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Table 1. Proportion of Children and Adolescents With Previous Measles According to Age at MMR Vaccination*
Image description not available.
Table 2. Prevalence Rates of Atopic Diseases Among MMR Vaccinees (N = 547,910) With and Without Measles History*
Image description not available.
Table 3. Age-Specific Prevalence Ratios of Atopic Diseases*
Image description not available.
Table 4. Prevalence Rates and Ratios of Atopic Diseases Among a Nationwide Subgroup (N = 23,785) of 6-Year-Old MMR Vaccinees With and Without Measles History*
Image description not available.
1.
Cookson WO, Moffatt MF. Asthma: an epidemic in the absence of infection?  Science.1997;275:41-42.
2.
Martinez FD. Role of viral infections in the inception of asthma and allergies during childhood: could they be protective?  Thorax.1994;49:1189-1191.
3.
Strachan DP. Hay fever, hygiene, and household size.  BMJ.1989;299:1259-1260.
4.
von Mutius E, Martinez FD, Fritsch C, Nicolai T, Reitmeir P, Thiemann HH. Skin test reactivity and number of siblings.  BMJ.1994;308:692-695.
5.
Matricardi PM, Rosmini F, Ferrigno L.  et al.  Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus.  BMJ.1997;314:999-1003.
6.
Shirakawa T, Enomoto T, Shimazu S, Hopkin JM. The inverse association between tuberculin responses and atopic disorder.  Science.1997;275:77-79.
7.
Shaheen SO, Aaby P, Hall AJ.  et al.  Measles and atopy in Guinea-Bissau.  Lancet.1996;347:1792-1796.
8.
Bodner C, Godden D, Seaton A. Family size, childhood infections and atopic diseases.  Thorax.1998;53:28-32.
9.
Holt PG. A potential vaccine strategy for asthma and allied atopic diseases during early childhood.  Lancet.1994;344:456-458.
10.
Krämer U, Heinrich J, Wjst M, Wichmann HE. Age of entry to day nursery and allergy in later childhood.  Lancet.1999;353:450-454.
11.
Peltola H, Karanko V, Kurki T.  et al.  Rapid effect on endemic measles, mumps, and rubella of nationwide vaccination programme in Finland.  Lancet.1986;1:137-139.
12.
Paunio M, Virtanen M, Peltola H.  et al.  Increase of vaccination coverage by mass media and individual approach: intensified measles, mumps, and rubella prevention program in Finland.  Am J Epidemiol.1991;133:1152-1160.
13.
Peltola H, Heinonen OP, Valle M.  et al.  The elimination of indigenous measles, mumps, and rubella from Finland by a 12-year, two-dose vaccination program.  N Engl J Med.1994;331:1397-1402.
14.
Louhiala PJ, Jaakkola N, Ruotsalainen R, Jaakkola JJ. Form of day care and respiratory infections among Finnish children.  Am J Public Health.1995;85:1109-1112.
15.
 Statistical Yearbook of Finland, 1987 . Helsinki: Central Statistical Office of Finland; 1987.
16.
Greenland S, Robins JM. Estimation of a common effect parameter from sparse follow-up data.  Biometrics.1985;41:55-68.
17.
Hayney MS, Poland GA, Jacobson RM.  et al.  Relationship of HLA-DQA1 alleles and humoral antibody following measles vaccination.  Int J Infect Dis.1998;2:143-146.
18.
Fox JP, Elveback L, Scott W, Gatewood L, Ackerman E. Herd immunity: basic concept and relevance to public health immunization practices.  Am J Epidemiol.1971;94:179-189.
19.
Soothill JF. Measles and atopy in African children [letter].  Lancet.1996;348:825.
20.
Campbell DE, Kemp AS. Measles and atopy in African children [letter].  Lancet.1996;348:825.
21.
Allen JE, Maizels RM. Th1-Th-2: reliable paradigm or dangerous dogma?  Immunol Today.1997;18:387-392.
22.
Holgate ST. Asthma genetics: waiting to exhale.  Nat Genet.1997;15:227-229.
Original Contribution
January 19, 2000

Measles History and Atopic DiseasesA Population-Based Cross-sectional Study

Author Affiliations

Author Affiliations: Department of Public Health, University of Helsinki (Drs Paunio and Heinonen), Department of Hospital Services, Association of Local and Regional Authorities (Dr Virtanen), Department of Infectious Diseases, National Public Health Institute (Dr Leinikki), and Hospital for Children and Adolescents, Helsinki University Central Hospital (Drs Patja and Peltola), Helsinki, Finland.

JAMA. 2000;283(3):343-346. doi:10.1001/jama.283.3.343
Context

Context Many recent cross-sectional studies have suggested that lack of early exposure to communicable diseases, including measles, in affluent countries may have increased rates of atopic disease.

Objective To study the association between natural measles infection and atopy.

Design and Setting Cross-sectional nationwide study in Finland using data gathered between November 1, 1982, and June 30, 1986.

Subjects A total of 547,910 individuals aged 14 months to 19 years who at the time of measles-mumps-rubella (MMR) vaccination had relevant information collected on the occurrence of measles and allergic rhinitis, eczema, and asthma.

Main Outcome Measures Lifetime occurrence of atopic manifestations in subjects who had had measles compared with those who had not, expressed as age-specific and age-adjusted prevalence ratios.

Results The age-adjusted prevalence ratio of atopic manifestations among those who had had measles (n = 20,690) compared with those who had not (n = 527,220) was 1.32 (95% confidence interval [CI], 1.27-1.36) for eczema, 1.41 (95% CI, 1.33-1.49) for rhinitis, and 1.67 (95% CI, 1.54-1.79) for asthma. The positive association between measles and atopy was evident at all ages, in both urban and rural dwellers, and among subjects with many or few contacts at home or in day care.

Conclusions Based on our data, measles and atopy occur more frequently together than expected, which does not support the hypothesis that experiencing natural measles infection offers protection against atopic disease.

Numerous recent scientific reports have suggested, mainly based on indirect evidence, that the reduction of communicable diseases as a result of vaccination in many Western countries may have resulted in an increased risk of atopic diseases110 and contributed to the contemporary asthma epidemic.1 To support these suggestions, an elaborate theory postulates that cell-mediated immunity has been altered in the absence of childhood viral infections and tuberculosis, resulting in T helper cell (TH2)–mediated responses that lead to IgE antibody responses, which are thought to be responsible for the manifestations of atopic diseases.1,8 Some direct evidence from West Africa7 endorses this theory. In Guinea-Bissau, a cohort of 395 children aged 6 years or younger was studied in 1978-1980 without surveying baseline information on atopic status. The cohort was followed up until 1994, when 262 children with reliable measles history were located alive, and the prick test with common allergens was performed. The survivors of measles had a prevalence of atopy about 50% lower than those who had not experienced the infection.

We explored the hypothesis that natural measles infection prevents allergic diseases using recorded information on the history of measles and atopic disease in Finland's national measles-mumps-rubella (MMR) vaccination program.1113 Measles did not disappear from Finland after the single-dose monovalent measles vaccination program started in 1975, and wild measles virus was still circulating in 1982 when the comprehensive MMR program was launched.

METHODS
Vaccinations and Setting

In Finland, children are vaccinated free of charge by public health nurses at child health care centers. Vaccinations are voluntary. When the triple vaccine was introduced, special arrangements were made to register all MMR vaccinations between November 1, 1982, and June 30, 1986. At the time of vaccination, data were collected on history of measles and atopic diseases and form the basis of this study. Details of the collected data and the vaccination setting have been described previously.1113 The MMR vaccination program was approved by Finland's National Board of Health.

Since 1982, the trivalent MMR vaccine (MMRII, Merck & Co Inc, West Point, Pa; distributed in Finland as Virivac) has been used exclusively and is administered routinely first at 14 to 18 months and again at 6 years. Between 1983 and 1986, children aged 18 months to 5 years were immunized with MMR whenever they visited child health care centers, with coverage reaching 97%. Catch-up programs for intermediate ages (19 months to 6 years) were also carried out. Of the 562,931 children born between November 1975 and June 1984 and whose records were maintained under computerized surveillance,12 547,910 were aged between 14 months and 19 years at the time of vaccination and had relevant information about measles and allergies. Nonvaccinated children aged 7 to 11 years were traced and vaccinated at schools in 1985. Some children outside the targeted age groups were vaccinated with MMR on their own initiative and were registered in the database.

Subjects and Data

A public health nurse vaccinated the child or adolescent and recorded data on the vaccinee by interview of the parent or adolescent; the data included social security number and age at vaccination. The nurse also asked whether the vaccinee had ever been diagnosed as having eczema, allergic rhinitis (hay fever), allergic conjunctivitis, asthma or repeated episodes of obstructive bronchitis, or measles. In a representative subsample of the vaccinees, all children who received their MMR shot in November and December 1982 (including 23,785 six-year-olds) were asked for the number of regular daily child contacts. In Finland practically all preschoolers attend day care groups of varying size; the law requires access to day care for all children and the majority of mothers work.14 Most popular are the local municipality nurseries, which tend to have large numbers (eg, 50-100) of preschoolers, from 10-month-old infants to 6-year-olds, under the same roof. The other type is family day care, which involves 4 to 5 preschoolers in addition to the children of the day care provider. The fertility rate in Finland in 1980-1985 was between 1.65 and 1.74,15 and the average number of children in families is close to 2.

Statistical Methods

The prevalences of allergic diseases among those who had and had not had measles were compared. Age adjustment for prevalence ratios was performed using the Mantel-Haenszel method (Epi Info Version 5.01, Centers for Disease Control and Prevention, Atlanta, Ga, 1993) over 11 age strata. The method of Greenland and Robins16 was used to estimate 95% confidence intervals (CIs) of the prevalence ratios. Because the prevalence of allergy and measles history might have differed between urban and rural areas, larger urban areas (towns with >100,000 inhabitants) and smaller municipalities were analyzed separately. First-order interactions with respect to age and urbanization were checked by stratified analysis. The effect of daily contacts on the prevalence ratio was analyzed among 6-year-old vaccinees and adjusted over 4 precoded daily child contact strata (<5, 5-6, 7-8, and >8), again using the Mantel-Haenszel method. Because bias may have been introduced if atopic and nonatopic children were vaccinated at different ages, MMR vaccination coverage in atopic and nonatopic vaccinees was compared during 1982-1984 in cities with more than 100,000 inhabitants.

RESULTS

Of 547,910 subjects, 20,690 had had measles; 52,087, eczema; 17,131, rhinitis; and 10,058, asthma. There was the expected increase with age in the proportion of vaccinees with a measles history, both in the municipalities with 100,000 or fewer inhabitants and in large towns (Table 1), since the comprehensive vaccination program launched in 1982 had reduced measles incidence rapidly. A history of measles was slightly more common in smaller municipalities than in large towns among 6- to 14-year-olds, possibly owing to urban/rural variations in vaccination coverage rates of the 1975-1982 monovalent measles vaccination program and also owing to different urban/rural housing densities.

The lifetime prevalences of the 3 allergic diseases were 32% to 67% higher after age adjustment among those who had experienced natural measles infection compared with those who had not (Table 2). The prevalence ratios were stable by age: in only 2 of 33 age strata was an allergic symptom more common among those without a measles history (Table 3). Restricting analyses to large towns and smaller municipalities, or adjusting for possible effects of age, did not change the findings. When no stratification by area was made, the age-adjusted prevalence ratio of atopic manifestations among those who had had measles compared with those who had not was 1.32 (95% CI, 1.27-1.36) for eczema, 1.41 (95% CI, 1.33-1.49) for rhinitis, and 1.67 (95% CI, 1.54-1.79) for asthma. The prevalence ratios for allergic diseases were slightly lower when analyses were restricted to vaccinees for whom there was information on the number of daily child contacts, but adjustment for daily contacts among these 6-year-old vaccinees did not change the direction of the association (Table 4). However, only the relationship between measles and asthma remained statistically significant, probably because of the much smaller sample size.

The vaccination coverage rate increased similarly among 1- to 7-year-old children with atopic manifestations and those without atopy in all large towns during the first 2 years after the national vaccination program was launched and measles incidence in the country decreased rapidly.

COMMENT

In this large national study, there was substantially more atopic disease among children and adolescents with a history of naturally occurring measles infection compared with those without a measles history. This is contrary to previous findings.7,8 However, although the study by Bodner and colleagues8 found a weak inverse association of measles and atopy, they found a positive association between measles, mumps, or varicella before age 3 years and atopy.

In a survey of this type, errors in the diagnosis of atopy and measles are unavoidable. Nevertheless, it is unlikely that erroneous diagnoses of allergic manifestations differed with respect to measles history, and vice versa. Thus, we do not believe that information bias could explain our results, especially because our hypothesis received public attention only in the late 1990s and could not have influenced the information obtained from the vaccinees. Selection bias due to measles-related mortality is also unlikely because Finland has had very low measles mortality for many decades, and overall only about 1% of the population died at younger than 20 years of age in the 1980s.15 It is also unlikely that atopic children with a previous measles history would have been especially prone to vaccination; approximately 97% of the target population was traced and vaccinated.12 In an environment in which measles exposure was changing rapidly, a slower increase in vaccination coverage among atopic vs nonatopic children may have resulted in a positive association between measles history and prevalence of allergic diseases. However, the vaccination coverage rates rose similarly among atopic and nonatopic children in all larger towns during the fastest decrease in measles incidence. In theory, it is possible that atopy-prone children might be more readily attacked by measles than others.17

Major sources of confounding, such as age and area of residence, were properly controlled for and did not change the result that those who had had measles had more atopy. An additional potential confounder is family size, especially because young siblings in large families tend to have a low risk of atopic disease.3,4,8 On the other hand, large family size increases the likelihood of previous measles at the time of vaccination.18 Thus, large family size tends to exaggerate the potential protective effect of natural measles infection against atopy, ie, it would act as a negative confounder. The number of daily child contacts has a similar effect on catching measles as family size.

All studies on the subject matter are limited by being cross-sectional.28,10 In fact, the original finding by Shaheen et al7 from Africa was criticized immediately19,20 on the basis that an interferon-related defect is positively associated with both atopy and death due to measles. Thus, an inverse association of history of measles with positive skin prick test results could occur if those atopy-prone children who had had measles were in excess among the 34% of children who had died of the virus, ie, the results could have resulted from cross-sectional bias. A finding that subjects with different HLA constitutions have different humoral responses to measles vaccine17 also supports the view that measles-related mortality might result from a genetic predisposition.

Due to the cross-sectional nature of this and other studies, the order of the studied phenomena cannot be determined. The remarkable stability of the positive association between measles and atopic manifestations in all age groups between 1 and 19 years reassures us that the observed associations in this study are valid, irrespective of the order of measles infection and atopic manifestations.

Prior to measles mass vaccination, ie, before 1975, almost all Finnish children contracted measles infection before 5 years of age. Thus, it is likely that a high proportion of children vaccinated in 1982, especially the adolescents, had had measles very early in life. Vaccination against measles with a 1-dose program from 1975 onward with an estimated coverage of 60% to 70%12 may have somewhat delayed measles for those who fell ill, particularly in large towns, after 1975.

Many authors1,2,47,10 have suggested causality based on the theory that lack of exposure to microbes early in life skews cell-mediated immunity toward TH2 responses, favoring atopic manifestations.1 However, immunological experts have warned against making oversimplifications from the theory.21 For example, the lack of communicable diseases in some island populations is not the only feasible reason for their high asthma prevalence rates.2 Because atopic asthma has a strong genetic predisposition,22 high rates could also be explained by the genetic founder effect.

In summary, a strong positive association between measles and atopy was observed in a large Finnish population. The most common allergic diseases were substantially more prevalent in children and adolescents with a measles history than without. We do not know whether this association reflects a causal effect. These findings do not lend support to the hypothesis that experiencing natural measles infection offers protection against the main atopic diseases.

References
1.
Cookson WO, Moffatt MF. Asthma: an epidemic in the absence of infection?  Science.1997;275:41-42.
2.
Martinez FD. Role of viral infections in the inception of asthma and allergies during childhood: could they be protective?  Thorax.1994;49:1189-1191.
3.
Strachan DP. Hay fever, hygiene, and household size.  BMJ.1989;299:1259-1260.
4.
von Mutius E, Martinez FD, Fritsch C, Nicolai T, Reitmeir P, Thiemann HH. Skin test reactivity and number of siblings.  BMJ.1994;308:692-695.
5.
Matricardi PM, Rosmini F, Ferrigno L.  et al.  Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus.  BMJ.1997;314:999-1003.
6.
Shirakawa T, Enomoto T, Shimazu S, Hopkin JM. The inverse association between tuberculin responses and atopic disorder.  Science.1997;275:77-79.
7.
Shaheen SO, Aaby P, Hall AJ.  et al.  Measles and atopy in Guinea-Bissau.  Lancet.1996;347:1792-1796.
8.
Bodner C, Godden D, Seaton A. Family size, childhood infections and atopic diseases.  Thorax.1998;53:28-32.
9.
Holt PG. A potential vaccine strategy for asthma and allied atopic diseases during early childhood.  Lancet.1994;344:456-458.
10.
Krämer U, Heinrich J, Wjst M, Wichmann HE. Age of entry to day nursery and allergy in later childhood.  Lancet.1999;353:450-454.
11.
Peltola H, Karanko V, Kurki T.  et al.  Rapid effect on endemic measles, mumps, and rubella of nationwide vaccination programme in Finland.  Lancet.1986;1:137-139.
12.
Paunio M, Virtanen M, Peltola H.  et al.  Increase of vaccination coverage by mass media and individual approach: intensified measles, mumps, and rubella prevention program in Finland.  Am J Epidemiol.1991;133:1152-1160.
13.
Peltola H, Heinonen OP, Valle M.  et al.  The elimination of indigenous measles, mumps, and rubella from Finland by a 12-year, two-dose vaccination program.  N Engl J Med.1994;331:1397-1402.
14.
Louhiala PJ, Jaakkola N, Ruotsalainen R, Jaakkola JJ. Form of day care and respiratory infections among Finnish children.  Am J Public Health.1995;85:1109-1112.
15.
 Statistical Yearbook of Finland, 1987 . Helsinki: Central Statistical Office of Finland; 1987.
16.
Greenland S, Robins JM. Estimation of a common effect parameter from sparse follow-up data.  Biometrics.1985;41:55-68.
17.
Hayney MS, Poland GA, Jacobson RM.  et al.  Relationship of HLA-DQA1 alleles and humoral antibody following measles vaccination.  Int J Infect Dis.1998;2:143-146.
18.
Fox JP, Elveback L, Scott W, Gatewood L, Ackerman E. Herd immunity: basic concept and relevance to public health immunization practices.  Am J Epidemiol.1971;94:179-189.
19.
Soothill JF. Measles and atopy in African children [letter].  Lancet.1996;348:825.
20.
Campbell DE, Kemp AS. Measles and atopy in African children [letter].  Lancet.1996;348:825.
21.
Allen JE, Maizels RM. Th1-Th-2: reliable paradigm or dangerous dogma?  Immunol Today.1997;18:387-392.
22.
Holgate ST. Asthma genetics: waiting to exhale.  Nat Genet.1997;15:227-229.
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