Refractory Graft Versus Host Disease After Pediatric Intestinal Transplantation—Beware of Pre-Existing Immunodeficiency

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Graft versus host disease (GVHD) has been reported in 8% to 10% of children after small bowel transplantation (SBTx) (1). A favorable outcome has been reported after treatment with high dose steroids. We describe an aggressive steroid-resistant fatal episode of GVHD in a child post-SBTx who had underlying subtle, uncharacterized immunodeficiency. A child with gastroschisis and short bowel syndrome on long-term parenteral nutrition developed secretory diarrhea, poor enteral feed tolerance, and protein losing enteropathy with hypoalbuminaemia and hypogammaglobulinaemia (low IgG with low levels of IgG antibodies to tetanus and diphtheria) which persisted throughout infancy. He had thrombosis of major vessels within his neck and was assessed for isolated SBTx (ISBTx). During the transplant assessment in addition to hypogammaglobulinemia, he was noted to have persistent T-cell lymphopaenia, with normal B and natural killer cell numbers. There was a normal response to phytohemagglutinin, pokeweed mitogen, and OKT3 stimulation. Chronic granulomatous disease was excluded. Apart from catheter related blood stream infection, the child did not have any other systemic life threatening infections. Despite extensive investigations his underlying immunodeficiency remained poorly defined and was not considered to be severe enough to preclude him from SBTx. He received an ISBTx with basiliximab induction (days 0, 4) and maintenance immunosuppression with FK506 (Tacrolimus) and prednisolone. The immediate posttransplant course was uneventful, with enteral feeds established within 3 weeks and no evidence of acute rejection or viral infection. His lymphocyte subset monitoring by flow cytometry, demonstrated persistent T-cell lymphopenia over the first 3 months post-ISBTx. Two and half months after ISBTx he developed abnormal liver function tests which were thought to be owing to an intercurrent viral infection. Two weeks later he developed a pruritic, erythematous maculopapular rash on the soles and palms consistent with GVHD. Biopsies of skin, native liver, and native gastrointestinal tract also demonstrated histological evidence of GVHD. The skin rash initially responded partially to high dose parenteral steroids followed by tapering of steroids and maintenance oral prednisolone. After reduction of oral steroids, the rash reappeared being refractory to high dose steroids, and he received a regime of Daclizumab (interleukin-2 receptor [CD25] monoclonal antibody) and Infliximab (anti- tumor necrosis factor-α monoclonal antibody) but without any improvement. The rash progressed with widespread blistering and desquamation affecting the entire body surface. He developed left sided ptosis and bulbar palsy secondary to a cerebellar abscess, and the family opted for palliative care, and he died at 5 months post-ISBTx. Our case highlights the aggressive steroid-resistant nature of GVHD in a child with a uncharacterized pre-existing immunodeficiency state. There are different approaches to the treatment of steroid resistant GVHD. One treatment approach is directly cytotoxic to the effector cells (Thymoglobulin, OKT3, sirolimus, so forth) of GVHD and the other option is to block cytokines involved in the pathogenesis of GVHD (antibodies against tumor necrosis factor and interleukin-2 antagonist) (2–4). Intestinal transplant children have a high risk of opportunistic infection and hence we chose the second option. Based on our experience we would like to make the following recommendations: (i) A high index of clinical suspicion with abnormal liver function tests even in the absence of rash in ISBTx should alert the clinician to the possibility of GVHD; (ii) every effort should be made to characterize the pre-existing immunodeficiency; (iii) early removal of graft in children with acute steroid resistant GVHD is an option in isolated intestinal transplantation; (iv) the potential use of a mature T-lymphocyte blocking agent should be considered in the primary induction regime of such patients, although it is entirely probable that the onset of GVHD may be delayed rather than prevented. James Davison Sue V. Beath Deirdre A. Kelly Girish L. Gupte Liver Unit (including small bowel transplantation)