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Approach to Infection in the Organ Transplant Recipient. Ajit P. Limaye, M.D. University of Washington Seattle, WA. General Concepts. Infection risk assessment PRE -transplant PPD, h/o TB exposure Travel/residence history (endemic mycoses, Strongyloides, T. cruzi) Baseline serologies

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approach to infection in the organ transplant recipient

Approach to Infection in the Organ Transplant Recipient

Ajit P. Limaye, M.D.

University of Washington

Seattle, WA

general concepts
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)
general concepts cont
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.)
prophylaxis
Prophylaxis

CMV: 3 months of antiviral (valganciclovir [valcyte],

valacyclovir [valtrex]) for D+R- 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

evaluation of the patient
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)
evaluation of the patient cont
Evaluation of the Patient (cont.)
  • Early and aggressive diagnostic investigation
    • - adequate tissue
    • - routine “staging”
  • Appropriate notification and coordination with pathology and microbiology laboratories
timetable of infections after organ transplantation
“Timetable” of Infections After Organ Transplantation
  • General guidelines, NOT absolute
  • Epidemiology altered by prophylaxis
  • Unusual timing may be a clue to unusual exposure
slide8

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)
slide9

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)
slide10

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
selected references
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 2007;357(25):2601-14

case fever abdominal pain in a kidney transplant recipient
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 D+R-, EBV+, VZV+, HSV1+/2-

Meds: tacrolimus, MMF, pred, Bactrim, Amlodipine.

PE: T 38.2, tired-appearing, non-focal except mild abdominal tenderness

cont fever abdominal pain in a kidney transplant recipient
cont. Fever & abdominal pain in a kidney transplant recipient
  • Differential diagnosis?
  • What diagnostic testing (labs & other studies) would you order?
  • Treatment? Complications of treatment?
cmv after organ transplantation epidemiology
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
cmv after organ transplantation clinical aspects
CMV After Organ TransplantationClinical 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)
cmv after organ transplantation diagnosis
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
cmv after organ transplantation treatment
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)
cmv after organ transplantation prevention
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)
what s new about cmv
What’s New About CMV?
  • · Changing epidemiology/late disease
  • · Ganciclovir resistance
  • Individualizing/tailoring therapy
  • · Valganciclovir
what s new about cmv changing epidemiology
What’s 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
    • D+R- and patients treated for rejection are at greatest risk
    • implications: education/coordination with referring providers re: diagnosis/testing/treatment
what s new about cmv ganciclovir resistance
What’s New About CMV?Ganciclovir Resistance
  • Newly recognized problem
  • Occurs late, KP and lung recipients at highest risk
  • Almost exclusively in D+R- 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
what s new about cmv individualizing therapy
What’s 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
what s new about cmv individualizing therapy1
What’s 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
what s new about cmv valganciclovir
What’s 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?
slide26

Case: skin lesion in an OLT recipient

It’s Friday 4:00 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 D+R-, EBV+, HSV-, VZV+

Meds: pred, tacrolimus, MMF, valcyte

PE: T-38.4, chronically-ill appearing, skin lesion as shown

case skin lesion in a liver transplant recipient
Case: Skin lesion in a liver transplant recipient

It’s Friday 4:00 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 D+R-, EBV+, HSV-, VZV+

Meds: pred, tacrolimus, MMF, valcyte

PE: T-38.4, chronically-ill appearing, skin lesion as shown

slide29

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?

aspergillosis after organ transplantation epidemiology
Aspergillosis After Organ Transplantation Epidemiology
  • Overall incidence is low (1-5%) and varies significantly according to organ transplanted and center
  • Lungs~ heart/lungs > livers > kidney/pancreas > heart > kidney
  • Sporadic cases and outbreaks have been described (especially in association with hospital construction or renovation)
aspergillosis after organ transplantation epidemiology1
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
aspergillosis after organ transplantation clinical aspects
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
aspergillosis after organ transplantation diagnosis
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
aspergillosis after organ transplantation treatment
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
aspergillosis after organ transplantation prophylaxis
Aspergillosis After Organ Transplantation Prophylaxis
  • Preemptive therapy for documented Aspergillus colonization
  • Targeted prophylaxis
    • History of disease or colonization
what s new about aspergillosis
What’s 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)
slide42
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)
the next appropriate step after clinical management of the patient is
The next appropriate step after clinical management of the patient is:
  • No further steps are necessary
  • Surveillance renal allograft biopsy
  • Increase maintenance immunosuppression
  • Celebrate the fact that Histoplasmosis was diagnosed and appropriately treated
  • Evaluate for donor-transmitted infection
next steps in the investigation
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)
slide46

Olympia, WA

Vaughn, MT

Eugene, OR

Seattle, WA

Portland, OR

Kansas City, KS

difficulties in recognizing organ transmitted infections
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
slide49

Washington Post

July 2, 2004

The Boston HeraldMay 23, 2005

Transplant shock as 3 die from hamster virus; Victims include 2 from Bay State

slide50
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
limitations of current system
Limitations of current “system”
  • Voluntary reporting
  • Lack of a centralized database (all via regional OPO’s)
  • No repository for isolates from suspected cases
  • Limited donor screening
    • blood donor screening >> organ donor screening
slide53

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 D+R-, EBV-, HSV-, VZV+

PE: 38.4, tenderness over lower spine.

Labs: nothing exciting

cont back pain in a liver transplant recipient
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?
post transplant lymphoproliferative disorder ptld epidemiology
Post-transplant Lymphoproliferative Disorder (PTLD): Epidemiology
  • Incidence varies with type of organ transplanted (heart/lung ~ small bowel > lung > liver > kidney)
  • Closely linked to EBV
  • Risk factors include:
    • EBV seronegativity,
    • CMV mismatch (i.e., D+R-), and
    • anti-lymphocyte antibodies
ptld clinical aspects
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)
post transplant lymphoproliferative disease ptld diagnosis
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)
post transplant lymphoproliferative disease ptld treatment
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
slide62

45 yo man undergoes KP tx, immuno=OKT3 + FK/MMF/Pred

1 & 6 mo Biopsy-confirmed rejection episodes, solumedrol

post-tx pulses. Baseline creat ~1.5

14 mo Elevated creat=2, 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

Immunosuppression 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

slide67

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)
slide68
hematogenous

dissemination

Primary infection Kidney & Urothelium (latency)

(respiratory route) (Chesters P et al. JID 1983;147:676)

Immunocompetent

- asymptomatic, transient shedding

- prevalence depends on sensitivity of assay

Immunocompromised

- persistent shedding, occasional disease

- frequency, extent, and duration >> immunocompetent

slide69

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)
slide70

Incidence & Timing of BKVN

Hirsch et al. NEJM 2002;347(7):488

  • Prospective study of 78 K tx recipients (Basel, Switzerland)
  • FK/Aza/Pred (47%), Csp/MMF/Pred (53%)

ManifestationIncidenceMedian Onset

Decoy cells 23 (30%) 16 (2-69 wks)

BK viremia 10 (13%) 23 (4-73 wks)

BKVN 5 (8%) 28 (8-86 wks)

bkv nephropathy pathogenesis
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

slide73

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%)
slide74

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
slide75

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)
case pneumonia 6 yr s p kidney tx
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 LFT’s normal, CXR as shown

case pleuritic chest pain in a kidney tx recipient
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, LFT’s normal

Chest CT shown

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

Differential Diagnosis?

Diagnostic w/u?

General treatment principles?