Infections in the Immunocompromised Host

1. Infections in the Immunocompromised Host Rontgene M. Solante, MD, FPCP, FPSMID

2. Overview • Definitions • Diagnostic approach • Treatment and prevention of infectious complications • Febrile neutropenia • Transplant recipients • Asplenia • HIV/AIDS

3. Immunocompromised Host • Alteration of the phagocytic, cellular or humoral immunity that increases the risk of infectious complications or an opportunistic process • Alteration or breaks in the skin or mucosal barriers that permits microorganisms to cause local or systemic infection

4. Specific ImmunocompromisedConditions 1. Severe Immunocompromise (Non-HIV) - active leukemia, lymphoma, generalized malignancy, aplastic anemia, graft versus host disease, congenital immunodeficiency, solid organ transplant, or bone marrow transplant within 2 years of transplantation; or persons whose transplants are of longer duration but who are still taking immunosuppressive drugs 2. Chronic Diseases with Limited Immune Deficits - asplenia, chronic renal disease, chronic hepatic disease (cirrhosis and alcoholism), diabetes, and nutritional deficiencies

5. Specific ImmunocompromisedConditions 3. Severe Immunocompromise Due To Symptomatic HIV/AIDS - HIV-infected persons with CD4 counts lower than 200, - history of an AIDS-defining illness, or - clinical manifestations of symptomatic HIV 4. Asymptomatic HIV Infection -Asymptomatic HIV-infected persons with CD4 counts from 200 to 500

6. Approach to an immunocompromised patient suspected to have an infection • Causes • Predisposing factors • Underlying diseases • Therapeutic interventions • Anti-infective strategy

7. ETIOLOGIC CAUSES:PROBLEMS • Associated signs and symptoms are often muted • Microbiologic confirmation in < 50% • Difficult to treat organisms or unusual pathogens

8. Diagnostic Evaluation • Careful history-taking • Extensive PE • Blunted inflammatory response • Unusual manifestations • Diagnostic tests • Microbiologic examinations • Antigen detection tests • Serologic tests • Imaging techniques

9. Management of Infectious Complications in the Immunocompromised Host

10. Febrile Neutropenia (FN) • Granulocytopenia • single most important risk factor for infection in patients with hematologic malignancy • 80% of pathogens from the patient’s endogenous microbial flora

11. Impact of Granulocytopenia • Most important risk factor for infection • Degree of granulocytopenia is inversely related to risk of infection • Fever develops in nearly all patients with granulocyte count < 100/cu.mm. • Risk of infection and infection-related mortality increases proportionally with time Bodey GP, Ann Intern Med 1996

12. 2002 IDSA Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer Walter Hughes, Donald Armstrong, Gerald Bodey, Eric Bow, Arthur Brown, Thierry Calandra, Ronald Feld, Philip Pizzo, Kenneth Rolston, Jerry Shenep, Lowell Young CID, March 2002

13. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer 2008 Update Alison Freifeld, Michael Boeckh, Eric Bow, James Ito, Craig Mullen, Issam Raad, Kenneth Rolston, Kent Sepkowitz, Jo-Anne Van Burik, John Wingard, Stuart Cohen (For publication, Clin Infect Dis)

14. Guideline comparison • Clinical features of the neutropenic patient • Evaluation of the patient • Initial antibiotic therapy • Clinical features • Risk assessment: definitions of high and low risk • Evaluation of the patient • Initial antibiotic therapy • High risk • Low risk 2002 Guidelines 2008 Update

15. Guideline comparison • Antibiotic prophylaxis • Use of antiviral drugs • Granulocyte transfusions • Economic issues • Antibacterial prophylaxis • Antifungal prophylaxis: empiric and pre-emptive therapy • Antiviral prophylaxis and treatment • Colony-stimulating factors • Catheter infections • Environmental precautions 2002 Guidelines 2008 Update

16. Febrile Neutropenia Guidelines for Empirical Treatment • Who requires empiric antibiotic therapy? • Candidates: ANC < 500/mm3 OR < 1000/mm3 if with evidence of decline (over the next 48 hours) PLUS Fever (single oral T > 38.3oC or > 38oC for > 1 hr)

17. Febrile Neutropenia Guidelines for Empirical Treatment • Who requires empiric antibiotic therapy? • Candidates: Afebrile neutropenic patients and have new onset of abdominal pain, mental status changes, respiratory symptoms or other signs or symptoms compatible with possible infection * Considered high risk candidates for empiric antibiotics

18. Febrile Neutropenia Guidelines for Empirical Treatment • What are necessary prior to the initiation of empiric antibiotic therapy? • Pre-antibiotic evaluation • Thorough Hx and PE • Microbiologic examinations of blood, catheter entry site discharge • Laboratory examinations: • Baseline CXR • Blood chemistries

19. Febrile Neutropenia What constitutes appropriate initial empirical therapy?

20. Defect in Neutrophil Function • Pathogens: • S. aureus and CoNS • Viridans strep and other streptococcal species • Enterococcus spp. • E. coli • P. aeruginosa • K. pneumoniae • Enterobacter spp. • Citrobacter spp. • Anaerobes • Fungi

21. IDSA (Infectious Disease Society of America) risk criteria for fever and neutropenia • High risk • Neutropenia anticipated to extend beyond 7 days • Medical co-morbidities • Hemodynamic instability • Oral or GI mucositis - dysphagia • Abdominal or peri-rectal pain • Nausea/vomiting • Diarrhea (6 loose stools daily) • Neurologic/mental status changes • Low risk • Neutropenia expected to resolve within 7 days • Absence of any co-morbidity listed in high risk criteria • Adequate hepatic and renal function

22. IDSA (Infectious Disease Society of America) risk criteria for fever and neutropenia • High risk • Medical co-morbidities • Intravascular catheter infection • New pulmonary infiltrate, hypoxemia or underlying COPD • Hepatic insufficiency (aminotransferase levels > 5x normal) • Renal insufficiency (creatinine clearance < 30 ml/min)

23. Initial empiric antibiotics: High risk patients • Monotherapy with an IV antipseudomonal ß-lactam: ceftazidime, cefipime, imipenem, meropenem or piperacillin-tazobactam (AI) • Ceftazidime may be a less reliable monotherapy • PCN-allergic patients: ciprofloxacin or aztreonam + clindamycin or vancomycin (CII) • Aminoglycoside, FQ and/or vanco may be added for mgt of complicated cases (i.e., hypotension, pneumonia) or if antimicrobial resistance is suspected/proven (AII) Paul Cochrane Database 2003; 2: CD003038; Furno Lancet ID 2002; 2: 231; Bow CID 2006; 43: 447; Glasmacher Clin Micro Infect 2005; 11 (S5): 17

24. Initial empiric antibiotics: Low risk patients • Inpatient IV or oral antibiotics • IV regimens as for high risk patients (AI) OR • Oral regimen: ciprofloxacin + amoxicillin/clavulanate (AI) • Oral regimen for PCN-allergic patients: levofloxacin, moxifloxacin, ciprofloxacin + clindamycin, ciprofloxacin + azithromycin (CIII) Freifeld NEJM 1999; 341: 305; Kern NEJM 1999; 341: 312; Rolston CID 1999; 29: 512; Chamilos Cancer 2005; 103: 2629; Cornely Int J Hematol 2004; 79: 74; Innes Supp Care Cancer Sept 25, 2007 epub.

25. Patient Follow-up How should the initial therapy be modified?

26. Modification of initial therapy during the first week • Daily examination while febrile and neutropenic • Modifications based on new findings • Identified focus of infection • Positive initial cultures - specific antibiotic • Superinfections or breakthrough infections • Clinical deterioration

27. Empiric antifungal therapy • After 4-7 days of broad spectrum antibiotics, high risk patients with continuing or recrudescent fever, should receive antifungal therapy (AII) • Amphotericin B (standard tx) • Others include: caspofungin, liposomal ampho B (AI); itraconazole, voriconazole (BII) • Investigate for systemic fungal infection • Chest CT scan can be performed on high risk patients with prolonged FN, to evaluate evidence of invasive mould infection (BIII) Winston Am J Med 2000; 108: 282; Walsh NEJM 2004; 351: 1391; Booegarts Ann Intern Med 135: 412; Maertens CID 2005; 41: 1242;

28. Treatment Duration How long should empirical antibiotic therapy be continued?

29. Duration of empiric antibiotic therapy • Documented infections • Treat for an appropriate length of time for the particular organism and site and continue through the period of neutropenia or beyond, as necessary (CIII) • FUO • ANC > 500/mm3 for at least one day with a rising trend; AND • Patient is afebrile for at least 2 days (CIII)

30. Prevention of Infection How do we prevent infection in the neutropenic host?

31. Antimicrobial Prophylaxis • Low risk • Antibacterial, antifungal, antiviral not routinely recommended (CIII) • Prophylaxis for Pneumocystis carinii • Mandatory for patients with ALL and for those who are receiving glucocorticoid containing chemotherapy regimen

32. Antibacterial prophylaxis • High risk • Ciprofloxacin or levofloxacin for patients with expected duration of neutropenia > 7 days (AI) • Antibiotic prophylaxis has been shown to reduce • Febrile episodes • Gram +/- bacteremias • Use of empiric antibiotics without an increase in antimicrobial resistance Gafter-Gvill Ann Int Med 2005; 142: 979; Bucaneve NEJM 2005; 353: 977; Crucianin JCO 2003; 21: 4127; Gimmema Ann Int Med 1991; 115: 7; von Baum JAC 2006; 58: 891; Leibovici Cancer 2006; 107: 1743

33. Antifungal Prophylaxis • High risk • AML induction: posaconazole (AI); itraconazole, fluconazole (CI) • Allogeneic HSCT: fluconazole (AI); itraconazole, micafungin (BI); • Autologous HSCT: fluconazole if patient is anticipated to develop severe mucositis (BI) • Mould-active agent for patients with prolonged neutropenia >14 days (BIII) Cornely NEJM 2007; 365: 348; Rotstein CID 1999; 28: 331; Winston Ann Int Med 1993; 118: 495; Glasmacher JAC 2006; 57: 317; Goodman NEJM 1992; 326: 845; Slavin JID 1995; 17: 1545; Winston Ann Int Med 2003; 138: 705; Marr Blood 2004; 103: 1557; van Burik CID 2004; 39: 1407

34. Colony Stimulating Factors (G-CSF, GM-CSF) • Should not be administered at the onset of FN, as adjuncts to empiric antibiotics, as they are not clinically useful (EI) Berghmans Supp Care Cancer 2002; 10: 181

35. Environmental Precautions • No specific protective gear (gowns, gloves, masks) for routine care of neutropenic patients (CIII) • Neutropenic patients do not require a single room or special ventilation, except allogeneic HSCT recipients (CIII) • “Neutropenic diet” generally recommended (BIII) • No plants, dried or fresh flowers; no pets (BIII) • All HCWs must have updated immunizations, especially yearly influenza vaccine (AI)

36. Infections inTransplant Recipients • Important problem due to its contribution to the failure and rejection of the transplanted organ • Clinical manifestations vary depending on: • infecting pathogen • prior immune status of the host • time after transplantation • level of pharmacologic immunosuppression • Often occur during the first 4-6 months

37. Factors that contribute to infection after transplantation • Pretransplant host factors • Underlying medical condition • Lack of specific immunity • Prior colonization • Prior latent infection • Prior medications • Transplantation factors - type of transplantation, surgical stress • Immunosuppression - therapy, infections • Allograft reactions

38. Effects of Immunosuppresants • Steroids • Inhibit migration of monocytes to areas of inflammation  Prevent induction of IL-1 and IL-6 in macrophages   Chemotactic activity and adhesion of neutrophils at the site of infection

39. Effects of Immunosuppresants • Cyclosporine •  Generation of CD4 (T-helper cells)   Proliferation of CD4 cells   Production of cytotoxic T-cells from the precursors • Mycophenolate mofetil • Inhibits inosine monophosphate dehydrogenase   Proliferation of B and T lymphocytes

40. Infections in bone marrow transplant recipients

41. Infections in solid organ transplant recipients VIRAL CMV Onset HSV CMV chorioretinitis EBV VZV PAPOVA ADENOVIRUS FUNGAL TB PNEUMOCYSTIS CNS Listeria Cryptococcus Aspergillus, Nocardia, Toxoplasma BACTERIAL Wound Pneumonia Line-related HEPATITIS Hep B Non-A, Non-B Hep UTI: BACTEREMIA, PYELITIS, RELAPSE UTI: BENIGN Transplant 1 2 3 4 5 6 MONTHS

42. Approach to suspected infection in a post-transplant patient • Careful history and PE • Focus of infection • Diagnostic Work-up • CXR • Microbiologic studies • CBC, LFTs, Renal Function tests • Viral studies (CMV) • Important to remember: • Infections may occur without fever • Not all fevers are due to infections

43. Diagnosis and Control of Infection • Routine Lab Tests • Before Transplantation • CMV / EBV / HSV / VZV IgG • Toxoplasma IgG • Hep B screening • Hep C ELISA • HIV Ab • PPD • Stool for ova and parasites • After Transplantation • Viral surveillance • Antibody studies (as indicated)

44. Prophylactic measures • Immunization • Passive • CMV-specific Ig for seronegative renal transplants • Active – inactivated vaccines

45. Prophylactic Agents

46. ASPLENIA • Postsplenectomy sepsis • Rapid deterioration accompanied by CV collapse, seizures, coma and DIC • High mortality rate • Diagnosis: Microbiologic exams of blood • Microbiology: S. pneumoniae, H. influenzae, N. meningitidis • Appropriate antibiotics against these organisms

47. Prevention of Infection in Asplenic Patients • Patient education • Vaccination - at least 2 weeks before elective surgery Prophylactic antibiotics ? • Spleen-sparing treatments • Potential immunologic measures • GM-CSF -  macrophage bactericidal activity • Corynebacterium parvum – stimulates RES

48. HIV • Antiretroviral therapy (HAART) • Treatment of concurrent infections • Prevention of opportunistic infections • General isolation procedures • Prophylactic antimicrobials

49. NATURAL COURSE OF HIV INFECTIONHIV initiates immunity loss Immunity HIV Fauci et al. Overt AIDS CD4 T cells RNA Anti-HIV Anti-HIV

50. Events HIV infection Loss of immunity Opportunistic infection Opportunistic cancer Death Pathogen HIV Many pathogens other than HIV Disease and PathogenHIV causes immune deficiency. Other pathogen triggers death.