1. Infections in Transplant Recipients

2. Learning Objectives General concepts –Solid Organ Transplantation (SOT) –Hematopoietic Stem Cell Transplantation (HSCT) Chronology of infections Clinical evaluation –Approach to the patient with SOT –Approach to the patient with HSCT Specific transplant infections

3. 50F with history of [solid organ] transplant presents with fever and chills x 1week. No localizing symptoms. How immunosuppressed is she? –What infections do I need to worry about –Inpatient or outpatient –Empiric antibiotics What do I need to look for in my evaluation?

4. Solid Organ Transplantation Type –Kidney < Heart, Liver, Pancreas < Intestine, Lung –Anatomic/Technical considerations Anastomotic leak Fluid collections – blood, bile, lymph, urine Surgical incision / poor wound healing ICU-related infections Organ specific –Kidney: complicated UTI. SPK: enteric vs bladder drainage –Heart: mediastinitis, LVAD-associated, aortic suture line –Liver: R-en-Y vs biliary anastomosis, HAT, biliary stricture –Lung: airway anastomosis, ischemia-reperfusion injury

5. Net State of Immunosuppression –Pre-transplant immunosuppression –Induction Varies with institution – no set standard Anti-lymphocyte therapy –Depleting: ATG, OKT3, alemtuzumab –Non-depleting: anti-CD25 –Maintenance Corticosteroids, Azathioprine, MMF, CNI, Rapamycin –Rejection –Duration Allograft function: good, injured, poor Solid Organ Transplantation

6. 50F with history of kidney transplant presents with fever and chills x 1week. No localizing symptoms. Kidney transplant 1 year ago ATG induction Rejection at 4 months and 11 months post-transplant – each treated with high dose corticosteroids Maintained on tacrolimus, MMF, and prednisone Assessment  High degree of immunosuppression –Inpatient evaluation –Empiric antibiotics probably warranted

7. Chronology - SOT NEJM 2007; 357: 2601-14

8. SOT – Early Vast majority of infections are surgical / ICU related –Nosocomial / MDR bacteria –Candida –C.diff Donor-derived infections –Unexplained infectious syndrome Recipient-derived infections –HSV reactivation [ Prophylaxis ] –Prior colonization or undiagnosed infection Opportunistic infections – very rare

9. SOT – Intermediate Classic opportunistic infections –CMV [ Prophylaxis ] –Nocardia, Listeria[ Prophylaxis ] –Pneumocystis [ Prophylaxis ] –Endemic mycoses –Toxoplasma[ Prophylaxis ] –Aspergillus Most common causes of fever –Viral infections: Respiratory viruses –Rejection Donor or Recipient derived –Mycobacteria, endemic mycoses, HCV, BK, other exotics Complicated / Persistent bacterial infections

10. SOT - Late Good graft function –Typical community acquired infections Severe presentation –VZV Poor graft function –Classic opportunistic infections during intermediate period –Exotic opportunistic infections – atypical molds Late infections –Delayed CMV –JCV - PML –EBV - PTLD

11. Clinical Evaluation Induction –May not be relevant if transplantation several years prior Rejection Prophylaxis –TMP/SMX vs Other[ 6 - 12 months ] –Ganciclovir [ 3 - 12 months ] Pre-transplant evaluation –HSV/VZV, CMV/EBV, HIV, HBV/HCV, RPR, Toxoplasma –Endemic mycoses, TB Immunosuppression = lack of inflammation –UTI without pyuria –Appendicitis without peritoneal signs

12. Donor Screening Am J Transplant 2009; 9(S4):S19-26

13. Donor-Derived Infections Am J Transplant 2009; 9(S4):

14. Case 56M s/p OLT 17 days ago for ESLD 2 0 NASH. No anti-lymphocyte induction Post-op course uncomplicated. No rejection episodes. Maintenance: Prograf, Cellcept, Prednisone Prophylaxis: Bactrim, Valcyte, Fluconazole Presents with 2 days of progressive ataxia, diplopia, decreasing alertness  obtunded, bladder and bowel incontinence. ER Vitals: T38.8 0 C, P88, BP 120/54, RR25 Exam – abdominal incision intact, opens eyes to verbal, non-communicative, intermittently obeys commands.

15. MRI Brain Differential? Next Steps?

16. Chronology - SOT NEJM 2007; 357: 2601-14

17. Brain biopsy – necrosis and abscess formation Family withdraws care hospital day #8 Donor-derived infection –Kidney-pancreas recipient with encephalitis / brain abscesses and hospitalized –Donor is a 27M landscaper with large skin lesion x6 months, cause of death was presumed stroke –Balamuthia identified from brain biopsy of liver and KP recipients & also donor liver.

18. SOT - Summary Variable infection risk –Type of transplant –Duration from transplant –Induction immunosuppression, rejection Chronology –Early ( 1 mo )– anatomic, technical, nosocomial –Intermediate ( 6 mo )– opportunistic infections –Late ( 6+ mo )– good vs poor graft function Prophylaxis –PJP, CMV, secondary prophylaxis Clinical presentation –Absence of inflammation –Severe manifestation

19. Hematopoietic Stem Cell Transplantation Graft type –Bone-marrow derived –Peripheral blood stem cell –Cord blood Donor type –Autologous –Allogeneic Matched sibling Matched unrelated

20. Hematopoietic Stem Cell Transplantation Conditioning –Myeloablative –Reduced intensity / Non-myeloablative Graft manipulation –T-cell depletion GVHD –Acute –Chronic

21. Chronology - HSCT BMT 2009; 44: 457-62

22. HSCT – Pre-engraftment R marrow suppression  D marrow reconstitution –Pathogenesis Mucositis, translocation, nosocomial HSV reactivation[ Prophylaxis ] Respiratory viral infections Engraftment syndrome Typical chemo-induced neutropenic infections –Neutropenic fever –Nosocomial / MDR bacteria [ Prophylaxis ] –C.diff –Neutropenic enterocolitis –Candida [ Prophylaxis ] –Aspergillus ( prolonged neutropenia ) [ Prophylaxis ]

23. HSCT – Post-engraftment Bacterial –Nosocomial –Translocation (Acute GVHD gut) Fungal –Candida [ Prophylaxis ] –Invasive molds [ Prophylaxis ]Acute GVHD –Pneumocystis [ Prophylaxis ] Viral –CMV [ Pre-emptive ]Acute GVHD –Respiratory viruses –HHV –BK Conditioning / Acute GVHD

24. HSCT – Late Phase Low risk –Matched allo-HSCT without GVHD –Infections: Encapsulated bacteria VZV, Respiratory viruses High risk –Acute / Chronic GVHD, active CMV, T-cell depleted graft –Infections: Encapsulated bacteria, Nocardia CMV, VZV, Respiratory viruses Invasive molds, Pneumocystis

25. Clinical Evaluation Infection risk –Time from transplant –GVHD –Ask your friendly BMT practitioner Prophylaxis –Bacterial Quinolone [ Pre-engraftment ] –Viral HSV / VZVAcyclovir [ 1 year ] CMVPre-emptive [ Post-engraftment ] –Fungal CandidaFluconazole [ Pre-engraftment ] Invasive MoldsVariable [ GVHD ] PJPBactrim [ Pre-engraftment to 6 months ] Pre-transplant evaluation –Same as for SOT –Hematologic malignancy associated infections

26. Antifungals 101 Azoles –Fluconazole: Candida, Cryptococcus, Coccidioides –Itraconazole: above, and Aspergillus, Blastomyces, Histoplasma –Voriconazole: above, first line for Aspergillus –Posaconazole: above, and Mucor Echinocandins –Candida and Aspergillus Amphotericin –Broad spectrum antifungal –Lipid formulations: Abelcet and Ambisome

27. Case 36M s/p MUD-BMT for ALL Day +64 Myeloablative conditioning, engraftment at Day +14 Acute GVHD (gut & skin) at Day +24 Discharged from hospital at Day +33 CMV viremia detected at Day +41 Medications: Pred 70mg qd, Prograf, Bactrim, Valcyte, Vori Presents with fever, cough productive of frothy white sputum and SOB x 1 week. VITALS: T38.8 0 C P120 BP149/80 RR32 O2 90%RA Exam – Diffuse lung crackles.

28. CT Chest Differential? Next Steps?

29. Chronology - HSCT BMT 2009; 44: 457-62

30. Labs: WBC 2.1 73% N Blood cultures –AFB positive Lung biopsy –Path: Acute lung injury with inflammatory necrosis, no granulomas. AFB smear positive. –Micro: Mycobacterium chelonae Tunneled CVC finally removed –IR notes that the CVC is green and slimy.

31. HSCT - Summary Variable infection risk –Type of donor, type of graft –Duration from transplant –Conditioning, GVHD Chronology –Pre-engraftment ( 30 d ) – neutropenic infections –Post-engraftment ( 100 d ) – opportunistic infections –Late phase ( 100+ d ) – low risk vs high risk Prophylaxis –You bet… and lots of it! –Breakthrough or resistant infections Clinical presentation –Severe manifestation – particularly viral infections –Need aggressive diagnostics

32. Case 34F s/p LDKT 20 yrs ago for ESRD 2 0 chronic VUR No episodes of rejection, good graft function. CMV D neg / R neg. Medications: Azathioprine, Cyclosporin – stable dosing PMH: S/P TAH for menorrhagia Married, monogamous. No children. No sick contacts. Presents with low-grade fevers, night sweats, myalgias and severe malaise x1 month. Also with odynophagia, epigastric pain, nausea, vomiting and diarrhea x 2 weeks. No urinary symptoms. VITALS: T38.4 0 C P89 BP117/82 RR14 Exam: comfortable appearing, no LAN, OP clear, + epigastric tenderness, lungs clear, no rash, no tenderness over allograft. Labs: WBC 1.9 43%N, LFTs normal

33. Chronology - SOT NEJM 2007; 357: 2601-14

34. CMV IgG & IgM positive CMV quantitative PCR: 576K copies/mL(NL < 200) Duodenal biopsy: + CMV inclusions + CMV immunostains How did she get CMV?

35. CMV Seroprevalence 40-70%. Latent infection G-M cell lines. Transplant recipients –Most common viral infection –Definitions: CMV infection – asymptomatic viral replication CMV disease –CMV syndrome –End-organ disease –Timing: Solid organ at 1-3 months HSCT at 40-50 days Late disease due to prophylaxis / pre-emptive therapy

36. CMV –Risk factors: Donor positive / Recipient negative Use of anti-lymphocyte antibodies, T-cell depletion –Diagnosis: Serum PCR sensitive and specific, test of choice Pathology - CMV immunostains Serologic testing not useful for active infection –Treatment: Ganciclovir / Valganciclovir (Valcyte) –Outcomes: SOT – increased risk of rejection and infections HSCT – CMV pneumonia with 50% mortality

37. Case 57F s/p OLT 15 months ago for PBC. No rejection. CMV D+/R+. EBV R+. Choledocholithiasis s/p ERCP 3 months ago. Presents with intermittent fevers/chills x 3 mo & RUQ pain.

38. Chronology - SOT NEJM 2007; 357: 2601-14

39. Monomorphic PTLD

40. EBV Seroprevalence 90%. Latent infection of B-cells. Post-transplant lymphoproliferative disorder –Clinical manifestations Benign polyclonal lymphoproliferation –Asymptomatic, mononucleosis-like illness Polymorphic or Monomorphic PTLD –Extra-nodal involvement: GI, liver, spleen, BM, allograft, lungs –Risk factors EBV 1 0 infection, EBV D pos / R neg Transplant type –SOT: Intestinal / Lung >> Kidney / Liver –HSCT: MUD, Cord, T-cell depletion

41. BK Virus Seroprevalence 80%. Latent infection – kidney, bladder, ureters. Kidney transplantation –BKV associated nephropathy Usually within 1 st year post-transplant ( 28-40 wks ) Screening – Urine BK PCR  Serum BK PCR Diagnosis – Biopsy with immunostain HSCT –BKV associated hemorrhagic cystitis Usually within first 2 months of transplant ( post-engraftment ) Acute, late-onset, long duration ( 2 wks )