1. Infections in HSCT Meng Yao Lu Department of Pediatrics National Taiwan University Hospital October 17, 2009

2. HSCT patients... Highly susceptible to infections primary diagnosis chemotherapy and anti-GVHD medicines pancytopenia indwelling catheters mucosal and skin breakdown parenteral nutrition broad spectrum antibiotics

3. Infections in transplant... prolonged fever in >90% 50% have documented infections bacterial >> fungal > viral infectious mortality of 4%-33% bacterial and fungal infections predominate in the first post-transplant month after 100 days, viral and encapsulated bacterial infections predominate risk depends on type of transplant allogeneic unrelated >> allogeneic related > autologous

4. Three Periods of susceptibility... early recovery or “pre-engraftment” first several weeks after transplant related to neutropenia, chemotherapy induced mucositis and CVL placement mid-recovery or “early post-engraftment” second and third months after transplant related to acute GVHD, decreased cellular immunity secondary to GVHD, immunosuppressive therapy and viral infections (e.g. CMV) and indwelling CVLs late recovery interval beyond three months after transplant related to decreased cellular immunity secondary to chronic GVHD, nonspecific suppressor cells due to chronic GVHD, reduced opsonization, decreased reticuloendothelial function, immunoglobulin G subclass deficiencies

5. Prevention Conscientious hand washing meticulous oral hygiene low bacterial diet fruits & fresh salads --> aerobic GN rods pepper --> Aspergillus HEPA filtration decontamination not universally practiced Laminar Air Flow (LAF) rooms Surveillance cultures

6. Timeline of Infections

7. Common sites of infection... blood (40.1%) GI tract (12.7%) skin (12.7%) upper respiratory tract (11.7%) lung (10.7%) urinary tract (6.8%) hepatobiliary system (1.6%) central nervous system (1.6%) eye (0.7%) Blood. November 1995, Ochs et al.

8. The common bacteria... Gram positives GP bacteremia rates now exceed GN rates enter via central lines, skin and occasionally via GI tract Staph epidermidis Staph aureus enterococcus α hemolytic strep Corynebacterium spp. Gram negatives the most virulent and a frequent cause of morbidity & mortality enter via mucosa/GI tract, damaged skin, or central lines Eschericia coli Klebsiella spp. P. aeruginosa Pseudomonas Enterobacter Acinetobacter Proteus Serratia

9. Antibacterial Therapy... Pre-Transplant Prophylaxis no longer routinely implemented at all transplant centers included oral nonabsorbable agents (e.g. Vancomycin, Gentamicin, neomycin, colistin and polymyxin B) use of anti-PCP therapy is universal for all centers Empiric Treatment prompt administration of broad spectrum coverage begin usually with third-generation cephalosporin or broad- spectrum penicillin, add aminoglycoside with septic picture reevaluate if fever persists (> 3 days) and no + cultures Specific Therapy tailor to identification and sensitivity panels may await confirmation of S. epidermidis infection with repeat cultures

10. The common fungi... Candida sp. granulocytopenia cell-mediated immunity reactivation or colonization TPN with high CHO broad spectrum antibiotics resistance to prophylaxis Aspergillus sp. granulocytopenia hi-grade GVHD broad spectrum antibiotics dusty building renovation hospital environment reactivation or colonization life style corticosteroids

13. Aspergillus... inhalation of spores colonization of the Sino-pulmonary tree invasion and dissemination lack of specific diagnostic test mortality approaches 90% with invasion

14. Epidemiology of Aspergillosis in HSCT Recipients Bimodal Distribution Neutropenic phase Depth Duration Post engraftment phase GvHD Steroid use CSA/Tacrolimus Mucosal disruption CMV disease

15. Aspergillosis : Clinical Manifestations Pneumonia Pleuritic pain Cough Hemoptysis Sinusitis Nasal congestion Eschars Epistaxis Palatal hemierythema Disseminated infection (CNS)

16. Antifungal Therapy... Prophylaxis Polyenes (nystatin) Amphotericin B broad spectrum extensive potential toxicities Azoles intravenous versus oral Echinocandins Caspofungin Micafungin Treatment Amphotericin B 0.5-1.5 mg/kg/day IV systemic greatly increased toxicities, especially with concurrent CYA Azoles Voriconazole Echinocandins Caspofungin Micafungin

17. The common viruses... Herpesviruses CMV- associated with high rates of mortality EBV - PTLD HSV- 70-80% of transplant pts. are seropositive VZV- 20-50% of transplant pts. develop zoster Epstein-Barr virus (EBV) 0.5% of allogeneic BMT recipients develop EBV-LPS HHV6 Respiratory Viruses RSV, parainfluenza viruses, rhinovirus and influenza A & B Enteroviruses adenovirus, coxsackie virus and rotavirus

19. Antiviral Therapy... Prophylaxis CMV CMV-neg. blood pdts ganciclovir HSV Acyclovir VZV usually unnecessary Treatment CMV Ganciclovir Foscarnet Cidofovir immunoglobulin HSV hi-dose acyclovir foscarnet VZV hi-dose acyclovir EBV donor lymphocytes

20. HSV 1 & 2 infection Predominantly during neutropenia and within day 30 of HSCT Mucocutaneous (oral/genital), esophageal, disseminated Routine prophylaxis use of acyclovir Resistance is uncommon

21. CMV infection CMV infection remains as an important cause of morbidity and mortality in children undergoing HSCT. Treatment Strategies Prophylactic therapy Pre-emptive therapy after periodic surveillance

22. 0.0 0.2 0.4 0.6 0.8 1.0 34567 Log viral load (genomes/ml) Probability of disease Cope et al (1997) J Infect Dis 176: 1484-90 Suppression of CMV reduces disease probability

23. Risk factor Transplant type and conditioning Peak incidence Day+ 45-60 days MUD > MRD > autograft BMT > PBSCT ? Conditioning Myeloablative> non-myeloablative < 100 days Myeloablative=non-myeloablative at 1 year T cell depletion In vivo (ATG, Campath) Ex vivo (CD34 selection)

24. Interventions to control CMV Primary infection Latency Reactivation ( +ve pp65 or PCR) Disease Prophylaxis Pre-emptive therapy CMV Naive Prevent infection CMV Neg Donor, Leokodepletion

25. CMV viral load and pre-emptive antiviral therapy

26. Therapeutic approaches to control CMV replication Prophylaxis Universal or targeted Eliminates direct and indirect effects of CMV Subset of patients remain at risk of late CMV infection/disease after cessation of prophylaxis Pre-emptive therapy Targets individuals based on their virologic markers Minimises drug exposure Patients may require more than one treatment May not eliminate the indirect effects of CMV Forum debate (2001) Rev Med Virol 11:73-86

27. CMV viral load and pre-emptive antiviral therapy Preemptive treatment : highly effective Detection = pp65 antigenemia assay = pp67 mRNA assay :sensitive but seldom use = DNA detection methods = Quantitative real-time PCR assays

28. EBV associated Post-Transplant Lmyphoproliferative Disorder

29. EBV PTLD

31. Therapy for EBV PTLD Decrease immunosuppression Rituximab Antiviral agent Donor-derived EBV-specific CTLs Chemotherapy

32. Herpes Zooster/Varicella Primary vs reactivated High mortality rate in disseminated infection High dose acyclovir Prevention Acyclovir prophylaxis VZIG within 96h of exposure Immunization of seronegative household membersw Contact and respiratory precautions

33. Immunoglobulins No role in Autologous transplant recipients Allogeneic recipients: 400-500 mg/kg weekly from day 7 to day 100+ Reported effects: decrease bacterial sepsis decrease CMV disease decrease interstitial pneumonitis decrease acute GVHD decrease bacterial infections decreased mortality