Infections in Transplant Recipients

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. Solid Organ Transplantation • 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

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 20 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: T38.80C, 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 / VZV Acyclovir[1 year] • CMV Pre-emptive[Post-engraftment] • Fungal • Candida Fluconazole[Pre-engraftment] • Invasive Molds Variable[GVHD] • PJP Bactrim[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: T38.80C 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 20 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: T38.40C 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 10 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 1st 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)