Case Presentation: A 41-year-old female with a history of orthotopic liver transplant for cirrhosis from non-alcoholic fatty liver disease presented with 1 week of fevers. Her liver transplant was 3 years prior to presentation. She reported a 3-month history of diarrhea and odynophagia preceding the onset of fevers (maximum 38.8 C).On presentation, initial vital signs and physical exam were unremarkable. Her basic lab work showed new leukopenia. An extensive infectious workup was notable for negative bacterial and fungal blood cultures, negative serum viral studies, negative viral hepatitis serologies, and negative infectious stool studies. CT chest, abdomen, and pelvis were largely unremarkable. Liver doppler showed stable restrictive indices in the transplant arteries. She developed glossitis, mucositis, and a painful erythematous rash on her trunk and palms. Punch biopsy of the rash showed vacuolar interface changes with ballooning keratinocyte degeneration. Biopsy of the sigmoid colon showed mild crypt apoptotic activity with immune cell depletion in the lamina propria. Viral stains from both biopsies were negative and pathologic findings were suggestive of graft versus host disease. Unfortunately, despite the use of high dose steroids, she clinically deteriorated and expired from multiorgan failure and sepsis.

Discussion: Graft versus host disease (GVHD) is a rare complication of solid organ transplant associated with greater than 80% mortality. The most common presenting symptoms are fever, pancytopenia, maculopapular rash of the trunk and the palms, mucositis, and diarrhea. Typically, symptoms begin to present 2-8 weeks post-transplant, although there have been very rare reports of late onset GVHD up to 5 years after transplantation (such as in this patient). Histopathology from skin biopsies classically show vacuolar alteration at the epidermal junction and apoptosis of keratinocytes in the epidermis. Intestinal biopsies in patients with GVHD demonstrate increased crypt epithelial apoptosis and neutrophilic infiltration. Although not performed in our patient, chimerism analysis can be helpful in establishing the diagnosis and results that exhibit donor lymphocyte macrochimerism in recipient tissues should be considered diagnostic of GVHD. The diagnosis of GVHD after solid organ transplantation is difficult to establish and requires a high degree of suspicion, as the presenting symptoms are nonspecific and can mimic other conditions (viral infections, drug reactions). There is no standard treatment for this rare complication of liver transplant, though strategies include decreasing immunosuppression to promote recipient immunity or, conversely, increasing immunosuppression to suppress alloreactive donor cells using high dose corticosteroids, antimetabolites, or cytokine inhibitors. Despite these treatment options, GVHD mortality remains high, with most patients developing fatal complications such as disseminated infections and multiorgan failure.

Conclusions: Although uncommon, GVHD in solid organ transplant recipients usually presents 2-8 weeks post-transplant. Delayed GVHD is more rare, with only a few cases having ever been described in the literature. General internists should maintain a high level of suspicion for GVHD in any solid organ transplant recipient with fever, skin rash, and diarrhea because timely recognition and proper management may prevent morbidity and mortality in this vulnerable population.

IMAGE 1: Painful glossitis and mucositis that patient developed during hospitalization

IMAGE 2: Histopathology from punch biopsy of skin rash showing subepidermal vesicle with reticular degeneration of the keratinocytes overlying the blister cavity