1. Management of Infectious Complications in Immunocompromised Patients Abhay Dhand M.D. Director, Transplant Infectious Diseases, Westchester Medical Center, Valhalla, NY

2. OBJECTIVES 1. To define an immuno-compromised host. 2. To understand the role of net immune suppression in mediating the risk of infections in susceptible host. 3. To understand the epidemiology and risk factors for infections in immuno-compromised patients. 4. To learn the preventative, and diagnostic strategies for management of infections in immuno-compromised patients

3. IMMUNOCOMPROMISED HOST CONGENITAL IMMUNOSUPPRESSION ACQUIRED IMMUNOSUPPRESSION

4. Immunosuppressive Therapy Microbial Infection Malignancy Disorders of biochemical homeostasis Autoimmune diseases Trauma

5. ACQUIRED IMMUNOSUPPRESSION : Immunosuppressive Therapy Chemotherapy for malignancy- Neutropenia Treatment of autoimmune disorders Bone marrow transplant- ablation, graft vs. host disease Solid organ transplant: induction, maintenance immunosuppression, treatment of rejection

6. ACQUIRED IMMUNOSUPPRESSION: Microbial Infection HIV/AIDS Hepatitis B/C, co-infection with HIV Herpes infection, Co-infection with HIV Bacterial infection (super antigens) Parasitic infections

7. ACQUIRED IMMUNOSUPPRESSION: Malignancy Lymphoma Leukemia Multiple Myeloma Solid tumors

8. ACQUIRED IMMUNOSUPPRESSION: Disorders of biochemical homeostasis Diabetes Mellius ESRD/Hemodialysis Cirrhosis/Hepatic insufficiency Malnutrition

9. ACQUIRED IMMUNOSUPPRESSION: Autoimmune diseases Systemic Lupus Erythematosis Rheumatoid Arthritis

10. ACQUIRED IMMUNOSUPPRESSION Pregnancy Stress Functional splenia Splenectomy Aging

11. Immune Defects and Commonly Associated pathogens Immune Defect Pathogen Barrier breakdown: Burns Pseudomonas, S. aureus Trauma Streptococcus pyogenes, S. epidermidis Phagocytic function: Absolute decrease Enteric gram negatives, Pseudomonas, Aspergillus spp., Candida spp. Chemotaxis S. aureus, Enteric gram negatives Microbial killing S. aureus, Enteric gram negatives, Aspergillus spp, Burkholderia

12. Immune Defects and Commonly Associated pathogens Immune Defect Pathogen Humoral Immunity: Hypogammaglobulinemia Streptococcus pneumoniae, Hemophilus IgA deficiencyPyogenic bacteria, Giardia lambia AspleniaStreptococcus pneumoniae, Hemophilus Complement deficiencyPyogenic bacteria, Neisseria spp. Cell mediated immunity:Intracellular organisms (e.g. Listeria) Viruses (e.g. Herpes family) Fungi ( e.g. Candida spp., Cryptococcus) Parasites(e.g. Toxoplasma)

13. Principles of Infection in Compromised Host: Neutropenia Nosocomial infections in neutropenic cancer patients occur at a rate of : 46.3 episodes per 1000 neutropenic days (48.3 episodes per 100 neutropenic patients) The risk for infection is correlated with the depth and duration of neutropenia “Different” presentation –Abscess –Pulmonary Infiltrate

14. Principles of Infection in Compromised Host Etiology can be ANYTHING Polymicrobial Infections can be seen more commonly Aggressive approach to diagnosis: CT scan, Bronchoscopy, Biopsy Presumptive treatment

15. Principles of Infection in Compromised Host Serologic testing is generally not useful in the acute diagnostic management of immunocompromised patients. They often fail to generate an adequate antibody response to infection. Microbiologic testing should include antigen detection and/or nucleic acid detection-based assays as well as cultures.

16. Principles of Infection in Compromised Host: Risk of Infection Timing post transplant Type of immunosuppression Net state of immunosuppression Pathogen-pathogen interaction (role of CMV) Type of transplant

17. Immunosuppressive Drugs and Mechanism of Action

19. Morbidity and Mortality in Organ Transplant Recipients - Major Causes Allograft Loss –life-long requirement - exogenous immunosuppression –major threat - chronic rejection - immunologically mediated, but poorly responsive to immunosuppression Life threatening infection –~ 67% transplant recipients develop infection in first year post - transplant; –~ 25% eventually die of infection Malignancy Cardiovascular complications

20. Infections in Solid Organ Transplantation patients

21. What are the Risk Factors for Infection in Organ Transplantation? Exposure to infectious pathogens (endogenous and exogenous) “Net State of Immunosuppression”

22. IMMUNOSUPPRESSION LESS - MORE REJECTION - LESS INFECTION/ MALIGNANCY - LESS REJECTION - MORE INFECTION/ MALIGNANCY MORE Relationship between Infection and Immunosuppression

23. INFECTIONS IN RECIPIENT INFECTIONS IN DONOR TECHNICAL COMPLICATIONS RELATED TO TRANSPLANT PROCEDURE PRE-TRANSPLANT IMMUNO SUPPRESSIO N INFECTIOUS EXPOSURES POST-TRANSPLANT RISK OF INFECTION

24. Complications of Transplantation that Predispose to Infection Contamination of the allograft during harvesting, transport or implantation Anastomotic leak Hematoma, infarcted tissue Presence of vascular access devices Presence and mismanagement of endotracheal tubes Presence of urinary, biliary or other drainage catheters

25. Net State of Immunosuppression Complex, poorly explained, combination of –exogenous immunosuppression –neutropenia –metabolic abnormalities (protein calorie malnutrition, uremia, etc.) –infection with immunomodulating viruses (Herpes group viruses particularly CMV, EBV, hepatitis viruses, HIV)

26. Potential Exposures - Post-transplant Nosocomial organisms (bacteria, fungi) Opportunistic organisms from environment (e.g. cryptococcus, aspergillus) Respiratory viruses and bacteria in the community Organisms in contaminated food and water (e.g. salmonella, listeria)

27. Immunosuppressive Therapy - what you need to know What was used for induction immunosuppression –induction with polyclonal, MAB preparations – increased risk for opportunistic infection What was used as maintenance immunosuppression –How quickly did the patient get to maintenance What and when was anti-rejection therapy used –The trouble makers

28. Induction Immunosuppression Anti-T/B cell preparations –Used in patients with highest risk of rejection, multiple prior transplants Allows delay in use of nephrotoxic immunosuppression (CyA, Tacrolimus) Result – Watch out - increase in infection

29. Maintenance Immunosuppression Renal –CyA/FK + mycophenolate + prednisone –problem = drug toxicities …organ dysfunction...infection Other solid organ transplants –FK + mycophenolate + prednisone –problem = drug toxicities …organ dysfunction...infection

30. Anti-rejection therapy Aggressive immunosuppression –higher doses of usual immunosuppression (e.g. steroid pulses, etc.) –Polyclonal AB and MABs Result –significant increase in infection – need for additional prophylaxis

31. When do Infections Occur in Transplant Recipients? HSV Months post-transplant

32. First Month, Post-transplantation Infection that was present pre-transplant (pneumonia, bacteremia/line sepsis, etc.) Infection from contaminated allograft Typical bacterial, Candidal infections seen in post-operative patients NOTE - NO OPPORTUNISTIC INFECTIONS - UNLESS UNUSUAL HAZARD PRESENT

33. Month 2-6, Post-transplantation Immunomodulating viruses - particularly CMV, EBV, hepatitis B, C Opportunistic pathogens - Listeria, PCP, Aspergillus Residual bacterial, fungal infections from transplant complications NOTE - MOSTLY OPPORTUNISTIC INFECTIONS

34. > 6 Months, Post-transplantation 80% patients - good allograft function, minimal immunosuppression - usual community acquired ID 10% patients - chronic viral infections ….. Progress to end organ failure, sepsis, etc. 10% patients - continuing acute, chronic rejection, more immunosuppression, continuing risk of opportunistic infection

35. What Type of Infections Occur in Transplant Recipients? Sources of infection –limitless, but usually follow a timetable –bacterial > viral > fungal Presentation of infection –infection difficult to recognize - signs blunted because of impaired immune response –unusual presentations –chronic or relapsing infection Therapy challenging –prolonged courses –adverse interactions with immunosuppressive agents

36. CMV and Solid Organ Transplantation CMV is still among the most important infectious complications after transplant In the absence of prophylaxis, CMV reactivation can occur in over 75% of solid organ transplant recipients depending on other risk factors Once CMV infection is established, then its replication is highly dynamic with rapid increases in viral load

37. Risk of Symptomatic CMV Disease Serologic status of donor and recipient Type of organ transplanted Type of immunosuppression

38. CMV Infection: Risk Categories in Solid Organ Transplant Recipients Risk Category Donor (D) or Recipient (R) Seropositivity (+/-) HighD+/R- Intermediate*D+/R+, D-/R+ LowD-/R- * D+/R+ generally at higher risk than D-/R+

39. Percent with CMV Disease CMV Disease in SOT

40. Indirect Effects of CMV Infection Altered host immune response Graft rejection; graft dysfunction Opportunistic infections: Bacterial fungal superinfection Decreased graft and patient survival Herpesvirus interactions: EBV/PTLD Indirect Effects

41. Strategies for Prevention of Infection in Transplant Patients Pre-transplant Peri-transplant Post-transplant

42. Strategies for Prevention of Infection in Transplant Patients: PRE-TRANSPLANT Evaluate for active infection Evaluate for colonization with MDROs Evaluate for latent infections Vaccination

43. Strategies for Prevention of Infection in Transplant Patients: PERI-TRANSPLANT Antibiotic prophylaxis: Goal: decrease the risk of surgical site infection, donor derived infection, disseminated infection, active treatment of latent/occult infection Type of transplant, h/o colonization, active localized infection, infection/colonization in the donor, antibiotic allergies

44. Strategies for Prevention of Infection in Transplant Patients: POST-TRANSPLANT Prophylaxis: Antibiotics: bactrim, ciprofloxacin Anti-viral: herpes viruses (CMV): valganciclovir Anti-fungal: candida, aspergillus, endemic funguses

45. Candida Prophylaxis Liver transplant: Atleast 2 risk factors: re-transplantation, Cr>2mg/dl, choledochojejunostomy, prolonged intra-operative time, use of >40 U of blood products, fungal colonization 2 days before and 3 days after transplant. Heart/Kidney: not required Pancreas, Small bowel

46. Aspergillosis Prophylaxis Heart transplant recipients: Isolation of aspergillus in airway cultures Repeat thoracic surgery CMV disease Posttransplant renal replacement therapy Liver transplant recipients: Retransplantation, renal replacement therapy Repeat intra-abdominal or thoracic surgery 4 weeks post transplant Transplant for fulminant hepatic failure

47. Prevention of Nosocomial Infections

48. “Ventilator Bundle” Head of bed elevation > 30 degrees* Daily “sedation vacation” and assessment of readiness to extubate* Oral care (chlorhexidine) Peptic ulcer disease prophylaxis* Deep vein thrombosis prophylaxis* *Institute for Healthcare Improvement Reduction in VAP from 6.6 to 2.7 (59%) per 1000 ventilator-days with > 95% compliance

49. Hospital-Acquired UTI 40% of healthcare-associated infections 80% due to indwelling urethral catheter Potential Strategies Insertion/care Catheter reminders/automatic stop orders Bladder US scanners Condom catheters Antimicrobial catheters Clin Infect Dis 2008;46:243-50

50. -Multimodal intervention -Bundle approach -The “last mile” may require the use of some technical device (chlorhexidine patch, coated catheters, antibiotic impregnated device, lock solutions…) Zero Central Line Associated Bloodstream Infections: …how to get there…

51. Colonization with Antibiotic Resistant Organisms: Risk of Nosocomial Infections

54. Decolonization and its Role in Prevention of Nosocomial Infections

55. Arch Intern Med 2006; 166:306-12 Chlorhexidine Body Wash in the ICU Arch Intern med 2007;167:2073-79 Decreased Acquisition of VRE Before and after, compared with soap and water Decreased Bloodstream Infections Cross-over, compared with soap and water 6.4 vs. 16.8 BSI per 1000 catheter-days

56. Selective Colonization: CDI

57. Restore microbiota: fecal bacteriotherapy Nontoxigenic Clostridium Difficle