Life-Threatening Food Allergy in a Child Treated with FK506

Introduced recently for use in the field of liver transplantation, FK506 (tacrolimus) is an immunosuppressive drug that is used in several centers as a first-line drug after liver transplant surgery. It has several advantages over cyclosporine, the most important being that patients treated with it have a lower rate of chronic rejection. Its main toxicities are renal, neurologic, and pancreatic (1). We describe here the case of a child with an atopic background, who developed very severe allergic reactions to cow's milk after liver transplantation. We discuss the role of FK506 in this situation. CASE REPORT The patient was the second daughter of French and American parents. Her mother had had asthma and eczema in childhood. Biliary atresia was diagnosed too late to be resolved with the Kasai procedure. The only treatment was a regimen of liposoluble vitamins, diuretic drugs, and ursodeoxycholic acid. The child was exclusively breast-fed for 3 months. Thereafter, a milk enriched with MCT (a protein hydrolysate, Pregestimil, Mead Johnson) was substituted. The diet was otherwise normal, including the introduction at 4 months of age of cheese, yogurt, and small amounts of nonfermented milk in cakes or in homemade desserts. The patient received at 7 months of age a living-related liver graft from her father. The drugs administered for primary immunosuppression were FK506, prednisone, and azathioprine. She experienced an episode of rejection 2 weeks after transplantation and received three courses of high-dose methylprednisolone, and 8 days of OKT3. She was then treated with ganciclovir for cytomegalovirus infection. She recovered uneventfully. Azathioprine was stopped 2 months after transplantation (at age 9 months), and prednisone tapered to 0.1 mg/kgˆday on alternate days. In accordance with the policy in the transplantation center, after surgery she was put on a diet excluding cow's milk. She was well until she reached 1 year of age, 5 months after transplantation, when she experienced episodes of diarrhea a few days apart and three episodes of severe angioedema and giant urticaria, which responded to high-dose steroids. One week later she was admitted to the intensive care unit for a severe attack of asthma, which responded to salbutamol, steroid drugs, and epinephrine. It was discovered that each episode followed a single ingestion of cow's milk. No other change in the diet or in the environment was evident. Total levels of immunoglobulin E (IgE) were elevated (190 kU/l; normal level for age, <30 kU/l) as were levels of specific IgE antibodies (normal readings for each in a radioallergosorbent [RAST] test <0.4 kU/l) against casein, egg yolk, peanut, and latex, with elevated levels of 210 kU/l, 330 kU/l, 11 kU/l and, 0.6 kU/l, respectively. A milk challenge was performed under medical supervision, and edema appeared around the mouth and extended to the whole face while the child was drinking minute amounts of cow's milk. After the last episode she was given a mixture of amino acids (Neocate, SHS), which she tolerated well. Other nutrients were reintroduced one by one, excluding all those known to be allergenic (fish, fruits). Latex was excluded from the environment. Nevertheless, she was readmitted several times for asthma and required intensive care three times, receiving mechanical ventilation. The triggering allergen was not always discovered but at least once was observed to be cow's milk, accidentally given to the patient by her older sister. No concomitant respiratory infection was present. She also developed severe eczema. Her antiallergic treatment at home was a diet free of cow's milk protein with a daily regimen of prednisone (0.25 mg/kg), increased to 1 or 2 mg/kg at times of crisis and subsequently tapered; ketotifen; sodium cromoglycate; and nebulizations of steroid drugs and salbutamol. Introduction of a protein hydrolysate was not attempted, and at her last visit at age 3.5 years she was receiving Neocate. A regimen of FK506 maintained blood concentrations of between 5 and 7 ng/ml. Liver tests continued normal. DISCUSSION A potent immunosuppressive drug, FK506 is thought to act mainly by inhibiting interleukin (IL)-2 production at the level of gene transcription. It binds to the intracytoplasmic immunophilin FKBP and blocks the calcium-dependent signal-transduction pathway, by inhibiting the phosphatase calcineurin and thus the dephosphorylation and the nuclear translocation of the nuclear factor of activated T cells mandatory for gene activation by IL-2 (2,3). Interleukin-2 is produced by a subset of T lymphocytes, called Th1 in the mouse, which also produce interferon-γ (IFN-γ), whereas IL-4, IL-5, IL-10, and IL-13 are produced by the subset of lymphocytes Th2, which do not secrete IL-2 and IFN-γ. Such a specialization of lymphocytes may exist also in humans. Such immunosuppressive drugs as cyclosporine and FK506 are supposed to act mainly on Th1 cells, whereas allergic reactions involve mainly Th2 cells and the secretion of IL-4 (4,5). Interleukin-4 and IL-13 induce secretion of IgE by promoting the switch of isotypes from immunoglobulin M to IgE on resting B cells, whereas IFN-γ inhibits both IL-4-induced and spontaneous IgE synthesis. Interleukin-4 and IL-10 induce the proliferation of mast cells, and IL-5 promotes the differentiation of eosinophils. Allergen-specific IgE antibodies bind to high-affinity receptors on mast cells and basophils, thus inducing the release of mediators and causing the expression of the allergic reaction (4-6). Severe allergic reactions to cow's milk are not rare in children (7). Such children do not tolerate even small amounts of milk, or the partially hydrolyzed proteins found in breast milk or in fermented products (8,9). Our patient did not have an unusually rich atopic background. She received milk uneventfully and had no allergy before liver transplantation, even at an age when eczema is common. She could, however, have been in a state of relative immune deficiency related to cirrhosis (10). After transplantation she manifested an unusual number of various allergic symptoms of uncommon severity, despite adequate treatment and eviction of potential allergens. We speculate that, in this child, FK506 induced an imbalance between the Th1 and Th2 leucocyte subsets, or in IFN-γ and IL-4 production, with a loss of control of the synthesis of IgE antibodies. FK506 could also have a yet unknown direct inhibitory effect on cytokines other than IL-2 that are involved in the counterregulation of the allergic reaction (for example, IL-8, Il-10, IL-12, and TGF-β). Unfortunately, we were not allowed by the parents to measure the plasma concentrations of cytokines to support this hypothesis. We were tempted to switch this child from FK506 to cyclosporine, but permission was denied by the family.