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Paunio M, Heinonen OP, Virtanen M, Leinikki P, Patja A, Peltola H. Measles History and Atopic Diseases: A Population-Based Cross-sectional Study. JAMA. 2000;283(3):343–346. doi:10.1001/jama.283.3.343
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.
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
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
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.11-13 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.
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.11-13
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.
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.
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.
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.
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.2-8,10
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
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
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.
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.