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Infections in the immunocompromised patient. Inger Karin Lægreid Avd for nyresykdommer St.Olavs Hospital Desember 2011.

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Presentasjon om: "Infections in the immunocompromised patient. Inger Karin Lægreid Avd for nyresykdommer St.Olavs Hospital Desember 2011."— Utskrift av presentasjonen:

1 Infections in the immunocompromised patient. Inger Karin Lægreid Avd for nyresykdommer St.Olavs Hospital Desember 2011

2 Immunocompromised patients: Organtransplanted – immunosuppressive medications Cancerpatients – cytotoxic drugs + xray Systemic illnesses – ex. Vasculitis, Lupus, RA - immunosuppressive medications + cytotoxic drugs HIV pos / AIDS

3 Risk factors for infections 1. High dosis of immunosuppressive medications -Because of treatment failure or rejection -Repeating treatments -Cumulative dosis 2.Leucopenia -Induced by a.medications: -Most often cytotoxic drugs and -azathioprine(Imurel), mycophenalate (Cell Cept or Myfortic) -or b.virus: CMV

4 Mecanisme of defense Granulocytes – ability to granulocytosis (BM), important with numbers and function Cellulær immunity – remove intracellulære patogens and virus- infected cells –Cytotoxic effector cells and spes. T cells Humoral immunity – remove extra-cellulare bacteria, B cells and Ag and plasmacells – Ab Skin-barriere broken: wound, venflone, catheter –entry for bacteria og virus Mucous membranes (mouth, GI tractus, urinary tract)

5 Types of agens Virus: -Cytomegalo CMV -Epstein Barr EBV -Varicella zoster VZV -HepatitisB HBV -Hepatitis C HCV -Herpesvirus HHV 6-7 -Polyomavirus -Influenza A, pandemic Bacteria: Gram neg –Pseudomonas, E.coli, Klebsiella, enterobacti Gram pos cocci –staf.cocci, streptococci -Legionella sp. -Listeria sp -Tbc

6 Cont. types of agens Fungi: Candida -Cryptococcus -Mucor -Aspergillus Protozoer: Pneumocystis jirovecii Toxoplasmose sp.A

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8 Am. cancerpopulasjon Causes of infection, fever and neutropenia Fever without known cause (drugfever) 39% Clinically def. infection (- pos. culture) 17% Bacteremia (pos.blodkultur) 35% - Gram neg 10% –Gram pos cocci 19% –Mixed 1 % –Polymicrobial 6% Non bacteremia 9% –Gram neg 2% –Gram pos cocci 3% –Mixed 1% –Polymikrobial 3%

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10 Kasuistikk Mann f.1944 Ulcerøs colitt Nyretransplantert 2002 Sarkoidose Står på trippel immunsuppresjon: –Sandimmun, Cellsept og Prednisolon Inntil det aktuelle: god almentilstand, kreatinin 160.

11 Kasuistikk Feber, tørrhoste, slapphet frå 3.12 Opps fastlege, får Ciproxin Ny kontakt pga ingen effekt/ forverring av symptomer → innlegges. Ved innk 10.12: feber, hoste, tungpust, CRP:130, kreatinin 204 (eGFR 28 ml/min) Rtg.thoraks: småflekka infiltrat bilat, mest utbredt perihilært. Atypisk pneumoni?? Starter Rocephalin (cephalosporin)

12 Kasuistikk Trass i Rocephalin – tilstanden forverres, økende dyspnoe, stigende CRP Utifrå klinikk, CT thoraks og rtg.thorax funn – atypisk pneumoni: ?? Pneumocystis Jirovecii Planlagt bronkoskopi med BAL – pas for dårlig. Starter Trim Sulfa (TMS) på mistanke, red dose pga nyresvikt Forverring → Respirator Bronkoskopi med BAL: Pneumoc J → høg dose TMS

13 Pneumocystis jirovecii pneumonia Typisk røntgenfunn Bilat hilusnære småflekka fortetninger

14 Kasuistikk Uendra resp.status over fleire dager Terapisvikt pga initial låg TMS dose? Høg dose → økende nyresvikt + rhabdomyolyse Red TMS, må seponeres : fortsatt på respirator, betring i nyrefunksjon (kreat 125), CRP 102, svært usikker prognose. Får spontan pneumothorax – vanskelig å ventilere Har ARDS, lungefibrose. Avslutter respiratorbehandling 5.1 –pas sovner inn samme dag

15 Pneumocystis jirovecii Incidens hos organ tranplanterte: 5 – 15% Reservoir: barn, symp og asympt immunkomprimerte pasienter Luftsmitte via mennesker – opptrer ofte i ”cluster” Riskofaktorer: alder, CMV infeksjoner, rejeksjoner, ↓ lymfocytter Obs. coinfection (Herpesvirus)

16 Listeria monocytogenes Listeria sepsis in adults nonpregnant: –Most are immunocompromised or elderly –Symptoms: fever and chills –Septic shock –Seeding of the brain and/or meninges –Meningoencephalitis or cerebritis –Diagnosis: culture of blood and cerebrospinal fluid (CSF) –Cerebral MRI

17 Piers Mook et al; Em Inf Dis 2011 Jan Listeria M Listeria RH autum 2007: –Kantine serverte upasteurisert gårdsost –15 persons got the disease –5 died, 3 immunocompromised and 2 unborn childs(twins) Eng. studie 10 års materiale (1999 – 2009): –Cancerpas har 5X større risiko for Listeria M –Hematologisk cancer mest utsatt (17x) –I tillegg til cancer: lever, nyresykdommer, bindevevs- sykdommer(Lupus) og inflammatoriske sykdommer (Crohns sykdom)

18 Listeria M Treatment: –Ampicillin –Gentamycin ( in combination the first days) Prognosis: –Total mortality: 25% –Higher by menigitis and sepsis

19 Legionella Pneumonia – predominantly clinical manifestation Cough – initially mild Chest pain High fever > 39 Gastrointestinal symptoms Headache

20 Legionella Diagnosis: –Xray of lungs: patchy infiltrates –Culture of blood ( specific medium) –BAL –Direct immunfluorescens –Antigen- test in urine

21 Legionella Treatment: –Erythromycin –In combination with ciprofloxacin or rifampicin Prognosis: Mortality: 5 – 30%

22 Cryptococcus Disseminated fungi infection in liver transplanted patient Six cutane lesions like this one Biopsi and serum antigen test – cryptococcus ”fleshy” border with centrale umbilication.

23 Invasive candidaisis Tender, erythematøse nodulare lesions in neutropen pasient with leucemia after induction chemotherapy.

24 Aspergillus Neutropen patient - stamcelle treatment Multiple necrotic lesions Biopsi showed infarctions caused by Aspergillus

25 Herpes Zoster 1. primær infeksjon: vannkopper 2. Herpes Zoster – reaktivering av endogent latente varizella zoster virus i sensoriske ganglier –Følger dermatomer 75% har prodromale smerter før utslettet Starter ofte med små røde flekker → blemmer Varizella zoster pneumonitt – alvorlig prognose

26 Herpes Zoster Important with early diagnosis and treatment Zovirax/ Valtrex early shortens the duration of the disease and reduces postherpetic pain ”common” by organ- transplanted (35% av BM tx)

27 Herpes Zoster HIV pos. Hemorrhagic vesicles Pustles = seint stadium Obs. sekundær infeksjon

28 Herpes Zoster Male b.1960.Refugee from Vietnam Cystic kidney disease,- renal transplanted april - 98 Rejection – Solumedrole + Thymoglobuline Creatinine at discharge from RH july 98 : 320 Aug -98: pain at left eye and ear. Opthalmoscopy: Shows vesicles, diagnosed as HZ optalmicus, gets general eyedrops.

29 Herpes Zoster II 1 week later- hospitalizes with widespread Herpes Zoster Oftalmicus with affection of left part of the face incl. left ear Zovirax (in reduced dosis because of reduced renal function) Discharged from hospital after 2 weeks.

30 Herpes Zoster III 1 week later – new hosp : fever, dyspnoe og cough Blood tests: High CRP og leucopenia Xray lungs: diffuse infiltrate – agents? Broncoskopi with BAL: stafylococcus aureus + CMV Sepsis- multiorgan failure – respirator – dialysis Sep 2 of 3 immunosuppressive medications Survives with a rel.good outcome status nov 2007: -- creat 130, chronic pain in left part of face, got perforation of tympanic membrane in -98, relapsing otitis later, planned operative treatment (myringoplastic surgery)

31 Herpes Zoster ophtalmicus Rammer Trigeminus dermatom Kan føre til corneal affeksjon og føre til synstap

32 Cytomegalovirus CMV Member of B-herpes family big ds DNA virus. Transmitted by : -contact (sexually, nursing) - blood / organ (CMV pos til CMV neg) - mother to child (in utero, perinatal, lactation) Asymptomatic primary infection, followed by lifelong latency, can be reactivated Age related increase in seroprevalence: - by age 20: - 40% -by age 30: - 50% -by age 50: - 65% -by age 80: - 90%

33 CMV The most common viral infection in organ-transplanted Lungs>heart>liver>pancreas>kidney ”CMV- syndrome” (viremi): -fever, malaise, ( ”influenza-symptoms”), leucopenia, trombocytopenia, hepatic aminotransferase elevations Tissue – invasive CMV: -GI – duodenitis, gastritis, colitis, ulcus -Lungs – pneumonitis -Transplantat – nephritis, hepatitis, pneumonitis -Eye - retinitis

34 CMV retinitis CMV infenction in patient with AIDS Retinitis with hemorhagies og papille-oedema In the periphery– can be difficult to localise with ophtalmoscopi

35 Epstein Barr virus EBV 20-30% of organtransplanted has active replication of EBV 80% of these have got antilymfocytt- antibodies (because of serious rejection). Cyclosporine A (Sandimmun), tacrolimus (Prograf) + Antilymfocytt-antibodies reactivate latent EBV infection EBV can give mononucleosis Important: the role of EBV in the pathogenesis of development of post-tx lymfoproliferative disease.

36 EBV II B celle lymfoproliferativ process – can change from benign polyclonale process to a highly malignant monoclonal lymphoma which is resistante to treatment. Post-tx disease – extranodale – brain, bonemarrow, organtransplant, GI-tractus and liver Important to reduce or take away immunsuppressive medications Most important that the patient survives, on the behalf of the transplanted organ.

37 Epstein Barr virus Primary infection to chronic infection EBV infect resting Bcells or epitelial cells EBV-infected cells are kept in check by killercells and cytotoxic T-cells Latente infected memory B cells (EBNA) can be reactivated and give chronic EBV infection

38 EBV lymfoproliferativ sjukdom A. Cerebral MRI- multiple tumor- nodules B. Biopsi from perirenal tissue: immunoblastic lymfoma C. EBV nuclear antigen - EBNA

39 Polyoma virus PV Ds DNA virus, two types ass. with humane disease: BK virus JK virus 60-80% av immuncompetente adults are seropos for PV Renal transplanted: --PV-BK can give acute tubulo-intestitiell nephritis, ureter stenosis, hemorragic cystitis, serious transplantat dysfunction --PV-JK reactivation can give progressive multifokal leukoencephalopati

40 Polyomavirus Diagnosis: ---cells who contains virale inclutionsbodies (”decoy cells”) in urine or biopsi of the transplant Treatment: ---- reduction in immunsuppression --- cidofovir – seldom in use, highly nephrotoksic

41 Polyoma-virus Infecting many types of cells, including kidney, brain, liver, retina, lungs, blood, lymfatic, heart, muskulature og vasculare endoteliale cells Virale particles binds to a spesific celle-surface reseptor and prod T antigen early in the infection cykel.

42 Genetic relationship among Human and Swine influenza viruses

43 The Two Mechanisms whereby Pandemic Influenza Originates – H1N1 virus closely related to avian virus adapted to replicate in humans 1957 and1968, reassortment events led to new viruses that resulted in pandemic influenza – Asian influenza 1968 – Hong Kong influenza Future pandemic strains could arise through either mechanism.

44 Influenza- virus

45 Infl.A H1N1 (svineinfluensa) Forekomst – alder og kjønn.

46 Influenza A (H1N1= svineflu) Status pr in Norway: – deceased persons – 1310 hospitalized – 170 intensive care 71% < 30 years –29 dead 23 had other chronic diseases.

47 Vaccination – immunocomprimised patients The use of immunosuppresive medication gives reduced effect of vaccination. These patients is recommanded 2 vaccination with 4 weeks interval. In periods with very high dosis of immunosuppresive medication (i.e just after renal tx, vaccination not recommanded, wait till 3-6 months after tx) Family members are recommanded vaccination

48 Treatment Influenza A Oseltamivir (Tamiflu) – capsules,recommended to all age groups. Reduced dosis at eGFR < 30, Not to dialysis patients (eGFR< 10). Zanavimir (Relenza) –aerosol, recommended to age groups > 5 years. No reduction in dosis with renal failure. Not recommended with serious lung disease.

49 Status A(H1N1) des-10/jan-11: Alv. utbrudd i England høst 2010 –Medio sept – medio des: 10 døde –Unge personer, fleste i risikogruppe –Medio des: 16 innl, fleste i intensivavd. Sverige: gutt 7 år døde, risikogr. Norge: 2 innl.; lite barn + mann i 60 åra –Høg vaksinasjonsfrekvens i 2009/2010 –Mange hadde mild sjukdom, gir immunitet –Antar få m alv sjukdom i Norge denne vinter.

50 Diagnosis – infection in immunocomprimised patients?: Anamnese: progress of the disease? fever? medication? Spesific symptoms? Pain? Cough? Abdominalia? Rash? Clinical examination: all organs, spec. skin – wounds? incl. mouth, Blood tests: Hb, trombocytes,leukocytes with cellcounting or only granulocytes, CRP, or SR renal function, liver function,

51 Cont. diagnosis Urine stix + culture Larynx Virus- serologi Bloodculture CBF - cerebrospinal fluid microscopy and culture Bronkoskopi – med lavage (BAL) Secrete from wounds Biopsi of affected organ. OBS! catheter – Radiologic – chest, sinus, US, CT, MR OBS: sikre diagnostiske prøver før start av antibiotika!!

52 Principles for antimicrobielle therapy Treatment of established clinically disease Prophylaxis – treat the entire patient-population prophylactic, fex all renal-transplant pat. get TMS as prophylaxis against Pneumocystis carini in 6 months post-tx Preemptive therapy – treat subpopulations fex renaltx with pos CMV test,before clinically symptoms. Obs. Studier må vise stor gevinst for å vege opp for risiko for resistensutvikling.

53 Anti-microbielle treatment Fever and neutropenia ( neutrophile < 0.5 x10 9 cells /L): (ex: nadirperiode etter tøffe cytostatika-kurer) Big risk for lifethreathening infections, spec. gram.neg bacteria Start with: benzylpenicillin + gentamicin With clear abdominal symptoms: piperacillin/ tazobactam (Tazocin) Dont hesitate – important with early start!!

54 Antifungal treatment After 3-5 days with neutropenia and fever –the risk for invasive mycosis is 25-30% The most common: candidasis Treatment: fluconazol (Diflucan) Suspicious for aspergillus and not- flucanozol- sensitive candidasis: voriconazol (VFEND)

55 Antiviral treatment Herpes simplex – valgancyclovir(Valcyte) -- acyclovir (Zovirax) -- valacyclovir (Valtrex) CMV –gancyclovir ( Cymvene) –valgancyclovir Herpes Zoster – acyclovir (Zovirax) Diagnostikk: PCR- test in blood IF (immunofluorescens) Biopsi = gold standard

56 Conclusions Immunocompromised pasients: –More vulnerable for infections –More often atypical infections, remember: virus, fungi, tbc –Can reacte different upon infections: Less fever Later signs on x-ray –Obs neutropenia –Obs medications EARLY DIAGNOSIS and SPESIFIC TREATMENT is important for a good outcome!


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