Immunocompromised Patients Dr Anita Verma MD Consultant Microbiologist Department of Medical Microbiology amp Institute of Liver Studies Kings College Hospital Foundation NHS trust London ID: 998350
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1. 1Challenges in Management of Invasive Fungal Infections in Immunocompromised PatientsDr Anita Verma MDConsultant MicrobiologistDepartment of Medical Microbiology & Institute of Liver Studies, King’s College Hospital, Foundation, NHS trust, London
2. Conflict of interestEducational grant and Speakers – Gilead , Astellas Investigator and speaker for a study - Pfizer
3. Challenges in Management of Invasive Fungal Infections (IFI) in Immunocompromised (IC) PatientsNew mycologic challenges in IC pateintsKnow the Changing Epidemiology of IFINonspecific presentation of IFI Inadequate diagnostic methodsAntifungal prophylaxis – Does it work ?Breakthrough Infections while on antifungal therapyRefractory to antifungal treatment3
4. Background: IFI in Immunocompromised PatientsIFI incidence is increasing in immunocompromised (IC) hosts (SOTR & HSCT recipients ) because of The pool of IC patients is increasing dramaticallyexternal pressures from antibiotic usageuse of newer and more potent chemotherapeutic agents their highly compromised immune status SOTR: solid organ transplants recipients, HSCT recipients : hematopoietic stem cell
5. Epidemiology of IFI in both SOTR & HSCT RecipientsIncreasing incidence of mold infectionsSOTRHSCTInvasive candidiasis53% 28%Invasive aspergillosis 19%43%Cryptococcosis8%-Non-aspergillus molds 8%-Endemic fungi (5%)5%-Zygomycosis2%-The Transplant-Associated Infections Surveillance Network (TRANSNET) -23 transplant centers in the US, prospective study from 2001 to 2006: epidemiology of IFI in both SOTR and HSCT recipients Clin Infect Dis. 2010, 50:1101–11, Clin Infect Dis. 2010, 50:1091–100.
6. Invasive AspergillosisType of IA ,% Disseminated Mortalitytransplant range (mean) aspergillosis, % rate, %Liver 1-8 (2) 50-60 92Lung 3-14 (6) 15-20 74Heart 1-15 (5.2) 20-35 78Kidney 0.9 - 0 4 (.7) 9-36 77Pancreas 1.1 - 2.9 (1.3) NA 100Small bowel 0 - 3.6% (2.2) NA 100
7. Mortality Of Invasive Aspergillosis in Relation To Underlying Disease Clin Infect Dis 2001;32:358100908070605040302010 leukemia /lymphoma bone marrow transplant kidney transplant lung /heart liver transplant AIDS
8. Inadequate Current diagnostic methods for IFI>30% Detected on autopsy In a case series involving patients with hematologic malignancyIFI high prevalence of IFI 31% detected at autopsy77% of the patients’ deaths were related to infectionThis highlighted the inadequacies of current diagnostic methods for IFIHaematologica. 2006, 91:986–9
9. Current limitations of classical and new Diagnostic test for IFI- IssusesConventional methods of Microscopy and culture rarely positive because: Invasive Candidiasis (IC) Patients on antifungal prophylaxisImaging not helpfulDiagnosis is mainly clinical Invasive Aspergillosis (IA); Initially affects the lungs , easily go unoticed because no clinical symptomsEven when recognized early, suitable specimens can be difficult to obtain In LTR pts with IA - 50% who had Aspergillus in BAL,22 fold at risk of IA (Singh et al 1997) Lack of adequate diagnoses makes estimating the prevalence and incidence of IFI unreliable
10. Diagnosis: Imaging- Invasive AspergillosisChest X-ray- nodular lesions, interstistial opacities, cavitary lesions, or pulmonary embolus pattern, or normal chest x-rayCT- valuable when chest –x-ray negative, can reveal disease as much as 5 days earlierAn 18-month-old girl - Aspergillus isolated from the lung. (a) Chest radiograph showed a round opacity behind the heart. (b) CT revealed a cavitating nodule in the left lower lobe.
11. Nonspecific Presentation In Immunocompromised Patients- Case Scinario18 yrs M LCH, had BMTAdmitted for Liver transplant - D1 post LTx - Ambisome -5mg/kg x7 days (fullfill criteria highrisk for mold infection)Persistant NeutropeniaChanged to caspofungin ( half dose because of abnormal LFTS)D18 post LT - multiple cutaneous lesions Prior to LTX multiple courses of antifungalPrevious lung Bx before LTx -veSkin Biopsy- + hyphaeCulture- Aspergilllus fumigatusStarted on voriconazole + AmbisomeNo response x 4 weeksImmunomodulation- leukocyte infusionResolution of skin lesion – negative for moldHowever 3 month later relapse of underlying dis (LCH)- BX provenWright stain;hyphae
12. Available Non Culture Methods Detection of circulating surrogate markers.1. Serological tests - detect fungal antigensAspergillus galactomannan ELISA(1→3)- β-D- glucanMannan & anti-Mannan antibodyPCR-based assays - detect fungal DNA.Imaging
13. Serological test:β-D- glucan (BDG)Cell wall component of wide variety of fungi (not zygomycetes or Cryptococcus).Indicated for the presumptive diagnosis of IFI Sensitive with a good negative predictive value i.e. good for excluding infection. A review of 23 & meta-analyses of 16 studies containing 2979 patients gave a pooled sensitivity of 76.8% & specificity of 85.3%. (Clin Infect Dis 2011;52(6):750-70. )Meta-analysis of 31 studies of IFD: sensitivity (80%) & specificity (82%) was found by a (excluding Pneumocystis infection). (J Clin Microbiol 2012; 50(1):7-15. )
14. ANTIFUNGAL STEWARDSHIPPRE-EMPTIVE TREATMENT BASED ON BDG+ RISK FACTORS
15. Intensive care unit (ICU) stay - >9 month No pos culture, ?suspected aspergillosis based on BDG+ risk factors pre-emptive treatment for IA Risk factors for IFIALF of unknown causeIntra-abdominal bleed, bowl perf, pancreatitis, dialysis dependent, multiple viral infction adeno, CMV, EBVAugmneted immunosuppressionICU stay >1year
16. Optimal Antifungal Strategy – no uniform consensus ?Invasive Fungal InfectionsIssuesProphylaxis- most effectiveVariable practiceEmperical: possible- Serology+ clinical ? Which antifungal?DurationPre-emptive: probable infection- serology+ radiology + clinicalSpecific Treatment : above + tissue diagnosis- proven infection-? role of combination therapy
17. TerbinafineAmBisomeGriseofulvinFluconazoleAmphocilAbelcetItraconazoleLicensed Antifungals024681012195019601970198019902000Amphotericin BNystatinKetoconazoleMiconazole5-Flucytosine201014VoriconazolePosaconazoleCaspofunginMicafungin Anidulafungin
18. Current Practices- Institutional practices of antifungal prophylaxis vary widely Survey by Singh etal LTX R(Am J Transplant 2008:8:426-31)40% centres till hospital stay 20% for 1month10% fo 3monthRemainder for varied duration
19. Risk of Antifungal Prophylaxis in Current EraOver one-third of the infections due to non-albicans Candida spp.Prior antifungal prophylaxis the only risk-factor for non-albicans Candida SppMortality 25 fold higher for cases than for controls (p = 0.0002); 58% for non-C.albicans, and 22.7% for C. albicans infections; Azole resistance due to prior fluconazole usuage;Husain et al., Transplantation 2003; 27: 2023-2029
20. Ecological Shift: Candidaemia in a specialist ICU 10 years epidemiology 20
21. 21Invasive candidiasis due to C albicans – Refractory to Fluconazole and AmbisomeSex/ageUnderlying diseaseRisk factorsAnti-fungal ProphylaxisInitial treatmentChanged to ResponseConcomitant infections 1 M 5 Yr BA, D20 Post , LTx BP, BLdrains in situFluconazole 6mg/kg x 2wksAmbisome 3mg/kg + fluconazole 12mg/kg x 3wksEchinocandinCleared after 2wks VRE +EBV2 M 16 yr2yr post tx Bowel perf, BL, drains in situ , Fluconazole-400mgAmbisome 3mg/kg + fluconazole 12mg/kg x 3wksEchinocandinCleared after 10 days CMV + HSVPresentation of Fungal infection –intrabdominal due to C albicans, BA –Biliary atresia, BP- bowel perforation, LTx – Liver transplant , BL-Biliary leak, C albicans came back very sensitive MICS value with normal rangeRefractory to Antifungal Treatment
22. 22‘Cerebral Aspergillosis While on Antifungal therapy Sex/ageLiver diseasePresentation of FI after LTxSite of FIAnti-fungalTherapyRisk factors TreatmentOutcome 1 F 51 PBC Brain Lesion on week 11Brain Ambisome 3mg/kgChronic LF, & RF Ambisome+ Voriconazolealive 2 F 50 ALF (Drug) Chest infection on week 3Lung, Brain CaspofunginPNG, RFAmbisome+ Voriconazole*Deceased3 M 33 ALF (POD) Chest infection on week 3Lung, Eye, Brain CaspofunginAcute RF,Re- Tx Ambisome+ VoriconazoleAlive FI; Fungal infection, ALF; acute liver falure, LF; Liver failure, RF;renal failure, PBC; primary biliary cirrhosis, PNG; primary nonfunctoning graft, LTx; Liver transplantation*patient 2 – had 9 month of treatment IA was treated however diedwhile awaiting for 2nd tx - because of graft failure and bacterial septic shockBreakthrough Infections
23. New Mycologic ChallengesRefractory to treatment develop breakthrough - needs further evaluationImpaired Host immune system- ?Tissue concentration of antifungals? Tolerance or Drug-resistant Finally, immune-enhancing strategies such as the use of growth factors and/or white blood cell transfusions for the prevention and treatment of opportunistic fungal infections in immunocompromised patients remain an important area of investigation. 23
24. Conclusions: Invasive Fungal InfectionsWay to improve IFI are- Selective antifungal prophylaxis- risk based Aggressive diagnostic approach- nonculture methods High degree of vigilance Early pre-emptive therapy Develop less damaging methods of immune suppressionImmunomodulation in very high risk patients
25. Thank you for your attention