Infection in the (non-hiv) immunocompromised host Advances in Infectious Diseases April 2011

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1 Infection in the (non-hiv) immunocompromised host Advances in Infectious Diseases April 2011 Brian S. Schwartz, MD Assistant Clinical Professor UCSF, Division of Infectious Diseases Are you involved in the care of the following types of pa6ents? A. Solid organ transplant B. Hematological malignancy C. Both D. Neither Solid organ transplants in the U.S # solid organ transplants/year 35,000 30,000 25,000 20,000 15,000 10,000 5, Years 1

2 Stem cell transplants in the US: Rheumatologists use of TNF inhib for RA Lee SJ. J Rheumatol Aug Lecture goals 1. Recognize the poten6al sources of infec6ons in immunosuppressed (IS) pa6ents 2. Recognize which IS states predispose pa6ents to which pathogens 3. Recognize which clinical condi6ons are associated with which IS states and infec6on 4. Recognize that clinical, radiographic, and pathological findings of infec6on can be altered in IS pa6ents 2

3 Risk of infec6on in IS pa6ent Environmental exposures ACTIVE INFECTION Host coloniza6on + Immunosuppression Latent infec6on Environmental exposures Opportunis6c pathogens PCP, aspergillus, cryptococcus Community pathogens Respiratory viruses, agents of CAP Nosocomial pathogens Mul6- drug resistant bacteria, C. difficile Host coloniza6on (altered) Common infec6ons are with bad bugs Pseudomonas, ESBL gram nega6ves MRSA, VRE Candida 3

4 Reac6va6on of latent infec6ons Viruses: CMV, EBV, HSV, VZV, Hepa66s B Bacterial: Tuberculosis Fungal: Endemic mycoses Parasites: Strongyloides, toxoplasmosis + IMMUNOSUPPRESSION Neutropenia Clinical scenarios Chemotherapy induced neutropenia Infec6on risk Bacterial pathogens (oral, GI, skin flora) Candida Aspergillus (if prolonged) 4

5 Hypogammaglobulinemia Clinical scenarios Chronic lymphocy6c leukemia Mul6ple myeloma Infec6on risk Bacterial pathogens, primarily sinopulmonary infec6ons TNF- alpha inhibi6on Clinical scenarios Rheumatoid arthri6s Inflammatory bowel disease Infec6on risk Mycobacteria, endemic mycoses, some increased risk for bacterial infec6ons Cell- mediated immunity Clinical scenarios Solid organ transplanta6on Some chemotherapy, stem cell transplanta6on Treatment of autoimmune disorders Infec6on risk Herpes viruses Pneumocys6s pneumonia Mycobacteria Molds Endemic mycoses Cryptococcus 5

6 Immunosuppressed popula6ons Solid organ transplanta6on Hematological malignancies Autoimmune diseases SOLID ORGAN TRANSPLANT (SOT) Why are SOT recipients at increased risk for infec6on? Immunosuppressive therapy Suppressed cell- mediated immunity Disrup6on of normal anatomy 6

7 Immunosuppression in SOT Degree of immunosuppression Lymphocyte depleting antibodies: Thymoglobulin, Campath IL-2 receptor blockers: Daclizumab, Basiliximab Antimetabolites: Mycophenolate (Cellcept, Myfortic) Calcineurin inhibitors: Tacrolimus (Prograf), Cyclosporine MTOR inhibitors: Sirolimus (Rapamune) Corticosteroids Months post- transplant Absolute lymphocyte counts following induc6on with thymoglobulin Mean Absolute Lymphocyte Count Normal Range of ALC Months post- transplant Brennan DC. Transp Proceed 1999 Risk of infec6on post- transplant: IS Degree of immunosuppression NOSOCOMIAL, TECHNICAL OPPORTUNISTIC CMV Aspergillus PCP Nocardia Listeria Toxo Cryptococcus Months post- transplant COMMUNITY ACQUIRED Endemic HSV mycoses VZV EBV Tuberculosis

8 SOT Case 1 55 year- old s/p liver transplant 5 weeks ago. Rou6ne labs: AST- 112, ALT- 133, AP- 230, Bili- 2.2 Brought to clinic for evalua6on Vitals: Afebrile and normal vital signs Exam: Mild RUQ tenderness to palpa6on (new) Abscess culture results Pa6ent underwent IR drainage and grew Viridans streptococcus Enterobacter cloacae Pseudomonas aeruginosa Enterococcus spp Lactobacillus spp 8

9 Dx:Biloma (liver abscess) Why did he get it? Why was he asymptoma6c? Pathogenesis of biloma Hepatic Artery Thrombosis Bile duct necrosis Biliary extravasation (bacteria present) Biloma Recurrent cholangitis (biliary stricture) Atypical clinical manifesta6ons of common infec6ons Symptom severity Normal host Transplant Immunosuppressed pa6ent pa6ent DuraYon of infecyon - - > 9

10 SOT Case 2 65 year- old Chinese woman 10 months post liver transplant with ear fullness and pain Diagnosed with mastoidi6s by MRI Mastoid biopsy: Bacterial and fungal cultures: nega6ve Path: lymphocyte predominant inflamma6on with no granulomas, no bacteria or fungi Case con6nued Pa6ent was discharged with IV cefepime Readmiied with con6nued ear pain, fa6gue ID team evaluated the pa6ent and ordered retes6ng of prior pathology specimens 10

11 What is the most likely diagnosis? A. Aspergillus fumigatus B. Candida albicans C. Mycobacterium tuberculosis D. Pseudomonas aeruginosa E. Scedosporium prolificans Dx: Disseminated TB w/ mastoidi6s Why was the diagnosed missed on pathology? Pathologists did not stain for Mycobacteria (AFB) because there were no granulomas present 11

12 HEMATOLOGICAL MALIGNANCIES Why pa6ents with hematological malignancies are at risk for infec6on? Disease Treatment Underlying disease Heme malignancies: neutropenia (BM infiltra6on) CLL and myeloma: hypogammaglobulinemia Tumors: anatomic obstruc6on 12

13 Treatment Chemotherapy Neutropenia and disrup6on of skin/gi mucosa Stem cell transplant Stem cell transplant Chemotherapy to eliminate pa6ent hematological cells Transplant Autologous (self) vs. Allogeneic (other) Stem cell source (Allogeneic only) Peripheral vs. Marrow vs. Cord Cell recovery post hematopoie6c stem cell transplant Neutrophils NK cells CD 8+ B- cells CD4+ % of normal counts Bacteremia Candida Aspergillus HSV CMV, VZV PCP Aspergillus Encapsulated bacteria, Respiratory viruses Weeks post- transplant Mackall C. BMT

14 Heme malignancy case 21 year- old with refractory ALL has been neutropenic for over 8 weeks and has been on prophylac6c moxifloxacin and fluconazole He presents to clinic with 3 days of fa6gue, mild cough, and pleuri6c chest pain LABS: 2.7>33<31, ANC = 0.23 Chest CT What is the most likely diagnosis based on his immune defect and prophylaxis regimen? A. Aspergillus fumigatus B. Candida albicans C. Candida glabrata D. Cryptococcus neoformans E. Mucor species 14

15 Neutropenia Infec6on risk Bacterial pathogens (oral, GI, skin flora) Candida fluconazole Aspergillus (if prolonged) moxifloxacin Case cont. Underwent bronchoscopy Bacterial, mycobacterial, and fungal cultures: neg BAL galactomannan: 10.5 (normal <0.5) Serum galactomannan: 1.4 (normal <0.5) Diagnosis: Invasive pulmonary aspergillosis Treatment: Voriconazole and caspofungin AUTOIMMUNE DISEASE 15

16 Why are pa6ents with autoimmune disease at increased risk for infec6on? Immunosuppressive therapy Inhibitors of cell mediated immunity Cor6costeroids, methotrexate, mycophenolate Biologics An6- B cell an6bodies TNF alpha inhibitors Tumor necrosis factor S6mulates neutrophil recruitment S6mulates killing organisms sequestered within macrophages TNF inhibi6on in the treatment of sep6c shock Fischer CJ. NEJM

17 Inhibitors of TNF- α pathway TNF- alpha receptor fusion protein Etanercept (Enbrel) An6- TNF- alpha an6body Infliximab (Remicade) Adalimumab (Humira) Certolizumab (Cemzia) Golimumab (Simponi) Infec6on and TNF inhibitors Bacteria: Serious bacterial infec6on (TNF +MTX vs. MTX) Hazard ra6o: 1.9 ( ) Fungi: Histoplasmosis, Coccidiodiomycosis Mycobacteria: (TB and nontuberculous) TB cases: 28-54/100,000 vs /100,000 Curtis JR. Arthritis and Rheumatism. 2007; Wallis RS. Clin Infect Dis Tuberculosis and infliximab Post- marke6ng survey of TB cases following release of infliximab ( ) 70 cases of TB Median 6me to diagnosis: 12 wks (range 1-52) TB characteris6cs Extrapulmonary disease: 40/70 (57%) Disseminated disease: 17/70 (24%) Keane J. NEJM

18 Pathology results of pa6ent with TB on infliximab CONTROL INFLIXIMAB Keane J. NEJM Recommenda6on for LTBI screening prior to use of TNF inhibitor PPD or interferon gamma release assay (IGRA) prior to start of therapy If evidence of latent TB, treat for at least 1 month prior to start of TNF inhibi6on Garden. Lancet ID Autoimmune Case 69 year- old woman with myasthenia gravis presents with 1 month of fa6gue and ulcers in her mouth and over her mons pubis. Meds: Prednisone 10 mg QD, Cellcept 250 mg BID Social history: lives in Stockton, CA and works as a librarian. No animal exposures 18

19 Physical exam Afebrile, VSS. Skin findings below, crackles at right base Labs: 8>35<350; Cr and LFTs - wnl Radiographic imaging Case con6nued Bronchoscopy: bacterial, mycobacterial, and fungal cultures nega6ve Serological studies: cryptococcal an6gen, cocci serologies, histoplasmosis an6gen all nega6ve Skin biopsy was performed 19

20 Case: Path skin bx What type of infec6on caused her clinical disease? A. Bacterial infec6on B. Fungal infec6on C. Mycobacterial infec6on D. Parasi6c infec6on E. Viral infec6on Case diagnosis EBV+, Non- hodgkin s lymphoma Began taper of immunosuppression All lesions resolved auer stopping immunosuppression alone 20

21 Cell- mediated immunity Clinical scenarios Solid organ transplanta6on Some chemotherapy, stem cell transplanta6on Treatment of autoimmune disorders Infec6on risk Herpes viruses Pneumocys6s pneumonia Molds Mycobacteria Endemic mycoses Cryptococcus Summary 1. Take a detailed history and medica6on review to determine net state of immunosuppression a. Solid organ transplant: recent treatment for rejecaon? b. Stem cell transplant: when was the transplant, GVHD? c. Autoimmune disease: Are they on a TNF inhibitor? 2. Based on the immune defect, determine which pathogens the pa6ent is at risk for acquiring 3. Be aware that IS host may have altered clinical, radiographic, and pathological manifesta6ons of infec6on brian.schwartz@ucsf.edu QUESTIONS? 21