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Luke Kostanjsek lpk17@ic.ac.uk Microbiology 2 A MedED LECTURESESSION STRUCTURE Immunocompromised Fever in the returning traveller Influenza Zoonoses Virology Fungal infections Pyrexia of unknown origin Prion disease Important disclaimers • I’m a sixth-year medical student who edited the microbiology section • I’m definitely not an infectious disease expert • This is not an exhaustive discussion of infectious disease • I’m not going to bore you with every single detail of the topics • If you’re further interested in this topic, I would highly recommend: • www.msdmanuals.com • Kumar and Clark’s Clinical Medicineimmunocompromised Causes of immunocompromise • Immunodeficiency syndromes • Acquired systemic immunocompromise • HIV • Iatrogenic • Lymphopaenia • Organ-specific e.g. • Structural lung disease • Splenectomy Consequences of immunocompromise • Unusual organisms • HIV – microsporidium, MAC • Cystic fibrosis – Burkholderia cepacia • Anti-TNFα – JC virus • Unusual site • HIV – CMV colitis, oesophageal candidiasis • Sickle cell disease – Salmonella septic arthritis • Prophylaxis • Vaccination pre-splenectomy • Cotrimoxazole in HIVInfluenza Pandemic influenza • Broadly split into InfluenzaA and B • Pandemic features • Novel antigenicity • Efficient replication in airways • Efficient transmission between people • Novel antigenicity results from two processes • Antigenic drift • Antigenic shift Neuraminidase and haemagglutinin • Two most important genes in Influenza virus • Haemagglutinin • Binds sialic acid, facilitates viral entry • Especially prone to antigenic drift • Neuraminidase • Cleaves sialic acid, facilitates viral release • RT-PCR diagnosis also determines strain Influenza antivirals • Neuraminidase inhibitors • Oral Oseltamivir most widely used • Inhaled Zanamivir • IV Peramivir • Endonuclease inhibitor • Oral Baloxavir • M2 antagonist • Oral amantadineVirology A note on antivirals • Antiviral vs val-antiviral • Increases bioavailability • Easier to take orally • In general, human herpes viruses • Start with aciclovir or ganciclovir • Foscarnet • Cidofovir • Non-herpes viral infection • Cidofovir Herpes simplex virus • HSV1 – Herpes labialis, HSV encephalitis • HSV2 – Genital herpes, HSV meningitis • Rarer presentations include • HSV oesophagitis/colitis • Eczema herpeticum • Herpetic whitlow • Disseminated cutaneous herpes • First line treatment is aciclovir Varicella zoster virus • Causative agent of chickenpox • Classically presents in children with fever, malaise, rash • Macules -> Papules ->Vesicles • Severe infection in adults, immunocompromised • First line treatment is aciclovir if high risk patient • Reactivation causes herpes zoster • Ophthalmic herpes zoster • Ramsay-Hunt syndrome Epstein-Barr virus • Presents with infectious mononucleosis • Fever, pharyngitis and lymphadenopathy • Also hepatitis ± splenomegaly • Diagnosis is suggested by • Atypical lymphocytes • Heterophile antibody (monospot) test • EBV serology • Lives dormant in B cells • Burkitt’s lymphoma • Post-transplant lymphoproliferative disease Cytomegalovirus • Typically asymptomatic, or infectious mononucleosis picture • Lives dormant in monocytes and dendritic cells • Visualise ‘Owl’s Eye’ inclusion bodies • Can reactivate in immunosuppressed patients • Pneumonitis • Retinitis • Colitis • Encephalitis • First line treatment is ganciclovir/valganciclovir Other human herpesviruses • HHV6 and HHV7 • Principally causes Roseola • Can (very) rarely cause encephalitis • HHV8, also known as KSHV • Kaposi’s sarcoma – esp. in HIV • Castleman disease • Primary effusion lymphoma Adenovirus, JC virus and BK virus • Adenoviruses are a growing concern in immunocompromised • Pneumonitis/pneumonia • Haemorrhagic cystitis • Meningoencephalitis • Colitis • JC virus can reactivate in immunosuppressed, causing PML • BK virus poses a significant threat in specific at-risk patients • BK nephropathy and BK haemorrhagic cystitis Hepatitis A and E • Both seen principally in people who have been travelling • Both present similarly: • Incubation period (classically 2-6 weeks for HepA) • Prodromal malaise • Jaundice, hepatitis, cholestasis • Resolution ~2 months later • Rarely cause fulminant hepatitis • HepA – higher risk in elderly • Hep E – very high risk in pregnant women Hepatitis B • Transmitted by bodily fluids, and vertically • Acutely presents with hepatitis picture • Can last up to six months • Rarely fulminant • 5-10% fail to clear HBV , become chronically infected • If uncontrolled, progresses to cirrhosis and HCC Hepatitis B serology • HBsAg – you have HBV • Anti-HBs – you have neutralising antibodies • By definition makes you immune • Anti-HBc – you have or had HBV • IgM – acute response • IgG – chronic response • HBeAg – suggests high infectivity • Anti-Hbe – suggests low infectivity Hepatitis B treatment • Whole bunch of different anti-HBV drugs • First-line is tenofovir or entecavir • Lots of other options • Six-monthly screening for HCC • Ultrasounds and serumAFP • Prevention is much more important • HBV vaccine Hepatitis D • Transmitted by bodily fluids, only causes infection in those with hepatitis B • Has three main manifestations • Coinfection – unusually severe acute HBV • Superinfection – acute exacerbation of chronic HBV • Aggressive, difficult to treat chronic HBV • If suspected, test for anti-HDV antibodies • Very difficult to treat Hepatitis C • Transmitted by bodily fluids, and vertically • Rarely presents with acute hepatitis • Occasional prodromal symptoms • 60-80% fail to clear HCV , become chronically infected • Unusual presentations – glomerulonephritis, cryoglobulinaemia, vasculitis • Test with HCV RNA, serology Hepatitis C treatment • Historically, ribavirin + pegylated IFNα • Direct acting antiviral (DAAs) revolutionised treatment • NS3/4 inhibitors –previrs • NS5a inhibitors –asvirs • NS5b inhibitors –buvirs • Treatment judged by sustained virologic response (SVR)unknown origin Defining pyrexia of unknown origin • Repeated pyrexia >38.3ᵒC for >3 weeks without a known cause, despite at least one week of investigation • Specific situations to be aware of • Nosocomial PUO • Neutropaenic PUO • HIV-associated PUO What else can cause a fever? • Non-obvious infections • Unusual infections, unusual focus • Autoimmune conditions • Rheumatology, vasculitis, Still’s disease • Malignancy • Rare familial diseases • Periodic fever syndromes, Fabry’s disease, immunodeficienciesreturning traveller Typhoid fever • Infection caused by Salmonella typhi or paratyphi • Classically travel from India, faecal-oral route • Presents after 1-2 week incubation • Fever, malaise, headache, epistaxis, constipation • Faget’s sign, rose spots, hepatosplenomegaly, cytopenias • Diagnose with cultures, or serology (Widal test) • Note that gold standard is blood/bone marrow culture • Treat with IV ceftriaxone > fluoroquinolones, azithromycin Dengue fever • Infection caused by 4 Denguevirus serovars • Travel from SEAsia, mosquito bites • Presents after up to two weeks incubation • Fever, rigors, myalgia, prostration • Retro-orbital headache, sunburn rash • Rarely, can present with two severe syndromes • Dengue shock syndrome • Dengue haemorrhagic fever Malaria • Parasitic infection caused by Plasmodium spp. • Endemic toAfrica, SouthAsia, SEAsia, Central and SouthAmerica • Variable incubation, then presents with • Paroxysms of fever and rigors • Anaemia, jaundice, hepatosplenomegaly, haemoglobinuria • Numerous potentially fatal complications • Shock,ARDS, Cerebral malaria, Blackwater fever, DIC • Diagnose with thick and thin blood films > serology Plasmodium species • Plasmodium falciparum • Responsible for almost all fatal disease • Tertian pattern – 48hr paroxysms • Plasmodium vivax and ovale • Require treatment of hypnozoites • Tertian pattern – 48hr paroxysms • Plasmdoium knowlesi • Quotidian fever – 24hr paroxysms • Plasmodium malariae • Quartan fever – 72hr paroxysms Treating malaria • Severe (falciparum) malaria requires IV artersunate • Clinically severe illness • Parasitaemia > 2% • Hypoglycaemia • Metabolic/lactic acidosis • Severe anaemia • Otherwise artemesin combination therapy, or chloroquine • Most common is artemether/lumefantrine • If vivax/ovale, subsequent primaquine is neededZoonoses Brucellosis • Infection caused by various Brucella spp. • Contracted from raw dairy, and farm animals • Presents after ~two week incubation period • Sudden onset of high fever, rigors, headaches, malaise, myalgias • Back/joint pain, hepatosplenomegaly, epididymo-orchitis, FLAWSy • Serious illness – endocarditis, osteomyelitis, CNS infection, epidural abscess • Diagnose with cultures > cultures • Treat with doxycycline and streptomycin Rabies • Infection caused by various Lyssaviruses • Contracted from animals – dogs and bats • Presents after 1-3 months incubation • Initially fever, headaches, malaise • Within days affects CNS – furious and dumb rabies • Excessive salivation, hydrophobia • Diagnose with fluorescent antibody test • CSF PCR also possible, Negri bodies pathognomonic • If bitten, pre-emptive rabies vaccine and immunoglobulins Plague • Infection caused by Y ersinia pestis • Contracted from rat fleas • Incubates for hours-a couple days • Bubonic plague – Fevers, rigors, buboes, dry gangrene • Pneumonic plague – Fevers, rigors, cough with bloody sputum,ARDS • Septicaemic plague – Fevers, rigors, DIC, peripheral gangrene • Diagnose with microscopy, culture or PCR • Treat with aminoglycosides or doxycycline Leptospirosis • Infection caused by Leptospira spp. • Spread by rat urine • Presents after ~one week incubation • Fevers, chills, rigors, myalgia, pharyngitis ± haemoptysis • Conjunctival suffusion, jaundice, meningitis • Pulmonary or GI haemorrhages, renal failure, haemolysis • Diagnose with cultures or serology • Treat with doxycycline, ceftriaxone if severe Bartonellosis • Infection by Bartonella henselae • Transmitted by cat scratches • Presents after ~one week incubation • Painless erythematous crusted papule at scratch site • Regional lymphadenopathy near inoculation site, fevers, malaise • Hepatitis, encephalitis, Parinaud oculoglandular syndrome • Diagnose by PCR, serology > cultures • Treat with doxycycline Lyme disease • Infection by Borrelia spp. • Transmitted by the Ixodes tick • Presents after incubating for days-weeks • Early localised – erythema migrans, esp. inoculation site • Early disseminated – fevers, myalgias, arthralgias, CNS/heart • Late disseminated – arthritis, skin lesions, polyneuropathies • Diagnose clinically, rash biopsy, serology • Treat with doxycycline, ceftriaxone if CNS involvement Leishmaniasis • Infection by Leishmania spp. • Transmitted by sand fly bites • Can present with • Cutaneous – well-demarcated lesion at site of inoculation • Mucocutaneous – follows cutaneous, destructive lesions around face • Diffuse cutaneous – widespread nodular rash • Visceral – gradual onset fever, hepatosplenomegaly, pancytopaenia • Diagnose by microscopy > serology, PCR • Treat with liposomal amphotericin B Anthrax • Infection by Bacillus anthracis • Found in farm/wild animals, can be spread by spores in hair • Presents in three major forms • Cutaneous – Boil that develops into an eschar, lymphadenopathy • GI – Haemorrhagic necrotic ulcers, lymphadenopathy, perforation • Pulmonary – Chest pain, haeomptysis, SOB, haemorrhagic mediastinitis • Diagnose by microscopy, culture > serology, PCR • Treat with doxycyclineFungal infections Superficial infections • Dermatophytoses • Tinea pedis –Athletes foot • Tinea cruris – Groin • Tinea corporis – Body • Tinea manuum – Hands/palms • Tinea capitis – Scalp/hair • Tinea unguium – Finger/toenails • Pityriasis versicolor • Multiple brown/tan lesions across the trunk, abdomen and face • Treat with antifungal shampoos and topical azoles Candidiasis • Infection caused by Candida spp. • Various presentations • Thrush and skin infections common • Oral and oesophageal candidiasis • Disseminated candidiasis • Diagnose with cultures • Positive beta-D-glucan, negative galactomannan • Treat with amphotericin B/echinocandins if severe illness Aspergillus • Infection caused by Aspergillus spp. • Various presentations • Aspergilloma – collection in pre-existing cavity • Invasive aspergillosis – pulmonary and/or extrapulmonary • ABPA – hypersensitivity reaction to colonisation • Diagnose with cultures • Positive beta-D-glucan and galactomannan • Treat with amphotericin B/voriconazole if severe illness Some other random bits • Sporotrichosis – caused by Sporothrix schenckii • Contracted from rose thorns • Spreading nodular necrotic rash from inoculation site • Can disseminate, producing abscesses in bones, joints, CNS • Mucormycosis – caused by Rhizopus and Mucor spp. • Rhinocerebral infection, necrotic destructive lesions around face • Vascular invasion follows, very high mortalityPrion disease Prion proteins • PrP is a protein expressed on the surface of neruones in the brain • Secondary structure primarily alpha-helical c Sc • PrP can misfold into a new structure, called PrP • Occurs sporadically, familially or infectiously • Secondary structure primarily beta-pleated sheets C Sc • Interacts with PrP , causing conformational change to PrP • Accumulation results in neuronal cell death Creutzfeldt-Jakob disease • Most common form of prion disease • Comes in three forms • Sporadic – 85% of cases • Familial – 5-15% of cases • Acquired – <1% of cases • Diagnosis is clinical, and supported by imaging • vCJD – tonsillar biopsy can exhibit PrPSc Other prion diseases • Kuru • Prion disease seen in Papau New Guinea • Spread through ritual cannibalism • Gerstmann-Sträussler-Scheinker disease • Autosomal dominant familial prion disease • Slower progression than others, life expectancy 5 years • Fatal Familial Insomnia • Autosomal dominant familial prion disease • Features prominent insomnia, paranoia and 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