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

Vaccination review

Infection history (recurrent Staph, etc)

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

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

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.)

Early and aggressive diagnostic investigation- adequate tissue- routine “staging”

Appropriate notification and coordination with pathology and microbiology laboratories

“Timetable” of Infections After Organ Transplantation

General guidelines, NOT absolute

Epidemiology altered by prophylaxis

Unusual timing may be a clue to unusual exposure

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)

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)

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

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

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

• Differential diagnosis?

• What diagnostic testing (labs & other studies) would you order?

• Treatment? Complications of treatment?

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

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 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 PCR3. buffy coat viral culture

Demonstration of CMV by histopathology and/or culture from affected site is the “gold standard” for diagnosis

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 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?

Changing epidemiology/late disease

Ganciclovir resistance

Individualizing/tailoring therapy

Valganciclovir

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

• 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

• 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 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

• 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?

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

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

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

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 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

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

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

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

Preemptive therapy for documented Aspergillus colonization

Targeted prophylaxis History of disease or colonization

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)

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:

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

Seattle, WA

Vaughn, MT

Histoplasma capsulatum Endemic Areas, U.S.

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)

Kansas City, KSKansas City, KS

Seattle, WA

Portland, ORVaughn, MT

Olympia, WA

Eugene, OR

Limaye et al N Engl J Med 2000

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

The Boston Herald May 23, 2005

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

Washington PostJuly 2, 2004

• 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”

• 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

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

• What is the differential diagnosis?

• What is he at high risk for?

• What work-up would you do?

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

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

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

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

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

1 & 6 mo Biopsy-confirmed rejection episodes, solumedrolpost-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 begunpost-tx

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)

hematogenousdissemination

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

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)

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%)

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)

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

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%)

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

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

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

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

Differential Diagnosis?

Diagnostic w/u?

General treatment principles?