Development of Anaphylaxis to Cow's Milk as Early as the First Week of Orthotopic Liver Transplantation

Introduction

In the last 2 decades, the number of life-threatening type I allergic reactions to food after orthotropic liver transplantation (OLT) has been increasingly reported.^1,2 It is thought that immunosuppressive treatment given to prevent rejection may have a role in the development of allergic reactions in cases that have undergone transplantation. On the other hand, transplant-acquired food allergy (TAFA) is not observed with every organ transplantation. In this respect, transplantation of organs rich in lymphocytes and antigen-presenting cells such as the liver, bone marrow, and small bowel are more frequently associated with TAFA.

Case Report

Maternal liver transplantation was performed to a female patient who was a 9-month old being followed with diagnosis of biliary atresia. Before transplantation, the patient was mainly fed with breastfeeding and occasionally with vegetable soup. The patient was fed by formula 4 times before OLT and had no history of allergic reaction. The patient or her mother was not on a dairy-free diet before transplant. After transplantation, the patient was fed by the parenteral route for 1 week. On the seventh day of transplantation, the patient developed stridor and flushing 10 min after feeding with a cow's milk-based formula. The systolic blood pressure was 95 mmHg. She was treated with 0.01 mg/kg adrenaline intramuscularly. This was the first time for oral feeding after transplantation. Laboratory investigations just after the reaction (AST: 48 U/L, ALT: 78 U/L, GGT: 41 U/L, ALP: 223 U/L, direct bilirubin: 0.20 mg/dL, and total bilirubin: 0.38 mg/dL) were normal. The patient was under methylprednisolone and tacrolimus treatment as the immunosuppressive regimen after transplantation. Serum tacrolimus level, peripheral eosinophilia, serum total IgE, and Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) serology before and after the reaction are summarized in Table 1. Atopic dermatitis, food allergy, and other allergic diseases were not identified either in the personal or in the family history of the infant. She was found sensitized to cow's milk by a skin-prick test (wheal: 3×3 mm) and a radioallergosorbent test (specific IgE level was class II) 6 weeks after the reaction. She was not sensitized to other common food allergens (egg, peanut, and wheat). Cow's milk and dairy products were eliminated from the mother's and the patient's diet; a fully hydrolyzed formula was recommended when the breastfeeding was inadequate. An adrenaline autoinjector (Epipen junior 0.15 mg) was prescribed. The family was informed about the importance of allergen elimination and trained to use adrenaline autoinjector in case of an unexpected anaphylactic reaction. She continues to take methylprednisolone and tacrolimus as immunosuppressive treatment. At the age of 28 months, after 20 months of diet elimination, she developed tolerance to cow's milk.

Discussion

Recently, TAFA has been increasingly reported in patients without an allergy history. The prevalence of liver TAFA (LTAFA) in children under tacrolimus immunosuppression has been reported to be 6%–21%.^3–5 The most frequently noted food allergens with LTAFA are egg, milk, and wheat.^5,6 In the published reports, TAFA was explained by several mechanisms. Passive transfer of donor's lymphocytes sensitized to the food allergen to the recipient is the first mechanism.^7,8 Inhibition of IL-2 secretion from T-helper 1 (Th 1) lymphocytes, which may lead to a shift toward T-helper 2 (Th 2) cells, which are involved in allergic reactions, is the second proposed mechanism.^2,9 Increased intestinal permeability due to immunosuppressive agents mostly by tacrolimus is another probability. ¹⁰ Besides, tacrolimus is more effective on immature cells as in infants. ⁹ Lastly, an EBV infection leading to IL-10 production by B-cell proliferation and polyclonal antibody secretion is suggested as another possibility for TAFA.^11,12

The first reported case of TAFA was a 54 years old cirrhotic patient who had anaphylaxis after eating peanut ice cream in the eighth day of OLT in 1997. ⁷ The donor of this case had also died of peanut anaphylaxis. The authors explained this case by passive transfer of donor's lymphocytes and peanut-specific IgE to the recipient. We believe that the underlying mechanism is different in our case, because we could not demonstrate sensitization to cow's milk in our donor either by serum-specific IgE or the skin-prick test.

TAFA has been increasingly recognized by some authors as an adverse event of tacrolimus therapy. In contrast, cyclosporine-induced acquired allergic reactions have been recognized less commonly. ⁶ Resolution of TAFA after switching therapy from tacrolimus to cyclosporine also supports this issue. ⁶ The time to develop LTAFA under tacrolimus immunosuppression was reported to be between 15 days and 45 months.^6,9 Surprisingly, our case had anaphylaxis on the seventh day of transplantation, which was the shortest period in the published reports without passive transfer of allergy from donor. Tacrolimus is a more-potent immunosuppressive agent than cyclosporine A in inhibition of IL-2 production and in augmenting IL-5 and IL-13 production, which are eosinophil- and IgE-promoting cytokines.^13,14 Also, tacrolimus was shown to inhibit energy production in intestinal mucosa with a disturbed barrier function in a dose- and exposure-dependent manner. ¹⁰ In the study by Gabe et al., ¹⁰ the authors demonstrated that tacrolimus inhibits cellular energy production in humans at clinically relevant doses, which was associated with an increased intestinal permeability, endotoxemia, and an impaired intestinal absorptive capacity within 7 days after liver transplantation. Therefore, tacrolimus may increase antigen uptake and possibility to develop allergy. However, our patient developed anaphylaxis at the first introduction of formula after OLT; therefore, we think that she might have sensitivity to cow's milk before transplantation, although we did not investigate for cow's milk-specific IgE at that time. Perhaps, tacrolimus might have accelerated the development of clinical allergy in our patient as early as 7 days. In addition, other exposures that might alter the immune balance after transplantation, such as infection with CMV or EBV, were not detected by serology.

Atopic susceptibility is another matter in development of LTAFA. Half of the patients who had undergone liver transplantation with TAFA were reported to have a family history of atopy. ⁶ However, our case had no personal or family history of any allergic diseases. IgE levels and peripheral eosinophil counts were reported to increase in TAFA patients after transplantation. ¹⁵ In addition, acute rejection and immune-suppressive drugs such as tacrolimus and cyclosporine may also cause hypereosinophilia and elevated IgE levels.^16,17 In our case, the peripheral eosinophil count increased while serum total IgE level was found normal.

Lastly, in a prospective analysis, Ozbek et al., ⁵ recognized that 4 of their 6 TAFA patients had a current EBV infection and developed hypereosinophilia. In contrast, none of nonfood allergic patients with EBV infection had hypereosinophilia. Therefore, they recommended that children who develop EBV viremia and hypereosinophilia after OLT to be evaluated for possible allergic reactions. Investigation of our case for recent EBV infection was negative.

In conclusion, this is the first case that developed anaphylaxis as early as a week, in which passive transfer of donor specific allergy did not exist. In addition, severe food allergy as anaphylaxis was reported between 10% and 13% in 2 recent pediatric case series after liver transplantation.^4,18 Therefore significant food allergy is not a rare condition in post-transplant children. Therefore, we recommend evaluation of food allergy in all candidates and in their donors before organ transplantation as well as educating care givers to recognize a possible reaction after transplantation.