Pulmonary Allograft Versus Host Disease.

Graft-versus-host disease (GVHD) is an uncommon phenomenon in solid-organ transplant (SOT) recipients, first reported in a liver transplant patient in 1988.[1] GVHD associated with lung transplantation is particularly rare and associated with poor outcomes, with mortality rates in the published literature exceeding 80%.[2-12]

CASE DESCRIPTION

A 52-year-old woman underwent bilateral lung transplantation for rheumatoid arthritis–associated interstitial lung disease. Her pretransplant course was notable for immunosuppressive therapy for rheumatoid arthritis with adalimumab, azathioprine, and prednisone. She exhibited extensive pretransplant allosensitization, including 3 low-intensity donor-specific antihuman leukocyte antigen antibodies predicted to react with the allograft, as well as a positive flow cytometric crossmatch at the time of transplant. As a result, her posttransplant induction immunosuppression included rabbit antithymocyte globulin (ATG), plasmapheresis, intravenous (IV) immunoglobulin, and rituximab. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF), prednisone, and monthly IV immunoglobulin. Antimicrobial prophylaxis included atovaquone, valganciclovir, and posaconazole. She was discharged from the hospital on posttransplant day 25.

She was rehospitalized on posttransplant day 41 with fever, shortness of breath, and cough. Extensive evaluation revealed no evidence of infection or allograft rejection. Leukopenia developed and persisted despite stopping mycophenolate and valganciclovir.

On posttransplant day 62, while still hospitalized, she developed an erythematous maculopapular rash predominantly on the palms, soles, flanks and abdomen (Figure 1). Skin biopsy revealed interface dermatitis with perivascular and interstitial inflammation with rare eosinophils. She simultaneously developed an elevated serum alkaline phosphatase, transaminitis, and conjugated hyperbilirubinemia with total bilirubin peaking at 17 mg/dL. Ultrasound and magnetic resonance imaging of the liver were unremarkable. Transjugular liver biopsy revealed patchy nonzonal hepatocellular necrosis with focal bile duct injury, no cholestasis or portal inflammation, and negative viral studies.

FIGURE 1

A macular rash on bilateral soles.

On posttransplant day 76, a peripheral blood short tandem repeat (STR) study revealed that 58.1% of her circulating lymphocytes were derived from the lung allograft donor. A diagnosis of acute GVHD was made, and she was treated with high-dose corticosteroid therapy (methylprednisolone 500 mg IV daily for 3 days, followed by prednisone 40 mg daily for 1 month) with rapid resolution of her symptoms and laboratory abnormalities (Figure 2). Prednisone was tapered over the next 3 months to 10 mg/day, tacrolimus was continued and mycophenolate was not restarted. A repeat STR study 11 months posttransplant showed 1.1% circulating donor-derived lymphocytes. She remains well, without recurrent GVHD, 24 months after transplant.

FIGURE 2

Bilirubin trend posttransplantation. Arrow indicates initiation of high dose corticosteroids (posttransplant day 80).

DISCUSSION

The requirements for developing GVHD described by Billingham in 1966 include the following: a graft must contain immunologically competent cells, the recipient must express tissue antigens not present in the donor, and the recipient must be incapable of mounting an effective immune response to destroy the transplanted cells.[13] The pathophysiology of GVHD involves allorecognition by passenger T lymphocytes from the allograft, leading to activation of these donor lymphocytes which then injure recipient tissues, often with skin, liver, or gastrointestinal tract involvement.[14] Among SOT recipients, small bowel recipients have the highest risk of GVHD, with an incidence of approximately 5% to 10%.[15] By comparison, GVHD in lung transplant recipients is extremely rare, with a literature search revealing only 8 previously reported cases in lung recipients and 6 additional cases after combined heart-lung transplantation.

Donor cells can be detected in the blood and tissue of allograft recipients years after SOT.[16] This chimeric state between recipient and donor leukocytes has been postulated to mitigate rejection by establishing a state of hyporeactivity against or tolerance to the transplanted organ.[17] However, when a high fraction of allogeneic donor lymphocytes are persistently present, acute GVHD can develop.[18] In our patient, we postulate that aggressive immunosuppression, both before and immediately after transplantation, may have allowed the engraftment of passenger lymphocytes and the development of GVHD. Another potential risk factor includes the age of the donor and recipient; in the liver transplant population, older recipients matched with younger donors are at higher risk for GVHD.[19] Notably, our recipient was 52 years old, whereas the donor was 27 years old.

Clinical manifestations of GVHD after SOT include fever, skin rash, diarrhea, liver function abnormalities, and bone marrow suppression.[1] Given that these nonspecific symptoms are commonly encountered in SOT recipients due to infection or medication side effects, the diagnosis of GVHD requires a high index of suspicion. STR-based chimerism assays of peripheral blood, in conjunction with a clinical syndrome consistent with GVHD, have generally been used to confirm the diagnosis of GVHD in SOT recipients.[20]

There is no consensus on treatment for GVHD after SOT. In case reports, therapy has been extrapolated from acute GVHD in hematopoietic stem cell transplant recipients, where corticosteroids are the first-line therapy. Still, 50% of hematopoietic stem cell transplant GVHD cases may be refractory to steroids[21] and alternative therapies including ATG,[22] alemtuzumab,[23] anti-interleukin 2 agents,[24] anti-TNF antibodies,[25] extracorporeal photopheresis,[26] MMF,[27] and sirolimus,[28] have been explored. One alternative approach to management of SOT GVHD, was attempted by Chinnakotla and colleagues[29] who withdrew immunosuppression in three cases of GVHD after liver transplantation. The rationale for this approach was to promote the recovery of the recipient immune system, thereby allowing recipient immune cells to clear the injurious donor lymphocytes. In this series, 2 of the 3 patients recovered rapidly, whereas the third patient progressed to severe GVHD and died. Given the markedly different and conflicting strategies for treating GVHD after SOT, more studies are needed to clarify the optimal approach.

To better understand GVHD after lung transplantation, we conducted a literature search and identified 11 publications documenting 14 cases of GVHD after lung transplantation. In this population, GVHD was associated with a high mortality rate, with only 2 of 14 previously reported cases surviving (Table 1). In most cases, as in the case presented here, there was a delay in diagnosis, with the presenting symptoms of rash, transaminitis, or leukopenia initially attributed to drug reaction. This frequent delay in diagnosis may contribute to the observed mortality. In the previously reported cases, many patients died of complications from marrow failure, presumably a result of progressive GVHD despite aggressive immunosuppressive therapy.

TABLE 1

Reported cases of GVHD after lung transplantation with diagnosis, treatment and outcomes

GVHD is an extremely rare and often fatal complication of lung transplantation. Diagnosis is challenging because the clinical findings often mimic those of more common infectious and pharmacologic complications in the posttransplant period. Palmoplantar involvement of rash can be suggestive of a diagnosis of GVHD, but is not pathognomonic. A chimerism study can aid in identifying a suspected case of GVHD by detecting an elevated percentage of circulating donor lymphocytes.