISK FACTORS ▪ More common in neonates, elderly individuals 219 Chapter 96 Rods TREATMENT MEDICATIONS ▪ Antimicrobials ▫ Carbapenems, aminoglycosides, fluoroquinolones, trimethoprimsulfamethoxazole, polymyxins SURGERY ▪ Drain abscesses OTHER INTERVENTIONS ▪ Remove invasive devices (e.g. central venous catheters) ESCHERICHIA COLI osms.it/escherichia-coli PATHOLOGY & CAUSES ▪ Frequent cause of variety of infections; Enterobacteriaceae family; encapsulated, motile; certain strains hemolytic (betahemolytic on blood agar); fast lactose fermenter (pink colonies on MacConkey agar); nonfastidious; beta-galactosidase positive (breaks down lactose into glucose, galactose); iron uptake system ▪ AKA E.Coli ▪ Natural reservoir ▫ Intestinal, vaginal flora ▪ Mode of transmission ▫ Person-to-person contact, contaminated food/water, dislocation from intestinal tract ▪ Growing conditions ▫ On selective media; aerobic, anaerobic; eosin-methylene blue (EMB) agar for isolation (colonies with green metallic sheen); 15–45°C/59–113°F (some strains more heat resistant) ▪ Virulence factors ▫ Fimbriae, K-capsule, lipopolysaccharides (LPS) endotoxin ▪ Pathogenic factors ▫ Fimbriae → cystitis, pyelonephritis ▫ K-capsule → pneumonia, neonatal meningitis ▫ LPS endotoxin → septic shock Commonly associated diseases ▪ Genitourinary tract infections ▫ Leading cause of cystitis, pyelonephritis, prostatitis ▪ Intra-abdominal infections ▫ Enteric infections, abscesses, cholecystitis, spontaneous bacterial peritonitis (E. coli most common cause) ▪ Pneumonia ▪ Meningitis (in neonates) TYPES Enteroinvasive (EIEC) ▪ Invades intestinal mucosa → necrosis, inflammation → dysentery Enterotoxigenic (ETEC) ▪ Heat-labile toxin (LT) → over-activates adenylate cyclase (cAMP) → ↑ Cl- secretion in gut, water efflux ▪ Heat-stable toxin (ST) → overactivates guanylate cyclase (cGMP) → ↓ resorption of NaCl, water in gut ▪ Produces LT, ST → travellers’ diarrhea (watery), mimics Vibrio cholerae illness Enteropathogenic (EPEC) ▪ Adheres to apical surface, flattens villi, prevents absorption → diarrhea Enterohemorrhagic (EHEC) ▪ Most commonly isolated serotype O157:H7 ▪ Produces Shiga-like toxin → enhances cytokine release ▫ Necrosis, inflammation → dysentery ▫ Endothelial damage → formation of microthrombi → hemolysis 220 (microangiopathic hemolytic anemia), platelet consumption (thrombocytopenia), ↓ renal blood flow (acute renal failure) → hemolytic uremic syndrome (HUS) ▫ O157:H7 most common serotype SIGNS & SYMPTOMS ▪ Depends on organ system affected ▪ Clinical manifestations generally nonspecific, except in enteric infections ▫ EHEC: bloody diarrhea, malaise, fever ▫ EIEC: dysentery, mimics shigellosis; bloody diarrhea, abdominal pain, tenesmus ▫ ETEC: watery diarrhea (travellers’ diarrhea), nausea, abdominal pain ▫ EPEC: fever, watery diarrhea; can last > two weeks; typically affects children DIAGNOSIS LAB RESULTS ▪ Culture to isolate E. coli, gram staining, ↑ fecal leukocytes (except ETEC), PCR assays ▪ Complete blood count ▫ Leukocytosis ▪ Urinalysis in UTIs ▪ Pyuria ▫ Leukocyte esterase + → evidence of white blood cell (WBC) activity ▪ Proteinuria, bacteriuria ▪ Nitrite test + → ↓ urinary nitrates → marker of infection TREATMENT MEDICATIONS ▪ Antimicrobial treatment (UTIs, pneumonia, meningitis, intra-abdominal infections, sepsis) ▫ Third-generation cephalosporins, quinolones, doxycycline, trimethoprim/ sulfamethoxazole (TMP/SMZ) ▪ Antidiarrheal medications ▫ Contraindicated in children, EIEC infections ▪ EHEC ▫ Antibiotics contraindicated; can increase risk of HUS, thrombotic thrombocytopenic purpura (TTP) complications ▪ ETEC ▫ Antibiotics useful; reduce diarrhea duration OTHER INTERVENTIONS ▪ Most enteric infections self-limited, managed conservatively ▫ Fluid, electrolytes correction 221 Chapter 96 Rods KLEBSIELLA PNEUMONIAE osms.it/klebsiella-pneumoniae PATHOLOGY & CAUSES ▪ Causative agent of infections, usually occur in immunocompromised individuals; major cause of hospital-acquired infections; Enterobacteriaceae family, facultative anaerobe, nonmotile; possesses prominent polysaccharide capsule; beta-lactamase positive (resistant to ampicillin, amoxicillin; susceptible to cephalosporins); urease positive, lactose fermenter, iron uptake system ▪ Natural reservoir ▫ Flora of human mouth, intestine; soil, water Commonly associated diseases ▪ Pulmonary infections ▫ Pneumonia, empyema, lung abscesses, bacteremia ▪ UTIs ▫ Cystitis, pyelonephritis, prostatitis, abscesses ▪ Pyogenic liver/splenic abscesses ▪ Infective endocarditis ▪ Spontaneous bacterial peritonitis ▪ Endophthalmitis ▪ CNS infections ▪ Meningitis, brain abscesses ▪ Deep neck infections ▪ Skin, soft tissue infections COMPLICATIONS ▪ Pneumonia can be fatal regardless of treatment SIGNS & SYMPTOMS ▪ Pneumonia presents as bronchopneumonia/bronchitis (acute onset of symptoms) ▫ Productive cough (e.g. mucoid; bloody sputum, AKA “currant jelly sputum”), high grade fever, chills, chest pain, dyspnea, tachypnea, crackles ▪ UTIS (frequency, urgency, dysuria) DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Findings suggestive of pneumonia LAB RESULTS ▪ Complete blood count ▫ Leukocytosis ▪ Specimen culture ▫ E.g. blood, sputum, urine ▫ Gram stain: Gram-negative, rod-shaped capsule appears as clear space TREATMENT RISK FACTORS ▪ Prolonged hospitalization ▪ Prior use of antibiotics ▪ Prolonged use of invasive devices (e.g. catheters) ▪ Underlying medical conditions ▫ Alcoholism, DM, underlying malignancy, hepatobiliary disease, COPD, renal failure ▪ Use of glucocorticoids MEDICATIONS ▪ Antimicrobial therapy ▫ Beta-lactams with beta-lactamase inhibitors, cephalosporins, fluoroquinolones, aminoglycosides, carbapenems SURGERY ▪ Drain abscesses ▪ Debride necrotic issues 222 LEGIONELLA PNEUMOPHILA osms.it/legionella-pneumophila PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Gram-negative, facultative intracellular (stain poorly with Gram stain); best visualized by silver stain; appears in specimens as short rod; longer, filamentous in culture; grows best on charcoal yeast extract medium with cysteine, iron; serogroup 1 most commonly associated with human infections ▪ Natural reservoir ▫ Water sources (e.g. air conditioning systems, tubing systems of domestic water supplies, water-cooling towers) ▪ Mode of transmission ▫ Water aerosol inhalation Legionnaires’ disease ▪ Incubation period ▫ 2–10 days ▪ Atypical pneumonia ▫ Mild cough (may cough bloody mucus), high grade fever, chills, dyspnea, chest pain, rales ▪ GI ▫ Diarrhea, nausea, vomiting, abdominal pain ▪ CNS ▫ Confusion, lethargy, headache, focal neurologic signs, hallucinations Commonly associated diseases ▪ Legionnaires’ disease ▫ Atypical form of pneumonia ▪ Pontiac fever ▪ Rare self-limited upper respiratory tract infection ▪ Extrapulmonary disease (rare) ▫ Heart most common extrapulmonary site (e.g. myocarditis, endocarditis) Pontiac fever ▪ Acute onset ▪ Mild, febrile, flu-like syndrome RISK FACTORS ▪ ↑ age, immunosuppression, smoking, chronic lung disease, organ transplant, renal failure, cardiac disease COMPLICATIONS ▪ Pneumonia ▫ Progresses rapidly, can be fatal (esp. immunosuppressed individuals) ▪ Renal failure DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray/CT scan ▪ Legionnaires’ disease ▫ Unilateral ▪ Diffuse, patchy inflammation of interstitium → consolidation involving ≥ one lobe LAB RESULTS ▪ Nonspecific findings ▫ Hyponatremia, thrombocytopenia, leukocytosis, hypophosphatemia ▪ Culture of respiratory specimens ▫ Many neutrophils, few microorganisms ▪ Urinary antigen test using enzyme-linked immunosorbent assay (test of choice along with culture) ▫ Rapid; sensitive, specific; legionella persists in urine for weeks 223 Chapter 96 Rods ▪ Fluorescent antibody test on sputum specimens ▪ Serological tests ▫ Serum antibodies develop after 8–10 days; fourfold rise in titre/single high titre ▪ PCR using sputum/other specimens (less sensitive than culture) TREATMENT MEDICATIONS ▪ Atypical pneumonia ▫ Macrolides, tetracyclines. fluoroquinolones, rifampicin OTHER INTERVENTIONS ▪ Eradication of organism from responsible water source to control disease NONTYPHOIDAL SALMONELLA osms.it/nontyphoidal-salmonella PATHOLOGY & CAUSES ▪ Causes salmonellosis (foodborne gastroenteritis); Enterobacteriaceae family; motile; encapsulated; facultative intracellular, anaerobes; nonlactose fermenter; oxidase-; possesses type III secretion system, iron uptake system; high infectious dose; H2S production on TSI agar; produces endotoxin ▪ Most common human pathogen ▫ S.enteritidis ▪ Natural reservoir ▫ Humans, animals; poultry, eggs, pets, turtles common sources ▪ Mode of transmission ▫ Food (e.g. undercooked meat, poultry, eggs, milk), fecal-oral route RISK FACTORS ▪ Age (usually affects young children, older adults); season (peak incidence in summer, fall); low gastric acidity (atrophic gastritis, use of acid-suppressive agents); immunodeficiency; sickle cell disease; hemolytic anemia; alcoholism; cardiovascular dysfunction; malignancies; IV drug use COMPLICATIONS ▪ Can disseminate via blood → extraintestinal manifestations (e.g. endocarditis, vascular infections, cholecystitis, hepatic/splenic abscesses) SIGNS & SYMPTOMS ▪ Present 24–48 hours after food ingestion ▪ Loose stools/diarrhea often bloody (can persist for two weeks) ▪ Nausea, vomiting ▪ Fever (resolves within two days) ▪ Abdominal cramps DIAGNOSIS LAB RESULTS ▪ Stool culture, ↑ fecal leukocytes, blood cultures to detect bacteremia; bone marrow aspiration, culture TREATMENT MEDICATIONS ▪ Antimicrobial therapy ▫ Generally not required, prolongs duration of fecal shedding of Salmonella, doesn’t shorten duration of symptoms 224 ▪ Antibiotics ▫ Only indicated in immunocompromised individuals; antimicrobial agents (e.g. ciprofloxacin) PROTEUS MIRABILIS osms.it/proteus-mirabilis PATHOLOGY & CAUSES ▪ Common cause of community acquired, nosocomial UTIs (e.g. primarily cystitis, pyelonephritis) ▪ Enterobacteriaceae family; highly motile; nonlactose fermenters; oxidase negative; expresses mannose-resistant hemagglutination, calcium dependent/ independent hemolysins; swarming growth in discontinuous manner on agar media; H2S production on TSI agar; resistance to polymyxins, tetracyclines ▪ Urease positive → converts urea to ammonia, CO2 → ↑ urine pH → ammonia combines with magnesium, phosphate → form magnesium-ammonium-phosphate (struvite) stones ▪ Pr. mirabilis causes 90% of infections ▪ Natural reservoir ▫ Intestinal flora ▪ Virulence factors ▫ Fimbria (important for adherence to tissue) Commonly associated diseases ▪ Urethritis, acute prostatitis, pyogenic liver abscesses RISK FACTORS ▪ Hospitalization; ↑ age (most common in elderly); multiple prior UTIs; prior use of antibiotics; urinary tract surgery; urinary catheterization; structural abnormalities/ obstructions of urinary tract; underlying medical conditions (e.g. DM, chronic kidney disease); neurogenic bladder; frequent sexual activity COMPLICATIONS ▪ Abscesses, sepsis, meningitis, chronic pyelonephritis, xanthogranulomatous pyelonephritis (chronic destructive granulomatous process of renal parenchyma) SIGNS & SYMPTOMS ▪ Nonspecific, disease-dependent: symptoms commonly associated with urethritis, acute prostatitis, pyogenic liver abscesses DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/CT scan ▪ Kidneys; indicated if therapy fails X-ray ▪ Struvite stones appear radiopaque LAB RESULTS ▪ Urine culture to isolate Proteus ▪ Complete blood count ▫ Leukocytosis ▪ Urinalysis ▫ Alkaline urine pH (> 7.0), pyuria, bacteriuria 225 Chapter 96 Rods TREATMENT MEDICATIONS ▪ Uncomplicated UTIs ▫ Cystitis: TMP/SMX, nitrofurantoin, quinolones, fosfomycin ▫ Pyelonephritis: quinolone/ampicillin, gentamicin/third-generation cephalosporin ▪ Complicated UTIs ▫ E.g. diabetes, nephrolithiasis, pregnancy, anatomic abnormalities of urinary tract ▫ Therapy should be prolonged SURGERY ▪ Drainage of collections (e.g. perinephric abscesses) ▪ Removal of struvite renal calculus Figure 96.3 Proteus species spread in a swarming fashion on an agar plate. PSEUDOMONAS AERUGINOSA osms.it/pseudomonas-aeruginosa PATHOLOGY & CAUSES ▪ One of most common causes of hospitalacquired infections in immunocompromised individuals; motile; aerobic; nonlactose fermenter (derives energy from carbohydrates by oxidation); nonfastidious; oxidase, catalase, elastase, leukocidin, hemolysin positive; resistant to many antibiotics ▪ Grows on variety of culture media ▫ Colonies greenish-blue due to production of procyanin (blue), pyoverdin (yellow-green); fruity, grapelike odor ▪ Natural reservoir ▫ Water, soil sources (e.g. rivers, ponds), animals, plants, hospital equipment; hospitalized individuals asymptomatic carriers ▪ Mode of transmission ▫ Direct contact with contaminated materials/infected individuals ▪ Virulence factors ▫ Exotoxin A → inactivates elongation factor (EF-2) → inhibition of protein synthesis → death of host cells ▫ Phospholipase C → degrades membranes ▫ Endotoxin → fever, shock ▫ Mucoid exopolysaccharide → biofilm formation → protection from immune system Commonly associated diseases ▪ Pneumonia; sepsis; genitourinary tract infections; skin, soft tissue infections; ear infections (e.g. external otitis, chronic otitis media); eye infections (e.g. keratitis); GI infections; bone, joint infections (usually affects vertebral column); infective endocarditis RISK FACTORS ▪ Prolonged hospitalization, catheterization, IV drug use, severe burns, contact lenses, eye trauma 226 ▪ Mechanical ventilation/endotracheal intubation ▫ P. aeruginosa second most common cause of ventilator-associated pneumonia ▪ Cystic fibrosis (CF) → chronic infection with P. aeruginosa ▪ Immune system deficits (e.g. neutropenia, diabetes) COMPLICATIONS ▪ Sepsis/necrotizing pneumonia can be fatal in immunocompromised individuals ▪ Chronic infections in CF → bronchiectasis, pulmonary fibrosis → pulmonary failure ▪ Disseminated intravascular coagulation due to sepsis ▪ Eye infections → vision loss SIGNS & SYMPTOMS ▪ Generally nonspecific, depend on organ system ▪ Eye infections (esp. cornea) extremely painful, rapidly destructive ▪ Ecthyma gangrenosum ▫ Due to sepsis, typically appears in immunocompromised individuals ▫ Well-demarcated, black, necrotic cutaneous lesion; rapidly progressive DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Pneumonia ▫ Bilateral bronchopneumonia with nodular infiltrates with/without pleural effusion LAB RESULTS ▪ Culture (blood/other specimens) on selective media ▫ Enhances production of procyanin ▪ Oxidase test ▪ PCR assays ▪ Complete blood count ▫ Leukocytosis ▪ Serological tests ▫ Only individuals with CF/COPD TREATMENT MEDICATIONS ▪ Antimicrobial therapy ▫ Extended-spectrum penicillins, betalactamase inhibitors, aminoglycosides, carbapenems, monobactams, polymyxins, fluoroquinolones, third/ fourth-generation cephalosporins Figure 96.4 Pseudomonas species will adopt a greenish hue when cultured on cetrimide agar. 227 Chapter 96 Rods SERRATIA MARCESCENS osms.it/serratia-marcescens PATHOLOGY & CAUSES ▪ Opportunistic microbe; uncommon cause of variety of hospital-acquired infections; Enterobacteriaceae family; motile; aerobic; slow, weak lactose fermenter; urease positive (struvite stones in individuals with recurrent UTIs); catalase positive; grows on media at 30–37°C/86–99°F, utilize most carbohydrates with production of acid, gas; produces red pigment (prodigiosin) colonies on agar; often resistant to commonly used antibiotics (e.g. ampicillin, macrolides, firstgeneration cephalosporins) ▪ Natural reservoir ▫ Water, soil sources ▪ Virulence factors ▫ Fimbria, cell surface components, longchain LPS, hemolysin Commonly associated diseases ▪ Respiratory infections (e.g. pneumonia), UTIs, wound infections, CNS infections (e.g. meningitis, cerebral abscesses), intra-abdominal infections, septicemia, endocarditis, otitis externa RISK FACTORS ▪ Neonates, infants ▪ More common in individuals who are biologically male ▪ Prolonged hospitalization; catheterization (e.g. intravenous, urinary catheters); mechanical ventilation; recent surgery/ obstruction of urinary tract; cardiac valve replacement; IV drug use; immune system deficits (e.g. neutropenia, chronic granulomatous disease, DM); head trauma/ brain surgery; contact lenses COMPLICATIONS ▪ Septic shock, stroke (due to endocarditis) SIGNS & SYMPTOMS ▪ Nonspecific, depend upon disease ▪ Symptoms associated with respiratory infections, UTIs, wound infections, CNS infections, intra-abdominal infections, septicemia, endocarditis, otitis externa DIAGNOSIS DIAGNOSTICS IMAGING Chest X-ray ▪ Pneumonia Abdominal ultrasound/CT scan ▪ Abnormalities of urinary tract, intraabdominal infections, abscesses Echocardiography ▪ Valvular vegetations Brain CT scan ▪ Follow with lumbar puncture in individuals with suspected meningitis Figure 96.5 Serratia marcessens grows red colonies when cultured on agar. 228 LAB RESULTS ▪ Complete blood count ▫ Leukocytosis, ↑ neutrophils with left shift, possible anemia TREATMENT MEDICATIONS ▪ Antibiotic therapy ▫ Aminoglycosides with antipseudomonal beta-lactam ▫ If infection persists, fluoroquinolones/ carbapenems SURGERY ▪ Drainage of collections (e.g. abscesses) SHIGELLA osms.it/shigella PATHOLOGY & CAUSES ▪ Causes acute infectious diarrhea (shigellosis), one of most common causes of bloody diarrhea; Enterobacteriaceae family; facultative anaerobe; nonmotile; nonlactose fermenter; urease, oxidase negative; resistance to low pH of gastric acids; highly virulent; possesses virulence plasmids; invades colonic mucosa via microfold (M) cells of Peyer patches ▪ Natural reservoir ▫ Human only; part of intestinal tract flora ▪ Mode of transmission ▫ Usually fecal-oral route, contaminated water, food; easy person-to-person spread TYPES ▪ S. dysenteriae: serogroup A ▫ Releases Shiga toxin, causes most severe form of shigellosis ▪ S. flexneri: serogroup B ▪ S. boydii: serogroup C ▪ S. sonnei: serogroup D COMPLICATIONS hypokalemia) ▪ Reiter’s syndrome ▫ Reactive arthritis, urethritis, conjunctivitis ▫ Affects HLA-B27+ individuals ▪ Hemolytic-uremic syndrome ▫ Hemolytic anemia, thrombocytopenia, acute renal failure ▫ Usually in infections due to S. dysenteriae ▪ Toxic megacolon ▪ Intestinal obstruction SIGNS & SYMPTOMS ▪ Incubation period ▫ 2–3 days/one week ▪ Sudden onset ▫ Abdominal pain ▫ Diarrhea that is initially watery, progresses to bloody (bacillary dysentery) in 50% of cases ▫ Tenesmus ▫ Fever, malaise, headache, anorexia ▪ Less common ▫ Nausea, vomiting ▪ Dehydration (due to fluid loss) ▪ Electrolyte imbalance (e.g. hyponatremia, 229 Chapter 96 Rods ▪ Subacute presentation in minority of individuals ▫ Several weeks of waxing/waning diarrhea DIAGNOSIS DIAGNOSTIC IMAGING Colonoscopy ▪ Hemorrhagic, ulcerated mucosa ▪ Most prominent in left colon, ileum also involved ▪ Pseudomembranes TREATMENT MEDICATIONS ▪ Antimicrobial therapy ▫ Shorten duration of symptoms, reduce fecal shedding of organisms, risk of complications; azithromycin orally, thirdgeneration cephalosporin parenterally ▪ Antidiarrheal medications contraindicated ▫ Delay fecal shedding of Shigella OTHER INTERVENTIONS ▪ Most cases self limited (resolve within one week), do not require antibiotics LAB RESULTS ▪ Stool culture ▪ ↑ leukocytes, blood in feces ▪ PCR testing of stools YERSINIA MARCESCENS osms.it/yersinia-marcescens PATHOLOGY & CAUSES ▪ Enterobacteriaceae family; facultative anaerobe, intracellular; motility depends on temperature (motile at 25°C/77°F, nonmotile at 37°C/99°F); nonlactose fermenter; oxidase negative ▪ Important human pathogens ▫ Y. pestis, Y.enterocolitica ▪ Natural reservoir ▫ Y. pestis: ground squirrels, gerbils, voles, rats ▫ Y. enterocolitica: cattle, deer, pigs, birds, pigs ▪ Virulence factors ▫ Adhesins to bind to host cell beta 1 integrins, endotoxin, coagulase, fibrinolysin, iron uptake system (mediates iron capture, transport) TYPES Yersinia enterocolitica ▪ Causes yersiniosis ▫ Gastrointestinal infections (e.g. ileum, appendix, right colon) ▪ Common types ▫ Enterocolitis, terminal ileitis, mesenteric lymphadenitis, pseudoappendicitis ▪ Mode of transmission ▫ Pet feces, inadequately cooked foods, contaminated pork, milk, water Yersinia pestis ▪ Causes human plague ▫ Zoonotic infection, highly fatal if untreated ▪ Subtypes ▫ Wild (sylvatic), urban plague (typically transmitted from rats, more severe) 230 ▪ Clinical forms ▫ Bubonic (more common), septicaemic, pneumonic (least common, high mortality rate) ▪ Mode of transmission ▫ Fleas from rats, other rodents COMPLICATIONS Yersinia enterocolitica ▪ Reiter’s syndrome, myocarditis, erythema nodosum, kidney disease, mucosal ulceration, bowel necrosis (due to mesenteric vessel thrombosis), septicemia (fatal if untreated) Yersinia pestis ▪ Bubonic plague → sepsis → secondary pneumonic plague/meningitis ▪ Systemic plague → hypotension, disseminated intravascular coagulation, multiorgan failure ▪ Pneumonic plague (rapidly fatal if untreated) SIGNS & SYMPTOMS Yersinia enterocolitica ▪ Enterocolitis (most common) ▫ Abdominal pain, acute diarrhea, low grade fever, nausea, vomiting ▪ Abdominal tenderness ▫ Right lower quadrant, mimics appendicitis (pseudoappendicitis) ▪ Extraintestinal features of pharyngitis, arthralgia, erythema nodosum (painful, red/ purple lesions, resolve spontaneously) Yersinia pestis ▪ Incubation period ▫ 2–8 days ▪ Bubonic plague (sudden onset) ▫ fever; painful lymphadenopathy (bubos), inguinal lymph nodes frequently involved; chills, fatigue ▪ Septicemic plague ▫ Fever; malaise, GI symptoms (nausea, vomiting, diarrhea) ▪ Pneumonic plague (sudden onset): ▫ Dyspnea, high grade fever, chest pain, cough with blood-containing sputum DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound/CT scan ▪ Yersinia enterocolitica: exclude appendicitis Colonoscopy ▪ Yersinia enterocolitica: aphthoid lesions in cecum; elevations, ulcers in terminal ileum Chest X-ray ▪ Yersinia pestis: pneumonic plague LAB RESULTS Yersinia enterocolitica ▪ Identification of microbe ▪ Stool culture ▫ Cefsulodin-irgasan-novobiocin (CIN) agar ▫ In extraintestinal disease, cultures of lymph nodes/blood may be positive ▪ PCR assays ▪ ↑ leukocytes in stool, blood ▪ Serological tests ▫ Tube agglutination, enzyme-linked immunosorbent assay (ELISA) Yersinia pestis ▪ Nonspecific findings ▫ Leukocytosis, thrombocytopenia ▪ Isolation of organism in blood culture ▫ Positive cultures in individuals with bubonic, septicemic plague ▪ Peripheral blood smear ▫ Wright–Giemsa stain reveals rodshaped bacteria, Wayson stain reveals characteristic “safety pin” appearance ▪ Rapid antigen testing in sputum/serum ▪ Serological tests ▫ Fourfold rise in serum antibody titers between acute, convalescent phase ▪ PCR assays 231 Chapter 96 Rods OTHER DIAGNOSTICS Yersinia pestis ▪ Clinical findings suggestive of plague, history of traveling to plague-endemic areas TREATMENT MEDICATIONS Yersinia enterocolitica ▪ Antimicrobial therapy ▫ TMP/SMX, aminoglycosides ▫ Alternative agents: third-generation cephalosporins, tetracyclines, fluoroquinolones Figure 96.6 The black, necrotic fingers of a man infected with Yersinia pestis. Yersinia pestis ▪ Antimicrobial therapy ▫ Aminoglycosides (streptomycin/ gentamicin) ▫ Alternative agents: doxycycline, tetracycline, fluoroquinolones, chloramphenicol OTHER INTERVENTIONS Yersinia enterocolitica ▪ ↑ fluid intake, good nutrition 232 NOTES NOTES SPIROCHETES MICROBE OVERVIEW Morphology ▪ Thin-walled, Gram-negative flexible spiral rods ▪ Length: 5–250μm; diameter: 0.1–0.6μm ▪ Unique double membrane separated by periplasmic space ▪ Corkscrew-like motility via axial filament situated lengthwise between inner and outer membranes (endoflagella) Replication ▪ Reproduction: sexual transverse binary fission BORRELIA BURGDORFERI (LYME DISEASE) osms.it/lyme-disease PATHOLOGY & CAUSES ▪ An obligate parasite that causes Lyme disease, a systemic inflammatory disease ▪ Non-spore forming ▪ Life cycle includes mammals, birds, and ticks (genus Ixodes), principally in North America ▪ Killed when exposed to hypotonic or hypertonic environments, drying, disinfectants (e.g. bleach), or temperatures > 50°C/122°F ▪ Transmission ▫ Via tick bite → enters blood → spreads to tissues and organs; especially joints, heart, nervous system ▪ Infection progresses through three stages 1. Localized disease (occurs 3–30 days after exposure) 2. Disseminated disease (days to months after exposure; multisystem involvement) 3. Late/chronic disease (months to years after exposure) RISK FACTORS ▪ Exposure to ticks in endemic areas ▫ Living in areas bordering forests ▫ Outdoor employment, recreation ▪ Most cases occur in late spring to summer COMPLICATIONS ▪ Meningitis, cranial neuropathy ▪ Lyme carditis ▫ AV block, myopericarditis ▪ Chronic joint inflammation ▪ Post–Lyme disease syndrome SIGNS & SYMPTOMS Early signs/symptoms of localized disease ▪ Erythema migrans (EM) rash ▫ Non-painful, gradually expanding “bull’s-eye” rash appearing at the site of tick bite; feels warm to palpation; may itch 233 Chapter 97 Spirochetes ▪ Constitutional ▫ Low grade fever, chills, headache, fatigue, myalgia, arthralgia, lymphadenopathy Disseminated signs/symptoms ▪ Severe headaches and neck stiffness ▪ Formation of additional EM ▪ Joint pain and swelling; especially knees, other large joints ▪ Facial palsy ▪ Palpitations (Lyme carditis) ▪ Episodic dizziness, dyspnea ▪ Pain ▫ Shooting pains, numbness, or tingling in the hands or feet ▪ Short-term memory loss Late/chronic disease ▪ Presence of nonspecific symptoms (e.g. headache, fatigue, joint pain) that persists after treatment for Lyme disease DIAGNOSIS LAB RESULTS CDC testing criteria ▪ Two tiered testing for lyme disease ▫ First test: enzyme immunoassay (EIA) or immunofluorescence assay (IFA) ▫ Second test (as needed): IgM and/or IgG western blot Other laboratory findings ▪ Blood chemistry ▫ ↑ ESR, serum creatine phosphokinase, aspartate aminotransferase (AST) and/ or alanine aminotransferase (ALT) ▪ Blood studies ▫ Anemia, leukocytosis, thrombocytopenia OTHER DIAGNOSTICS ▪ History of exposure to ticks in an endemic area and characteristic clinical presentation TREATMENT MEDICATIONS ▪ Antibiotics ▫ Doxycycline, amoxicillin, or cefuroxime axetil Figure 97.1 A bulls-eye-shaped rash, known as erythema migrans, at the site of infection with Borellia burgdorferi, the causative agent of Lyme disease. 234 BORRELIA SPECIES (RELAPSING FEVER) osms.it/borrelia-species PATHOLOGY & CAUSES ▪ Relapsing fever: bacterial infection caused by Borrelia spirochetes Tick-borne relapsing fever (TBRF) ▪ Endemic ▪ Found in endemic areas ▫ Mountainous areas of North America, plateau regions of Mexico, Central and South America, Mediterranean, central Asia, Africa ▪ Caused primarily by Borrelia hermsii, Borrelia turicatae, Borrelia parkeri in North America ▪ Spread by soft tick species Ornithodoros parkeri and Ornithodoros turicata ▪ Risk factors ▫ Occupying rodent-infested cabins, caves, or other dwellings ▫ Camping near rodent nests ▪ Tick attaches to human host (usually at night during sleep) → bites and feeds on blood → saliva and spirochete enter host’s circulation Louse-borne relapsing fever (LBRF) ▪ Epidemic ▪ Caused by Borrelia recurrentis ▪ Spread person-to-person via body louse ▪ Risk factors ▫ Primarily seen in low resource countries ▫ Famines, wars; causes epidemics among refugees, migrant populations ▫ Homelessness (exposure to lice) ▫ Poor hygiene ▪ B. recurrentis grows in the body cavity Pediculus humanus corporis → human host crushes louse/louse feces with fingers → spirochete enters either through bite site, through breaks in the skin caused by scratching, or through conjunctiva when fingers touch eyes After entry into human host ▪ Spirochete divides every 6–12 hours (can number up to 106–108 per mL) → leaves blood and enters tissues: brain, eye, inner ear, liver, heart, testes, and other organs Pattern of intermittent illness ▪ Relapsing fever caused by spirochetemia ▪ Characterized by recurrent episodes of fever and constitutional symptoms with intermittent periods of general well-being ▫ Interval range between fevers is 4–14 days ▫ Pattern of intermittent illness caused by outer membrane lipoproteins called variable major proteins (VMPs) ▫ Employed as multiphasic antigens to evade host adaptive immunity ▫ TBRF: multiple febrile periods last 1–3 days each ▫ LBRF: first episode lasts 3–6 days, followed by a single milder episode Complications ▪ Neurological ▫ Meningitis, subarachnoid hemorrhage, cranial nerve neuritis, Bell’s palsy, hearing loss ▪ Ocular ▫ Iridocyclitis, panophthalmitis, vision loss ▪ Cardiac ▫ Myocarditis, cardiac failure ▪ Respiratory ▫ Bronchopneumonia, acute respiratory distress syndrome ▪ Hematologic ▫ Thrombocytopenia ▪ Other ▫ Hepatitis, splenic rupture ▪ During pregnancy 235 Chapter 97 Spirochetes ▫ Spontaneous abortion, prematurity, neonatal death ▪ Jarisch–Herxheimer reaction ▫ During treatment with antibiotics → release of proinflammatory cytokines triggered by products released from dead microbes SIGNS & SYMPTOMS ▪ Characteristics of febrile episodes ▫ Sudden onset of high fever → crisis phase: chills, ↑ ↑ temperature, ↑ HR, ↑ BP → diaphoresis, ↓ fever, ↓ BP ▫ ↑ mortality during crisis and immediate aftermath ▪ Constitutional ▫ Sudden onset of high fever and chills; followed by headache, myalgia, arthralgia, nausea ▪ Neurologic ▫ Dizziness, delirium, stupor, facial palsy ▪ Cardiac ▫ Prolonged QTc interval. ▪ Respiratory ▫ Nonproductive cough, signs of respiratory distress ▪ Hematologic ▫ Epistaxis, petechiae, ecchymoses, blood-tinged sputum ▪ Other ▫ Hepatomegaly, abdominal pain, photophobia, skin rash DIAGNOSIS LAB RESULTS Visualization of microbe ▪ Blood: thick or thin smears ▫ Giemsa, Wright, or acridine orange stain ▫ Direct or indirect immunofluorescence ▫ Phase contrast or dark field microscopy ▪ PCR, culture, serology ▪ Tissue specimen ▫ Silver stain (e.g. Warthin-Starry, modified Dieterle) ▫ Immunofluorescence TREATMENT MEDICATIONS ▪ Antibiotics ▫ Penicillin G, ceftriaxone, doxycycline OTHER INTERVENTIONS Prevention ▪ Avoidance and eradication of vector 236 LEPTOSPIRA osms.it/leptospira PATHOLOGY & CAUSES ▪ A spirochete that causes the disease leptospirosis ▫ AKA Weil's disease, Weil–Vasiliev disease, swineherd's disease, rice-field fever, waterborne fever, nanukayami fever, cane-cutter fever, swamp fever, mud fever, Stuttgart disease, canicola fever ▪ Infected mammal excretes microbe in urine which remains viable in stagnant water and wet soil → environmental exposure by humans → microbe usually enters via non-intact skin, mucous membranes, or conjunctivae (rarely via contaminated food, water, or aerosols) ▪ Effects of microbe ▫ Damages blood vessel endothelium → organ damage ▫ Inhibits the Na+-K+-Cl- cotransporter activity in the thick ascending limb of Henle → hypokalemia, hyponatremia COMPLICATIONS Electrolyte imbalance, kidney failure Hepatitis, hepatic hemorrhage Aseptic meningitis Pulmonary hemorrhage, acute respiratory distress syndrome (ARDS) ▪ Uveitis, optic neuritis ▪ Myocarditis ▪ Rhabdomyolysis ▪ ▪ ▪ ▪ ▫ Nonproductive cough ▫ Pharyngitis ▫ Myalgias, arthralgias ▫ Conjunctival suffusion (redness without exudate) ▫ Lymphadenopathy ▫ Jaundice ▫ Uremia, bacteremia, oliguria, hypokalemia DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Nodular densities, consolidation; may have a ground-glass appearance LAB RESULTS ▪ Identification of microbe ▫ PCR, ELISA, microscopic agglutination ▪ Other laboratory studies ▫ Leukocytosis with left shift ▫ Hypokalemia, hyponatremia ▫ ↑ hepatic transaminases, ↑ direct bilirubin ▫ Urinalysis: proteinuria, pyuria, granular casts, hematuria, ↑ creatine kinase ▫ CSF: neutrophilic pleocytosis, ↑ protein OTHER DIAGNOSTICS ▪ History and physical examination SIGNS & SYMPTOMS ▪ Variable clinical course ▫ Ranges from mild disease that resolves uneventfully to severe and potentially fatal ▪ Common symptoms ▫ Abrupt onset of fever, chills ▫ Headache 237 Chapter 97 Spirochetes OTHER INTERVENTIONS TREATMENT MEDICATIONS ▪ Antibiotics ▫ Doxycycline (mild cases), penicillin (severe cases) ▪ Address complications ▪ Prevention ▫ Avoidance of potential infectious sources of infection, domestic animal vaccination TREPONEMA PALLIDUM (SYPHILIS) osms.it/syphilis PATHOLOGY & CAUSES ▪ The spirochete bacterium that causes syphilis, a localized and systemic disease ▪ Transmission ▫ Sexually: by direct contact with an infectious lesion (primarily) → enters via microscopic abrasions ▫ Perinatally: crosses placenta easily → congenital syphilis ▪ Progresses through stages ▫ Primary: localized sores (chancre) appear after about three weeks at site of infection ▫ Secondary: 2–8 weeks after chancre resolution, hematogenous bacterial dissemination causes systemic symptoms ▫ Latent: asymptomatic ▫ Tertiary (late): organ damage develops 10–30 years after initial infection ▪ Neurosyphilis and ocular syphilis can occur at any stage ▫ Neurosyphilis begins when the microbe invades the CSF RISK FACTORS Unprotected sex Multiple sexual partners Biologically male Biologically-male individuals engaging in same-sex sexual contact (MSM) ▪ IV drug use ▪ Existing sexually-transmitted disease, especially HIV ▪ ▪ ▪ ▪ COMPLICATIONS ▪ Cardiovascular: syphilitic aortic aneurysms, dilated aorta, aortic valve regurgitation; coronary artery narrowing ▪ Congenital syphilis: hemolytic anemia, deafness, keratitis, periostitis ▪ Neurosyphilis: dementia, meningitis, brain or spinal cord ischemia/infarction, seizures, ischemic stroke ▪ Ocular syphilis: uveitis, vitritis, retinitis, optic neuropathy, blindness ▪ Otosyphilis: hearing loss, tinnitus SIGNS & SYMPTOMS Stages ▪ Presentation will vary according to stage of disease ▪ Primary ▫ Chancre: painless ulcers at inoculation site (in contrast to painful lesions seen in genital herpes or chancroid) ▫ Single or multiple; usually firm, round, painless ▫ Heals with or without treatment; treatment prevents progression to secondary stage ▪ Secondary ▫ May be asymptomatic ▫ Rash: diffuse rough, reddish-brown maculopapular on extremities, palms of hands and/or soles of feet, back; raised, gray-whitish lesions on mucous membranes ▫ Condylomata lata 238 ▫ Myalgia ▫ Fatigue ▫ Lymphadenopathy ▫ Fever ▫ “Moth-eaten” alopecia ▫ Resolves without treatment; treatment prevents progression to latent and tertiary stages ▪ Latent ▫ Positive serology; asymptomatic ▪ Tertiary (late) ▫ Gummas: non-cancerous, granulomatous growths on internal organs, bones, skin; more common in HIV-infected individuals ▫ Evidence of organ involvement; charcot joints, aoritis (due to destruction of vasa vasorum) Complications ▪ Neurosyphilis ▫ Meningitis: headache, nausea and vomiting, stiff neck ▫ Tabes dorsalis: muscle weakness, locomotor ataxia, ↓ proprioception, incoordination ▫ General paresis (paralytic dementia) ▫ Facial and limb hypotonia, intention tremors ▫ Forgetfulness, personality changes ▪ Ocular syphilis ▫ ↓ visual acuity; loss of vision ▫ Argyll Robertson pupil: small pupils that constrict poorly in response to direct light ▪ Serum treponemal tests ▫ Fluorescent treponemal antibody absorption (FTA-ABS) ▫ Treponema pallidum particle agglutination assay (TPPA) ▫ Syphilis enzyme immunoassays (EIAs) ▪ If neurologic symptoms, lumbar puncture and CSF examination ▫ ↑ lymphocytes, ↑ protein ▫ CSF-VDRL reactivity OTHER DIAGNOSTICS ▪ History and physical examination Figure 97.2 A painless penile chancre, seen here, is the clinical manifestation of primary syphilis. Congenital syphilis ▪ Presents with vesicular/bullous rash, rhinitis, hepatosplenomegaly, jaundice, and pseudoparalysis DIAGNOSIS LAB RESULTS ▪ Identification of microbe ▪ Serum nontreponemal tests (may be nonreactive in late neurosyphilis) ▫ Venereal disease research laboratory (VDRL) ▫ Rapid plasma reagin (RPR) Figure 97.3 Condylomata lata, seen here, are the clinical manifestation of secondary syphilis. 239 Chapter 97 Spirochetes TREATMENT MEDICATIONS ▪ Parenteral (IM/IV) penicillin G ▫ Doxycycline or tetracycline (PO); ceftriaxone (IM, IV) if penicillin allergy OTHER INTERVENTIONS ▪ Treat partners ▪ Screening during first prenatal visit (VDRL or RPR) 240 NOTES NOTES STAPHYLOCOCCUS MICROBE OVERVIEW ▪ Staphylococcus: genus of Gram-positive bacteria responsible for many diseases ▪ Aerobic, facultative anaerobic ▪ Frequent skin colonization: up to half of population Genetic material ▪ All staphylococci are catalase-positive Taxonomy ▪ Staphylo-: cluster; -coccus: berry Morphology ▪ Organized in grape-like clusters ▪ Gram stain: round, Gram-positive (purple) bacteria; thick peptidoglycan cell wall Antibiotic resistance mechanisms ▪ β-lactamase: hydrolysis of β-lactam antibiotics; some β-lactam antibiotics are resistant to the enzyme (e.g. oxacillin, nafcillin, flucloxacillin) ▪ mecA gene → penicillin binding protein (PBP2a) → reduced affinity for β-lactam antibiotics; present in methicillin-resistant strains ▪ vanA gene → modifies cell wall peptidoglycans → vancomycin cannot bind to bacteria STAPHYLOCOCCUS AUREUS osms.it/staphylococcus-aureus PATHOLOGY & CAUSES ▪ Staphylococcus aureus: common bacterium, causes infections in most organ systems ▪ Aureus: golden colonies in mannitol salt agar, due to mannitol fermentation ▪ Skin colonization: approx. 30% of population ▫ Primary colonization site: nostrils ▪ Pathogen transmission: direct contact, fomites Virulence factors ▪ Cytolysins: alpha-toxin, Panton–Valentine leukocidin (PVL); both destroy neutrophils ▫ PVL related to severe skin, lung infections ▪ Hemolysins: form pores in host cells (e.g. erythrocytes, macrophages, lymphocytes) ▪ Superantigens: enterotoxins, toxic shock syndrome toxin-1 (TSST-1) ▫ Superantigens stimulate activation of excessive amount of T-cells → increased production of cytokines → uncontrolled inflammation ▪ Epidermolytic toxins A and B: skin blistering ▪ Coagulase: activates prothrombin → coagulation ▪ Bacterial spread: protease degrades proteins; lipase degrades lipids ▪ Protein A: inactivates immunoglobulins → phagocytosis evasion ▪ Can form biofilms ▫ Biofilm: adherence of cells to polymer 241 Chapter 98 Staphylococcus surfaces (e.g. catheters) ▫ Properties allow immune evasion CAUSES ▪ Common cause of infections and toxinmediated diseases acquired from community/healthcare environment ▫ Endocarditis, ocular infections, pneumonia, meningitis, osteomyelitis, septic arthritis, prosthetic device infections, catheter-associated infections Skin/soft tissue infections ▪ E.g. surgical site infections, abscesses, impetigo, cellulitis, erysipela, fasciitis, mastitis Toxic shock syndrome (TSS) ▪ Mediated by toxic shock syndrome toxin-1; commonly caused by growth of S. aureus in vagina/surgical sites → multiple organ dysfunction Staphylococcal scalded-skin syndrome (Ritter disease) ▪ Mediated by epidermolytic toxins A and B Foodborne illness ▪ Caused by ingestion of S. aureus endotoxins SIGNS & SYMPTOMS Skin/soft tissue infections ▪ Erythema, swelling, warmth, localized warmth/fever ▫ Staphylococcal scalded-skin syndrome (Ritter disease): fever, erythema, fluidfilled bullae on the skin → skin loss Systemic infections ▪ Joint pain, abdominal pain, headache, CVA tenderness, new onset heart murmur TSS ▪ Fever, hypotension, rash, coagulopathy, tissue necrosis (site of infection) Foodborne illness ▪ Nausea, vomiting, diarrhea, abdominal pain DIAGNOSIS LAB RESULTS ▪ Culture-based observation ▫ Clustered golden Gram-positive cocci ▫ Catalase-positive; coagulase-positive ▪ Polymerase chain reaction (PCR) amplification ▪ May be guided by further studies depending on site of infection RISK FACTORS ▪ Immunosuppression, IV drug use, recent invasive procedure, foreign material in body (e.g. prosthetics, catheters, sutures), dialysis COMPLICATIONS ▪ Sepsis, bacteremia, invasive infection ▪ Antibiotic resistance: all strains resistant to penicillin G; some strains resistant to methicillin (MRSA) or vancomycin (VRSA); some strains have intermediate resistance to vancomycin (VISA) ▫ Resistant strains are common pathogens in nosocomial infections Figure 98.1 Staphylococcus takes on a golden colour when cultured with mannitol containing media. 242 TREATMENT MEDICATIONS Topical antibiotics ▪ Superficial skin infections Oral/IV antibiotics ▪ Treatment based on the pathogen’s antibiotic susceptibility ▫ Oxacillin/nafcillin/cefazolin ▫ MRSA: vancomycin/trimethoprimsulfamethoxazole ▫ VRSA: linezolid SURGERY ▪ Abscess drainage (if applicable) ▪ Foreign material removal in body (if applicable) STAPHYLOCOCCUS EPIDERMIDIS osms.it/staphylococcus-epidermidis PATHOLOGY & CAUSES ▪ Staphylococcus epidermidis: bacteria commonly associated with infections of surgical sites, indwelling catheters, and prosthetic devices ▪ Part of skin and mucous membrane natural flora ▪ Does not produce exotoxins CAUSES ▪ Skin/mucous colonization → barrier rupture → infection ▪ Can form biofilms on foreign materials in body; biofilm properties allow immune evasion ▪ Polymer surface adhesion → extracellular matrix production → polysaccharide intercellular adhesin (PIA) secretion → multi-layered bacteria ▪ Common S. epidermidis infections: catheter-associated infection, intravascular catheter infection, prosthetic joint infection, endocarditis (frequently associated with prosthetic valves), surgical site infection RISK FACTORS COMPLICATIONS ▪ Sepsis, bacteremia ▪ Neonates: pneumonia, urinary tract infections, meningitis, enterocolitis, omphalitis SIGNS & SYMPTOMS Local ▪ Pain, tenderness, swelling, warmth, erythema, drainage at incisional site Systemic ▪ Fever, hypotension, leukocytosis DIAGNOSIS LAB RESULTS Culture-based observation ▪ Blood, urine, synovial fluid, surgical site ▫ Clustered Gram-positive cocci ▫ Catalase-positive; coagulase-negative; novobiocin-sensitive PCR amplification ▪ Immunosuppression, neonates, recent invasive procedure, foreign material in the body (e.g. prosthetics, catheters), dialysis 243 Chapter 98 Staphylococcus TREATMENT MEDICATIONS SURGERY ▪ Remove foreign material from body (if applicable) Oral antibiotics ▪ Empiric treatment: vancomycin ▪ If proven methicillin sensitivity: oxacillin/ nafcillin; may be combined with rifampicin, gentamicin ▪ Fusidic acid for skin infections (if available) STAPHYLOCOCCUS SAPROPHYTICUS osms.it/staphylococcus-saprophyticus PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Staphylococcus saprophyticus: bacteria that commonly produces urinary tract infections (UTI) in young, biologicallyfemale individuals ▪ Frequently part of vagina’s natural flora ▪ Tropism for urinary tract: surface fibrillar protein (Ssp) and hemagglutinin/adhesin allow pathogen’s adherence to uroepithelial cells ▪ Does not produce exotoxins ▪ Etiologic agent: community-acquired UTIs (occasionally) ▪ Usually presents as symptomatic cystitis (bladder inflammation) ▪ Dysuria (painful urination), urinary urgency, increased urinary frequency, suprapubic pain, occasional hematuria RISK FACTORS DIAGNOSIS LAB RESULTS Urinalysis ▪ Presence of leukocytes, erythrocytes, bacteria, negative urine nitrate Culture-based observation ▪ Clustered Gram-positive cocci ▪ Catalase-positive; coagulase-negative; novobiocin-resistant ▪ Biologically-female (shorter urethra), recent sexual activity (“honeymoon cystitis”), diabetes, immunosuppression, indwelling urinary catheter Quantitative PCR COMPLICATIONS MEDICATIONS ▪ Pyelonephritis TREATMENT ▪ Oral antibiotics ▪ Symptomatic therapy (e.g. phenazopyridine) 244 AfraTafreeh.com exclusive NOTES NOTES STREPTOCOCCUS MICROBE OVERVIEW Morphology ▪ Spherical, Gram-positive bacteria; appear in chains/pairs; catalase, coagulase negative ▪ Produce extracellular substances (e.g. cytolysins, enzymes) → enhance pathogenicity STREPTOCOCCUS AGALACTIAE (GROUP B STREP) osms.it/streptococcus-agalactiae PATHOLOGY & CAUSES ▪ AKA Group B Streptococcus (GBS) ▪ Encapsulated, facultative anaerobe ▪ Colonizes human genital, gastrointestinal (GI) tracts; upper respiratory tracts of young infants ▪ Beta-hemolytic ▫ Blood agar plates, hemolysins degrade lipid membranes → colonies surrounded by narrow zone of hemolyzed cells → complete (beta-)hemolysis Virulence factors ▪ Complex capsular polysaccharides ▫ Inhibit complement deposition on microbe surface components ▪ Hypervirulent GBS adhesin (HvgA) ▫ ↑ ability to invade blood-brain barrier ▪ Cluster of virulence responder/sensor (CovR/S) mutation ▫ Accelerate failure of amniotic barrier → ↑ ability to penetrate chorioamniotic membranes ▪ Pilins ▫ Act as adhesins → ↑ ability to invade central nervous system, form biofilm ▪ Direct cytotoxicity to host phagocytes Common infectious agent ▪ Adults (nonpregnant) ▫ Broad spectrum of infections ▪ Pregnant individuals ▫ Chorioamnionitis ▪ Neonates ▫ GBS infection, sepsis RISK FACTORS ▪ Adults (nonpregnant) ▫ Chronic disease (e.g. diabetes, liver disease, malignancy; > age 65, esp. residents of nursing homes) ▪ Pregnancy ▪ Neonates ▫ Ascending infection from mother (e.g. rupture of membranes, chorioamnionitis) ▪ Hospitalization ▫ Nosocomial/hospital-acquired infections 245 Chapter 99 Streptococcus COMPLICATIONS ▪ Cystitis, pyelonephritis, urethritis, prostatitis; osteomyelitis, septic arthritis; endocarditis; meningitis; pneumonia; sepsis; toxic shock-like syndrome ▪ Neonates ▫ Preterm birth, bacteremia, sepsis, pneumonia, meningitis, neonatal mortality SIGNS & SYMPTOMS ▪ Fever, chills; malaise; cough ▪ Local tissue infection ▫ Red, warm, swollen, presence of drainage ▪ Hippurate hydrolysis test ▫ Detections hippurate hydrolysis by GBS OTHER DIAGNOSTICS ▪ Clinical history, physical examination TREATMENT MEDICATIONS ▪ Antibiotics (e.g. penicillin G, ampicillin) OTHER INTERVENTIONS ▪ Prenatal screening DIAGNOSIS LAB RESULTS Identification of microbe ▪ E.g. blood, cerebrospinal fluid ▪ Gram stain, characteristic morphology ▪ Culture ▫ Beta-hemolysis on blood agar ▪ CAMP test ▫ Identifies presence of CAMP factor ▪ Latex agglutination tests ▫ Detects antibodies produced in response to GBS Figure 99.1 The three classes of streptococcus cultured on a blood agar plate. Alpha (left) shows partial hemolysis, beta (centre) shows complete hemolysis and gamma (right) shows no hemolysis. STREPTOCOCCUS PNEUMONIAE osms.it/streptococcus-pneumoniae PATHOLOGY & CAUSES ▪ Causative agent for numerous clinical syndromes in children, older adults ▪ Alpha-hemolytic, lancet-shaped diplococci ▪ Lysis by bile (deoxycholate), optochin sensitive ▪ Fastidious; prefers 5% carbon dioxide ▪ Pyogenic ▪ Virulence factors ▫ Resistance to phagocytosis (conferred by 92 polysaccharide serotypes) ▫ Adherence proteins ▫ Biofilm formation ▫ Pneumolysin toxin ▪ Asymptomatic colonization → direct spread from site of colonization,hematogenous spread → clinical syndromes 246 ▪ Typical infections caused by S. pneumoniae range from mucosal to invasive diseases ▫ Meningitis ▫ Otitis media ▫ Pneumococcal community-acquired pneumonia ▫ Sinusitis RISK FACTORS ▪ Age (< 2, ≥ 65 years) ▪ Underlying disease (e.g. liver, kidney, heart, lung, diabetes, malignancies) ▪ Crowded conditions (e.g. daycare centers, military camps, prisons) ▪ Immunodeficiency (e.g. HIV, genetic immune defects, solid organ/bone transplant) ▪ Smoking, alcohol abuse COMPLICATIONS ▪ Pneumococcal endocarditis, empyema, bacteremia, sepsis SIGNS & SYMPTOMS ▪ Common clinical presentation ▫ Fever, altered mental status, malaise ▪ Typical findings related to clinical syndrome ▫ Meningitis: headache, neck stiffness ▫ Otitis media: ↓ tympanic membrane mobility/bulging membrane, otorrhea, pain ▫ Pneumonia: cough, bronchial breath sounds, rales ▫ Sinusitis: purulent rhinitis, mucous membrane edema, headache DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Infiltration, consolidation (pneumonia) LAB RESULTS Identification of organism ▪ Gram-positive diplococci, positive culture, polymerase chain reaction (PCR) ▪ Urine antigen analysis (bacteremia) OTHER DIAGNOSTICS ▪ Clinical history, physical examination TREATMENT MEDICATIONS ▪ Antibiotics ▫ Pneumonia: beta-lactam antibiotic ▫ Otitis media: amoxicillin-clavulanate (children) ▫ Sinusitis: amoxicillin (amoxicillin– clavulanic acid may be preferable) OTHER INTERVENTIONS Prevention ▪ Pneumococcal vaccine 247 Chapter 99 Streptococcus STREPTOCOCCUS PYOGENES (GROUP A STREP) osms.it/streptococcus-pyogenes PATHOLOGY & CAUSES ▪ AKA Group A Streptococcus (GAS) ▪ Colonizes human skin, mucous membranes ▪ Cell-wall structure ▫ Peptidoglycan backbone + lipoteichoic acid components → structural stability ▪ Beta-hemolytic ▫ Blood agar plates, hemolysins degrade lipid membranes → colonies surrounded by clear zone of hemolyzed cells → complete (beta-) hemolysis ▪ Primarily infects skin, soft tissue Virulence factors ▪ Vary with specific strain ▪ M proteins ▫ Protect microbe from humoral immune surveillance, phagocytosis by polymorphonuclear leukocytes ▪ Binding proteins ▫ Bind to IgG, IgM, IgA → may interfere with complement activation ▫ Protein F: binds to fibronectin → ↑ adherence to epithelial surfaces ▪ Cytolysins ▫ Streptolysins: bind to cholesterol on eukaryotic cell membranes → cell lysis ▫ Hyaluronidase: hydrolyzes hyaluronic acid → facilitates infection spread ▫ Streptokinase: proteolytically converts bound plasminogen to active plasmin → cleavage of fibrin; medically useful as clot-busting drug ▫ Nicotinamide adenine dinucleotidase (NADase): exact function unclear; likely ↑ invasiveness ▫ Deoxyribonuclease: promotes production of anti-deoxyribonuclease (DNase) antibody following pharyngeal/ skin infections ▪ Pyrogenic exotoxins (type A, B, C) ▫ Induce fever, act as superantigens → T-cell proliferation → ↑ cytokine production → promotes shock ▪ Streptococcal inhibitor of complement (SIC) ▫ Inactivates complement membrane attack complex ▪ Opacity factor (OF) ▫ Lipoprotein lipase Causative agent in several disorders ▪ Pyogenic diseases ▫ Pharyngitis, cellulitis (abscess formation in dermis, subcutaneous fat layers), necrotizing fasciitis (progressive destruction of deep soft tissue), impetigo ▪ Toxigenic disease ▫ Scarlet fever, toxic shock syndrome, GAS endometritis (puerperal sepsis) ▪ Immunologic disease ▫ Rheumatic fever (antibodies against streptococcal cell cross-react with cardiac tissue); poststreptococcal glomerulonephritis (immune complexes deposited in glomeruli) RISK FACTORS ▪ Susceptible host + encounter with streptococcus expressing specific virulence factors COMPLICATIONS ▪ Local spread (e.g. otitis media, sinusitis, mastoiditis); tissue destruction; valvular, renal disease; sepsis, shock, multiorgan failure; disseminated intravascular coagulation; pediatric autoimmune neuropsychiatric disorder associated with group A streptococci (PANDAS) 248 DIAGNOSIS SIGNS & SYMPTOMS ▪ Pharyngitis ▫ Acute onset of sore throat, fever, pharyngeal edema, patchy tonsillar exudates ▪ Cellulitis ▫ Erythema, edema, abscess formation ▪ Impetigo ▫ Papules, vesicles, pustules surrounded by erythema pustules → breaks down, forms crusts ▪ Scarlet fever ▫ Erythematous rash ▪ Toxic shock syndrome ▫ Shock, multiorgan failure ▪ GAS endometritis ▫ Postpartum fever, uterine tenderness LAB RESULTS Identification of microbe ▪ Gram positive cocci ▪ Positive culture ▪ Blood studies ▫ Rapid antigen detection test (RADT) for GAS OTHER DIAGNOSTICS ▪ Clinical history, physical examination TREATMENT MEDICATIONS ▪ Antibiotics (e.g. penicillin G, clindamycin) SURGERY ▪ Surgical debridement STREPTOCOCCUS VIRIDANS osms.it/streptococcus-viridans infections (e.g. abdominal, central nervous system, lung, skin, soft tissue, sepsis) ▫ Abscess formation ▫ Viridans streptococcal shock syndrome PATHOLOGY & CAUSES ▪ Heterogeneous collection of alpha/ nonhemolytic streptococci, cause variety of diseases ▪ Some species produce greenish color on blood agar plates ▪ Not bile soluble, optochin resistant ▪ Approx. 30 species classified into six groups ▪ Part of microbiome of oropharynx, GI, genitourinary tract ▪ May be invasive, produce variety of diseases ▫ Dental caries, periodontal disease, maxillofacial infections, exudative pharyngitis, infective endocarditis ▫ Invades circulation → systemic RISK FACTORS Immunocompromised state Periodontal disease More common in children than adults Comorbidities (e.g. mucositis, cystic fibrosis, malignancies) ▪ Altered microbiome ▪ ▪ ▪ ▪ SIGNS & SYMPTOMS ▪ Clinical presentation varies widely depending on infection 249 Chapter 99 Streptococcus DIAGNOSIS LAB RESULTS Identification of organism ▪ Gram-positive cocci, positive culture OTHER DIAGNOSTICS ▪ Clinical history, physical examination TREATMENT MEDICATIONS ▪ Antibiotics (depending on sensitivity, resistance) ▫ Penicillin + aminoglycoside; broadspectrum cephalosporin, vancomycin SURGERY ▪ Abscess debridement/drainage 250 NOTES NOTES SYSTEMIC MYCOSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES DIAGNOSIS ▪ Fungal infections in internal organs (esp. lungs) DIAGNOSTIC IMAGING CAUSES LAB RESULTS ▪ Dimorphic species of fungi ▪ Transmitted by spore inhalation; lymphohematogenous dissemination SIGNS & SYMPTOMS ▪ X-ray, CT scan, MRI ▪ Culture-based observation, direct microscopy, serologic tests, lab tests (e.g. abnormal blood exams) TREATMENT MEDICATIONS ▪ Cough, chest pain, fever ▪ Antifungal agents BLASTOMYCES SPP. osms.it/blastomyces PATHOLOGY & CAUSES ▪ Blastomycosis ▫ Systemic fungal infection caused by Blastomyces dermatitidis, B. gilchristii; usually manifests as chronic pneumonia ▪ Incubation period: 3–6 weeks ▪ Spore inhalation → conversion to yeast in lungs → phagocytosis by macrophages → acute suppurative inflammation ▪ Immune response: mainly cellular, mediated by T-lymphocytes, macrophages ▪ Common sites of infection: primarily lungs (90%); skin, bones, genitourinary tract, central nervous system (CNS) Blastomyces spp. ▪ Size: 8–15μm ▪ Broad-based budding (wide connection between two cells before splitting apart during reproduction) ▪ Thermal dimorphism ▫ Mold form (< 37°C/98.6°F): produces spores ▫ Yeast form (37°C/98.6°F): multinucleate; antiphagocytic (e.g. thick cell wall) ▪ Virulence ▫ Thick cell wall: resistance to phagocytosis ▫ BAD-1: cell surface glycoprotein; adhesin ▫ Binds yeast to extracellular matrix, macrophages 251 Chapter 100 Systemic Mycoses ▫ Blocks production of tumor necrosis factor (TNF) alpha (proinflammatory cytokine) Clinical syndromes ▪ Pulmonary blastomycosis ▫ Pneumonia, mostly chronic ▫ Frequently affects upper lobes ▪ Primary cutaneous blastomycosis ▫ Ulcerative/verrucous skin lesions ▪ Disseminated blastomycosis ▫ Osteomyelitis; prostatitis, epididymoorchitis (inflammation of epididymis/ testicles); meningitis; intracranial abscesses RISK FACTORS Outdoor occupations (e.g. farming) Recreational exposure to soil Immunosuppression High prevalence in North America Recent travel to endemic areas (e.g. Ohio, Mississippi river valleys) ▪ Comorbid conditions ▪ ▪ ▪ ▪ ▪ COMPLICATIONS LAB RESULTS Culture-based observation ▪ tissue, sputum, body fluids ▫ Sabouraud dextrose agar without cycloheximide ▫ Confirmation requires conversion (mold → yeast) at 37°C/98.6°F Direct microscopic examination ▪ Periodic acid–Schiff stain ▪ Differentiation: size, yeast morphology Lab tests ▪ Anemia, leukocytosis, ↑ erythrocyte sedimentation rate Tissue biopsy ▪ Pyogranulomatous response ▪ Skin ▫ Epithelial hyperplasia, intraepidermal abscesses, multinucleated cells ▪ Fungus observation Serologic tests ▪ Polymerase chain reaction (PCR) ▫ Antigen detection assays ▪ Acute respiratory distress, multiorgan disease, chronicity SIGNS & SYMPTOMS ▪ Cough, fever, weight loss, sputum production, dyspnea, night sweats, chills, hemoptysis, arthralgia, soft tissue swelling ▪ Verrucous skin lesions with irregular borders, ulcerative skin lesions DIAGNOSIS TREATMENT MEDICATIONS ▪ Antifungal treatment ▪ Amphotericin B; followed by azole ▫ Liposomal amphotericin B: CNS infections SURGERY ▪ Resection of abscesses, devitalized bone, empyemas, pericardial effusion DIAGNOSTIC IMAGING X-ray ▪ Pneumonia ▫ Lobar consolidation, alveolar infiltrates, fibronodular infiltrates, cavitation, nodules, pleural effusion ▪ Osteomyelitis ▫ Well-defined, osteolytic bone lesions 252 COCCIDIOIDES SPP. osms.it/coccidioides ▫ Metalloproteinase: inhibits phagocytosis ▫ Alteration of pulmonary surfactant proteins PATHOLOGY & CAUSES ▪ Coccidioidomycosis ▫ Systemic fungal infection caused by Coccidioides immitis, C. posadasii; usually manifests as acute pneumonia ▪ AKA San Joaquin Valley Fever/“desert rheumatism” (associated with arthralgia) ▪ Arthroconidium inhalation → conversion to spherules → activation of T-lymphocytes → production of cytokines → inflammation → acute pneumonia ▫ In infected tissue, spherules grow, septate → release endospores → infection spreads ▪ Immune response ▫ Mainly mediated by Th1 cells ▫ Interleukin 17, TNF alpha, interferongamma ▪ Incubation period: 1–4 weeks ▪ Common sites of infection: lungs, skin, bones, CNS ▪ High prevalence areas: arid, dry regions in U.S. (e.g. California, Southwest), Mexico, Central America, South America Coccidioides spp. ▪ Size: 20–70μm ▪ Dimorphism ▫ Mold form: found in soil ▫ Yeast form: parasitic ▪ Produces arthroconidia (barrel-shaped, multinucleated spores) ▫ Production stimulated by human sex hormones ▫ Arthroconidia convert to spherules (2–5μm; in infected tissues) ▪ Infectious particles: arthroconidia ▪ Virulence ▫ Enzyme with elastase activity: ↑ infection, inflammation ▫ Cell surface glycoprotein with adhesin activity Clinical syndromes ▪ Acute pneumonia ▪ Dermatologic lesions ▫ Wart-like lesions on face ▫ Erythema nodosum/multiforme ▪ Osteomyelitis ▪ Meningitis RISK FACTORS ▪ Outdoor occupations; recreational exposure to soil (e.g. gardening, camping); immunosuppression; recent travel to endemic areas; comorbid conditions COMPLICATIONS ▪ Adult respiratory distress syndrome; fatal multilobar pneumonia; pyopneumothorax; meningitis; chronicity SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ ▪ Mostly mild/asymptomatic Non-specific: fever, malaise Cough, pleuritic pain, hemoptysis, arthralgia Erythema nodosum/multiforme Wart-like lesions on face (e.g. nasolabial folds) DIAGNOSIS DIAGNOSTIC IMAGING X-ray ▪ Pneumonia ▫ Parenchymal infiltrates, thin-walled cavities ▪ Osteomyelitis ▫ Osteolytic bone lesions 253 Chapter 100 Systemic Mycoses LAB RESULTS TREATMENT ▪ Culture-based observation Serologic tests ▪ IgM, IgG antibody detection (e.g. enzyme immunoassays) ▪ Antigen detection Direct microscopic observation ▪ Spherules in sputum, blood, body fluid samples Lab tests ▪ ↑ erythrocyte sedimentation rate ▪ Eosinophilia (mostly with dissemination) MEDICATIONS High risk of dissemination ▪ E.g. immunosuppression, pregnancy ▫ azoles Severe ▪ Amphotericin B SURGERY ▪ Debridement of abscesses, devitalized bone, pyopneumothorax Extrathoracic tissue biopsy ▪ Essential for diagnosis of Coccidioides dissemination ▪ Pyogranulomatous inflammation ▪ Presence of spherules Spherulin skin test ▪ Positive after resolution; not available in U.S. Figure 100.1 Numerous spores in the lungs of an individual with coccidioidomycosis. 254 HISTOPLASMA CAPSULATUM osms.it/histoplasma-capsulatum PATHOLOGY & CAUSES ▪ Histoplasmosis ▫ Systemic fungal infection caused by Histoplasma capsulatum; usually manifests as acute pneumonia ▪ Most frequent systemic mycoses in U.S. ▪ Microconidia inhalation → conversion to yeast form → macrophage phagocytosis → inflammation → pneumonia ▪ Immune response: mainly cellular, mediated by T-lymphocytes, macrophages, TNF alpha, interferon-gamma ▪ Infection sites: primarily lungs; may disseminate to other organs Histoplasma capsulatum ▪ Size: 2–3μm x 3–4μm ▪ Thermal dimorphism ▫ Mold form (< 35°C/95°F); produces microconidia (spores, 2–5μm) ▫ Yeast form (37°C/98.6°F) ▪ Infectious particles: microconidia ▪ Bird, bat fecal material promotes growth Pulmonary histoplasmosis clinical syndromes ▪ Pneumonia: acute (diffuse/localized); chronic ▪ Broncholithiasis Disseminated histoplasmosis clinical syndromes ▪ Progressive disseminated histoplasmosis: excessive reticuloendothelial infection ▪ Adrenal perivasculitis (common) ▪ Endocarditis ▪ Mediastinal granuloma ▪ Mediastinitis ▪ Meningitis ▪ Ocular histoplasmosis (e.g. retinal lesions) ▪ Lesions: intestinal (e.g. ulcers, polyps), skin (e.g. dermatitis, papules) RISK FACTORS ▪ Outdoor occupations (e.g. construction, excavation) ▪ Outdoor activities (e.g. camping) ▪ Immunosuppression ▪ High prevalence regions: U.S. (Ohio, Mississippi river valleys), Mexico, Central America, South America ▪ Recent travel to endemic areas ▪ Comorbid conditions ▪ Extremes of age COMPLICATIONS ▪ Fatal acute diffuse pneumonia, mediastinal granuloma, mediastinitis, chylothorax, pleural effusion SIGNS & SYMPTOMS ▪ Mostly asymptomatic Acute pulmonary histoplasmosis ▪ Systemic ▫ Fever, headaches, fatigue ▪ Chest pain (pleuritic/substernal), dry cough, myalgia, arthralgia, erythema nodosum/ multiforme Chronic pulmonary histoplasmosis ▪ Systemic ▫ Fever, fatigue, night sweats, weight loss ▪ Productive cough, hemoptysis, dyspnea ▪ Consolidation: dullness to percussion, crackles DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Hilar/mediastinal lymphadenopathy, patchy/ nodular pulmonary infiltrates, occasional cavitation 255 Chapter 100 Systemic Mycoses LAB RESULTS ▪ Culture-based observation ▪ Direct microscopic observation Serologic tests ▪ Antibody detection (e.g. immunodiffusion, complement fixation assays) ▪ Antigen detection in urine, sputum, body fluids (e.g. enzyme immunoassays) Lab tests ▪ Anemia, ↑ erythrocyte sedimentation rate, progressive disseminated histoplasmosis (e.g. pancytopenia) Tissue biopsy ▪ Granulomas, lymphohistiocytic aggregates, mononuclear cell infiltrates, fungi visualization TREATMENT Figure 100.2 Grocott methenamine silver stain highlights spores in the lung tissue of an immunocompromised individual with histoplasmosis. MEDICATIONS ▪ Progressive disseminated/prolonged/severe pulmonary histoplasmosis ▫ Corticosteroids: ↓ inflammation ▫ Antifungal treatment: amphotericin B, azoles PARACOCCIDIOIDES BRASILIENSIS osms.it/paracoccidioides-brasilienses PATHOLOGY & CAUSES ▪ Paracoccidioidomycosis ▫ Systemic fungal infection caused by Paracoccidioides brasiliensis, P. lutzii; usually manifests as chronic lung disease ▪ AKA South American blastomycosis ▪ Spore inhalation → conversion to yeast form in lungs → phagocytosis by macrophages → inflammation → pneumonia ▪ Immune response: mostly cell-mediated ▪ Common sites of infection: mainly lungs; oral mucosa, skin, adrenal glands, CNS Paracoccidioides spp. ▪ Size: 4–40μm ▪ Thermal dimorphism ▫ Mold form (22–26°C/71.6–78.8°F): present in soil ▫ Yeast form (37°C/98.6°F): “pilot’s wheel” appearance ▪ Stimulated by sex hormones Clinical syndromes ▪ Acute/subacute paracoccidioidomycosis ( juvenile) ▫ Hepatosplenomegaly, 256 lymphadenopathy, skin lesions, pulmonary manifestations (rare) ▪ Chronic paracoccidioidomycosis (adult) ▫ Progressive pulmonary fibrosis (esp. lower lobes), ulcers (mouth, larynx); adrenal involvement RISK FACTORS ▪ High prevalence regions: Central, South America (80% in Brazil) ▪ Outdoor occupations ▪ Outdoor activities: contact with soil ▪ More common in individuals who are biologically male ▪ Immunosuppression COMPLICATIONS ▪ Bone marrow, adrenal dysfunction; chronic respiratory failure SIGNS & SYMPTOMS ▪ Generally asymptomatic (95%) ▪ Non-specific symptoms: fever, weight loss ▪ Cough, dyspnea, hepatosplenomegaly, lymphadenopathies, odynophagia, sialorrhea, skin lesions (ulcers, nodules) ▪ Compressive manifestations: jaundice (bile duct obstruction) Figure 100.3 A child with numerous lesions on the face caused by Coccidioidomycosis brasiliensis. Serologic tests ▪ Detection of antibodies through immunodiffusion TREATMENT MEDICATIONS ▪ Antifungal treatment: azoles ▪ Trimethoprim-sulfamethoxazole DIAGNOSIS DIAGNOSTIC IMAGING X-ray/CT scan ▪ Acute/subacute paracoccidioidomycosis ▫ Lymph node enlargement ▪ Chronic paracoccidioidomycosis ▫ Pulmonary disease: alveolar/interstitial infiltrates, consolidation, masses/ nodules, cavitation ▫ CNS disease: ring enhancing lesions ▫ Articular disease: effusion, erosions, space narrowing LAB RESULTS ▪ Direct microscopic observation ▪ Culture-based observation 257 NOTES NOTES TOGAVIRUSES MICROBE OVERVIEW ▪ Pathogenic viruses in Togaviridae family ▪ Capsid symmetry: icosahedral ▪ RNA structure: linear, positive polarity EASTERN EQUINE ENCEPHALITIS VIRUS (EEEV) osms.it/eastern-equine-encephalitis PATHOLOGY & CAUSES ▪ Highly pathogenic; causes central nervous system illness in humans, horses (equines) ▪ Genus: Alphavirus ▪ Spherical, approx. 69nm diameter (including glycoprotein spikes) ▪ Enveloped, single-stranded, positive-sense RNA genome ▪ Glycoproteins associated with neurovirulence, cellular apoptosis ▪ Potential bioterrorism agent use (aerosol route) ▪ Range ▫ Atlantic, Gulf-coast states in eastern USA ▪ Four lineages ▫ Group I: endemic in North America, Caribbean (causes most human disease) ▫ Groups IIA, IIB, III: primarily cause equine illness in Central, South America ▪ Viral life-cycle: wild birds, Culiseta melanura mosquito (enzootic vector) ▫ C. melanura rarely bites humans ▫ Human transmission requires other mosquito species (e.g. Aedes, Coquillettidia, Culex) to bridge between infected birds, humans ▫ Infected mosquito bite → 4–10 day incubation period → prodromal period → neurological symptom development occurs rarely RISK FACTORS ▪ Rural residence; living in/visiting woodland habitats, swampy areas ▪ Outdoor occupation/recreational activity COMPLICATIONS ▪ Encephalitis; cerebral edema; coma; residual brain damage (mild–severe, esp. young children); death (some) SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Prodromal period: high fever, headache, nausea, vomiting ▪ Neurologic presentation: cranial nerve palsy, seizure, stupor → coma ▪ Infants: fever, bulging fontanel, generalized flaccid/spastic paralysis 258 DIAGNOSIS TREATMENT DIAGNOSTIC IMAGING ▪ No specific treatment MRI ▪ Focal lesions in basal ganglia, thalamus, brainstem MEDICATIONS LAB RESULTS ▪ Leukocytosis; left shift ▪ Hyponatremia ▪ Serology ▫ IgM antibody presence ▪ Cerebrospinal fluid (CSF) examination ▪ Lymphocytic pleocytosis, ↑ neutrophils; ↑ protein; IgM antibodies (assay); virus isolation ▪ Supportive: anticonvulsants, corticosteroids (↓ inflammation) OTHER INTERVENTIONS ▪ Supportive: IV fluid, respiratory support, monitor intracranial pressure ▪ Prevention ▫ Insect repellent (DEET, picaridin, IR3535, oil of lemon eucalyptus) ▫ Protective clothing ▫ Vector control OTHER DIAGNOSTICS Electroencephalography (EEG) ▪ Generalized slowing; disorganized pattern RUBELLA VIRUS osms.it/rubella-virus PATHOLOGY & CAUSES ▪ Highly communicable virus → German measles ▪ Enveloped, positive-sense, single-stranded RNA virus ▪ Family: Togaviridae ▪ Genus: Rubivirus ▪ Three structural proteins ▫ C: capsid protein surrounding virion RNA ▫ E1, E2: glycosylated proteins forming transmembrane antigenic sites ▪ Humans are the only natural hosts ▪ Transmission: droplet inhalation/direct contact with infectious nasopharyngeal secretion ▪ Viral contact → 12–23 day incubation → nasopharyngeal cell, regional lymph node viral replication → viremia → maculopapular rash eruption → rash resolution (approx. two days) ▫ Contagious via virus shedding before, after rash appears ▫ ↑ contagiousness during rash eruption ▪ Spreads transplacentally RISK FACTORS ▪ Unvaccinated ▪ Travel (especially abroad) ▪ Contact with febrile rash individuals COMPLICATIONS ▪ Thrombocytopenic purpura ▪ Encephalitis (rare) ▪ If infected during pregnancy: congenital rubella syndrome (CRS) 259 Chapter 101 Togaviruses ▫ ↑ risk of miscarriage, fetal death, stillbirth ▫ CRS: A ToRCHeS (see mnemonic) infection; ↑ first trimester risk; extramedullary hematopoiesis (“blueberry muffin” rash), cataract, heart defect, hearing impairment, intellectual disability MNEMONIC: ToRCHeS Perinatal infections passed from mother to child Toxoplasmosis, toxoplasma gondii Other infections Rubella Cytomegalovirus Herpes Simplex virus-2/ neonatal herpes simplex SIGNS & SYMPTOMS ▫ Reverse transcription-PCR (rubella virus RNA performed on amniotic fluid) OTHER DIAGNOSTICS ▪ Clinical diagnosis ▪ High suspicion index ▫ Febrile rash, unvaccinated status TREATMENT ▪ No specific antiviral therapy OTHER INTERVENTIONS ▪ Infection control measures ▫ Prompt isolation for seven days after rash development ▪ Vaccine: live-attenuated measles-mumpsrubella (MMR)/measles-mumps-rubellavaricella (MMRV) ▫ First dose: 12–15 months old ▫ Second dose: 4–6 years old ▪ Maculopapular rash ▫ Pink/light red macules: coalesce to form evenly-colored desquamating rash ▫ Initially: face → generalized rash within 24 hours ▫ Duration: three days ▪ Lymphadenopathy; primarily posterior auricular/suboccipital lymph ▪ Low-grade fever ▪ Mild nonexudative conjunctivitis ▪ Forchheimer spots on soft palate ▪ Arthralgias ▪ Orchitis ▪ Asymptomatic (half of cases) DIAGNOSIS LAB RESULTS ▪ Polymerase chain reaction (PCR) testing/ molecular typing ▫ Throat, nasal, urine specimens ▪ Serologic testing ▫ Enzyme immunoassay (EIA) detects rubella-specific IgM antibodies ▪ Pregnancy Figure 101.1 A child with rubella showing a characteristic maculopapular, erythematous rash. 260 WESTERN EQUINE ENCEPHALITIS VIRUS (WEE) osms.it/western-equine-encephalitis PATHOLOGY & CAUSES ▪ Causes central nervous system illness in humans, horses (equines) ▪ Genus Alphavirus ▪ Spherical, approx. 69nm diameter (including glycoprotein spikes) ▪ Enveloped, single-stranded, positive-sense RNA genome ▪ Contain glycoproteins associated with neurovirulence, cellular apoptosis ▪ Range: most commonly US states, Canadian provinces west of Mississippi River ▪ Virus life-cycle: wild birds, other vertebrates, Culex tarsalis mosquito (enzootic vector) ▫ Culex tarsalis (another human vector) ▪ Potential bioterrorism agent use (aerosol route) ▪ Infected mosquito bite → 2–10 day incubation period → sudden onset of severe headache, fever/chills, dizziness, chills, myalgias, malaise, tremor, irritability, photophobia, neck stiffness → rapid neurological manifestation development → recovery ▫ Most adults: no residual neurological effects ▫ Infants, children: ↑ long-term neurologic sequelae risk RISK FACTORS ▪ Most cases June–September ▪ Bimodal age pattern: < one year; ↑ risk in elderly ▪ Biologically-female ▪ Rural residence ▪ Outdoor occupation/recreational activity COMPLICATIONS ▪ Encephalitis, coma, respiratory failure, death ▪ Infants: intellectual disability, cerebellar damage, spastic paralysis, developmental delay SIGNS & SYMPTOMS ▪ Neurological manifestations ▫ Generalized weakness; somnolence; hand, tongue, lip tremor; cranial nerve palsy; motor weakness; ↓ deep tendon reflexes ▪ Infants: poor feeding, fussiness, fever, vomiting, tense/bulging fontanelle DIAGNOSIS LAB RESULTS ▪ Serology ▫ Enzyme-linked immunosorbent assay (ELISA): IgM antibodies ▫ Hemagglutination-inhibition, neutralizing antibody presence ▪ CSF ▫ ELISA: IgM antibodies ▫ Lymphocytic pleocytosis ▫ ↑ protein TREATMENT ▪ No specific treatment MEDICATIONS ▪ Supportive: anticonvulsants, corticosteroids 261 Chapter 101 Togaviruses OTHER INTERVENTIONS Prevention ▪ Insect repellent (DEET, picaridin, IR3535, oil of lemon eucalyptus) ▪ Protective clothing ▪ Vector control 262 NOTES NOTES TREMATODES (FLATWORMS) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ AKA flukes; parasitic flatworm; infects internal organs ▪ Phylum: Platyhelminthes Characteristics ▪ Adult morphology: flattened oval/elongated ▪ Structures ▫ Tegmentum (outer body covering) ▫ Ventral, oral suckers ▫ Pharynx → esophagus → caeca ▫ Testes, uterus/ovary (hermaphrodites) ▪ Eggs generally operculated (lidded); except schistosomes ▪ Obligate parasites of mollusks, vertebrates Development 1. Egg 2. Miracidium (ciliated, lacks mouth; infects first intermediate host) 3. Sporocyst (elongated sac, produces rediae) 4. Redia (larval stage with oral sucker) 5. Cercaria (larval stage; may be infectant) 6. Metacercaria (encysted cercaria) 7. Adult DIAGNOSIS DIAGNOSTIC IMAGING ▪ Medical imaging (e.g. ultrasound, CT scan, MRI) LAB RESULTS ▪ E.g. blood tests ▪ Direct microscopy OTHER DIAGNOSTICS ▪ Serologic tests TREATMENT MEDICATIONS ▪ Anthelmintic SIGNS & SYMPTOMS ▪ See individual trematodes 263 Chapter 102 Trematodes (Flatworms) CLONORCHIS SINENSIS osms.it/clonorchis-sinensis PATHOLOGY & CAUSES ▪ Parasitic fluke; invasion of biliary tree → liver infection ▪ AKA Chinese liver fluke ▪ Morphology ▫ Adult: flat, elongated body; 25 x 5mm ▫ Egg: oval-shaped; 30 x 15μm ▪ Intermediate hosts ▫ First: freshwater snail (e.g. Parafossarulus manchouricus) ▫ Second: freshwater fish/shrimp ▪ Reservoirs: cats, dogs ▪ Transmission ▫ Ingestion of raw/undercooked fish/ shrimp ▪ Infectious form: metacercariae ▫ Ingestion of metacercariae → excyst in duodenum → migration to biliary tract → inflammation, epithelial hyperplasia ▪ Endemic to Eastern Asia (e.g. China, Japan, Philippines, Vietnam) RISK FACTORS ▪ Recent travel to endemic areas ▪ Consumption of raw/undercooked fish/ shrimp COMPLICATIONS ▪ Pancreatitis, cholangitis, liver abscesses, cholangiocarcinoma DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, CT scan, MRI ▪ Enlarged gallbladder, hepatomegaly, bile duct inflammation, dilated/thickened intrahepatic bile ducts Endoscopy ▪ Visualization of adult organisms LAB RESULTS ▪ Acute infection ▫ Eosinophilia, ↑ IgE ▪ Chronic infection ▫ ↑ alkaline phosphatase, ↑ bilirubin ▪ Direct microscopy ▫ Detection of Clonorchis eggs in stool samples ▫ Formalin ethyl-acetate concentration technique (FECT) → parasite separation from faeces ▪ Serologic tests ▫ E.g. ELISA ▪ Polymerase chain reaction (PCR) TREATMENT MEDICATIONS ▪ Anthelmintic (e.g. praziquantel) SIGNS & SYMPTOMS ▪ Mostly asymptomatic ▪ Acute infection: fatigue, right upper quadrant abdominal pain, indigestion, diarrhea, flatulence ▪ Chronic infection: fatigue, weight loss, abdominal discomfort, diarrhea, dyspepsia, jaundice (severe cases) Figure 102.1 An adult Clonorchis sinensis worm. 264 AfraTafreeh.com exclusive PARAGONIMUS WESTERMANI osms.it/paragonimus-westermani PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Parasitic flatworm; causes pulmonary paragonimiasis ▪ AKA Japanese lung fluke ▪ Morphology ▫ Adult: oval-shaped body with spines; 15 x 8mm ▫ Egg: oval-shaped, thick shell; 100 x 55μm ▪ Intermediate hosts ▫ First: freshwater snails (e.g. Semisulcospira spp.) ▫ Second: crustaceans (e.g. crabs, crayfish) ▪ Transmission ▫ Ingestion of raw/undercooked crustaceans (e.g. crab, crayfish) ▪ Infectious form: metacercariae ▫ Ingestion of metacercariae → excyst in duodenum → penetration of peritoneal wall → migration to lungs → encapsulate, mature → inflammation, fibrosis ▪ Endemic to Eastern Asia (e.g. China, Japan, Philippines, Vietnam) Pulmonary ▪ Early infection ▫ Systemic: fever, malaise ▫ Pulmonary: dyspnea, cough, pleuritic pain ▫ Gastrointestinal: diarrhea, epigastric pain ▪ Late infection ▫ Malaise ▫ Recurrent, chocolate-colored hemoptysis RISK FACTORS X-ray, CT scan, MRI ▪ Brain ▫ Skull X-ray: soap-bubble calcifications; calcified cysts ▫ CT/MRI: grape clusters; conglomerated, cystic lesions ▪ Lungs ▫ Pleural effusion, parenchymal cysts/ nodules, cavitary lesions, parasite migration tracts ▪ Poor sanitary conditions ▪ Seafood consumption in endemic areas COMPLICATIONS ▪ Meningitis, encephalitis, seizures Extrapulmonary ▪ Cerebral: headache, fever, vomiting, seizures, papilledema, paresis/paresthesias, visual disturbances (e.g. diplopia) ▪ Abdominal: nausea/vomiting, hematoquezia (bloody stool), pain, hematuria ▪ Subcutaneous: tender, firm, painless, mobile nodules DIAGNOSIS DIAGNOSTIC IMAGING 265 Chapter 102 Trematodes (Flatworms) LAB RESULTS ▪ Eosinophilia, ↑ IgE ▪ Direct microscopy ▫ Detection of eggs in stool, sputum, bronchoalveolar lavage ▪ Serologic tests ▫ Enzyme-linked immunosorbent assay (ELISA), immunoblot TREATMENT MEDICATIONS ▪ Anthelmintic (e.g. praziquantel, triclabendazole) SCHISTOSOMES osms.it/schistosomes PATHOLOGY & CAUSES ▪ Blood flukes; parasitize mesenteric veins/ vesical venous plexus → gastrointestinal/ genitourinary tract infections ▪ AKA bilharziasis/snail fever ▪ Morphology ▫ Adult: elongated body, 1–2cm/0.39– 0.79in ▫ Eggs: not operculated ▪ Intermediate host ▫ Snails ▪ Transmission ▫ Contaminated freshwater contact ▪ Infectious form: cercariae ▫ Contact with cercariae in fresh water → skin penetration → schistosomulae → migration to liver through circulation → adult form → migration to mesenteric venules/vesical venous plexus → egg deposits → inflammation → fibrosis ▪ High-prevalence area is sub-Saharan Africa RISK FACTORS ▪ More common in individuals who are biologically male, rural areas ▪ Recent contact with fresh water bodies in endemic areas COMPLICATIONS ▪ Bacteremia, infertility, intestinal obstruction, nephrotic syndrome, renal failure, cardiomegaly, acute myelopathy Figure 102.2 A scanning electron micrograph of a S. japonicum flatworm. SIGNS & SYMPTOMS Acute infection ▪ Swimmer’s itch ▫ Pruritic papular/urticarial rash, esp. legs/ feet ▪ Acute schistosomiasis syndrome/Katayama fever ▫ Non-specific symptoms (fever, urticaria, chills, arthralgia, myalgia, headaches) ▫ Angioedema, dry cough, abdominal pain, diarrhea Chronic infection ▪ Intestinal: abdominal pain, poor appetite, diarrhea ▪ Hepatosplenic: hepatosplenomegaly, portal 266 hypertension (e.g. collateral circulation, gastrointestinal bleeding, ascites) ▪ Pulmonary: dyspnea; pulmonary hypertension → cor pulmonale (enlarged right cardiac chambers) ▪ Urogenital: hematuria, pyuria, dysuria, increased urinary frequency ▪ Neuroschistosomiasis (acute myelopathy): seizures, sensory/motor impairment, cerebellar syndrome (incoordination) prednisone) ▪ Manageme pruritus (e.g. antihistamines) OTHER INTERVENTIONS ▪ Prevention ▫ Water sanitation programs ▫ Mass therapy ▫ Control of snails (e.g. molluscicides) DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray, CT scan, MRI, abdominal ultrasound ▪ Brain: contrast-enhancing infiltrates ▪ Bladder: wall irregularities/fibrosis ▪ Liver: widened periportal space, periportal fibrosis, collateral pathways ▪ Lungs: patchy infiltrates, miliary nodules ▪ Spinal cord: radicular thickening, intramyelinic lesions LAB RESULTS Figure 102.3 Calcified eggs of the flatworm Schistosoma japonicum in the submucosa of the colon of an individual previously treated for schistosomiasis. ▪ Bladder/rectum biopsy ▫ Egg-filled granulomas in mucosa ▪ Direct microscopy ▫ Detection of eggs in stool/urine samples ▫ Kato–Katz method (thick smear) ▫ FLOTAC stool concentration method ▪ Lab tests ▫ Acute infection: eosinophilia ▫ Chronic infections: anemia ▫ Portal hypertension: thrombocytopenia (splenic sequestration) ▫ Urogenital infection: hematuria/ leukocyturia in urinalysis ▪ Serologic testings ▫ E.g. ELISA, indirect hemagglutination TREATMENT MEDICATIONS ▪ Anthelmintic (e.g. praziquantel, oxamniquine) ▪ Corticosteroids (e.g. prednisolone, Figure 102.4 A CT scan of the abdomen and pelvis demonstrating calcification of the bladder secondary to schistosomiasis. 267 Chapter 102 Trematodes (Flatworms) 268 NOTES NOTES TRICHOMONA MICROBE OVERVIEW ▪ Trichomonas vaginalis: pear-shaped (pyriform), flagellated protozoa; infects genitourinary tract ▪ Causative agent of trichomoniasis (trich), common sexually transmitted disease (STD) Morphology ▪ Size ▫ 9 x 7 micrometers ▪ Motile via four flagella, undulating membrane ▪ Rigid axostyle runs through cell from anterior to posterior end ▪ Contains hydrogenosomes (unique energyproducing organelles) Replication/Multiplication ▪ Humans only host ▫ Does not survive well in external environments ▫ Multiplies when vaginal pH basic ▫ Incubation period: 5–28 days ▫ No cyst stage TRICHOMONAS VAGINALIS osms.it/trichomonas-vaginalis PATHOLOGY & CAUSES ▪ Resides in lower genital tract of individuals who are biologically female; urethra, prostate of individuals who are biologically male → trophozoite stage (infective stage) → transmitted sexually → infects squamous epithelium of lower genital tract → replicates by longitudinal binary fission → inflammatory response RISK FACTORS ▪ Sexual activity with infected partner ▪ Multiple sexual partners ▪ More common in individuals who are biologically female COMPLICATIONS ▪ Pregnancy ▫ ↑ risk of premature rupture of membranes, preterm delivery, low birth weight ▪ Urethritis, cystitis SIGNS & SYMPTOMS ▪ May be asymptomatic ▪ Individuals who are biologically female ▫ Watery, foul-smelling vaginal discharge; burning; pruritus; dysuria, urinary frequency; lower abdominal pain; dyspareunia; vulvar, vaginal erythema ▪ Individuals who are biologically male ▫ Urethral discharge; pruritus; burning after urination/ ejaculation ▪ ↑ risk of contracting HIV due to genital inflammation 269 Chapter 103 Trichomona DIAGNOSIS LAB RESULTS Microbe identification ▪ Saline microscopy (wet mount of genital secretions) ▫ Characteristic organism ▫ ↑ polymorphonuclear leukocytes ▪ ↑ vaginal pH (> 4.5) ▪ T. vaginalis assay ▫ Detects species-specific ribonucleic acid (RNA); vaginal swab/urine specimen ▪ Nucleic acid amplification testing (NAAT) ▪ Trichomonas rapid test TREATMENT MEDICATIONS ▪ Systemic 5-nitroimidazole drugs (e.g. metronidazole, tinidazole) ▫ Treat both partners OTHER INTERVENTIONS ▪ Rate of transmission decreased with consistent use of condoms, spermicidal agents (e.g. nonoxynol-9) OTHER DIAGNOSTICS ▪ Speculum exam ▫ Punctate hemorrhages cervix (strawberry cervix) 270 NOTES NOTES TRYPANOSOMA GENERALLY, WHAT ARE THEY? DIAGNOSIS PATHOLOGY & CAUSES ▪ Genus of flagellated parasitic protozoa Morphology ▪ Elongated body ▪ Flagellum: forms undulated membrane along body ▪ Kinetoplast: functions as mitochondrion Transmission ▪ Through vectors ▪ Incubation period: 1–2 weeks ▪ ▪ ▪ ▪ Direct microscopy Serologic testings Laboratory findings Additional diagnostic tests may be necessary (severity, infection sitedependent) TREATMENT ▪ See individual pathogens SIGNS & SYMPTOMS ▪ See individual pathogens TRYPANOSOMA BRUCEI osms.it/trypanosoma-brucei PATHOLOGY & CAUSES ▪ Protozoan, extracellular parasite → African trypanosomiasis ▪ AKA “sleeping sickness” ▫ Neurologic alterations during meningoencephalitis stage (e.g. somnolence) Virulence factors ▪ Antigenic variation ▫ Changes variant surface glycoprotein (VSG) → immune response evasion ▪ ↑ interferon gamma → ↑ host T. brucei susceptibility (mechanism unknown) Morphologic forms (life-cycle) ▪ Epimastigote → procyclic trypomastigote (in tsetse fly midgut) → metacyclic trypomastigote (infectious form) Subspecies ▪ Trypanosoma brucei rhodesiense (acute, more severe disease course) ▪ Trypanosoma brucei gambiense (progressive, milder disease course) Reservoirs ▪ Domestic animals, lions, hyenas, antelopes 271 Chapter 104 Trypanosoma brucei Vector ▪ Male/female Glossina flies, AKA tsetse flies ▫ Ideal conditions: warm, humid climate (e.g. near river/lake); altitude < 1800m/5905ft Transmission ▪ Saliva inoculation via fly bite; vertical/ parenteral transmission very rare ▪ Endemic regions: sub-Saharan Africa; Democratic Republic of Congo (most cases) Pathogenesis ▪ Glossina bite → subcutaneous metacyclic trypomastigote inoculation → lymph vessels → bloodstream → ↑ tumor necrosis factor (TNF) alpha, interleukin 6 (IL-6), nitric oxide → ↑ capillary permeability → vasculitis → organ invasion, e.g. central nervous system (CNS) Disease stages ▪ Hemolymphatic (early) stage ▪ Meningoencephalitis (late) stage ▪ Symptom severity related to number of organisms in affected tissue (e.g. blood, CNS) RISK FACTORS ▪ Recent endemic area travel ▪ Dense vegetation near human settlement COMPLICATIONS ▪ Meningitis ▪ Myocarditis, heart failure ▪ Aspiration → bacterial pneumonia; associated with altered state of consciousness (meningoencephalitis stage) SIGNS & SYMPTOMS Hemolymphatic stage ▪ Systemic symptoms ▫ Intermittent fever, headache, malaise, weakness, pruritus, rash ▪ Trypanosomal chancre ▫ Rubbery, painful, erythematous, wellcircumscribed lesion at fly bite site approx. one week post-inoculation ▪ Lymphadenopathy ▫ Winterbottom’s sign: enlarged mobile, soft posterior cervical triangle lymph nodes ▪ Hepatosplenomegaly ▪ Dyspnea ▪ Chest pain ▪ Altered thyroid function ▪ Impotence (biologically-male), amenorrhea (biologically-female) ▪ Pain, Kerandel sign (deep hyperesthesia) Meningoencephalitis stage ▪ AKA “Sleeping sickness” ▪ Cachexia ▪ Sleep disturbances (e.g. diurnal somnolence, nocturnal insomnia) ▪ Headaches ▪ Altered state of consciousness ▪ ↓ cognitive function ▪ Personality, behavioral change ▪ Muscle spasms, ataxia, tremor, flaccid paralysis, choreiform movements ▪ Psychiatric manifestations (e.g. psychosis) DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Cerebral ▫ May show multifocal white matter hyperintensity (indicates late-stage disease) LAB RESULTS Serologic testings ▪ Card agglutination test for trypanosomiasis (CATT) ▫ Blood + drop of reagent with trypanosomal antigen ▪ Immunofluorescence ▪ Enzyme immunoassays Cerebrospinal fluid (CSF) examination ▪ Disease staging essential ▪ ↑ leukocytes ▪ ↑ proteins ▪ IgM/Trypanosoma presence 272 ▪ Morula/Mott cells (pathognomonic) ▫ IgM-filled plasma cells Direct microscopy ▪ Organism observation in lymph node aspiration, bone marrow, CSF, blood (thin/ thick Giemsa-stained smears) Laboratory findings ▪ Hemolytic anemia; leukocytosis; thrombocytopenia; ↑ erythrocyte sedimentation rate; hypergammaglobulinemia; hypoalbuminemia, hypocomplementemia; ↑ C-reactive protein; coagulation abnormalities Histological observation ▪ Meningoencephalitis stage (CSF sample) ▫ Morula/Mott cells in white matter (pathognomonic), edema, microhemorrhages, perivascular proliferation OTHER DIAGNOSTICS Electroencephalogram (EEG) ▪ Late stage: abnormal, slow delta waves TREATMENT MEDICATIONS ▪ Antiprotozoal medication ▫ Hemolymphatic stage: pentamidine, suramin ▫ Meningoencephalitis stage: eflornithine, eflornithine + nifurtimox, melarsoprol OTHER INTERVENTIONS ▪ Prevention ▫ Vector control, surveillance ▫ Protective clothing TRYPANOSOMA CRUZI osms.it/trypanosoma-cruzi PATHOLOGY & CAUSES ▪ Protozoan, intracellular parasite ▫ Causes American trypanosomiasis, AKA Chagas disease ▪ Morphologic forms (life cycle) ▫ Amastigote (intracellular, no flagellum) → epimastigote (in triatomine midgut) → trypomastigote (infectious form) ▪ Reservoirs ▫ Opossums, armadillos, canines ▪ Vectors ▫ Triatomine bugs (“kissing bugs”) ▫ Common species: Rhodnius prolixus, Triatoma dimidiata, Triatoma infestans ▫ Characteristics: size (2–3cm/0.79– 1.18in); obligated hematogenous; feeds at night; lives in dark, warm sites (e.g. closets, thatched roofs) Transmission ▪ Triatomine bite → fecal wound contamination ▪ Contaminated food/water ingestion (infection through mucous membranes) ▪ Parenteral (e.g. blood transfusion, sharing syringes) ▪ Vertical (mother → fetus) Endemic regions ▪ Rural areas of southern U.S., Latin America Pathogenesis ▪ T. cruzi trypomastigote inoculation → bloodstream → organ invasion (heart, enteric nervous system) → interstitial inflammation → tissue destruction → fibrosis Disease stages ▪ Acute phase: 8–12 weeks ▪ Indeterminate phase: decades 273 Chapter 104 Trypanosoma brucei ▪ Chronic phase: cardiac/gastrointestinal disease RISK FACTORS ▪ Recent endemic area travel, immunosuppression, blood transfusion, organ transplant, intravenous drug use COMPLICATIONS ▪ Heart failure, acute myocarditis, meningoencephalitis, systemic/pulmonary embolism, sudden death SIGNS & SYMPTOMS Acute phase ▪ Mostly asymptomatic ▪ Systemic: malaise, fever, anorexia, headaches ▪ Chagoma: nodular skin lesion at infection site; usually on face/extremities ▪ Romaña’s sign: unilateral eyelid edema, conjunctivitis, preauricular lymphadenitis; follows conjunctival inoculation ▪ Lymphadenopathy ▪ Hepatosplenomegaly Indeterminate phase ▪ Asymptomatic Chronic phase ▪ Cardiac manifestations: dyspnea, fatigue, palpitation, chest pain, edema, mitral/ tricuspid regurgitation murmur, splitting of S2 ▪ Gastrointestinal manifestations: megacolon (constipation, bloating, abdominal pain); megaesophagus (dysphagia, regurgitation) Congenital disease ▪ Systemic: low birthweight, anasarca, fever ▪ Petechiae ▪ Hepatosplenomegaly ▪ Neurologic abnormalities (e.g. hypotonia, tremor) DIAGNOSIS DIAGNOSTIC IMAGING ▪ Further studies: stage, clinical syndrome dependent Figure 104.1 The kissing bug, Triatoma infestans, is found in Central and South America and is a vector for Chagas disease. Chest X-ray, MRI, echocardiogram ▪ Enlarged cardiac silhouette (cardiomegaly) ▪ Pericardial effusion ▪ Valvular regurgitation ▪ Left ventricular aneurysm Barium studies ▪ Megacolon, megaesophagus LAB RESULTS ▪ Polymerase chain reaction (PCR) 274 ▪ Blood culture Direct microscopy ▪ Organism observation in thin/thick blood smears; for acute phase disease (high parasitemia) Serologic testing ▪ E.g. enzyme-linked immunosorbent assay (ELISA), immunofluorescence Xenodiagnosis ▪ Feed laboratory triatomes with person’s blood → examine feces weeks later Cardiac tissue microscopy ▪ Acute disease: intracellular pseudocysts (amastigotes inside myocardiocytes), interstitial inflammation ▪ Chronic disease: mural thrombi, interstitial fibrosis, myocardiocyte necrosis Figure 104.2 Trypanosoma species seen on a peripheral blood smear from an individual with Chagas disease. OTHER DIAGNOSTICS ECG ▪ Arrhythmia evidence: bundle branch/AV block TREATMENT MEDICATIONS ▪ Antitrypanosomal treatment ▪ Advanced cardiac disease: cardiac arrest prevention, ventricular fibrillation through antiarrhythmic medication OTHER INTERVENTIONS Prevention ▪ Vector control, treat parasitemia before conception 275 NOTES NOTES TUBERCULOSIS MICROBE OVERVIEW ▪ Tuberculosis (AKA Mycobacterium tuberculosis) mycobacterium that primarily infects lungs but may infect any bodily organ/tissue ▪ Important properties ▫ Curved rod shaped bacteria often wrapped together in cord-like formations ▫ Obligate aerobe ▫ Impervious to Gram staining due to waxy cell wall composed of fatty acids (e.g., mycolic acid) ▪ ▪ ▪ ▪ ▪ ▫ Staining: acid-fast stains like Ziehl– Neelsen, fluorescent stains like auramine/rhodamine Clumped colonies Distinctly slow growing (up to 6 weeks for visible growth) Grown on Lowenstein–Jensen media Resistant to weak disinfectants, can survive on dry surfaces for months Can avoid mucus traps, getting into deep airways (alveoli) MYCOBACTERIUM TUBERCULOSIS osms.it/mycobacterium-tuberculosis PATHOLOGY & CAUSES TYPES Primary tuberculosis Reactivation tuberculosis ▪ In about 5–10% cases of primary TB Extrapulmonary tuberculosis ▪ May involve any organ (most commonly kidneys, meninges, lymph nodes, etc.) ▪ Systemic miliary tuberculosis STAGING ▪ Transmitted by inhaling infectious aerosol droplets from individual with active TB (e.g. coughing, sneezing, speaking, etc.) ▪ TB enters lungs, gets phagocytized by macrophages → TB produces enzymes that inhibit lysosome and phagocytic vacuole fusion → bacteria survives, proliferates, creates localized infection → primary tuberculosis development ▫ TB infiltrated macrophage fusion → Langhans giant cells ▫ Cell-mediated immunity activation → granuloma forms within infected area → caseous necrosis inside granuloma → Ghon focus ▫ Lymphatic dissemination of TB → lymph node caseation ▫ Ghon focus + involved lymph node → Ghon complex ▫ Ghon complex fibrosis, calcification → Ranke complex ▪ Primary infection resolution ▫ Mycobacteria killed by immune system ▫ Bacteria walled off in granuloma remains dormant but viable → latent tuberculosis with no further complications in immunocompetent 276 individuals ▪ Compromised immune system → more caseous necrosis areas → cavity formation → reactivation tuberculosis RISK FACTORS ▪ Immunocompromised states ▫ HIV ▫ Diabetes mellitus ▫ Hematologic malignancy ▫ Chronic lung disease (especially silicosis) ▫ Malnutrition ▫ Aging ▪ Substance abuse ▫ Alcoholism ▫ Injection drug users ▪ Close contact with individuals with active TB infection ▫ Healthcare providers ▫ Incarceration ▪ Lower-income, medically underprivileged countries ▫ Recent immigrants from highprevalence countries COMPLICATIONS ▪ Bronchopneumonia ▪ Pneumothorax ▪ Extrapulmonary tuberculosis ▫ Kidney → dysuria, pyelonephritis with sterile pyuria ▫ Meninge → meningitis ▫ Lumbar vertebrae → Pott disease ▫ Liver and gallbladder → hepatitis, obstructive jaundice ▫ Lymph nodes → cervical tuberculous lymphadenitis (scrofula) ▫ Peritonitis ▫ Pericarditis ▪ Systemic infection Figure 105.1 The gross pathological appearance of a Ghon focus. SIGNS & SYMPTOMS ▪ Primary tuberculosis ▫ Usually asymptomatic (90-95% of cases) ▫ Mild flu-like illness ▫ Rarely pleural effusion ▪ Reactivation tuberculosis ▫ Constitutional symptoms (fever, chills, night sweats, fatigue, appetite loss, weight loss, pleuritic chest pain) ▫ Cough (dry cough, prolonged cough producing purulent sputum, hemoptysis—suggesting advanced TB) ▫ Crepitations during lung auscultation ▪ Extrapulmonary tuberculosis ▫ Depending on affected organ/tissue ▪ Miliary (disseminated) tuberculosis ▫ Can affect any organ (e.g. choroidal tubercles in eye, granulomas within organs) ▫ Weight loss ▫ Fever, chills ▫ Dyspnea 277 Chapter 105 Tuberculosis DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Used in PPD/IGRAs positive ▪ Ranke complex → sign of healed primary TB ▪ Cavities → active TB sign Antibiotic resistance ▪ Multiple-drug-resistant TB ▫ Resistant to isoniazid and rifampin ▪ Extensively drug-resistant TB ▫ Resistant to both isoniazid and rifampin, any fluoroquinolone, at least one second-line drug LAB RESULTS PPD intradermal skin test (tuberculin test) ▪ Screening test for people at high risk for TB ▫ Tuberculin injection between dermal layers, induration area measurement within 48–72 hours ▪ Induration area ≥ 5mm: positive in immunocompromised individuals, persons with primary TB radiographic evidence/ close contact with those with active TB ▪ Induration area ≥ 10mm: positive in residents/immigrants from high-prevalence countries, children > four years of age, high risk populations (e.g., medical employees) ▪ Induration area ≥ 15mm: considered positive in individuals with no known risk factors ▪ Cannot be used for differentiation between active and latent TB ▪ PPD result interpretation ▫ Positive → exposure evidence ▫ False-positive → previously immunized with BCG vaccine ▫ Negative → no exposure evidence ▫ False-negative → sometimes seen in individuals with sarcoidosis, malnutrition, Hodgkin’s lymphoma Figure 105.2 An X-ray image of the chest demonstrating diffuse interstitial granular densities in an individual with milliary tuberculosis. Sputum testing ▪ Used for definitive diagnosis ▪ Staining, culture, PCR OTHER DIAGNOSTICS Interferon gamma release assays (IGRAs) ▪ Alternative for PPD ▪ Unlike PPD, doesn’t show false-positive results in BCG vaccinated Figure 105.3 Multifocal patchy opacities in the right upper lobe of an individual who presented with night sweats, weight loss and persistent cough. The presenting symptoms and radiological appearance are consistent with pulmonary tuberculosis. 278 TREATMENT MEDICATIONS ▪ Prophylactics ▫ BCG vaccine (some countries) ▪ Latent TB ▫ Isoniazid for 9 months ▪ Active TB ▫ First line anti-TB drugs: isoniazid, rifampin, pyrazinamide, ethambutol/ streptomycin ▪ Antibiotic resistance ▫ For multiple-drug-resistant TB, treatment requires second-line drugs (amikacin, kanamycin, capreomycin) OTHER INTERVENTIONS Figure 105.4 The histological appearance of a tuberculosis granuloma. The granuloma is formed of epithelioid macrophages and giant cells with a focus of caseating necrosis at the centre and a rim of lymphocytes at the periphery. ▪ Active TB ▫ Compulsory isolation (until sputum negative for TB) 279