Pediatr Allergy Immunol 2002: 13 (Suppl. 15): 2328 Printed in UK.

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Copyright # 2002 Blackwell Munksgaard

Clinical course of cows milk protein allergy/ intolerance and atopic diseases in childhood
Hst A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K. Clinical course of cows milk protein allergy/intolerance and atopic diseases in childhood. Pediatr Allergy Immunol 2002: 13 (Suppl. 15): 2328. # 2002 Blackwell Munksgaard A cohort of 1,749 newborns from the municipality of Odense, born during 1995 at the Odense University Hospital, were followed up prospectively for the development of cows milk protein allergy/intolerance (CMPA/I) during the rst year of life. Once a diagnosis of CMPA/I was conrmed, a milk-free diet was continued until a new milk challenge had shown development of tolerance. All infants with CMPA/I were rechallenged at 12 months of age and, in the event of continued clinical sensitivity to cows milk protein, controlled rechallenges were performed every 6 months up to 3 years of age; and thereafter every 12 months until the age of 15 years. From the same birth cohort, 276 infants were randomly selected at birth for prospective non-interventional follow-up in order to investigate the natural course of sensitization and development of atopic disease during childhood. Standardized questionnaires on atopic heredity, environmental factors and presence of atopic symptoms were answered at 0, 6, 12 and 18 months and at 5, 10 and 15 years of age. Interviews on atopic history and environmental factors as well as physical examination were carried out at 18 months, 5, 10 and 15 years of age. Skin prick test and specic sIgE (Pharmacia CAP) testing were performed at 18 months, 5, 10 and 15 years of age against a panel of inhalant allergens (birch, grass, mugwort, dog, cat, horse, Dermatophagoides pteronyssinus, Dermatophagoides farinae, alternaria and cladosporium herbarum). Furthermore, lung function measurements were performed in children when 10 and 15 years of age. Based on controlled milk elimination and challenge procedures, the diagnosis of CMPA/I was conrmed in 39 out of 117 infants, with symptoms suggestive of CMPA/I, thus resulting in a 1-year incidence of CMPA/I of 2.2%. The overall prognosis of CMPA/I was good, with a total recovery of 56% at 1 year, 77% at 2 years, 87% at 3 years, 92% at 5 and 10 years and 97% at 15 years of age. In children younger than 10 years of age, 41% developed asthma and 31% rhinoconjunctivitis. Children with non-IgE-mediated CMPI had a good prognosis, whereas children with IgE-mediated CMPA in early childhood had a signicantly increased risk for persistent CMPA, development of other food allergies, asthma and rhinoconjunctivitis. During early infancy, recurrent wheezing was the most prevalent disease (20%), followed by atopic dermatitis (14%) and food allergy (7%) at 18 months of age. Physician diagnosed asthma increased from 2% at 1.5 years of age to 9% at 10 years of age. Rhinoconjunctivitis increased from <1% at 1.5 years of age to 9% at 10 years of age. Overall, the current prevalence of any atopic disease was 20% at 1.5 years of age, declining to 14% at 5 years of age and followed by an increase to 25% at 10 years of age. Sensitization to inhalant and/or food allergens (specic IgE of !class 2; CAP RAST) showed a low rate of sensitization among asymptomatics (3%, 10% and 12%) compared with higher rates of sensitization of 8%, 39% and 30% among symptomatic atopics at 1.5, 5 and 10 years of age respectively. The highest rate of sensitization (53%) was found among children with current asthma at 10 years of age. Arne Hst1, Susanne Halken2, Hans P. Jacobsen1, Anne E. Christensen1, Anne M. Herskind1 and Karin Plesner1
Department of Pediatrics, 1Odense University Hospital, Odense, Denmark and 2Snderborg Hospital, Snderborg, Denmark

Key words: atopy; children; cows milk allergy; food allergy; prognosis Arne Hst, Department of Pediatrics, Odense University Hospital, DK-5000 Odense C, Denmark Tel.: 45 6541 2080 Fax: 45 6591 1862 E-mail: [email protected]

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Hst et al. The aims of the present prospective study were to investigate the natural course of cows milk protein allergy/intolerance (CMPA/CMPI), sensitization and atopic diseases in a 1-year birth cohort of unselected Danish children followed up to 15 years of age. From this study population we have previously reported in detail on the incidence and manifestations of CMPA/CMPI in presumably exclusively breast-fed infants (1), and the clinical course of CMPA/CMPI during the rst 3 years of life was described in relation to clinical and immunological types of hypersensitivity reaction (2). Recurrent wheezing in relation to environmental risk factors in infancy has been described in a random sample of 276 children (16%) of the same birth cohort (3). The predictive value of cord-blood immunoglobulin E (IgE), as regards development of atopic disease, has been revealed in three publications (46). Furthermore, from the same birth cohort the development of atopic symptoms in infancy has been described in high-risk infants (7), and clinical, epidemiological and immunological aspects of CMPA/CMPI in this study population have been reviewed and evaluated in relation to other studies on this subject (8).
Materials and methods Cows milk protein allergy and intolerance

A cohort of 1,749 newborns from the municipality of Odense, born during 1985 at the Odense University Hospital, were followed-up prospectively for the development of CMPA/CMPI during their rst year of life. A total of 1,758 infants were born alive, nine died neonatally, and therefore 1,749 were followed up. During the rst year, one infant died and 14 left the municipality, none of whom developed symptoms of CMPA/CMPI. During 1985, 99.2% of the births in Odense took place at the University Hospital. More than 99% of the infants were followed up regularly during the rst year of life by 20 health visitors. The infants were referred to the paediatric clinic at the hospital when one or more of the following symptoms occurred: recurrent wheezing; rhinitis; atopic eczema; urticaria; erythema/exanthema; vomiting and/or diarrhoea not caused by coincidental infections or other demonstrable causes; infantile colic not disappearing after advice on feeding technique; and failure to thrive. This part of the study has been described in detail previously (1,2). The diagnosis of CMPA/CMPI was established by the following, generally accepted, criteria (1,2,8): 24

 a denite disappearance of symptoms after each of two dietary eliminations of cows milk and cows milk products;  recurrence of identical symptoms after one challenge; and  exclusion of lactose intolerance and coincidental infection. All challenges were carried out in the hospital under professional observation. The challenge procedure was open. The results of the rst 10 positive open-milk challenges were conrmed by double-blind placebo-controlled challenge, as described previously (9). Subsequently, all milk challenges performed at intervals of 6 months until 3 years of age were open, and in the event of equivocal results the challenge was repeated in a double-blind placebo-controlled manner (9). Details on elimination and challenge procedures have been described previously (1,2,8,9). Once a diagnosis of CMPA/CMPI was conrmed, the milk-free diet was continued until a new milk challenge had shown development of tolerance to cows milk protein. All infants with conrmed CMPA/CMPI were rechallenged at 12 months of age, and in the event of continued clinical sensitivity to cows milk protein, rechallenges were performed as open challenges, as described above (1,2,9), at 18, 24 and 36 months of age. Up to 3 years of age, all infants with CMPA/CMPI during the rst year of life were investigated every 6 months. Thereafter, rechallenge was performed every 12 months, until the age of 15 years, to assess continued clinical sensitivity. With symptoms suggestive of reactions to other foods, the food in question was eliminated from the diet for 4 weeks, followed by an open controlled challenge (2). With symptoms suggestive of inhalant allergy, a skin-prick test and specic serum IgE (sIgE) test, against a panel of inhalant allergens, was performed (2). Skin-prick testing (2) and specic sIgE testing (Pharmacia CAP RAST; Pharmacia Diagnostics, Sweden) were carried out against inhalant allergens (birch, grass, mugwort, dog, cat, horse, Dermatophagoides pteronyssinus, Dermatophagoides farinae, alternaria and cladosporium herbarum) and food allergens (milk and egg) in all children with CMPA/CMPI during the rst year of life; specic sIgE testing was also carried out in children at 1.5, 3, 5, 10 and 15 years of age. Furthermore, lung function measurements (Vitalograph, Spiropharma, Copenhagen) were performed in children when 10 and 15 years of age.

Cows milk protein allergy/intolerance

From the birth cohort described above, 276 infants were randomly selected at birth for prospective follow-up in order to investigate the natural course of sensitization and development of atopic disease during childhood. Standardized questionnaires on atopic heredity, environmental factors (breast feeding, introduction of solid foods, exposure to tobacco smoke, pets, housing conditions, socio-economic status, and other factors) and presence of atopic symptoms, were answered at 0, 6, 12, and 18 months and at 5, 10, and 15 years of age. Interviews on the same factors, mentioned above, as regards the standardized questionnaire (atopic heredity, environmental factors and atopic symptoms), as well as physical examination, were carried out at 18 months, 5, 10, and 15 years of age. Skin-prick (2) and specic sIgE (Pharmacia CAP) testing were performed in children at 18 months and 5, 10, and 15 years of age to the same panel of inhalant and food allergens described above. At the interviews and clinical examinations at 18 months, 5, 10 and 15 years of age, the childrens individual case history and data were recorded, with special attention given to infections, including respiratory tract infections and symptoms/ signs of possible atopic disease, described in the following.
Diagnostic criteria for atopic diseases

and chronically/relapsing with duration of at least 3 months were recorded. Allergic urticaria. Registered when a physician diagnosed at least two episodes caused by the same allergen. Rhinoconjunctivitis. Registered when a physician diagnosed typical symptoms lasting at least 1 month or recurring on exposure to the same allergen. Gastrointestinal symptoms. Dened as recurrent colic, vomiting and/or diarrhoea after excluding ordinary eating problems, coincidental infections and lactose intolerance. Food allergy/intolerance (FA/FI). Diagnosed by the following generally accepted criteria:  denite disappearance of symptoms after each of two dietary eliminations of the food in question;  recurrence of identical symptoms after one controlled challenge; and  exclusion of other possible non-allergic reactions (e.g. lactose intolerance, coincidental infection). All challenges were performed in hospital under professional observation. The challenge procedure was open, but when equivocal results were recorded, the challenge was repeated in a doubleblind placebo-controlled manner. Social status. Registered according to the social grouping system of the Danish Social Research Institute. This grouping system resulted in ve social classes (IV), according to education and employment on which the family income was gained, with class V being the lowest.
Diagnostic criteria for sensitization

The diagnostic criteria for atopic diseases are given below. Atopic symptoms. Any atopic symptoms were dened as one or more of the following: asthma; atopic dermatitis; allergic rhinoconjunctivitis; food allergy/intolerance; and/or allergic urticaria. Current atopic disease. Dened as manifestations of the disease within the previous 12 months. Asthma. Dened as three or more episodes with expiratory wheezing diagnosed by a physician and requiring treatment with beta-2 agonist and/or inhaled steroids. Recurrent wheezing (wheezy bronchitis). Recorded when the child had a history of a least two physician-diagnosed episodes with expiratory wheezing associated with upper respiratory tract infection requiring bronchodilator treatment. Atopic dermatitis. Diagnosed if physical examination showed areas of scaly, erythematous and itchy eczematous rash primarily of the face and scalp, behind the ears and at the exural folds. Only eczema localized to at least two typical areas

Sensitization was determined by the measurement of specic sIgE (Pharmacia CAP). The cut-off value for class I was 0.35 kU/l and for class 2, 0.70 kU/l.
Ethics

The study was approved by the Ethical Committee of the counties of Funen and Vejle. All the parents were supplied with information orally and in writing, and the patients gave informed consent before their children entered the study.
Statistics

Data management and statistical analyses were performed using the PC programme SPSS, version 10.0 for Windows. For comparison of groups the chi-square test or Fishers exact test was used. All calculations on p-values were based on the 25

Hst et al.
Table 1. Prognosis of cows milk protein allergy/intolerance diagnosed in 39 infants of a 1-year birth cohort comprising 1,749 newborns Age (years) 1 2 3 5 10 15 Recovery 22 30 34 36 36 38 (56%) (77%) (87%) (92%) (92%) (97%) 95% CI 4072% 6189% 7396% 7998% 7998% 87100%

Results are expressed as recovery rate and 95% confidence interval (CI).

Fig. 1. Prospective study of 1-year birth cohort from 1985 in Odense, Denmark. CMP, cows milk protein; CMPA/I, cows milk protein allergy/intolerance. Some 117/1749 (6.7%) had symptoms suggestive of cows milk protein allergy/intolerance (CMPA/I) during the first year of life. Based on controlled milk eliminations and challenge procedure the diagnosis of CMPA/I was confirmed in 39/117, resulting in a 1-year incidence of CMPA/I of 2.2% with 95% confidence interval of 1.52.9%. Nine of 39 infants with CMPA/I were confirmed to react against cows milk protein in human milk, corresponding to 0.5% of the birth cohort (95% confidence interval of 0.20.9%).

Table 2. Prognosis of cows milk protein allergy/intolerance (CMPA/I) up to 10 years of age in 39 infants At follow-up at 10 years of age Persisting CMPA/I Other food allergies Asthma Allergic rhinitis Asthma and allergic rhinitis Asthma or allergic rhinitis 3/39 7/39 16/39 12/39 9/39 19/39 (8%) (18%) (41%) (31%) (23%) (48%)

95% CI 221% 834% 2658% 1748% 1139% 3265%

two-tailed tests, and the p-value of signicance was 0.05.

Results are expressed as current prevalence of atopic diseases and 95% confidence interval (CI).

During the rst year of life, 117 infants (6.7%) of the birth cohort of 1,749 infants had symptoms suggestive of CMPA/CMPI. Based on strict elimination/milk-challenge procedures in a hospital setting, the diagnosis of CMPA/CMPI was conrmed in 39 infants, giving a 1-year incidence of 2.2% (95% condence interval: 1.52.9). Nine of the 39 infants with CMPA/CMPI were conrmed to react to cows milk protein in human milk (Fig. 1). Of the 39 infants with CMPA/CMPI, 21 had IgE-mediated CMPA [positive skin-prick test and/or radioallergosorbent test (RAST) of !class 2 to cows milk protein] and 18 non-IgEmediated CMPI. Most infants had cutaneous symptoms (64%), and gastrointestinal and respiratory symptoms were encountered in 56% and 33%, respectively. Mono-symptomatology (atopic dermatitis) was seen only in three infants (8%) and the majority (72%) had symptoms from two or more organ systems. The overall prognosis of CMPA/CMPI was good, with a total recovery of 56% at 1 year, 77% at 2 years, 87% at 3 years, 92% at 5 years and 10 years, and 97% at 15 years of age (Table 1). Adverse reactions to other foods developed in a total of 54%, and 18% were still intolerant at 26

10 years of age. Before 10 years of age, 19/39 (48%) developed asthma or rhinoconjunctivitis, 16/39 (41%) asthma, and 12/39 (31%) rhinoconjunctivitis (allergic rhinitis) (Table 2). In comparison to those with CMPI, the children with CMPA had a signicantly increased risk of persisting CMPA and development of persisting adverse reactions to other foods, asthma and rhinoconjunctivitis at 10 years of age (Table 3).
Sensitization and atopic diseases in childhood

In the random sample of 276 newborns from the total birth cohort of 1,749, 256 were followed-up at 5 years of age (93%), 223 at 10 years (81%), and 250 (90%) at 15 years. Blood samples for determination of specic IgE were obtained in 84%, 77%, 82%, and 85% at 1.5, 5, 10, and 15 years of age, respectively. The development of atopic
Table 3. Prognosis of cows milk protein allergy (CMPA) and cows milk protein intolerance (CMPI) among 39 children followed up to 10 years of age CMPA (n 21) Persisting CMPA/I Other food allergies Asthma Allergic rhinitis 3 7 13 11 (14%) (33%) (62%) (52%) CMPI (n 18) 0 0 3 1 (0%) (0%) (17%) (6%) p-Value 0.29 0.015 0.0098 0.0034

Fishers exact test, two-tailed. Results are expressed as current prevalence of atopic diseases (%).

Cows milk protein allergy/intolerance

5 years (n 256) (%) 18 (7%) 4 (2%) 14 (6%) 9 (4%) 7 (3%) 35 (14%)

10 years (n 223) (%) 21 0 24 19 15 54 (9%) (11%) (9%) (7%) (24%)

4 (2%) 51 (20%) 36 (14%) 1 (0.4%) 19 (7%) 51 (20%)

Only children who participated at 5 years of age are included. yAny asthma, atopic dermatitis, rhinoconjunctivitis, urticaria and/or food allergy.

Table 5. Rate of sensitization, specific serum immunoglobulin E (sIgE) of ! class 2 (!0.7 kUA/l) at 1.5, 5and 10 yearsof agein 276unselectedchildrenof a random sample from a 1-year birth cohort of 1,749 infants Age All No symptoms Any symptom Current asthma Current atopic dermatitis 18 months 4% 3% 8% 25% 9% 5 years 14% 10% 39% 39% 78% 10 years 16% 12% 30% 53% 29%

Specific IgE was determined by Pharmacia CAP against birch, grass, mugwort, dog, cat, horse, Dermatophagoides pteronyssinus, Dermatophagoides farinae, alternaria alternata, cladosporium herbarum, milk and egg.

diseases in this unselected group is described in Table 4. In early infancy the most prevalent symptoms are recurrent wheezing (wheezy bronchitis) (20%), atopic dermatitis (14%) and food allergy (7%). The prevalence of these diseases decline during childhood, being replaced by an increasing prevalence of asthma (9%) and rhinoconjunctivitis (9%) at 10 years of age. The rate of sensitization, as determined by specic sIgE of !class 2 to one or more inhalant/food allergens, is described in Table 5. An increasing rate of sensitization is found during childhood, with a higher sensitization rate among those with atopic symptoms/disease, especially among those with current asthma, where a sensitization rate of 53% is found at 10 years of age. Sensitization to food allergens was most prevalent in early infancy, being replaced by sensitization to inhalant allergens later in childhood.
Conclusion

15 years of age. In children younger than 10 years of age, 41% (16/39) developed asthma and 31% (12/39) rhinoconjunctivitis. Children with nonIgE-mediated CMPI have a good prognosis, whereas children with IgE-mediated CMPA in early childhood have a signicantly increased risk for persistent CMPA, development of other food allergies, asthma and rhinoconjunctivitis. From the same birth cohort of 1,749 children, a random sample of 276 was followed-up at 1.5, 5, 10 and 15 years of age. During early infancy, recurrent wheezing was the most prevalent disease (20%) followed by atopic dermatitis (14%) and food allergy (7%). Physician-diagnosed asthma increased from 2% at 1.5 years of age to 9% at 10 years of age. Rhinoconjunctivitis increased from <1% at 1.5 years of age to 9% at 10 years of age. A high prevalence of atopic dermatitis at 1.5 years of age was followed by a declining prevalence in later childhood. Overall, the current prevalence of any atopic disease was 20% at 1.5 years of age, declining to 14% at 5 years of age and followed by an increase to 25% at 10 years of age. These results show the wellknown allergic march, with atopic dermatitis and food allergy being prevalent in early childhood followed by an increasing prevalence of inhalant allergies asthma and rhinoconjunctivitis in later childhood. Sensitization to inhalant and/or food allergens (specic IgE of !class 2; CAP RAST) showed a low rate of sensitization among asymptomatics (3%, 10% and 12%) compared to a higher rate of sensitization of 8%, 39% and 30% among symptomatic atopics at 1.5, 5 and 10 years of age, respectively. The highest rate of sensitization (53%) was found among children with current asthma at 10 years of age. Sensitization in early childhood may predict sensitization and allergic disease later in childhood. The data on inhalant allergies at 15 years of age, and the relationship between atopic heredity, environmental factors and development of allergic diseases, remain to be analysed.
References
1. HST A, HUSBY S, STERBALLE O. A prospective study of cows milk allergy in exclusively breast-fed infants. Acta Paediatr Scand 1988: 77: 66370. 2. HST 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: 58796. 3. HALKEN S, HST A, HUSBY S, HANSEN LG, STERBALLE O, NYBOE J. Recurrent wheezing in relation to environmental risk factors in infancy. A prospective study of 276 infants. Allergy 1991: 46: 50714.

Close follow-up until 15 years of age of 39 infants with conrmed CMPA/CMPI during their rst year of life has shown that the overall prognosis of CMPA/CMPI was good, with a total recovery of 34/39 (87%) at 3 years of age and 38/39 (97%) at

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Hst et al.
4. HANSEN LG, HST A, HALKEN S, et al. IgE screening in 2814 newborn children. Cord Blood IgE I. Allergy 1992: 47: 3916. 5. HANSEN LG, HST A, HALKEN S, et al. Prediction of atopic disease. A follow-up at the age of 18 months. Cord blood IgE II. Allergy 1992: 47: 397403. 6. HANSEN LG, HST A, HALKEN S, et al. Prediction of IgE high-response and allergy. A follow up at the age of 18 months. Cord blood IgE III. Allergy 1992: 47: 40410. 7. HALKEN S, HST A, HANSEN LG, STERBALLE O. Effect of an allergy prevention programme on incidence of atopic symptoms in infancy. A prospective study of 159 high risk infants. Allergy 1992: 47: 54553. 8. HST A. Cows milk protein allergy and intolerance in infancy: Some clinical, epidemiological and immunological aspects. Pediatr Allergy Immunol 1994: 5 (Suppl.): 536. 9. HST A, SAMUELSSON E-G. Allergic reactions to raw, pasteurized and homogenized/pasteurized cow milk: A comparison. Allergy 1988: 43: 1138.

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