Zoonotic Infections

1. Zoonotic Infections PBL March 4th 2011

2. Anthrax • Bacillus anthracis(G+ rod-shaped bacterium) - in farm and wild animals spores. • Epidemiology: 20,000 and 100,000 cases of anthrax each year. It spread by exposure to animals, esp. in Africa, Asia, China, Eastern Europe and Haiti. • Clinical manifestations • Cutaneous anthrax (95%)- painless, pruritic papule that develops over 2 days. Oedema  black eschar. Bacteraemia is rare. • Inhalation anthrax occurs when the spores are inhaled carried by phagocytes to lymphocytes  germinate and release toxins  haemorrhagic mediastinitis. 1-6 days of fever, cough and abdominal pain, then acute onset of fever, hypoxia and sweating, often including anthrax meningitis from bacteraemia. It rapidly leads to shock and death within 1-2 days. • Gastrointestinal anthrax is an uncommon form of infection contracted by eating undercooked meat. Initially, nausea, abdominal pain and vomiting but it is followed by severe, bloody diarrhoea with a mortality of over 50%. • Morphology: Anthrax lesions are typified by necrosis and exudative inflammation. Inhalation causes numerous foci of haemorrhagic in the mediastinum with haemorrhagic, enlarged hilar and peribronchial lymph nodes. • Investigations: CXR and gram stain are diagnostic. • Treatment: • Cutaneous disease: Ciprofloxacin 500mg/12h PO for up to 60d. • Pulmonary or GI: Ciprofloxacin 400mg/12h IVI + clindamycin 900mg/8h IVI + rifampicin 300mg/12h IVI. Oral drugs are used when stable to for 60d. • Prevention: Immunise animals at risk and enforce sound food-handling carcass hygiene

3. Anthrax - Pathogenesis • Pathogenesis: The anthrax toxin has A and B subunits. • B subunit = protective antigen • The A subunit can be either oedema factor (EF) or lethal factor (LF). • 3 A subunits bind to a B heptamer and the complex is endocytosed into the host cell, and the low pH causes the complex to move into the cytoplasm. • EF converts ATP to cAMPleading to efflux of water and interstitial oedema • LF is a protease that binds MAP kinases and cause cell death.

5. Bubonic Plague • Yersinia pestis= G- It causes the invasive, frequently fatal infection called plague or the Black Death. • Y. enterocoliticacauses faecal-oral transmitted ileitis and E. pseudotuberculosis causes mesenteric lymphadenitis. • Epidemiology: It killed an estimated 100 million people in Egypt and Byzantium in the 6th century, 25% of Europe’s population in the 14th and 15th centuries and tens of millions in India, Myanmar and China at the beginning of the 20th century. • About 1000-3000 cases of plague occur each year worldwide with 10-15 in the USA. • Pathogenesis:Yersinia proliferates with lymphoid tissue. The complex of genes called the Yop virulon enable the bacteria to kill host phagocytes. Its proteins form a hollow syringe-like structure that projects from the bacterial surface, binds to host cells and infects bacterial toxins called Yops(Yersinia outercoat proteins). Yops then inhibit actin polymerisation and block phagocytosis. • Y. pestis ensures its spread by forming a biofilm that obstructs the gut of the infected flea, causing the flea to regurgitate and continually feed and therefore infect the rodent or human it is biting. • Morphology: Y. pestis causes buboes (lymph node enlargement), pneumonia or sepsis with neutrophilia. Distinctive histologic features are • Massive proliferation of the organisms • Early appearance of protein and polysaccharide-rich effusions with few inflammatory cells and marked tissue swelling • Necrosis of tissues and blood vessels with haemorrhage and thrombosis • Neutrophilic infiltrates that accumulate adjacent to necrotic areas

6. Clinical presentation: Incubation normally lasts for 1-7 days. • Bubonic plague usually occurs from an infected fleabite on the legs marked by a small pustule or ulcer. The draining lymph nodes (usually inguinal) enlarge dramatically within a few days and become soft, pulpy, plum-coloured and may infarct or rupture through the skin. • Pneumonic plague presents as severe, confluent, haemorrhagic and necrotizing bronchopneumonia often with fibrinous pleuritis. Symptoms include dyspnoea, cough, copious bloody sputum and a fatal haemorrhagic illness. • Septicaemic plague presents as systemic lymphadenopathy with foci of necrosis. Fulminant bacteraemias induce DIC. • Diagnosis: Phage typing of bacterial culture or a 4-fold rise in antibodies to F antigen • Treatment: • Isolate suspects. • Streptomycin 15mg/kg/12h IM for 10d. • If in 1st trimester of pregnancy, amoxicillin 250-800mg/8h PO • If later in pregnancy, co-trimoxazole 480mg/12h PO • Children: co-trimoxazole • Once stables patient must stay at home or quarantined (with inspections daily for 1 week) with insect sprays to legs and bedding. • Post-exposure prophylaxis involved doxycycline 100mg/12h PO for 7d • Prevention: Avoiding dead animals and good hygiene helps stop spread. Vaccinations give no instant protection so multiple doses may be needed.

7. Pathogenesis:Yersinia proliferates with lymphoid tissue. The complex of genes called the Yop virulon enable the bacteria to kill host phagocytes. Its proteins form a hollow syringe-like structure that projects from the bacterial surface, binds to host cells and infects bacterial toxins called Yops(Yersinia outercoat proteins). Yops then inhibit actin polymerisation and block phagocytosis. • Y. pestis ensures its spread by forming a biofilm that obstructs the gut of the infected flea, causing the flea to regurgitate and continually feed and therefore infect the rodent or human it is biting.

8. Lyme Disease • Borrelia burgdorferi is an arthritis associated with skin erythema transmitted to people by Ixodesdeer ticks. • Epidemiology: 23,000 cases in 2005 in the USA, particularly in Northeastern states. In endemic areas, as many as 50% of ticks are infected with B. burgdorferi (and can also be infected with Ehrlichiaand Babesia) • Morphology: Skin lesions caused by B. burgdorferi are characterised by oedema and a lymphocytic infiltrate. In early Lyme arthritis, the synovium resembles early RA with villous hypertrophy and lymphocytes in the subsynovium. • Lyme arthritis characteristically causes arteritis that produces onionskin-like lesions similar to lupus. • Diagnosis is clinical with serology but PCR can also be done on infected tissue • Treatment: • Skin rash: Doxycycline 100mg/12h PO (amoxicillin or penicillin is <8yrs or pregnant) for 14-21d. • Later complications: Use IV benzyl penicillin or ceftriazone • Removing ticks is best done by suffocating the tick (such as with petroleum jelly) then by grasping close to mouth parts and twisting them off, then cleaning the skin. • Prevention: Keep limbs covered, use insect repellent, tick collars for pets, check skin in risky areas. Vaccination is available and prophylactic doxycycline (200mg PO within 72) can be given after a tick bite.

9. Clinical presentation: Lyme disease is a multiple organ system and is divided into three stages • In stage I, spirochetes multiple and spread in the dermis at the site of a tick bite, causing an expanding area of redness, often with a pale centre. This skin lesion is called erythema chronicummigransand can be accompanied by fever and lymphadenopathy. It usually disappears in 4-12 weeks • Stage II is the early disseminated stage. Spirochetes spread shaematogenously throughout the body and cause secondary skin lesions, lymphadenopathy, migratory joint and muscle pain, cardiac arrhythmias and meningitis, often with cranial nerve involvement • Stage III is the late disseminated disease and occurs 2-3 years after the initial bite. Lyme borreliae cause a chronic arthritis sometimes with severe damage to large joints and a polyneuropathy and encephalitis

10. Rickettsial Infections • Rickettsiales are vector-borne obligate intracellular bacteria that cause epidemic typhus (Rickettsia prowazekii), scrub typhus (Orienta tsutsugamushi) and spotted fevers (Rickettsia ricketsii and others). These organisms are structurally Gram negative and rod shaped bacteria though they stain poorly with a gram stain. • Distribution of types: • Epidemic typhus is transmitted from person-to-person by body lice (Pediculushumanus) from their faeces or through the skin. It is associated with wars and human deprivation, when individuals are forced to live in close contact without changing clothes. • Scrub typhus is transmitted by chiggers and was a major problem for US soldiers in the Pacific in WWII and in Vietnam. • Rocky mountain spotted fever (RMSF) is transmitted to humans by dog ticks feeding on humans. • Tick typhus (Mediterranean spotted fever) is caused by R. Conoriiand is the chief imported rickettsial disease in the UK. It is endemic in Africa, the Mediterranean area (such as Croatia), parts of Asia and sporadic in Laos and Korea. The rash starts in the axillae and becomes purpuric as it spreads. Other signs include conjunctival suffusion, jaundice, deranged clothing, meningoencephalitis, cerebritis and renal failure. • Murine typhus is caused by R. typhi and is spread by fleas from rats to humans. It is more prevalent in warm, coastal ports (such as Dalmatia or Laos).

11. Pathogenesis: • Rickettsiae do not produce significant toxins. • The rickettsiae that cause typhus and spotted fevers mainly affect vascular endothelial cells (particularly of the lungs and brain). Bacteria enter the cells by endocytosis but escape from the endosome to proliferate in the cytoplasm. They then either: • Lyse the cell (if in the typhus group) • Spread to adjacent cells by actin-mobilised motion (if in the spotted fever group) • The innate immune response to rickettsial infection is mounted by NK cells which produce IFN-γ. Subsequent CTL responses are required to eliminate infection. • Brill-Zinsser disease is a delayed relapse of epidemic typhus.

12. Morphology: • Typhus fever: In mild cases, there is a rash and small haemorrhages due to vascular lesions. In more severe cases, there are areas of skin necrosis and gangrene on the tips of the fingers, nose, earlobes, scrotum, penis and vulva. The rash is first truncal, then peripheral, which is the opposite of spotted fever. • Irregular ecchymotic haemorrhages can also be found internally, mainly in the brain, heart muscle, testes, lungs, kidneys and serosal membranes. • The most prominent microscopic changes are small-vessel lesions with focal haemorrhage and inflammation. A cuff of mononuclear inflammatory cells usually surrounds the affected vessel, sometimes with luminal thrombosis but rarely with necrosis of the vessel wall. • Scrub typhus is a mite-borne infection that is a milder form of typhus fever. The rash is usually transitory or might not appear. Vascular necrosis or thrombosis is rare but there may be prominent inflammatory lymphadenopathy. • Rocky Mountain Spotted Fever presents as a haemorrhagic rash over the entire body, including the palms of the hands and soles of the feet. An eschar at the site of the tick bite is uncommon. Vascular lesions that underlie the rash often lead to acute necrosis and fibrin extravasation. In severe RMSF foci of necrotic skin appear, particularly on the fingers, toes, elbows, ears and scrotum. Vascular lesions in the brain can produce microinfarcts and pulmonary oedema can result in ARDS.

14. Diagnosis is usually done clinically and confirmed by serology, but it is difficult because the presentation is often non-specific and organisms are difficult to grow. • Investigations: • The standard antibody Weil-Felix tests are insensitive and non-specific. Latex agglutination, indirect immunofluorescence, ELISA and PCR can be done on the eschar. • Skin biopsy can be diagnostic in Rocky Mountain spotted fever • Treatment: Doxycycline 100mg/12h PO/IV for 7d or chloramphenicol 500mg/6h PO for 10-14d (note resistance has been reported in Thailand). Azithromycin 500mg (1 dose) may work in tick and scrub typhus.

16. Leishmania • Leishmaniasis is a chronic inflammatory disease of the skin, mucous membranes or viscera caused by protozoan parasites transmitted through the bite of infected sandflies. • Distribution:It is endemic in the middle East, South Asia, Africa and Latin America. Leishmanial infection is exacerbated by conditions that interfere with T-cell function, such as AIDS. Reservoirs of Leishmania include rodents, dogs and foxes.

17. Pathogenesis of Leishmania • The life cycle of Leishmania involves two forms: • The promastigotedevelops and lives extracellularly in the sandfly vector. These produce abundant surface glycoconjugates which inhibit complement function. • The amastigotemultiplies intracellulary in host macrophages. They differentiate into promastigotes and multiple with the GIT of the sandfly and then to the salivary gland, where they are posed for transmission when the sand fly bites. • After being bitten, the promastigotesare released into the host dermis along with the sandfly saliva, which potentiates the infectivity. • The promastigotes are phagocytosed by macrophages and the low pH triggers the formation of amastigoteswith a kinetoplast. Amastigotes proliferate inside the macrophage which then dyes so progeny amastigotes to infect adjacent macrophages.

19. Morphologies of Leishmania • In visceral leishmaniasis (kalaazar), L. donovani and L. chagasiinvade macrophages and cause severe systemic disease marked by hepatosplenomegaly, lymphadenopathy, pancytopaenia, fever and weight loss. The spleen can weigh as much as 3kg and lymph nodes up to 5cm in diameter. • Phagocytes are filled with Leishmania. • In late stage, the liver becomes increasingly fibrotic • In people from South Asia, there is hyperpigmentation of the skin. • The kidneys may undergo immune complex-mediate mesangioproliferative glomerulonephritis or amyloid deposition. • Cutaneous leishmaniasis is caused by L. minor, L. Mexicana and L braziliensis. It is relatively mild and consists of a localised ulcer on exposed skin. It usually heals by involution after 6-18 months without treatment. • On microscopic examination, the lesion is granulomatous with many giant cells and few parasites • Mucocutaneous leishmaniasis is caused by L. braziliensisand found only in the New World. It manifests as moist lesions which can be ulcerating or non-ulcerating, and often disfiguring. • Histology shows mixed inflammatory infiltrate with parasite-containing macrophages with lymphocytes and plasma cells.Inflammation later becomes granulomatous and the number of parasites declines. • Diffuse cutaneous leishmaniasis is a rare form of dermal infection only found in Ethiopia and Central America. It begins as a single skin nodule but continues to spread along the entire body.

20. Diagnosis is usually done with culture or histologic examination. Leishman-Donovan bodies are found in the marrow (sensitivity 80%), node or splenic aspirates (95%). Serology may be negative if HIV +ve. • Treatment: • Cutaneous leishmaniasis: Fluconazole 200mg/d PO for 6 weeks for L. major • Visceral leishmaniasis: WHO regimen is sodium stibogluconate(Sb) 20mg/kg/24h IV/IM for up to 850mg/d, for 30d. • SE: malaise, cough, substernal pain, arrhythmias. Regimen is changing (possibly to 10mg/kg/8h for 10d) as 25% fail to respond or relapse.