Gross endoscopic findings in the infants with AC included diffuse erythema, friability, LNH and/or punctate ulcerations in 12 infants and normal appearing mucosa in 2 infants. Endoscopic findings in infants with histologically normal biopsies included erythema, ulceration and/or LNH in 2 and normal mucosa in 3. All infants with nonspecific colitis on initial biopsy had evidence of erythema, friability, ulceration and/or LNH. Our results suggest that endoscopic findings alone are not specific for AC.
One initially recruited subject was found to have Aeromonas infection by stool culture and was excluded from the study. No subject was anemic. Mean serum eosinophil counts in the infants with AC were 0.88 + 1.15 103/mm3 compared with 0.17 + 0.11 103/mm3 in infants with normal histology (P = 0.04) (Fig. 2, A). The mean serum IgE level in infants with AC was 7.48 U/mL and 0.79 U/mL in normal biopsy infants. These means were statistically different after log transformation. The mean natural log of the serum IgE level was 1.33 + 1.22 in infants with AC and −0.35 + 0.60 (P = 0.01) in normal biopsy infants (Fig. 2, B). Serum eosinophil counts and natural-log IgE could not be used to discriminate between infants with AC and normal biopsies.
Resolution of Bleeding
Seven of 14 infants with AC were initially formula-fed and underwent dietary change to PHF. One of these was also breast-feeding, and his mother was instructed to eliminate all cow's milk protein from her diet. Six of these 7 infants consuming PHF were followed through the 9-week study period; one was lost to follow-up after the first week. In those with complete follow-up (6), rectal bleeding resolved in 1.8 weeks (range, 1 to 5 weeks). Of those with a repeat biopsy at week 3, histology was normal (n = 2), improved (n = 1) or unchanged (n = 1); the parents of 2 subjects refused week 3 biopsies. The infant with unchanged histology had persistent rectal bleeding and had a diet change to LAA with resolution of bleeding by week 5 and improvement in histology by the week-6 biopsy.
Seven infants with AC were breast-feeding. One infant initially had normal histology, but was re-biopsied at week 3 because of worsening bleeding. This biopsy revealed AC, and the infant's diet was changed to PHF without subsequent improvement. The week 6 biopsy was unimproved, leading to initiation of LAA formula; bleeding resolved by week 8, and no further biopsies were performed. Of the 6 infants diagnosed with AC at the first biopsy, 1 was lost to follow-up after a week-3 biopsy that showed unchanged histology. Rectal bleeding persisted at week 3; therefore a response to PHF could not be assessed. Of the remaining 5, 2 infants had normal week 3 biopsies, 2 improved and 1 was unchanged. Although 1 of the infants with normal histology at week 3 had persistent rectal bleeding during the duration of the study, the bleeding decreased significantly, so no further dietary changes were made. Of the 5 breast-feeding infants with complete follow-up during the 9-week period and resolution of bleeding, average time to resolution was 5.6 weeks (range, 2 to 8 weeks).
Rectal bleeding resolved in 4 of 5 infants with normal histology in an average of 3.25 weeks (range, 2 to 5 weeks). One infant with normal histology but continued rectal bleeding was lost to follow-up after week 3.
Two of 3 infants with nonspecific colitis had resolution of bleeding by week 5 or 6. The third had a family history of ulcerative colitis (mother) and continued to have persistent bleeding throughout the study. Repeat biopsy off protocol at 8 weeks demonstrated the presence of chronic colitis and cryptitis, and he was subsequently diagnosed with infantile inflammatory bowel disease.
Forty-nine (88%) of 56 Ohio NASPGHAN members responded to our three-question survey of standard practice in diagnosis and treatment of presumed AC. Forty-one of 49 (83.6%) responded that they would empirically treat an infant with rectal bleeding either by changing a formula-fed infant to a hypoallergenic formula or by instructing a breast-feeding mother to eliminate all cow's milk protein from her diet. None of the gastroenterologists surveyed recommended discontinuation of breast-feeding in favor of a hypoallergenic formula as an initial intervention. Four (8.2%) would change a formula-fed infant directly to an LAA rather than PHF. Only 4 (8.2%) would confirm the diagnosis with biopsy before initiating dietary change. Forty-one (84%) of the pediatric gastroenterologists surveyed accepted the histologic definition of AC that we used in our study.
If bleeding continued for longer than 3 weeks after dietary change, 20 (40.8%) would recommend empirically changing a formula-fed infant from a PHF to LAA formula and stopping breast-feeding in favor of a PHF. However, an additional 20 (40.8%) would obtain biopsies before instituting further dietary changes. Eight (16%) would wait a further 4 to 6 weeks before further evaluation or dietary change.
Although AC is believed to be a common cause of rectal bleeding in healthy infants, the lack of a specific, noninvasive test for AC makes it difficult to calculate the true prevalence among healthy infants. The majority of cases are empirically diagnosed and treated. The lack of specific signs and symptoms of AC also complicates diagnosis (11).
The reported prevalence of cow's milk-induced allergy varies widely, ranging from 0.3% to 7.5% of all healthy infants (12, 13). Most prospective studies are limited by referral bias and small size (14, 15). In our cohort, the prevalence of biopsy-proven AC among healthy infants with rectal bleeding was 64%. Although our study is also limited by small size, we recruited subjects from pediatrician's offices, the emergency department and our clinic to minimize referral bias. However, the study design did exclude infants who already had a formula or maternal diet change as a result of the presumptive diagnosis of AC.
AC is thought to be secondary to an allergic reaction to a protein or proteins in the diet. Cow's milk contains many immunogenic proteins, of which beta-lactoglobulin is the most common antigen related to allergy (13). Soy proteins also have antigenic properties (13). It is reported that as many as 30% of patients are allergic to both cow milk and soy protein (12). Breast-feeding does not prevent AC; in our study, half of the subjects with AC were exclusively breast-fed. In breast-fed infants, the colitis presumably results from dietary antigens transmitted through breast milk (7,10,15-17).
Current therapy for infants with AC is the elimination of suspected triggering antigens. As shown by our survey, formula-fed infants typically have are changed to a more expensive PHF or LAA. Not all infants with rectal bleeding have AC, however, and empirically treating all otherwise healthy infants with rectal bleeding as AC may lead to unnecessary and expensive formula changes. In our study, 36% of infants would have had their diet unnecessarily changed. Often these formulas are continued for the entire first year. Although our study was not designed to conduct a cost analysis, our data suggest that considerable cost savings could be achieved by decreasing unnecessary formula changes. In addition, switching to hypoallergenic formulas empirically may encourage the parents to view their child as sick or vulnerable and they may continue unnecessary dietary restrictions later in childhood (18).
In breast-fed infants with rectal bleeding, cow's milk protein is often first eliminated from the maternal diet or the infant's diet is changed to PHF. Elimination of cow's milk proteins from the diet of breast-feeding mothers is challenging and may discourage continued breast-feeding.
Our study confirms that gross endoscopic findings in healthy infants with rectal bleeding are often nonspecific and not helpful in diagnosing AC. LNH has also been described as a sign of food allergy in children (19, 20). However, in our study several infants with LNH but without histologic evidence of AC had spontaneous resolution of bleeding over a period of a few weeks with no dietary change. This suggests that LNH may be a self-limited finding associated with rectal bleeding in otherwise healthy infants. Conversely, we may have missed the diagnosis of AC because of the focal nature of eosinophilic infiltration. AC has been shown to be a very focal disease with variability both within specimens and between specimens taken from different locations in the rectosigmoid colon (10). Thus, despite taking specimens at 5, 10 and 15 cm from the anal verge, there is the possibility that we could have misclassified some cases as normal or nonspecific colitis. However, as bleeding resolved without intervention in the majority of infants with normal mucosa or nonspecific colitis, this suggests that either AC was not missed or was self-limited in some infants.
Mean peripheral blood eosinophil counts and serum IgE were statistically higher in infants with AC, These tests were not useful discriminators between infants with AC and normal histology, however, because of overlap in the ranges (5,9,14,15). Elevation of serum IgE is consistent with observations in atopic variants of other eosinophilic gastrointestinal disorders; however these are thought to be polygenic disorders that involve both IgE-mediated and delayed T helper cell type 2 responses to allergens (21). Likewise, not all cow's milk hypersensitivity in infants is IgE-mediated (22,23). Recent reports have suggested that decreased cow's milk specific IgE levels at time of diagnosis may predict infants that are more likely to develop tolerance to cow's milk in early childhood (24,25).
We found that bleeding resolved with avoidance of cow's milk protein for the majority of infants with AC in an average of 1 to 3 weeks. There was a trend for a longer resolution period in breast-feeding infants. Only 2 infants required a change to an LAA formula because of a lack of response to PHF. In infants without AC, the majority also had resolution of their bleeding without intervention. The only exception was an infant with a maternal history of ulcerative colitis who had continued bleeding throughout the study period leading to re-biopsy at study conclusion and diagnosis of infantile inflammatory bowel disease. This suggests that close follow-up of infants will identify those who fail to respond.
We conclude that the prevalence of AC in our population-based study of healthy infants with rectal bleeding was 64%. Although the confidence interval is wide because of the difficulty in recruiting a larger cohort, these findings suggest that empiric diagnosis of AC in otherwise healthy infants with rectal bleeding may lead to unnecessary and expensive formula changes or changes in maternal diet that may discourage continuation of breast-feeding.
An important question that our study did not address is whether all infants with AC need dietary treatment or whether AC spontaneously resolves in some or all infants. It is possible that the focal nature of eosinophilic infiltration in AC may have led to misclassification of some infants in our study into the normal or nonspecific colitis groups. Resolution of bleeding without intervention occurred in the majority of infants with either normal histology or nonspecific colitis. The benign clinical course of most infants with AC and the spontaneous resolution of bleeding in the majority of infants with normal histology or nonspecific colitis suggest that a larger prospective study of outcome of bleeding without dietary change in otherwise healthy infants with AC might be warranted.
The authors thank Stacy Poe, MS and Judy Bean, PhD for assistance with statistical analysis.
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Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
Allergic colitis; Eosinophilia; Rectal bleeding; Cow's milk protein hypersensitivity; Flexible sigmoidoscopy