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The “Net State of Immunosuppression” and Infection in Transplantation

The “Net State of Immunosuppression” and Infection in Transplantation. Jay A. Fishman, M.D. Professor of Medicine, Harvard Medical School Director, Transplant Infectious Disease and Compromised Host Program Associate Director, MGH Transplant Center, Massachusetts General Hospital

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The “Net State of Immunosuppression” and Infection in Transplantation

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  1. The “Net State of Immunosuppression” and Infection in Transplantation Jay A. Fishman, M.D. Professor of Medicine, Harvard Medical School Director, Transplant Infectious Disease and Compromised Host Program Associate Director, MGH Transplant Center, Massachusetts General Hospital Boston, MA, USA

  2. Conflict of Interest Disclosure I have no financial relationship(s) within the last 12 months relevant to my presentation My presentation does not include discussion of off-label or investigational use

  3. Consider … New Renal Transplant recipients with discharge serum creatinine 1.8 and falling – similar presentations

  4. Diagnosis of infection is more difficult in immunocompromised hosts: • Diminished signs of inflammation • Dual infections (or processes) are common • Infection is advanced at presentation • Antimicrobial resistance is common • Toxic effects of drugs (antimicrobial agents) • Anatomic and surgical alterations • Multiple immune deficits in each patient.

  5. Key Concepts: Infection in Immunocompromised Hosts • More effective immunosuppressive regimens have reduced rates of acute graft rejection. However: • Persistence of “Chronic Allograft Dysfunction” • More atypical presentations (humoral) • Multiple factors contribute to risk for infection • Infections are common • Presentations are often atypical without fever or other signs • Infection exceeds rejection as a cause of hospitalization. • Prophylaxis is effective in delaying infection(not indefinitely) • Infection is increasingly recognized as a risk factor in decreased graft survival (chronic allograft dysfunction and graft rejection). • Microbiological assays (molecular) are routinely used in diagnosis and management.

  6. What do I need to know? • Multiple processes – broad DDx • Imaging (collections, vascular issues, drainage) • Prophylaxis: What don’t they have? (Maybe) • Drugs and interactions • Calcineurin inhibitors: prerenal vasoconstriction – all have diminished renal function • Azoles:  CNI levels 2-3 fold or more • Toxicity of aminoglycosides and amphotericin • Can sacrifice kidneys to save a life • Urgency for specific diagnosis • Prior microbiology (including VRE, MRSA, MDRO, molds) • Always consider CMV status (viral load) = Fever and relative leukopenia • Graft function (rejection)

  7. Pathogenesis of chronicallograftnephropathy CMV Bacterial infections Viral infections BK virus Pascual M et al. N Engl J Med 2002; 346: 580

  8. Chronicallograftdysfunction BKV Aspergillus, Pseudomonas Chronicallograftnephropathy (CAN) Chronicallograftlungdysfunction (CLAD) CARV CMV HCV Chronicallograftvasculopathy (CAV) Vanishing bile duct syndrome (VBDS)

  9. General Principles: Diagnosis and Treatment of Infection • Demonstration of Anatomy (CT/MRI) • Tissue Histology -- invasive procedures (biopsy), special stains • Demonstration of nucleic acids or proteins (Note: serologic tests are not generally useful for acute diagnosis) • Early and aggressive therapy (surgical debridement) – cannot eradicate infection unless primary source is resolved (e.g. hematoma) • Infection contributes to immunologic graft injury

  10. Fever is unreliable as a sign of infection in solid organ recipients In transplant recipients, fever is defined as an oral temperature of 37.8°C or greater on at least two occasions during a 24-hour period Antimetabolites (mycophenolatemofetil, and azathioprine) are associated with significantly lower maximum temperatures and leukocyte counts Patients with significant infection (bowel perforation) may lack fever or localizing signs

  11. Newer Pathogens in Transplantation • Bacteria: Non-TB mycobacteria, Antimicrobial Resistance: MDRO including VRE, MRSA, Carbapenem-Resistant GNR (CRE) • Fungi: Azole-resistant Candida spp. Candida auris, Mucor,Scedosporium, Dematiaceous molds. • Viruses: Zika, multidrug-resistant CMV, adenovirus vectors, parainfluenza in HSCT, SARS, HHV6,-7,-8, • Parasites: Cryptosporidium, T. cruzi, Leishmania, Strongyloides.

  12. Why New Pathogens?Challenges of Infection in Transplantation • Prolonged patient survival • Broad geographic exposures (endemic infections, travel, employment) – C. auris& global warming? • Increased antimicrobial resistance in nosocomial flora (prolonged hospitalizations, organ shortage) • Routine prophylaxis (fluconazole, vancomycin, cephalosporins, antivirals) • Renal, hepatic, pulmonary dysfunction (sicker patients) • Improved diagnostic assays • Intensified Immunosuppression

  13. Risk for infection is a semiquantitative relationship between: Epidemiologic exposures and “The Net State of Immune Suppression” (including latent infections) After: Robert Rubin (1970’s)

  14. Recent Nosocomial flora Catheter-related Complex Surgery Community acquired Urinary tract infection Aspiration Cryptococcus Legionella Donor-derived* Distant Tuberculosis Non-tuberculous mycobacteria Colonization (remote) - MDRO Strongyloides Herpesviruses Toxoplasmosis Leishmania, T. cruzi Histoplasmosis, Coccidioides HTLV, HIV, HCV, HBV Careful Medical History: Epidemiologic Exposures May Be Recent or Distant *e.g., Dengue, Chikungunya, LCMV, Rabies, VRE, MDRO, Candida, TB HTLV, human T-cell lymphotrophic virus; HIV, human immunodeficiency virus.

  15. “Net State of Immune Suppression” • Immunosuppressive Therapy: Type/Temporal Sequence/Intensity -- “AUC” • Prior therapies (Chemotherapy, Antimicrobials) • Role of disrupted Microbiome? • Altered colonization patterns (MDRO), C. difficile • Preexisting immunity • Mucocutaneous Barrier Integrity (catheters) • Neutropenia, Lymphopenia (depth, duration) • Underlying Immune Deficiency & Metabolic conditions: Uremia, Malnutrition, Diabetes, Alcoholism/cirrhosis, Anatomy (leaks, COPD/bronchiectasis), Age. • Viral Co-Infection (CMV, Hepatitis B and C, RSV): Immune Modulation/Rejection/Cancer

  16. “Net State of Immunosuppression” • We lack tools that measure immune function relative to infection AND grafts (solid organs or stem cells) in an individual. • Inability to measure risk for rejection or infection • Intracellular ATP • Genetic signatures • Improved ability to measure immunity to specific pathogens (e.g., CMV) • Need to reduce side effects of immune suppression • Many aspects of allograft injury (humoral, vasculopathy, fibrosis) are incompletely understood.

  17. Immunosuppression and Infection: The Basics(Can the risk for infection be reduced?)

  18. General Immunosuppression Protocols Bacterial/viral ppx for 6mo Tacrolimus (trough ~8-10) MMF 2gm/d May stop in selected cases Thymoglobulin (1.5mg/kg daily x4 dose) 0 +1 +2 +3 +4 +5 +6 +7 Days after Transplant

  19. T-cell “Synapse” = TCR (“Signal 1”)+ Costimulatory Receptor (“Signal 2”) Note: Effects of Steroids and CMV on APC Modulation belatacept CD28 & CTTLA4 Depletion

  20. Linkage of Immunosuppression to Infections and Prophylaxis • Corticosteroids • Bacterial infections • Pneumocystis jiroveci • Fungal infections • Accelerated Hepatitis B, possibly HCV • Azathioprine & Mycophenylatemofetil– cell cycle inhibitors • Neutropenia, papillomavirus? • Bacterial infection, late CMV? • Calcineurin inhibitors: • viral replication, PML • Intracellular pathogens (TB, Listeria, Nocardia) • Fungal infection (Cryptococcus, Aspergillus, Pneumocystis) • Parasites (T. gondii, Toxoplasma, Leishmania, Strongyloides) • mTOR inhibition: Rapamycin/Sirolimus: • Poor wound healing, idiosyncratic pulmonary edema & pulmonary infections • Less CMV?

  21. Anti-CD40 Depletion Anti-CD22 Anti-CD20 Proteosome Anti-C5 Humoral response Antigen presentation B-cell regulation of T-cell responses

  22. Sensitization and Humoral graft rejection Immunosuppression: B-cells and Antibodies • Plasma cell: Bortezomib • Proteosome inhibitor • Neurotoxicity • Shingles • Complement: (Eculizumab – terminal factor C5) • Blocks neutrophil migration • Antibody-mediated rejection, desensitization • Encapsulated organisms including Pneumococcus, H. influenza, and Neisseria meningitidis  requires meningococcus A and B vaccination! • Anti-CD20 on pre- and mature B-cells (Rituximab - chimeric) • Depletion 3 to 12 months • Fever, bronchospasm • Nonchimeric -> severe infections • Hepatitis B activation • Encapsulated organisms • Anti-CD22 (Epratuzumab) • B cell activation • Anti-CD52 (Alemtuzumab) • Differentiation (B-cell activating factor BAFF/BlyS) (Belimumab) • Severe pneumonias, low Ig

  23. The Timeline of Post-Transplant Infections Donor or Recipient NOSOCOMIAL TECHNICAL From COMMON TO ZEBRAS* OPPORTUNISTIC, RELAPSED, RESIDUAL HSV, CMV, HBV, HCV, LISTERIA, PCP, TOXO TRANSPLANT LONG TERM 4 WEEKS ~6-12 MOS. Exposure to nosocomial pathogens Period of most intensive immune suppression • COMMON VARIABLES in IMMUNE SUPPRESSION: • MANY DIFFERENT REGIMENS (steroid-free, CNI-free, Antibody Induction, costimulatory blockade) • TREATMENT OF REJECTION -- “Resets clock” • NEUTROPENIA (virus or drug-induced) • VIRAL INFECTIONS (CMV, HCV, EBV, RSV …)

  24. Immune Monitoring: Who can have Immunosuppression Reduced? • Cell counts (differential, T-cell subsets) • Repletion of immunoglobulins (few data) • Gene Polymorphisms (e.g., Mannose binding lectin) • Immune Function Assays: • Phytohemagglutinin (PHA) as nonspecific mitogen to stimulate cell division in CD4 T-lymphocytes regardless of their antigenic specificity or memory status – not actionable? • Innate and Adaptive Immunity(Quantiferon-Monitor) • Gene Expression Profiling: identifies cardiac/renal rejection • Risk for Immune Reconstitution Syndrome (IRIS)? • Risk for rejection (based on inflammatory response)? BK experience (good) vs. PTLD (~32%).

  25. What happens when we reduce immunosuppression?Immune Reconstitution? • Two main forms of IRIS are observed: • (1) unmasking of occult, previously asymptomatic infection • (2) paradoxical worsening of clinical symptoms without other explanation and despite appropriate antimicrobial therapy. • Notably, a high organism or antigen burden in an unfavorable anatomic location  Such as an allograft? Or CNS? • IRIS observed with many organisms including: • Fungi (Cryptococcus, Histoplasma, Pneumocystis species) • Bacteria (Mycobacteria species including tuberculosis, leprosy, M. avium species, and bacillus Calmette-Guerin) • Viruses (JC polyomavirus, hepatitis B and C viruses, herpesviruses) • Parasites:  Leishmania species

  26. Opportunities Pathogen-specific immunity (TB, CMV) Immunity relative to graft (MHC, genetic signatures) Individual immune function relative to graft and infection   Novel immune function assays e.g., Mass cytometry or CyTOF

  27. Thank you!! If I can help: jfishman@mgh.harvard.edu

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