CASE REPORT: AN EXAMPLE OF COW'S MILK–INDUCED ENTEROCOLITIS
The patient was a full-term male infant who was initially fed with a cow's milk–based formula. Between 7 and 14 days of age, progressive vomiting developed, with heme-positive diarrhea, and subsequent lethargy. He was admitted for a full sepsis evaluation (negative), and the symptoms resolved after he underwent intravenous hydration. He was discharged from the hospital with a soybean-based formula that was tolerated in the hospital. Because of mild symptoms of colic, at 8 weeks of age the formula was switched to a casein hydrolysate. Two hours after a first feeding of this formula, protracted vomiting occurred, and the soybean-based formula was therefore resumed. Accidental ingestion of a small amount of cow's milk at 5 months of age resulted in protracted vomiting (1 hour later), diarrhea (6 hours later), and acidemia and cyanosis requiring hospital admission. Milder symptoms occurred after ingestion of a tiny amount of cheese at 11 months of age.
The patient successfully avoided cow's milk from 11 months to 6 years of age. Results of prick skin tests and radioallergosorbent test (RAST) for cow's milk were negative. He was admitted to the hospital, and intravenous access was obtained. He received 1 oz (approximately 0.06 g/kg) of cow's milk protein in a single-blind challenge. He was without symptoms until 90 minutes after the ingestion, when abdominal pain and repetitive vomiting began and continued for 3 hours. At that time the peripheral blood PMN leukocyte count (including immature forms) had increased by 14,713 cells/mm3. There were no skin or respiratory symptoms. The diastolic blood pressure decreased by 10 mmHg. He was treated with intravenous fluids and then intravenous steroids. Symptoms resolved, and he was discharged home. Loose stools were noted the next day.
To summarize the observations of Powell (11,12,16), infantile FPIES is a severe syndrome of vomiting and diarrhea caused by milk and/or soy in infants. Confirmation of the allergy includes a negative search for other causes, improvement when not ingesting the causal protein, and a positive response to oral challenge, as described. Infants with symptoms consistent with severe enterocolitis who fulfilled, or are highly likely to have fulfilled, these criteria are included in many reports of milk or soy allergy of infancy (17–24). Some additional information about the clinical characteristics of these infants has emerged (Table 3). In a review of 17 infants admitted to hospitals with FPIES, Murray and Christie (25) reported six infants with acidemia (mean pH 7.03) and methemoglobinemia. It was hypothesized that this resulted from increased heme oxidation caused by an elevation of nitrites in the intestine. This elevation of nitrites can occur with severe intestinal inflammation, resulting in reduced catalase activity. The association of methemoglobinemia with FPIES was noted in the current case report and in our published experience with FPIES (13).
Several other clinical features of infantile FPIES have emerged from our studies (13) (16 patients) and a study by Burks et al. (24) (43 patients). All the infants studied had negative skin-prick and/or RAST responses to the causal proteins (cow's milk and/or soy). Approximately half the infants reacted to both milk and soy. Sensitivity to milk was lost in 60% and to soy in 25% of the patients after 2 years from the time of initial occurrence. Lastly, while Powell challenged with approximately 0.6 g protein/kg body weight, in children with severe prior reactions as described in the current case report, lower doses may be adequate (0.06–0.6 g/kg)
Powell noted (12) that her strict challenge criteria for infantile FPIES would potentially exclude some patients who might have a similar or identical clinical manifestation or underlying pathophysiology but with differences in particular specific features or severity. Additionally, some patients who fulfill the challenge criteria may have particular features that do not satisfy the general description of infantile FPIES (13) : reactions to foods other than cow's milk or soy, onset of symptoms beyond 9 months of age, and development or presence of IgE antibody directed toward the causal protein. For example, symptoms consistent with FPIES in infants have been described with foods including rice (26), poultry (13,27), fish (28), and pea (13). Similar to the the patient described earlier, some patients with FPIES have experienced reactions to the residual protein in hydrolyzed cow's milk formula (13,29). Onset of FPIES outside of infancy may also occur (13). Lastly, we (13) have noted two patients who had typical infantile FPIES with negative skin-prick and RAST test results in whom positive test results were obtained 1 and 3 years after the diagnosis. In addition, three patients with positive skin-prick responses and RAST results to soybean (ages 7 months, 1 year, 9 years) showed only symptoms consistent with FPIES when orally challenged with soy. All five of these patients who eventually showed or had shown IgE antibody to the causal protein remained sensitive.
DIAGNOSIS AND MANAGEMENT
As noted, the diagnosis rests on clinical and challenge criteria. In practicality, many patients would not undergo a formal challenge as infants because the diagnosis becomes self-evident after elimination of the causal protein. Unfortunately, this has been a hindrance to better studies of this syndrome. For treatment, as noted earlier, most infants do well consuming a casein hydrolysate formula. Because there is a high percentage of patients with sensitivity to both cow's milk and soy, switching directly to a hydrolysate is recommended. For the rare patients reactive to hydrolysate, an amino acid–based formula is appropriate (29). Families must be instructed about the careful avoidance of cow's milk or soy. Lists containing code words indicating cow's milk protein (i.e., casein, whey, natural flavoring, and others), and soy should be provided.
Follow-up challenges should be performed at intervals to determine tolerance (approximately every 18–24 months, depending on the clinical severity). These challenges should be performed under a physician's supervision with emergency medications immediately available, because dramatic reactions, including shock, can occur. Re-evaluation for development of antigen-specific IgE antibody may be helpful (13). Our (13) experience has been that approximately half of positive challenges require treatment (usually intravenous fluids). Because of the presumed pathophysiology, corticosteroids have been administered for severe reactions. The role of epinephrine for treatment is not known, but it should be available for severe cardiovascular reactions.
Unfortunately, because infantile FPIES is a diagnosis that can be made clinically, there are no series in which biopsies have been performed solely in patients fulfilling Powell's criteria. Thus, specific descriptions of the histologic findings are not available, and only assumptions can be drawn by considering descriptions from case reports or series that probably included these patients. The findings from endoscopy and biopsy in FPIES are nonspecific. Colonic specimens in symptomatic patients reveal crypt abscesses and a diffuse inflammatory cell infiltrate with prominent plasma cells, and small bowel specimens reveal edema, acute inflammation and mild villus injury (15,30–33). In some cases, focal erosive gastritis and esophagitis are found, with prominent eosinophilia and villus atrophy (31,34,35).
Van Sickle et al. (36) studied patients fulfilling Powell's strict criteria for FPIES and noted that in vitro stimulation of peripheral blood mononuclear cells with the causal antigen resulted in greater cell proliferation than in children with negative challenges. Also, an increase in serum antigen-specific IgA has been noted in these patients (37). The pathophysiologic ramifications and clinical implications of these findings remain unanswered. In other studies in patients who may have fulfilled the criteria for FPIES, a number of interesting observations have been made. Morphologic studies of the intestine show an increase of IgG-and IgM-containing plasmocytes, as well as an increase of intraepithelial lymphocytes (21). However, the presence of plasmocytes may be the result of a nonspecific immune response caused by an increased passage of antigen through the gut mucosa. The immune response to antigen in the gastrointestinal tract may primarily involve T cells. Cytokines secreted by activated T cells significantly influence the integrity of the mucosal barrier of the gut on exposure to the antigen. Heyman et al. (22) demonstrated that tumor necrosis factor (TNF)-α secreted by circulating milk protein-specific T cells increased intestinal permeability, thus contributing to the influx of antigen into the submucosa with further activation of antigen-specific lymphocytes. Fecal TNF-α was also found in increased concentrations after positive milk challenge in patients with enterocolitis (38). Benlounes et al. (23) showed that significantly lower doses of intact cow's milk protein stimulates TNF-α secretion from peripheral blood mononuclear cells of patients with active intestinal CMA, compared with patients whose sensitivity resolved or with those with skin, rather than intestinal, manifestations of cow's milk hypersensitivity. Interferon (IFN)-γ significantly enhances the action of TNF-α on intestinal epithelial cells, and interleukin (IL)-4 has been determined to have a similar effect on the gut mucosa (39). Conversely, transforming growth factor (TGF)-β1 protects the epithelial barrier of the gut from the penetration of foreign antigens by preventing the detrimental action of IFN-γ(40).
THE SYNDROME IN PERSPECTIVE
As has been described, infantile FPIES appears as a particularly severe gastrointestinal reaction to milk or soy protein. However, FPIES is also part of a clinical spectrum of non–IgE-mediated gastrointestinal food-allergic disorders. It may simply represent a more severe, generalized form of food-associated enteropathy, (14,23,41) proctocolitis, (31,42) or an earlier occurrence of eosinophilic gastroenteritis, (43) or it may be a distinct pathologic entity. The relationship of atypical FPIES to these food-allergic disorders remains to be clarified. It may be that older patients, even adults, with, for example, shellfish-induced vomiting and diarrhea in the absence of specific IgE antibody have a form of FPIES with a pathophysiologic basis similar to that of the infantile form. Clearly, further study (including histologic and immunologic correlates, and long-term clinical follow-up) of this and the other IgE and non–IgE-mediated food-allergic disorders affecting the gut is needed.
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