Download Infection in Solid-Organ Transplant Recipients

Infection in Solid-Organ
Transplant Recipients
Jay A. Fishman
NEJM 2007;357:2601-14
 Potent immunosuppressive agents
 Incidence of rejection of transplanted organs
 Susceptibility to opportunistic infections and cancer
 Patterns of opportunistic infections – altered by
 Routine antimicrobial prophylaxis for P. jirovecii & CMV
 Emergence of new clinical syndromes (BK nephropathy)
 Infection due to organisms with antimicrobial resistance
 New quantitative molecular and antigen-based
microbiologic assays  detection of previously
unrecognized transplantation-associated pathogens
(lymphocytic choriomeningitis virus)
General concepts
 Infection in transplant recipients – difficult to recognize
 Sign & symptoms are often diminished
 Noninfectious cause of fever (allograft rejection)
 Antimicrobial therapy
 Toxic effects
 Interactions with immunosuppressive agents
 Broad spectrum of pathogens
 Early and specific microbiologic diagnosis
 Essential for guiding treatment and minimizing
nonessential drug therapy
Risk of Infection
Modifications in immunosuppression  changes in risk of infection after transplantation
Epidemiologic exposures
 Donor-derived infections and screening
 Via transplanted organs
 CMV, TB, Trypanosoma cruzi – latent in tissues
 Active donor infection – viremia, bacteremia
 Nosocomial organisms resistant to routine surgical
antimicrobial prophylaxis (VRE, azol-resistant candida spp.)
 Pneumonia from donor-
derived HSV infection
 Fever & pneumonia (D3)
 Abnormal LFT
 Blood & sputum – HSV
 Donor serum – HSV
PCR (+)
 Other recipients (heart,
liver, other kidney) –
HSV (+)
 Antiviral therapy
 Screening of transplant donor – limited by
 Available technology
 Short period during which organs from deceased donors
can be used
 Routine evaluation
 Ab detection for common infections
 Seroconversion
 Unidentified pathogens
 Improved donor screening
 More sensitive and rapid assays by organ procurement
organizations
 Transplantation of organs from deceased donors with
fever or viral syndrome – controversial
 Need for improved microbiologic screening tools
 Recipients-derived infections and detection
 Active infection should be eradicated before
transplantation
 Common recipient-derived pathogens
 TB
 certain parasites (Strongyloides stercoralis & T. cruzi)
 Viruses (CMV, EBV, HSV, VZV, HBV, HCV & HIV)
 Endemic fungi (Histoplasma capsulatum, Coccidoides
immitis, & Paracoccidioides brasiliensis)
 Nosocomial infections and antimicrobial resistance
 Colonization with nosocomial, antimicrobial-resistant
organisms
 After transplantation, pneumonia and, infection of
hematomas, ascitic fluid, wounds, and catheters
 Community infections
 Relatively benign in normal host  major infection
 Common microorganisms: pathogens in soil (aspergillus,
nocardia spp.), C. neoformans in birds, respiratory viruses
with subsequent bacterial/fungal superinfection
Net state of immunosuppression and monitoring of
immune function
Dose, duration,
and sequence of
immunosuppressive
therapy
The factors contributing to the degree of immunologic impairment and
standard assays that assess the patient’s risk of infection will be supplemented
in the future by new quantitative measures of allograft- and pathogen-specific
immune function and the risk of infection
Multiple simultaneous quantitative (multiplex) assays
Genomic arrays measuring the upregulation or down-regulation of host
genes during infection
Lytic and latent epitopes – viral Ags
presented in either the lytic or latent
phase of EBV
Prevention of Infection
 Antimicrobial prophylaxis  altered incidence & severity
of post-transplantation infections
 3 general preventive strategies
 Vaccination
 Universal prophylaxis
 Preemptive therapy
 Vaccination
 Before transplantation – need for immunization against
measles, mumps, rubella, diphtheria, pertussis, tetanus,
HBV infection, poliomyelitis, varicella, influenza, and
pneumococcal pneumonia?
 Less effective during immunosuppression
 Live vaccines – generally contraindicated after
transplantation
 Lifestyle changes after transplantation
 To limit exposures to some potential pathogens
 Hand washing after food preparation, gardening, & contact
with feces or secretions
 Avoiding close contact with people with respiratory illness,
and environments such as construction sites
 Avoidance of well & lake water, undercooked meats,
unwashed fruits & vegetables, and unpasteurized diary
products
 Routine surgical prophylaxis
 Organ transplanted & local epidemiologic factors
 Known colonization patterns with pseudomonas, MRSA,
VRE or fungi
 Antifungal prophylaxis
 Risk and epidemiologic factors
 Most invasive fungal infections
 Non-albicans candida and aspergillus spp.
 Greatest risks associated with early fungal infections
 Aspergillus at the tracheal anastomosis after lung
transplantation
 Candida spp. after pancreas or liver transplantation
 IFI – most common in liver recipients requiring admission
to ICU, surgical re-exploration or retransplantation, or
transfusion of large amounts of blood products and in
liver recipients with metabolic dysfunctions, respiratory
failure, CMV infection, or HCV infection
 After broad-spectrum antimicrobial therapy
 TMP-SMZ prophylaxis for ≥3mo
 PCP, Toxoplasma gondii, Isospora belli, Cyclospora
cayetanensis, nocardia & listeria spp., common urinary,
respiratory, & GI pathogens
 Alternative agents for PCP
 Dapsone, atovarquone, & pentamidine
 Prevention of post-transplant CMV and other herpesvirus
 Oral antiviral agents
 Universal prophylaxis vs. preemptive therapy
Changing the Pattern of Infection
 Corticosteroid-sparing regimens & PCP prophylaxis 
less common pneumocystis pneumonia
 Antiviral prophylaxis  uncommon herpesvirus infection
 Changes in typical immunosuppression  new patterns
of infection
 Sirolimus-based regimens – idiosyncratic noninfectious
pneumonitis
 T-lymphocyte-depleting Ab – viral activation
 Cellular depletion after induction therapy beyond the
period of antimicrobial prophylaxis  Late infections with
viruses (CMV, JC polyomavirus,..), fungus and malignant
conditions
CT showing a liver abscess at the
site of an ischemic graft injury
Opportunistic infections
are generally absent
Viral pathogens and
allograft rejection
Chronic viral infections
 allograft injury
Common Infections in
Transplantation
CMV
EBV
Polyomavirus
CNS
pneumonitis
CMV infection
 Epidemiology
 Primary infection, reactivation or viral superinfection
 Serologic assays
 Useful in determining patient’s risk of infection
 Little useful in diagnosis of acute infections
 Prevention
 Universal prophylaxis and preemptive therapy
 Special consideration
 Induction therapy with depleting antilymphocyte Ab
 Heart and lung transplant – longer prophylaxis
 Ganciclovir resistance – uncommon
 UL97 gene or UL54 gene
 Diagnosis and therapy
 Diagnosis
 Qauntitative diagnostic assays
 PCR, Ag detection (pp65 antigenemia)
 Biopsy
 Treatment
 Oral valganciclovir
 IV ganciclovir – preferred for the initiation of therapy for GI
disease
EBV and PTLD
 PTLD
 3-10% of adult SOT recipient
 Mortality of 40-60%
 More than half of post-transplantation malignant conditions
in pediatric SOT recipients
 Risk factors
 Primary EBV infection after transplantation
 Allograft rejection
 Exposure to antilymphocyte antiserum
 CMV coinfection
 CD20+ & B cell origin PTLD in the 1st yr – related to EBV
 Later disease – EBV (-), T ell, NK cell or null cell, poor Px
 Diagnosis
 Quantitative EBV viral-loading testing, flow cytometry,
analysis of immunogolbulin gene rearrangements and
histologic analysis with staining for EBV-derived RNA
 Treatment
 Reduction of immunosuppression  regression of
polyclonal form PTLD
 CTx, irradiation, anti-CD20 Ab
 Adoptive immunotherapy – under investigation
Polyomavirus BK and JC
 BK virus
 nephropathy & ureteral obstruction
 JC virus
 Progressove multifocal leukoencephalopathy (PML)
 Diagnosis
 Detection of BK virus nucleic acid in blood & urine in BK
nephropathy
 Treatment
 No effective antiviral therapy
 Reduction in immunosuppression
 Experimental therapy: cidofovir, leflunomide, IVIG
CNS infection
 Broad spectrum of causative organisms
 Listeria, HSV, JC virus, & C. neoformans
 DDx – noninfectious causes
 Toxic effect of calcineurin inhibitors
 Lymphoma
Pneumonitis and pneumocystis infection
 PCP
 Marked hypoxemia, dyspnea, and cough in spite ofa
paucity of P/Ex or radiologic findings
 Noninfectious causes of pneumonitis
 Toxic effects of sirolimus