Clinical Course Cmpi

7/29/2019 Clinical Course Cmpi

1/6

Clinical course of cows milk protein allergy/

intolerance and atopic diseases in childhood

Pediatr Allergy Immunol 2002: 13 (Suppl. 15): 2328 Copyright # 2002 Blackwell MunksgaardPrinted in UK. All rights reserved

Hst A, Halken S, Jacobsen HP, Christensen AE, Herskind AM,Plesner K. Clinical course of cows milk protein allergy/intolerance andatopic 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 during1995 at the Odense University Hospital, were followed up prospectivelyfor the development of cows milk protein allergy/intolerance (CMPA/I)during the first year of life. Once a diagnosis of CMPA/I was confirmed,a milk-free diet was continued until a new milk challenge had showndevelopmentof tolerance. Allinfantswith CMPA/Iwererechallenged at 12

months of age and, in the event of continued clinical sensitivity to cowsmilk protein, controlled rechallenges were performed every 6 months upto 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 birthfor prospective non-interventional follow-up in order to investigate thenatural course of sensitization and development of atopic diseaseduring childhood. Standardized questionnaires on atopic heredity,environmentalfactorsandpresenceofatopicsymptomswereansweredat0,6, 12 and 18 months and at 5, 10 and 15 years of age. Interviews onatopic history and environmental factors as well as physical examinationwere carried out at 18 months, 5, 10 and 15 years of age. Skin prick testandspecificsIgE(PharmaciaCAP)testing were performedat 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 inchildren when 10 and15 years of age. Based on controlled milk eliminationand challenge procedures, the diagnosis of CMPA/I was confirmed in 39outof117infants,withsymptomssuggestiveofCMPA/I,thusresultingina1-year incidence of CMPA/I of 2.2%. The overall prognosis of CMPA/Iwas good, with a total recovery of 56% at 1 year, 77% at 2 years, 87% at3 years, 92% at 5 and 10 years and 97% at 15 years of age. In childrenyounger than 10 years of age, 41% developed asthma and 31%rhinoconjunctivitis. Children with non-IgE-mediated CMPI had a goodprognosis, whereas children with IgE-mediated CMPA in earlychildhood had a significantly 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%) at18 months of age. Physician diagnosed asthma increased from 2% at 1.5years of age to 9% at 10 years of age. Rhinoconjunctivitis increased from


2/6

The aims of the present prospective study were toinvestigate the natural course of cows milk pro-tein allergy/intolerance (CMPA/CMPI), sensiti-zation and atopic diseases in a 1-year birth cohortof unselected Danish children followed up to15 years of age. From this study population wehave previously reported in detail on the incidence

and manifestations of CMPA/CMPI in presum-ably exclusively breast-fed infants (1), and theclinical course of CMPA/CMPI during the first3 years of life was described in relation to clinicaland immunological types of hypersensitivity reac-tion (2). Recurrent wheezing in relation to envir-onmental risk factors in infancy has beendescribed in a random sample of 276 children(16%) of the same birth cohort (3). The predictivevalue of cord-blood immunoglobulin E (IgE), asregards development of atopic disease, has beenrevealed in three publications (46). Furthermore,from the same birth cohort the development ofatopic symptoms in infancy has been described inhigh-risk infants (7), and clinical, epidemiologi-cal and immunological aspects of CMPA/CMPIin this study population have been reviewed andevaluated in relation to other studies on thissubject (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 Uni-versity Hospital, were followed-up prospectivelyfor the development of CMPA/CMPI during theirfirst year of life. A total of 1,758 infants were bornalive, nine died neonatally, and therefore 1,749were followed up. During the first year, one infantdied and 14 left the municipality, none of whomdeveloped symptoms of CMPA/CMPI. During1985, 99.2% of the births in Odense took placeat the University Hospital. More than 99% of theinfants were followed up regularly during the firstyear of life by 20 health visitors. The infants werereferred to the paediatric clinic at the hospital

when one or more of the following symptomsoccurred: recurrent wheezing; rhinitis; atopiceczema; urticaria; erythema/exanthema; vomitingand/or diarrhoea not caused by coincidentalinfections or other demonstrable causes; infantilecolic not disappearing after advice on feedingtechnique; and failure to thrive. This part ofthe study has been described in detail previously(1,2).

The diagnosis of CMPA/CMPI was establishedby the following, generally accepted, criteria(1,2,8):

a definite disappearance of symptoms aftereach of two dietary eliminations of cows milkand cows milk products;

recurrence of identical symptoms after onechallenge; and

exclusion of lactose intolerance and coinciden-tal infection.

All challenges were carried out in the hospitalunder professional observation. The challengeprocedure was open. The results of the first 10positive open-milk challenges were confirmed bydouble-blind placebo-controlled challenge, asdescribed previously (9). Subsequently, all milkchallenges performed at intervals of 6 monthsuntil 3 years of age were open, and in theevent of equivocal results the challenge was re-peated in a double-blind placebo-controlled man-ner (9). Details on elimination and challengeprocedures have been described previously(1,2,8,9).

Once a diagnosis of CMPA/CMPI was con-firmed, the milk-free diet was continued until anew milk challenge had shown development oftolerance to cows milk protein. All infants withconfirmed CMPA/CMPI were rechallenged at12 months of age, and in the event of continuedclinical sensitivity to cows milk protein, rechal-lenges were performed as open challenges, asdescribed above (1,2,9), at 18, 24 and 36 monthsof age. Up to 3 years of age, all infants withCMPA/CMPI during the first year of life wereinvestigated every 6 months. Thereafter, rechal-

lenge was performed every 12 months, until theage of 15 years, to assess continued clinical sensi-tivity.

With symptoms suggestive of reactions to otherfoods, the food in question was eliminated fromthe diet for 4 weeks, followed by an open con-trolled challenge (2).

With symptoms suggestive of inhalant allergy,a skin-prick test and specific serum IgE (sIgE) test,against a panel of inhalant allergens, was per-formed (2).

Skin-prick testing (2) and specific sIgE testing(Pharmacia CAP RAST; Pharmacia Diagnos-

tics, Sweden) were carried out against inhalantallergens (birch, grass, mugwort, dog, cat, horse,Dermatophagoides pteronyssinus, Dermatopha-goides farinae, alternaria and cladosporium her-barum) and food allergens (milk and egg) in allchildren with CMPA/CMPI during the firstyear of life; specific sIgE testing was also carriedout in children at 1.5, 3, 5, 10 and 15 years ofage. Furthermore, lung function measurements(Vitalograph, Spiropharma, Copenhagen) wereperformed in children when 10 and 15 years ofage.

Hst et al.

24


3/6

Sensitization and atopic diseases in childhood

From the birth cohort described above, 276infants were randomly selected at birth for pro-spective follow-up in order to investigate thenatural course of sensitization and developmentof atopic disease during childhood. Standardized

questionnaires on atopic heredity, environmentalfactors (breast feeding, introduction of solidfoods, exposure to tobacco smoke, pets, housingconditions, socio-economic status, and other fac-tors) and presence of atopic symptoms, wereanswered at 0, 6, 12, and 18 months and at 5,10, and 15 years of age.

Interviews on the same factors, mentionedabove, as regards the standardized questionnaire(atopic heredity, environmental factors and ato-pic symptoms), as well as physical examination,were carried out at 18 months, 5, 10, and 15 yearsof age. Skin-prick (2) and specific sIgE (Pharma-cia CAP) testing were performed in children at18 months and 5, 10, and 15 years of age to thesame panel of inhalant and food allergensdescribed above.

At the interviews and clinical examinations at18 months, 5, 10 and 15 years of age, the childrensindividual case history and data were recorded,with special attention given to infections, includ-ing respiratory tract infections and symptoms/signs of possible atopic disease, described in thefollowing.

Diagnostic criteria for atopic diseases

The diagnostic criteria for atopic diseases aregiven below.Atopic symptoms. Any atopic symptoms weredefined as one or more of the following: asthma;atopic dermatitis; allergic rhinoconjunctivitis;food allergy/intolerance; and/or allergic urticaria.Current atopic disease. Defined as manifesta-tions of the disease within the previous 12months.Asthma. Defined as three or more episodes withexpiratory wheezing diagnosed by a physician and

requiring treatment with beta-2 agonist and/orinhaled steroids.Recurrent wheezing (wheezy bronchitis). Re-corded when the child had a history of a leasttwo physician-diagnosed episodes with expiratorywheezing associated with upper respiratory tractinfection requiring bronchodilator treatment.Atopic dermatitis. Diagnosed if physical exami-nation showed areas of scaly, erythematous anditchy eczematous rash primarily of the face andscalp, behind the ears and at the flexural folds.Only eczema localized to at least two typical areas

and chronically/relapsing with duration of at least3 months were recorded.Allergic urticaria. Registered when a physiciandiagnosed at least two episodes caused by thesame allergen.Rhinoconjunctivitis. Registered when a physiciandiagnosed typical symptoms lasting at least

1 month or recurring on exposure to the sameallergen.Gastrointestinal symptoms. Defined as recurrentcolic, vomiting and/or diarrhoea after excludingordinary eating problems, coincidental infectionsand lactose intolerance.Food allergy/intolerance (FA/FI). Diagnosed bythe following generally accepted criteria: definite disappearance of symptoms after each

of two dietary eliminations of the food inquestion;

recurrence of identical symptoms after onecontrolled challenge; and

exclusion of other possible non-allergic reac-tions (e.g. lactose intolerance, coincidentalinfection).

All challenges were performed in hospital underprofessional observation. The challenge proce-dure was open, but when equivocal results wererecorded, the challenge was repeated in a double-blind placebo-controlled manner.Social status. Registered according to the socialgrouping system of the Danish Social ResearchInstitute. This grouping system resulted in fivesocial classes (IV), according to education and

employment on which the family income wasgained, with class V being the lowest.

Diagnostic criteria for sensitization

Sensitization was determined by the measurementof specific sIgE (Pharmacia CAP). The cut-offvalue for class I was 0.35 kU/l and for class 2,0.70 kU/l.

Ethics

The study was approved by the Ethical Commit-

tee of the counties of Funen and Vejle. All theparents were supplied with information orally andin writing, and the patients gave informed consentbefore their children entered the study.

Statistics

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

25

Cows milk protein allergy/intolerance


4/6

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

Results

Cows milk protein allergy and intolerance

During the first year of life, 117 infants (6.7%) ofthe birth cohort of 1,749 infants had symptoms

suggestive of CMPA/CMPI. Based on strict elim-ination/milk-challenge procedures in a hospitalsetting, the diagnosis of CMPA/CMPI was con-firmed in 39 infants, giving a 1-year incidence of2.2% (95% confidence interval: 1.52.9). Nine ofthe 39 infants with CMPA/CMPI were confirmedto react to cows milk protein in human milk(Fig. 1). Of the 39 infants with CMPA/CMPI,21 had IgE-mediated CMPA [positive skin-pricktest and/or radioallergosorbent test (RAST) of!class 2 to cows milk protein] and 18 non-IgE-mediated CMPI. Most infants had cutaneoussymptoms (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 fromtwo or more organ systems.

The overall prognosis of CMPA/CMPI wasgood, with a total recovery of 56% at 1 year,77% at 2 years, 87% at 3 years, 92% at 5 yearsand 10 years, and 97% at 15 years of age(Table 1).

Adverse reactions to other foods developed in atotal of 54%, and 18% were still intolerant at

10 years of age. Before 10 years of age, 19/39(48%) developed asthma or rhinoconjunctivitis,16/39 (41%) asthma, and 12/39 (31%) rhinocon-

junctivitis (allergic rhinitis) (Table 2). In compari-son to those with CMPI, the children with CMPAhad a significantly increased risk of persisting

CMPA and development of persisting adversereactions to other foods, asthma and rhinocon-

junctivitis at 10 years of age (Table 3).

Sensitization and atopic diseases in childhood

In the random sample of 276 newborns from thetotal birth cohort of 1,749, 256 were followed-upat 5 years of age (93%), 223 at 10years (81%), and250 (90%) at 15 years. Blood samples for deter-mination of specific IgE were obtained in 84%,77%, 82%, and 85% at 1.5, 5, 10, and 15 yearsof age, respectively. The development of atopic

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

Table1. Prognosis of cows milk protein allergy/intolerance diagnosed in 39

infants of a 1-year birth cohort comprising 1,749 newborns

Age (years) Recovery 95% CI

1 22 (56%) 4072%

2 30 (77%) 6189%

3 34 (87%) 7396%

5 36 (92%) 7998%

10 36 (92%) 7998%15 38 (97%) 87100%

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

Table2. 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 95% CI

Persisting CMPA/I 3/39 (8%) 221%

Other food allergies 7/39 (18%) 834%

Asthma 16/39 (41%) 2658%

Allergic rhinitis 12/39 (31%) 1748%

Asthma and allergic rhinitis 9/39 (23%) 1139%Asthma or allergic rhinitis 19/39 (48%) 3265%

Results are expressed as current prevalence of atopic diseases and 95%

confidence interval (CI).

Table3. 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)CMPI

(n 18) p-Value

Persisting CMPA/I 3 (14%) 0 (0%) 0.29

Other food allergies 7 (33%) 0 (0%) 0.015

Asthma 13 (62%) 3 (17%) 0.0098

Allergic rhinitis 11 (52%) 1 (6%) 0.0034

Fishers exact test, two-tailed.

Results are expressed as current prevalence of atopic diseases (%).

26

Hst et al.


5/6

diseases in this unselected group is described inTable 4. In early infancy the most prevalent symp-

toms are recurrent wheezing (wheezy bronchitis)(20%), atopic dermatitis (14%) and food allergy(7%). The prevalence of these diseases declineduring childhood, being replaced by an increasingprevalence of asthma (9%) and rhinoconjunctivi-tis (9%) at 10 years of age.

The rate of sensitization, as determined byspecific sIgE of !class 2 to one or more inha-lant/food allergens, is described in Table 5. Anincreasing rate of sensitization is found duringchildhood, with a higher sensitization rate amongthose with atopic symptoms/disease, especiallyamong those with current asthma, where a sensi-

tization rate of 53% is found at 10 years of age.Sensitization to food allergens was most prevalentin early infancy, being replaced by sensitization toinhalant allergens later in childhood.

Conclusion

Close follow-up until 15 years of age of 39 infantswith confirmed CMPA/CMPI during their firstyear of life has shown that the overall prognosis ofCMPA/CMPI was good, with a total recovery of34/39 (87%) at 3 years of age and 38/39 (97%) at

15 years of age. In children younger than 10 yearsof age, 41% (16/39) developed asthma and 31%(12/39) rhinoconjunctivitis. Children with non-IgE-mediated CMPI have a good prognosis,whereas children with IgE-mediated CMPA inearly childhood have a significantly increased riskfor 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%) andfood allergy (7%). Physician-diagnosed asthmaincreased from 2% at 1.5 years of age to 9% at10 years of age. Rhinoconjunctivitis increasedfrom


6/6

4. HANSEN LG, HST A, HALKEN S, et al. IgE screening in2814 newborn children. Cord Blood IgE I. Allergy 1992:47: 3916.

5. HANSEN LG, HST A, HALKEN S, et al. Prediction ofatopic disease. A follow-up at the age of 18 months. Cordblood IgE II. Allergy 1992: 47: 397403.

6. HANSEN LG, HST A, HALKEN S, et al. Prediction ofIgE 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. Effectof an allergy prevention programme on incidence ofatopic symptoms in infancy. A prospective study of 159high risk infants. Allergy 1992: 47: 54553.

8. HST A. Cows milk protein allergy and intolerance ininfancy: Some clinical, epidemiological and immunologicalaspects. Pediatr Allergy Immunol 1994: 5 (Suppl.): 536.

9. HST A, SAMUELSSON E-G. Allergic reactions to raw,

pasteurized and homogenized/pasteurized cow milk: Acomparison. Allergy 1988: 43: 1138.

28

Hst et al.

Clinical Course Cmpi

Documents

Transcript of Clinical Course Cmpi