Approach to Infection in the Organ Transplant Recipient

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Approach to Infection in the Organ Transplant
Recipient

• Ajit P. Limaye, M.D.
• University of Washington
• Seattle, WA

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General Concepts

• Infection risk assessment PRE-transplant
• PPD, h/o TB exposure
• Travel/residence history (endemic mycoses,
  Strongyloides, T. cruzi)
• Baseline serologies
• Vaccination review
• Infection history (recurrent Staph, etc)

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General Concepts (cont.)

• Signs and symptoms of infection are muted by
  immunosuppression
• Specific, predictable risk periods for specific
  pathogens (unusual timing may be a clue to
  exposure)
• Link between immunosuppression and infection risk
  
• Consider the possibility of donor-derived
  infection (viral, fungal, bacterial,
  mycobacterial, etc.)

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Prophylaxis

• CMV 3 months of antiviral (valganciclovir
  valcyte,
• valacyclovir valtrex) for DR- and R
• PCP 6-12 mo TMP/SMX (or dapsone, pentamidine)
• UTI 1-3 mo TMP/SMX (or quinolone) for K txp
• Candida all KP, selected liver transplant
  recipients
• 1-3 mo fluconazole

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Evaluation of the Patient

• Baseline patient data critical for appropriate
  work-up
• Donor/recipient serologies (CMV, EBV, HSV, VZV,
  Toxoplasma)
• Underlying disease
• Time post-transplant
• Allograft function
• Prophylactic medications
• Rejection (and its treatment)

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Evaluation of the Patient (cont.)

• Early and aggressive diagnostic investigation
• - adequate tissue
• - routine staging
• Appropriate notification and coordination with
  pathology and microbiology laboratories

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Timetable of Infections After Organ
Transplantation

• General guidelines, NOT absolute
• Epidemiology altered by prophylaxis
• Unusual timing may be a clue to unusual exposure

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• Early Period (first post-transplant month)
• Nosocomial/surgical infections
• Multi-drug resistant organisms (e.g., GNR, MRSA,
  VRE)
• Importance of adjunctive therapy (anatomical
  problems, adequate drainage)
• Opportunistic infections are uncommon (except
  Aspergillus, Candida, HSV in absence of
  prophylaxis)

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• Middle Period (from post-transplant months 2-6)
• Greatest risk period for classic opportunists
  (e.g., PCP, Aspergillus, Toxoplasma,
  Cryptococcus, etc.)
• Immunomodulating viruses (e.g., CMV, EBV, HHV-6)

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• Late Period (after the 6th post-transplant month)
• Typical community-acquired infections in
  patients with good allograft function
• Continued risk of opportunistic infections in
  patients with poor allograft infection and/or
  chronic rejection

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Selected References
1. AST Guidelines for the Prevention Treatment
of Infections in Solid Organ Transplant
Recipients. Am J Transplant 2009 (supplement
4) 3. Fishman JA. Infection in organ transplant
recipients. N Engl J Med 2007357(25)2601-14
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Case fever abdominal pain in a kidney
transplant recipient

• A 54 yo woman 3 mo s/p kidney transplant presents
  with 10
• days of fatigue, weakness, vague abdominal
  symptoms.
• Serologies CMV DR-, EBV, VZV, HSV1/2-
• Meds tacrolimus, MMF, pred, Bactrim,
  Amlodipine.
• PE T 38.2, tired-appearing, non-focal except
  mild abdominal tenderness

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cont. Fever abdominal pain in a kidney
transplant recipient

• Differential diagnosis?
• What diagnostic testing (labs other studies)
  would you order?
• Treatment? Complications of treatment?

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CMV After Organ TransplantationEpidemiology

• Typically occurred 1-3 months post-transplant (in
  the absence of prophylaxis)
• Later disease in the era of routine antiviral
  prophylaxis (4-12 months)
• May result from primary infection, reactivation,
  or super-infection
• Most important risk factors for infection and
  disease are donor/recipient serostatus, organ
  transplanted, and immunosuppression

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CMV After Organ Transplantation Clinical Aspects

• Manifestations
• CMV syndrome (60) vs Tissue-invasive CMV
  (40)
• CMV syndrome systemic febrile illness without
  specific localizing symptoms
• Tissue invasion/focal organ involvement
  (pneumonitis, enteritis, hepatitis, nephritis,
  retinitis)
• Associated with increased risk for other
  opportunistic infections (fungal infections,
  PTLD)
• Bi-directional association with allograft
  rejection
• Independently associated with increased risk of
  death (mediated through indirect effects)

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CMV After Organ Transplantation Diagnosis

• CMV disease CMV infection AND compatible
  symptoms or histopathology)
• Ubiquitous virus (distinguishing CMV excretion
  from CMV disease is critical)
• Most useful screening tests for diagnosing CMV
  infection are
• 1. buffy coat CMV pp65 antigen
• 2. blood/plasma PCR
• 3. buffy coat viral culture
• Demonstration of CMV by histopathology and/or
  culture from affected site is the gold standard
  for diagnosis

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CMV After Organ TransplantationTreatment

• Typical duration of therapy 3-4 weeks, guided
  by
• blood CMV levels
• (? longer for GI disease)
• IV Ganciclovir is standard therapy
• Oral valganciclovir for SELECTED cases
• Foscarnet for ganciclovir-resistant CMV disease
• ? CMV-IG or IVIG (often used in combination with
  antivirals for CMV pneumonitis)

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CMV After Organ TransplantationPrevention

• Major strategies
• Prophylaxis
• Preemptive therapy
• Agents
• High dose acyclovir (800 mg QID)
• Valacyclovir (2 g QID)
• Oral ganciclovir (1g TID)
• Valganciclovir (900 mg BID)

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Whats New About CMV?

• Changing epidemiology/late disease
• Ganciclovir resistance
• Individualizing/tailoring therapy
• Valganciclovir

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Whats New About CMV?Changing Epidemiology

• Emergence of late CMV infection disease
• Median onset of CMV disease is now 4-5 months
  post-transplant (compared to 1.5 months post-
  transplant in the past)
• result of effective prophylaxis
• DR- and patients treated for rejection are at
  greatest risk
• implications education/coordination with
  referring providers re diagnosis/testing/treatmen
  t

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Whats New About CMV?Ganciclovir Resistance

• Newly recognized problem
• Occurs late, KP and lung recipients at highest
  risk
• Almost exclusively in DR- patients
• Diagnostic tests are limited (must suspect on the
  basis of slow clinical and/or virologic response)
• Treatment includes foscarnet ganciclovir,
  decrease immunosuppression, ?CMVIG
• ?Reduced incidence with valganciclovir

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Whats New About CMV?Individualizing Therapy

• Change from previous one size fits all approach
  (i.e., 2-3 weeks of IV ganciclovir)
• Identification of risk factors for relapse after
  therapy
• Sia et al J Infect Dis 2000, Humar et al J
  Infect Dis 2002
• High viral load
• Kinetics of viral load reduction (time to viral
  clearance)
• Persistent viral load at end of therapy

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Whats New About CMV? Individualizing Therapy

• Implications for managing CMV disease
• obtain baseline (pre-treatment) viral load
• monitor viral load on therapy (Q week)
• treat until viral load has cleared
• minimum of 14-21 days
• may require prolonged duration in some patients

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Whats New About CMV?Valganciclovir

• FDA-approved for treatment of CMV retinitis in
  HIV-infected patients
• Better bioavailability than oral ganciclovir
• Theoretically better compliance? (QD vs tid,
  fewer pills)
• Price is same as oral ganciclovir
• Toxicity (similar to oral gcv, higher rate
  leukopenia)
• What is the correct dose?
• trials used 900 mg po QD
• many centers anecdotally using 450 mg po QD
• Possibly lower risk of resistance?

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Case skin lesion in an OLT recipient Its
Friday 400 pm before a long weekend. A 54 yo man
who is 2 mo s/p OLT is found to have a small
non-painful skin ulcer on his leg during a
routine post-txp f/u visit. No trauma to site. He
was recently discharged after long hospital stay,
and wants to go back to her home in Eastern
Washington. Post-op course delayed graft
function, hemodialysis-dependent, rejection
treated with steroid pulse and ATG Serologies
CMV DR-, EBV, HSV-, VZV Meds pred,
tacrolimus, MMF, valcyte PE T-38.4,
chronically-ill appearing, skin lesion as shown
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Case Skin lesion in a liver transplant recipient

• Its Friday 400 pm before a long weekend. A 54
  yo man who is 2 mo s/p OLT is found to have a
  small non-painful skin ulcer on his leg during a
  routine post-txp f/u visit. No trauma to site. He
  was recently discharged after long hospital stay,
  and wants to go back to her home in Eastern
  Washington.
• Post-op course delayed graft function,
  hemodialysis-dependent, rejection treated with
  steroid pulse and ATG
• Serologies CMV DR-, EBV, HSV-, VZV
• Meds pred, tacrolimus, MMF, valcyte
• PE T-38.4, chronically-ill appearing, skin
  lesion as shown

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What is the differential diagnosis? What should
be the pace of the work-up (in- versus
out-patient, etc.)? What diagnostic w/u should
be done?
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Aspergillosis After Organ Transplantation
Epidemiology

• Overall incidence is low (1-5) and varies
  significantly according to organ transplanted and
  center
• Lungs heart/lungs gt livers gt kidney/pancreas gt
  heart gt kidney
• Sporadic cases and outbreaks have been described
  (especially in association with hospital
  construction or renovation)

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Aspergillosis After Organ Transplantation
Epidemiology

• Corticosteroids, antilymphocyte antibodies,
  allograft dysfunction, neutropenia, renal
  failure, smoking (especially marijuana), CMV
  infection, intra-op and post-op variables are
  risk factors
• Specific risk factors vary according to organ
  transplanted
• Peak onset is within the first several months
  post-transplant

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Aspergillosis After Organ Transplantation
Clinical Aspects

• Pulmonary disease is most common (cough, fever
  and pulmonary infiltrate)
• No specific clinical or laboratory findings
• Evaluation for dissemination is mandatory
• 10-20 mortality

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Aspergillosis After Organ Transplantation
Diagnosis

• Diagnosis is complicated by ubiquity of the
  organism in the environment and by occasional
  colonization or contamination of cultures
• NEVER ignore Aspergillus in a transplant patient
  (requires thorough evaluation for invasive
  disease)
• Biopsy of affected site for histopathology and
  culture is gold standard
• Serum/BAL/CSF galactomannan, PCR
• Evaluation for dissemination is mandatory for all
  patients

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Aspergillosis After Organ Transplantation
Treatment

• Voriconazole (Vfend) now considered treatment of
  choice
• Major drug interactions
• Hepatotoxicity, visual symptoms
• Combination therapy
• Vori Caspo
• Ampho Caspo
• Modulation of immunosuppression, especially
  corticosteroid dose
• ? surgical excision for localized disease

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Aspergillosis After Organ Transplantation
Prophylaxis

• Preemptive therapy for documented Aspergillus
  colonization
• Targeted prophylaxis
• History of disease or colonization

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Whats new about Aspergillosis?

• Antifungal agents
• Extended spectrum azoles voriconazole,
  posaconazole
• Combination therapy (echinocandin either
  polyene OR azole)
• Newer diagnostic tools (Galactomannan,
  B-1,3-D-Glucan, PCR)

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• A 31 yo man from Montana receives a cadaveric
• kidney transplant. Post-transplant course
  uneventful,
• good allograft function. Immunosuppression
• tacrolimus, steroids, MMF.
• 8 months post-transplant
• admitted for evaluation of fevers, weight loss,
  and pan-cytopenia
• blood cultures positive for Histoplasma
  capsulatum (disseminated disease)
• treatment with amphotericin (good clinical
  response)

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The next appropriate step after clinical
management of the patient is

1. No further steps are necessary
2. Surveillance renal allograft biopsy
3. Increase maintenance immunosuppression
4. Celebrate the fact that Histoplasmosis was
   diagnosed and appropriately treated
5. Evaluate for donor-transmitted infection

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Histoplasma capsulatum Endemic Areas, U.S.
Seattle, WA
Vaughn, MT
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Next Steps in the Investigation

• Contact the organ procurement organization (OPO)
• Report suspicion of donor transmission
• Additional donor information
• donor clinical history
• clinical findings
• autopsy results
• Status of other recipient(s)

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Seattle, WA
Portland, OR
Kansas City, KS
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Limaye et al N Engl J Med 2000
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Difficulties in recognizing organ-transmitted
infections

• Prolonged period between transplant and infection
• Naturally-occurring community-acquired infections
• distinguishing community-acquired from
  organ-transmitted
• Distribution of organs across broad geographic
  regions
• better organ preservation techniques
• new rules for organ allocation

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Washington Post July 2, 2004
The Boston Herald May 23,
2005 Transplant shock as 3 die from hamster
virus Victims include 2 from Bay State
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• 40 persons received organs or other tissues from
  HCV seronegative donor (HCV PCR)
• Index case occurred 1.5 yr AFTER donor
  death--reported by primary provider
• Recipients located in 16 states and 3 countries
• 8 of 30 (27) recipients developed hepatitis C
  infection
• 3 of 8 recipients diagnosed with acute Hep C
  (before the index case) NOT recognized as
  transplant-transmitted

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Limitations of current system

• Voluntary reporting
• Lack of a centralized database (all via regional
  OPOs)
• No repository for isolates from suspected cases
• Limited donor screening
• blood donor screening gtgt organ donor screening

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CASE Back pain and fever after liver transplant
A 53 yo man who is 8 mo s/p liver transplant
comes to clinic for evaluation of low grade temps
and back pain. Post-txp course rejection x 2
(requiring pred pulse, ATG), and episodes
Candida/Staph bacteremia. He as had some low
grade temps and feels tired Meds pred, csp,
aza, diltiazem Serologies CMV DR-, EBV-,
HSV-, VZV PE 38.4, tenderness over lower
spine. Labs nothing exciting
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cont. Back pain in a liver transplant recipient

• What is the differential diagnosis?
• What is he at high risk for?
• What work-up would you do?

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Post-transplant Lymphoproliferative Disorder
(PTLD) Epidemiology

• Incidence varies with type of organ transplanted
  (heart/lung small bowel gt lung gt liver gt
  kidney)
• Closely linked to EBV
• Risk factors include
• EBV seronegativity,
• CMV mismatch (i.e., DR-), and
• anti-lymphocyte antibodies

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PTLD Clinical Aspects

• Fever of unknown origin with no localizing signs
  or symptoms
• Focal mass, ulcer (esp. GI tract) or infiltrate
  (commonly localized to the allograft)
• Multifocal or disseminated disease (CNS, GI,
  pulmonary)

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Post-transplant Lymphoproliferative Disease
(PTLD) - Diagnosis

• Requires biopsy of affected site(s) for
  histopathology and EBV markers
• Histopathologic appearance may be similar to
  allograft rejection (EBV markers are helpful)
• ? markers of systemic EBV replication (EBV DNA
  PCR from serum or blood)

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Post-transplant Lymphoproliferative Disease
(PTLD) - Treatment

• Reduction in immunosuppression
• Interferon-?, chemotherapy, radiation, anti-CD20
  antibodies (Rituxan), anti-IL6 antibodies,
  adoptive immunotherapy
• Surgical resection of localized disease
• No definite role for antiviral therapy for
  established disease

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45 yo man undergoes KP tx, immunoOKT3
FK/MMF/Pred 1 6 mo Biopsy-confirmed rejection
episodes, solumedrol post-tx pulses. Baseline
creat 1.5 14 mo Elevated creat2, biopsy
patchy tubulitis, ?tubular post-tx epithelial
cell inclusions, ICC positive for CMV, Rx
IV gcv--no improvement. ISH neg for
HSV/VZV/CMV/Adeno but for BK Immunosuppres
sion reduced. 15 mo Repeat biopsy
inflammation, persistent post-tx inclusions, no
rejection. ICC positive for BK virus. 19
mo Creat 4.9, hemodialysis begun post-tx
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BK Virus

• Polyoma virus (BK, JC, SV40)
• Non-enveloped, ds DNA
• Small genome (5000 bp)
• Acquired by respiratory route at young age
• (80-100 of adults seropositive)

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• hematogenous
• dissemination
• Primary infection Kidney Urothelium (latency)
• (respiratory route) (Chesters P et al. JID
  1983147676)
• Immunocompetent
• - asymptomatic, transient shedding
• - prevalence depends on sensitivity of assay
• Immunocompromised
• - persistent shedding, occasional disease
• - frequency, extent, and duration gtgt
  immunocompetent

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BKVN Epidemiology Incidence

• Single prospective study
• Hirsch et al NEJM August 2002
• Rarely reported prior to 1995 (cyclosporine
  era)
• - verified by clinical experience
• - confirmed by retrospective pathology reviews
• Incidence estimates range from 1-5
• - wide variability among centers (differences in
  immuno-
• suppression, definitions, follow-up)

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Incidence Timing of BKVN

• Hirsch et al. NEJM 2002347(7)488
• Prospective study of 78 K tx recipients (Basel,
  Switzerland)
• FK/Aza/Pred (47), Csp/MMF/Pred (53)
• Manifestation Incidence Median Onset
• Decoy cells 23 (30) 16 (2-69 wks)
• BK viremia 10 (13) 23 (4-73 wks)
• BKVN 5 (8) 28 (8-86 wks)

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BKV nephropathy Pathogenesis

• Latency in renal tubular cells uroepithelium
• - immunosuppression
• Viral reactivation(decoy cells, viruria)
• - tubular injury
• - ?other factors (host, viral)
• BKV nephropathy
• - interstitial nephritis
• - acute tubular injury/necrosis

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BKV nephropathy Clinical Features

• Late complication (median onset 9 mo. post-tx)
• Not associated with extra-renal signs or symptoms
• Most patients have a history of rejection
• Most common presentations
• - failure to respond to anti-rejection therapy
• - unexplained renal dysfunction
• High rate of graft loss (50)

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BKV nephropathy Diagnosis

• Non-invasive (presumptive)
• urine cytology (decoy cells)
• PCR (urine, blood)--DNA or mRNA
• EM (urine)
• Invasive (definitive)
• biopsy (can be focal sampling error)
• - inclusions
• - immunocytochemistry with commercial antibodies
  (JC, BK, and SV40 will be positive)
• - in situ hybridization
• - PCR

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BKV nephropathy Treatment

• Non-standardized, no controlled trials
• Increased immunosuppression progressive renal
  dysfunction/graft loss
• Reduce and/or modify immunosuppression
• - stabilization of renal function
• - can precipitate rejection (especially dual tx
  recipients)
• - poor long term outcome (chronic allograft
  nephropathy)
• ?antiviral therapy (eg. cidofovir, leflunomide,
  IVIG)

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Case pneumonia 6 yr s/p kidney tx

• A 58 yo woman who is 6 yr s/p a renal tx
  (idiopathic GN) presents to clinic in January for
  evaluation of a cough and low grade fever. The
  illness began 5 d earlier with the sudden onset
  of myalgias, fever, and nasal congestion. Over
  the last day, he has developed productive cough
  and mild R-sided chest pain.
• PE ill-appearing, T 38.2, BP 158/92, HR 100, RR
  20, mild pharyngeal erythema, decreased breath
  sounds and crackles R lower lung fields.
• Labs WBC 16,000 (90 PMN), Creat 1.5 (at
  baseline), lytes and LFTs normal, CXR as shown

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Case Pleuritic chest pain in a kidney tx
recipient

• A 52 yo Phillipino man presents to clinic for
  evaluation of pleuritic chest pain and diarrhea.
  He received a cadaveric renal transplant 1 yr
  earlier. About 2 months earlier, he
  self-discontinued all immunosuppressive meds
  before leaving for a mong long rip to the
  Phillipines. Two weeks PTA, he received pulse
  steroids and ATG for severe rejection. He now
  presents with fever, mild cough and pleuritic
  chest pain.
• PE cushingoid, febrile, o/w unremarkable
• Labs Creat 3.5, WBC 5.0, LFTs normal
• Chest CT shown

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cont. pleuritic chest pain and cavitary lung
lesion in a kidney tx recipient

• Differential Diagnosis?
• Diagnostic w/u?
• General treatment principles?

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