ments with Dey Pharmaceutical, has received grant support from Merck and

Foodalle

rgy,anaphylaxis,

derm

atology,anddrugalle

rgySystem FEIA (Phadia, Uppsala, Sweden). The diagnosis of CMA was

made on the basis of a history of symptoms clearly associated with

exposure to milk, a positive oral food challenge, and/or a clear

improvement in eczema or other symptoms with milk avoidance.

IgE-mediated disease was defined as having a skin prick test with a

wheal diameter 3 mm and/or a cm-IgE 0.35 kU/L.The diagnosis of asthma, eczema, or allergic rhinitis was made by

the investigator. These data were collected on all patients from their

initial visit and then updated from their last visit available. Allergy to

Genentech, and is on the speakers bureau for Dey, Merck, and Glaxo. The

rest of the authors have declared that they have no conflict of interest.

Received for publication May 21, 2007; revised August 8, 2007; accepted for

publication August 8, 2007.

Available online October 12, 2007.

Reprint requests: Robert A. Wood, MD, CMSC 1102, Johns Hopkins Hospital,

600 North Wolfe St, Baltimore, MD 21287. E-mail: rwood@jhmi.edu.

0091-6749/$32.00

2007 American Academy of Allergy, Asthma & Immunologydoi:10.1016/j.jaci.2007.08.023

1172The natural history omilk allergy

Justin M. Skripak, MD, Elizabeth C. Matsu

and Robert A. Wood, MD Baltimore, Md

Background: Cows milk allergy (CMA) is the most common

food allergy in infants and young children, affecting 2% to 3%

of the general population. Most studies have shown the

prognosis of developing tolerance to cows milk to be good, with

most outgrowing their allergy by age 3 years.

Objective: To define the natural course of CMA and identify

the factors that best predict outcome in a large referral

population of children with CMA.

Methods: Clinical history, test results, and final outcome were

collected on 807 patients with IgE-mediated CMA. Patients

were considered tolerant after they passed a challenge or

experienced no reactions in the past 12 months and had a cows

milk IgE (cm-IgE) level

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atology,anddrugallergyother foods was defined as having had a clear symptomatic reaction to

the food and/or having had a positive SPT or food-specific IgE level.

The primary outcome of interest was acquisition of oral tolerance.

Oral milk challenges were routinely performed when, in the judgment

of the principal investigator, the patient had at least a 50% chance of

passing the challenge.9 Patients who were not likely to have acquired

tolerance, on the basis of either a history of recent reactions or

elevated cm-IgE levels, typically did not undergo oral challenges,

but continued to be followed.

For this study, several definitions of oral tolerance were used to

estimate a range of incidence rates for oral tolerance. The definitions

of oral tolerance were based on criteria that ranged from most

stringent to least stringent (Table I). During analysis of the data, each

definition was applied to the entire population. Under the most strin-

gent set of criteria (criteria 1), only patients who passed a formal milk

challenge or successfully introduced milk or concentrated milk pro-

ducts at home were considered tolerant. All other patients were con-

sidered to have persistent milk allergy. To take into account the fact

that some patients who had not undergone a milk challenge at home

or in the clinic could have acquired tolerance, a second definition

(criteria 2) of tolerance was also used. Under this second definition,

patients who had a cm-IgE level

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rgyseven percent of clinic challenges were passed, and 24%of home challenges were passed. Three sets of criteriawere created to define the acquisition of milk tolerance.Each set of criteria was applied separately to the entirepopulation (n 5 807). When tolerance was defined usingthe most stringent criteria, as passing a milk challenge, wefound that only 5% outgrew their allergy by age 4 years,21% by age 8 years, 37% by age 12 years, and 55% by age16 years. When tolerance was defined as passing achallenge or a cm-IgE

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atology,anddrugallergymodel, peak cm-IgE was stratified into 3 categories (20 kU/L), and each step upin peak cm-IgE category was associated with a 68%reduction in the likelihood of acquiring oral tolerance(hazard ratio [95% CI], 0.32 [.27-.38]).

DISCUSSION

In this referral population of children with milk allergy,the prognosis for developing tolerance is worse thanpreviously estimated. Using 3 sets of increasingly broadcriteria to define tolerance, incidence rates of tolerance at 4years ranged from

en

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rgydeveloping tolerance. We realize that peak cm-IgE can bean impractical measure because it cannot be applied withthe same confidence to younger children. However, highercm-IgE levels were associated with poorer prognosis atall ages and, even in younger children, the peak cm-IgEcategories can be applied as a best case scenario incounseling families about prognosis. These data are inagreement with several previous studies that support thisassociation between increasing cm-IgE level and worseprognosis.4,5,10,11

The presence of both asthma and allergic rhinitis werealso associated with a lower likelihood of developingtolerance. These factors remained significant even in themultivariate analysis when controlling for peak cm-IgE

level. In previous studies, markers of atopy or IgE-mediated diseasefor example, the presence of urticariaor IgE-sensitization to certain foods such as egghavebeen associated with worse prognosis.6 However, it is im-portant to note that asthma and rhinitis may appear to beassociated with a poorer prognosis because children whoare followed longer are more likely to carry these diagno-ses as well as more likely to have retained milk allergy.

FIG 3. Relationship of peak cm-IgE level to resolution of IgE-

mediated CMA over the period of the first 18 years of life. Patients

were stratified by peak cm-IgE level, and survival curves for each

stratum of peak cm-IgE level were plotted. The number of patients

in each stratum was as follows:

In this population, the presence of other food allergies wasalso associated with a worse prognosis, although thisassociation was not statistically significant. In addition,a worse prognosis was observed among patients whohad ever received formula. However, this associationmay be biased because these data were missing for 20%of the population, and these findings should be confirmedin future studies.

In previous studies, rates of development of tolerancefor IgE-mediated or immediate-onsettype allergy havevaried: 76% by age 3 years,4 74% by age 5 years,6 and22% by age 18 months to 13 years.5 The wide differencesin these rates are likely related most to the population stud-ied, with the study by Host and Halken4 including an un-

significantly worse than what has been previously re-ported. Sensitivity persists into school age and beyond inthe majority of our patients. cm-IgE is highly predictive ofoutcome and should be used in counseling patients onprognosis. Prospective studies are needed to confirm thispotential increasing persistence of CMA.

We thank Elizabeth Johnson, MS, for her review of the statistical

analyses.

REFERENCES

1. Bock SA. Prospective appraisal of complaints of adverse reactions to

foods in children during the first 3 years of life. Pediatrics 1987;79:683-8.

2. Saarinen KM, Juntunen-Backman K, Jarvenpaa AL, Kuitunen P, Lope L,

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atology,anddrugallergyselected group of children with milk allergy, and the studyby Hill et al5 focusing on a referral population more sim-ilar to ours. Most previous studies did not report details oncm-IgE levels, but from the information available, itappears that our population has higher levels on average,with peak cm-IgE levels exceeding 2 kU/L in 80% ofthe population, and exceeding 50 kU/L in 30%. Othermarkers of the high degree of atopy in our population in-clude 91% having at least 1 other food allergy, 49% withasthma, 40% with allergic rhinitis, and 71% with eczema,although these rates of asthma, eczema, and allergicrhinitis are consistent with those found in previousstudies.6,10,12

Although the poor prognosis demonstrated in this studymay be a result of this highly atopic referral population, itmay also be that the character of CMA has changed overtime, and that CMA may now truly be a more persistentdisease. In fact, many of the previous studies in this areaare now nearly 2 decades old. In our clinic population, wecontinue to see an increasing number of children whosemilk allergy persists into school age and even intoadolescence. We speculate that the factors driving therising prevalence of food allergy and other atopic condi-tions may also be contributing to the changing character ofCMA, and potentially other food allergies.

In conclusion, we have found in the largest cohort ofchildren with milk allergy ever reported that the prognosisfor the resolution of IgE-mediated CMA appearsRenlund M, et al. Supplementary feeding in maternity hospitals and the

risk of cows milk allergy: a prospective study of 6209 infants. J Allergy

Clin Immunol 1999;104:457-61.

3. Schrander JJ, van den Bogart JP, Forget PP, Schrander-Stumpel CT,

Kuijten RH, Kester AD. Cows milk protein intolerance in infants under

1 year of age: a prospective epidemiological study. Eur J Pediatr 1993;

152:640-4.

4. Host A, Halken S. A prospective study of cow milk allergy in Danish

infants during the first 3 years of life: clinical course in relation to clinical

and immunological type of hypersensitivity reaction. Allergy 1990;45:

587-96.

5. Hill DJ, Firer MA, Ball G, Hosking CS. Natural history of cows milk

allergy in children: immunological outcome over 2 years. Clin Exp Al-

lergy 1993;23:124-31.

6. Saarinen KM, Pelkonen AS, Makela MJ, Savilahti E. Clinical course and

prognosis of cows milk allergy are dependent on milk-specific IgE sta-

tus. J Allergy Clin Immunol 2005;116:869-75.

7. Bishop JM, Hill DJ, Hosking CS. Natural history of cow milk allergy:

clinical outcome. J Pediatr 1990;116:862-7.

8. Hill DJ, Davidson GP, Cameron DJ, Barnes GL. The spectrum of cows

milk allergy in childhood. Clinical, gastroenterological and immunologi-

cal studies. Acta Paediatr Scand 1979;68:847-52.

9. Perry TT, Matsui EC, Kay Conover-Walker M, Wood RA. The relation-

ship of allergen-specific IgE levels and oral food challenge outcome.

J Allergy Clin Immunol 2004;114:144-9.

10. Sampson HA. Utility of food-specific IgE concentrations in predicting

symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6.

11. Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA. Determina-

tion of food specific IgE levels over time can predict the development of

tolerance in cows milk and hens egg allergy. J Allergy Clin Immunol

2004;114:387-91.

12. Vanto T, Helppila S, Juntunen-Backman K, Kalimo K, Klemola T, Korpela

R, et al. Prediction of the development of tolerance to milk in children with

cows milk hypersensitivity. J Pediatr 2004;144:218-22.

The natural history of IgE-mediated cows milk allergyMethodsStatistical analysis

ResultsStudy populationCMA resolutionPredictors of prognosis

DiscussionReferences