1. Post transplant infections and its management

2. Introduction  Recognizing the presentation of infections in transplanted patients is paramount  However, immuno-suppressed patients often present atypically, and with far advanced stages of infection  Fever is a non-specific finding, which can be attributed to medications and acute rejection  Invasive testing is often required to make an accurate and timely diagnosis

3. PATHOGENESIS DISEASE DETERMINANTS MicrobeHost Inoculum or OrganismsVirulenceLatency DefenseMechanisms

4. HOST DEFENSE MECHANISMS  Intact skin and mucous membranes Disrupted due to trauma, burns, ulceration, IV catheters, surgery  Types of infection Wound infections, burn sepsis, diabetic foot infection, line sepsis  Usual organisms Bacteria – environmental, endogenous Fungi – environmental, nosocomial

5. HOST DEFENSE MECHANISMS  Physical removal / clearance of micro-organisms Respiratory muco-ciliary clearance Peristalsis and dynamics of hollow viscus (gut, bile ducts, ureter, fallopian tube) Maybe abnormal due to underlying disease, surgery, smoking etc.  Intact sphincters/valves  Types of infection Pneumonia, urosepsis, biliary sepsis  Usual organisms Bacteria – environmental, endogenous

6. HOST DEFENSE MECHANISMS  Endogenous microflora Oropharyngeal, gut, skin, vagina Important for preventing colonization with disease causing organisms (competitive) Antibiotics remove natural flora E.g. C. difficile colitis  Chemical antimicrobial agents Gastric acidity, cutaneous fatty acids

7. HOST DEFENSE MECHANISMS  Inflammatory response Number (mass) and function of circulating and tissue phagocytic cells Neutrophils, monocytes, macrophages, spleen  Humoral Mediators Complement, fibronectin

8. HOST DEFENSE MECHANISMS  Specific Immune response T-lymphocytes  CD4+, CD*+ (helper, cytotoxic)  Number, function B-lymphocytes  Make antibodies  IgG, IgA

9. Common problems Host Defect: Inflammatory response Common microbes Neutropenia (<0.5) Splenectomy Gram negative bacilli, Staph, Candida, Aspergillus S. Pneumonia, H. influenza, N. Meningitis

10. Common problems Host Defect: Complement Common microbes Early (C3, C5) Late (C6,7,8) S. Aureus, S. Pneumonia, gram negative bacilli Neisseria species

11. Common problems Host Defect: Immune response Common microbes T- Lymphocyte e.g. HIV, organ transplant B-Lymphocyte Numerous microbes S. Pneumonia, H. influenza, Giardia

12. INFECTION: BASIC PRINCIPLES  Inflammatory response attenuated by immunosuppressants  may abolish typical signs/symptoms  decreased sensitivity of serological, radiological tests  Effects of established infection may be devastating  Treatment may have more toxicities  Rifampin - decrease CsA  Erythromycin, azoles increase CsA  Synergistic nephrotoxicity - aminoglycosides, AmB, septra, cipro, vancomycin, pentamidine

13. INFECTIONS IN TRANSPLANTATION Three main determinants of the risk of infection in transplant recipients Infections related to technical / surgical problems

14. TECHNICAL COMPLICATIONS  Liver - biliary tree - leaks, strictures  Lung - bronchial anastomosis necrosis, dehiscence ; mediastinal fluid collection  Kidney - uroterocystostomy - leak, urinoma  Pancreas - duodenum-bladder; duodenum-bowel: anastomotic leaks, abscess

15. INFECTIONS IN TRANSPLANTATION Major determinants of the risk of infection The net state of ImmunosuppressionEpidemiologicalexposures

16. NET STATE OF IMMUNOSUPPRESSION  Immunosuppressive therapy: dose, duration, temporal sequence - ‘area under the curve’  Underlying immune deficiency  Mucocutaneous barrier integrity: intubation, drains, catheters, central lines  Devitalized tissue, fluid collection  Neutropenia, lymphopenia

17. NET STATE OF IMMUNOSUPPRESSION  Metabolic conditions  Uremia  Malnutrition  Diabetes  Viral infection: Immune modulation  Cytomegalovirus  Epstein-Barr virus  Hepatitis B, C, HIV

18. Epidemiology  The risk, rate, and type of infection vary over time from transplantation  Currently, there are no assays to measure risk/susceptibility to infection  Risk of infection is an interplay between Exposure history (of donor and recipient) Intensity and quality of immunosuppression Use of prophylactic medications

19. Classification of Infections  Donor-derived  Recipient-derived  Nosocomial  Community-acquired

20. Donor-derived Infection  Most are latent CMV, TB, T.cruzi  Rarely can be acute Bacteremia/viremia at time of procurement West Nile, rabies, HIV, hepatitis, LCV  The majority of these are sub-clinical in healthy patients, but can be catastrophic when transplanted into an immuno-suppressed patient  At present, routine evaluations of donors for infectious diseases relies upon serologic antibody testing, and thus sensitivity is not 100% for those that may not have had time to seroconvert

21. Donor-derived  Transplantation of organs from deceased donors with viral syndromes is controversial  Livers with known Chagas or Hep B infection may be used as there are effective treatments for these infections  Hep C infected organs are sometimes transplanted into Hep C(+) donors

22. Fishman J. N Engl J Med 2007;357:2601-2614

23. Recipient-derived Infections  Infections that can be treated or controlled do not necessarily preclude transplantation  Most commonly screened for: TB syphilis Viral: CMV, EBV, VZV, HSV, HIV, HBV, HCV  Other things to think of T.cruzi, strongyloides, cryptococcus Endemic fungi: histoplasma, coccidioides, paracoccidioides, aspergillus, blastomycosis

24. Polyoma Viruses  2 major clinical manifestations are known BK virus JC virus both of these are members of the papovaviridae family  JC virus is primarily associated with progressive multifocal leukoencephalopathy in AIDS pt’s  BK virus is primarily associated with nephropathy and ureteral obstruction  Both are asymptomatic infections acquired in childhood that remain latent

25. BK virus  First recognized in 1971, not truly appreciated until mid 1990’s when recognized as a cause for renal allograft loss (~5% incidence)  Has a tropism for the uro-genital tract, tends to affect “diseased” kidneys  Clinical manifestations asymptomatic hematuria hemorrhagic cystitis ureteral stenosis interstitial nephritis (nephropathy)

26. BK virus  Viruria can be detected in many populations, but the most clinically important is renal transplant recipients  Exact pathogenesis of the infection is poorly understood  Diagnosis must be made histologically (biopsy) Special stains and PCR can help solidify the diagnosis

27. BK virus  Treatment Only effective therapy is immune reconstitution (i.e. reduction of immunno-suppressant therapy) Cedofivir and leflunomide are effective in reducing viral load, but do very little to change the course of disease, and are both nephrotoxic  One must effectively walk the tightrope between progressive renal destruction secondary to infection, and acute rejection causing graft loss

28. BK virus  Several case reports exist for BK nephropathy in non-renal transplant recipients Bone marrow Heart Lung  However, these are rare, and are at level of case report

29. Fishman J. N Engl J Med 2007;357:2601-2614

30. Immunizations  Pt’s should be current on the following vaccines MMR HBV Influenza Strep pneumoniae Tetanus Diphtheria Pertussis Polio VZV – if never infected  Consideration should be given to boosters for any of the above prior to transplantation as live vaccines are generally contraindicated post-transplant, and immunologic memory will become impaired

31. Peri-operative Prophylaxis  Liver Skin, enterococcus, anaerobes, enterobacteriaceae Most common site of invasive fungal infection  Lung GNR, molds, endemic fungi MRSA and VRE according to antiobiogram prevalence Second most common site of invasive fungal infection

32. Nosocomial Infections  MRSA  VRE  fluconazole-resistant Candida species associated with surgical site and indwelling catheters  C.diff  Resistant gram-negative bacilli, Pseudomonas,  Aspergillus

33. Community Infections  Aspergillus  Nocardia  Cryptococcus neoformans (birds)  Respiratory viruses  Community acquired pneumonia pathogen  HIV, hepatitis viruses  Environmental fungi  Secondary bacterial superinfection Enteric bacterial pathogens (salmonella) TB, zoonosis,

34. Monitoring Immunosuppression  There are no specific tests currently available to determine the overall susceptibility of patients to infection…  …but they are on the horizon  Currently, the known determinants contributing to the overall risk of infection are the dose, duration, and sequence of immunosuppressive therapies

35. Fishman J. N Engl J Med 2007;357:2601-2614 Dynamic Assessment of the Risk of Infection after Transplantation

36. Fishman J. N Engl J Med 2007;357:2601-2614 Changing Timeline of Infection after Organ Transplantation

37. Early post-transplant period (30d)  Opportunistic infections are rare in the first month post-transplant  >1 month of medical therapy is required to effectively deplete cell-mediated therapy  One exception is large, prolonged doses of corticosteroids  Infections are generally donor-derived or associated with complications from the surgery itself

39. TIMETABLE: 0-1 MONTH  Infections usual to post-op patients nosocomial pneumonia, wound, line sepsis, UTI  Key factors: nature of the operation, technical skill  Lung, heart, liver at highest risk longer intubation, ICU stay, lines, catheters  Most OI’s (eg. PCP) absent in the first month Exceptions – HSV, HHV6, Candida, Aspergillus

40. TIMETABLE: 0-1 MONTH  Also may see Infection transmitted with the allograft: eg. lung transplant with pneumonia or a donor bacteremia which seeds the vascular anastamosis Pre-existing infection within the recipient made worse by the transplant

41. Intermediate period (1-6mos)  Viral infections and allograft rejection account for the majority of febrile episodes  Adherence to Cotrimoxazole and antiviral prophylaxis renders infections such as PCP, UTI’s, listeria, toxoplasmosis, and herpes very unlikely  Fungi, cryptococcus, T.cruzi, strongyloides can surface  Other: polyoma virus (BK and JC), recurrent HCV

43. TIMETABLE OF INFECTION One to 6 months post-Tx Maximal period of immunosuppression Effect of sustained immunosuppression or ‘area under the curve’ Opportunistic infections in the absence of excessive epidemiological hazard

44. TIMETABLE - 1 TO 6 MONTHS VIRAL CMV, EBV, VZV, HHV-6, Adenovirus, Influenza, RSV BACTERIAL Nocardia, Legionella, Listeria, TB FUNGAL PCP, Aspergillus, Cryptococcus, endemic mycosis PARASITIC Toxoplasma, Strongyloides

45. Late post-transplant period (>6mos)  Risk wanes as immunosuppressive therapy is tapered  Risk profile however, is “reset” with each episode of acute rejection  Chronic viral infections can cause allograft injury HCV  cirrhosis BOOP in lungs CMV  coronary vasculopathy PTLD Skin/anogenital cancers  Fungi/molds, viruses and “typical” bugs still remain on radar

47. TIMETABLE - > 6 MONTHS GROUP 1: Good graft function, minimal immunosuppression Community acquired pneumonia, UTI, OI based on intense exposure GROUP 2: Recurrent or chronic rejection, high level immunosuppression, chronic viral replication Continued risk of opportunistic infections

48. Long-term Prophylaxis  Co-trimoxazole for at least 3 months, sometimes for life  CMV and HSV prophylaxis is not standardized, and varies according to immunno-suppressive regimen and institution  Rarely chronic suppressive antifungal Rx for pt’s with history of significant disease

49. CMV PREVENTION  Universal prophylaxis: anti-viral therapy to all ‘at- risk’ patients  Pre-emptive therapy: anti-viral therapy to subgroups of ‘at-risk’ patients usually based on further diagnostic tests aimed at identifying early viral reactivation

50. PRE-EMPTIVE THERAPY + _ ++++ ___ ++ _ 048 12 weeks Could have initiated pre-emptive therapy CMV disease TEST

51. CMV IN LIVER TRANSPLANT RECIPIENTS PRE-TRANSPLANT: Donor and recipient CMV serology POST-TRANSPLANT:  D+/R+, D-/R+ Week 2-12: E very clinic visit :  CMV antigenemia  CMV quantitative PCR  D+/R-: G anciclovir prophylaxis 12 weeks  Bloodwork at week 12, 14, 16, 18.  CMV antigenemia and quantitative PCR testing

52. General Lifestyle Recommendations  Avoid sick contacts, esp respiratory  Avoid dusty sites (i.e. construction sites)  Avoid ingestion of well and lake water  Avoid undercooked meats  Avoid soft cheeses and unpasteurized dairy products  Avoid unwashed fruits/veggies

53. Summary  Be aware of the time frame from transplant leading you to the most likely type of infection  <30d think nosocomial or donor-derived  1-6mos, reactivation of viruses and atypical infections “classic” for transplant pt’s  >6mos, think of “typical” or community- acquired bugs as their risk returns to somewhat normal

54. Fishman J. N Engl J Med 2007;357:2601-2614 Assessment of the Risk of Infection at the Time of Transplantation