PEDIATRICS Vol. 107 No. 3 March 2001, p. e36
ELECTRONIC ARTICLE:
Delayed Hypersensitivity to Tuberculin, Total Immunoglobulin E,
Specific Sensitization, and Atopic Manifestation in Longitudinally
Followed Early Bacille Calmette-Guérin-Vaccinated and
Nonvaccinated Children
,
, ,
From * Children's Hospital, Charité Campus Virchow,
Medical Faculty of Humboldt Universität; and the Institute of
Medical Statistics, Klinikum Benjamin Franklin, Freie
Universität, Berlin, Germany.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
References
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Background. Bacille Calmette-Guérin (BCG) is a strong T helper 1 incentive and, thus, may contribute to a decreased risk of T helper 2-dependent atopic disease.
Objective. To investigate the natural course of specific immunoglobulin E (IgE) responses and atopic disease in BCG-vaccinated and nonvaccinated children.
Participants. Seven hundred seventy-four children from a prospectively followed birth cohort.
Outcome Measures. Physical examination and case history were performed at 3, 6, 12, 18, 24, 36, 48, 60, 72, and 84 months of age. Total and specific serum IgE levels to 9 common inhalant and food allergens were determined (CAP; Pharmacia, Freiburg, Germany) at 12, 24, 36, 60, 72, and 84 months of age. Purified protein derivative (PPD) skin testing was performed at 84 months.
Results. Period and lifetime prevalences of atopic
dermatitis and recurrent wheezing tended to be lower in the
BCG-vaccinated group early in life, whereas no such trend was found
after the second birthday or for allergic rhinitis. The proportion of
children remaining free of clinical manifestations tended to be higher in the BCG-vaccinated group but differences decreased over time. No
statistically significant differences were found for total IgE levels
(median). Atopic sensitization tended to be lower among BCG-vaccinated
children during the first 2 years of life. The diameter of the skin
reaction to PPD did not correlate with total serum IgE. Clinical and
serologic correlates of atopy were not significantly different between
children with a skin test diameter of 
5 mm and those with a smaller
diameter.
Conclusion. These results do not support the hypothesis that BCG vaccination in early infancy is associated with a subsequently markedly decreased risk of atopic sensitization or allergy. In addition, PPD skin test reactivity was not impaired in atopic individuals. Key words: Bacille Calmette-Guérin, atopy, total immunoglobulin E, allergic sensitization, allergy prevention, delayed type hypersensitivity.
Exposure to mycobacteria results in preferential secretion
of T helper cell (Th) 1 cytokines and subsequent activation of macrophages.1 Balancing release of Th2 cytokines has been
observed repeatedly later in the course of mycobacterial
infection2 but seems to play a less important
role.3,4 Hence, it seems to be possible that vaccination
with bacille Calmette-Guérin (BCG) may skew the cytokine
microenvironment toward preferential selection of Th1 cytokines and
contribute to a decreased risk of Th2-dependent atopic disease. This
hypothesis is supported by data from murine systems in which
BCG-infected mice show a cytokine shift toward a Th1-like pattern and
subsequent development of airway allergy is inhibited.5,6
In humans, an inverse correlation between purified protein derivative
(PPD) skin test reactivity, total immunoglobulin E (IgE), and atopic
disease in Japanese BCG-vaccinated schoolchildren was described,
leaving open the degree of contribution of subclinical infection.7 Evidence for a possible inhibiting effect of
mycobacterial infection on atopy comes from 2 cross-sectional studies.
In adolescents, national tuberculosis notification rates were found to
be inversely associated with wheeze and asthma lifetime
prevalences.8 In a Finnish retrospective study, a
protective effect on the prevalence of respiratory allergies was found
for female adults if they were infected before 17 years of
age.9 In contrast to natural infection, cross-sectional
studies in Scandinavian BCG-vaccinated children and nonvaccinated
controls revealed no differences in atopic sensitization and
disease.10-12 However, in Guinea-Bissau, BCG-vaccinated
children were less allergic to local indoor aeroallergens, and the
skin-prick tests were particularly negative among those children who
were vaccinated during their first week of life.13
This study was designed to investigate longitudinally the effect of
exposure to BCG vaccination in early childhood on development of total
IgE levels, specific sensitization, and atopic disease in
BCG-vaccinated and nonvaccinated individuals of a prospectively followed birth cohort of 1314 children from the former West Germany during their first 7 years of life. In addition, the size of
delayed-type hypersensitivity (DTH) to tuberculin was investigated in
relation to serum IgE and manifestations of atopic disease.
Study Participants
In 1990, a cohort of 1314 neonates recruited in 5 German cities
(Berlin, Düsseldorf, Freiburg, Mainz, and Munich) was selected for a prospective observational study (MAS-90). Of these, 499 neonates
(38%) were selected as being at high risk for atopy (2 or more close
atopic family members and/or cord-blood IgE values above 0.9 kU/L), and
the remainder were at random risk.
The 1314 cohort infants and their parents were regularly seen for
follow-up visits at ages 3, 6, 12, 18, 24, 36, 48, 60, 72, and 84 months. Parents filled in a questionnaire and gave a structured interview about their children's diseases and atopic symptoms. To keep
the reporting bias low, parents kept a diary in which details of the
children's diseases were recorded. Parents recorded information in the
diary whenever the child became sick. The study coordinators monitored
the diary at the indicated examination intervals. The children received
a standardized physical examination by trained study physicians.
Definition of Atopic Diseases and Allergic Sensitization
A basic description of morphologic skin phenomena and their
localization was used to construct a computer algorithm for the definition of atopic eczema according to the morphologic criteria given
by Seymour et al.14 A similar but more simple scheme was
completed by the mothers regarding the case history of the preceding
period.15 Obvious recurrent wheezing bronchitis required
at least 2 wheezing episodes with shortness of breath. Obvious atopic
rhinitis was diagnosed in the case of stuffed and/or running nose
without a cold lasting for 2 or more months during the preceding
observation period, plus the diagnosis by a physician.15
An infant was considered sensitized if the IgE antibody titer of 1 or
more of the 9 allergens tested was BCG Vaccination
In Germany, children believed to be at increased risk for
tuberculous infection used to be vaccinated within their first weeks of
life. Vaccination documents were available for all children of the
cohort. BCG vaccinations were performed with an attenuated BCG strain
(105 bacteria, Copenhagen strain 1331, BCG vaccine; Behring, Marburg, Germany).
PPD Skin Testing
Skin testing with mycobacterial antigen was performed at 7 years
of age by intradermal injection of 10 IU PPD (Behring) at the volar
aspect of the arm. The average diameter of the induration at the test
site was evaluated 72 hours after administration.
Determination of Allergen Concentration in House Dust
The levels of major mite (Der p 1 and Der f 1) and cat (Fel d 1)
allergens were determined from domestic carpet dust samples by sandwich
enzyme-linked immunosorbent assay as described
previously.16
Determination of IgE
Venous blood samples were obtained at birth (cord-blood), 12, 24, 36, 60, 72, and 84 months of age. Serum was separated by centrifugation at 3500 rpm for 13 minutes, and serum samples were stored at Statistical Methods
Statistical analysis was performed by using the SPSS for
Windows, Version 7.0 (SPSS, Chicago, IL). Pearson's
Ethics
The parents of all participating children in the study gave
their informed consent. The research protocol was approved by the local
ethics committee.
Of the 1314 cohort children, 169 were BCG-vaccinated (12.9%).
Nine hundred eighty-two of the cohort children were seen at a follow-up
visit at 7 years of age (participation rate: 74.7%). Seven hundred
eighty-seven children (59.9%) were examined at all scheduled
examination dates up to their seventh birthday The 774 children did not differ significantly from the whole cohort in
terms of gender, season of birth, atopic family history, cord-blood IgE
levels, cat or mite allergen exposure, number of siblings at birth or
at 5 years of life, and typical childhood infections (measles, mumps,
rubella, and pertussis). However, the breastfeeding rate (>4 weeks)
was significantly higher among the 774 continuously followed children
compared with the whole cohort (78.0% vs 69.1%; P < .001). Also, vaccination rates were significantly higher in the 774 children than in the whole cohort (vaccinations against
diphtheria/tetanus, 85.4% vs 78.5%; measles, 64.6% vs 51.9%; mumps,
65.6% vs 52.5%; rubella, 64.7% vs 51.8%; P < .001)
except vaccination against pertussis (28.9% vs 25.2%; P = .061).
Among the 774 continuously followed children, the BCG-vaccinated and
nonvaccinated were similar in those characteristics. However,
non-German children were overrepresented in the BCG-vaccinated group
(9.8% vs 3.5%, P = .011) and a high proportion of the
BCG-vaccinated children (39.1%) were born in Mainz, 1 of the 6 study
centers (Table 1).
TABLE 1
METHODS
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Abstract
Methods
Results
Discussion
References
0.35 kU/L.
20°C until analysis. Sera were analyzed for total IgE and
specific IgE against 9 common inhalant outdoor (birch t3, grass g6),
indoor (mite d1, cat e1, dog e2), or food allergens (egg f1, milk f2,
wheat f4, soy f14). Analysis was performed in one laboratory by
CAP-RAST FEIA (Pharmacia, Freiburg, Germany). At 5 years of age, CAP
test results of 418 children were compared with skin prick test results
for 5 respiratory allergens (cat, dog, mite, birch, and grass). Skin
tests were considered positive if the maximum wheal diameter was >3 mm
without reaction of negative control (saline) and the skin index was
>0.6. The skin index was calculated as the ratio of the diameter of
the allergen wheal to the histamine (histamine-dihydrochloride 10 mg/L)
wheal. The overall efficiency, calculated as the proportion of
concordant positive and negative results, is 92.2%. The sensitivity
and specificity are 83.8% and 92.5%, respectively.
2 tests were applied for the assessment of
association in 2-dimensional contingency tables.17
Fisher's exact test was used when the expected frequency of any cell
was <5. The Mann-Whitney U test was used for comparisons of
continuous variables. For correlations, Spearman's 
was calculated. For categorization of clinical diagnoses, only definite diagnosis was
regarded as atopic disease. Specific IgE antibodies to food and
inhalant allergens were grouped into values below detection limit
(<0.35 kU/L) and detectable values (0.35 kU/L). Cord-blood IgE
levels were categorized as not elevated (<0.9 kU/L) or elevated (0.9
kU/L). An infant with documented BCG vaccination was regarded as
vaccinated; all other infants were regarded as nonvaccinated. Statistical significance was defined by a 2-sided 
level of 0.05. Bonferroni's adjustments were used for multiple comparisons.
RESULTS
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Abstract
Methods
Results
Discussion
References
100 of the
BCG-vaccinated children (59.2%) and 687 of the nonvaccinated children
(60.0%). Children were excluded from the analysis because of a history
suggestive of tuberculosis infection (n = 5) or BCG vaccination after their first birthday (n = 8). The
resulting population consists of 774 children, including 92 children
(11.9%) who were BCG-vaccinated in their first year. The difference
between this BCG vaccination rate and the rate of early BCG-vaccinated children in the whole cohort (12.1%) was not statistically significant (P = .899). The median age for BCG vaccination was 30 days (range: 1-343 days).
Patient Characteristics
Period prevalences of atopic manifestations were not statistically different between the BCG-vaccinated and the nonvaccinated group and any time point (Fig 1). There was a tendency toward lower period prevalences of atopic dermatitis in the first year of life (Fig 1A). Period prevalence of recurrent wheezing followed a biphasic course in both groups and prevalences of the BCG-vaccinated group were nonsignificantly lower during the first phase (Fig 1B). Allergic rhinitis was not prevalent in the first 2 years of life and no significant differences between both groups were found thereafter (Fig 1C). Comparing the period prevalences of any of these clinical manifestations, no significant differences were found between groups (Fig 1D).
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Lifetime prevalences of atopic dermatitis tended to be nonsignificantly lower in BCG-vaccinated children. Similarly, wheezing bronchitis tended to be lower among BCG-vaccinated children up to 5 years of age. Statistical significance of this difference was achieved at 12 months of life. No statistically significant differences were found for the lifetime prevalences of allergic rhinitis (Table 2). In the first 3 years of life, the proportion of infants remaining free of atopic manifestations over time tended to be nonsignificantly higher in the BCG-vaccinated group (P = .343; Fig 2).
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Total serum IgE values (median) were not lower in the BCG-vaccinated group than in the nonvaccinated group at any age (Fig 3). Using 0.35 kU/L as a cutoff level for specific sensitization to 1 or more of 9 common inhalant and food allergens (birch, timothy grass, egg, milk, soy, wheat, mite, cat, and dog), sensitization rates tended to be lower among the BCG-vaccinated group than among the nonvaccinated group during the first 2 years. Statistical significance was achieved at 2 years (Fig 3). At this time point, the sensitization rate was 12.7% in the BCG-vaccinated group and 25.1% in the nonvaccinated group (P = .033). Calculating the percentage of positive specific IgE tests from the total number of tests performed at the indicated time points, a nonsignificantly lower proportion of tests were positive in the BCG-vaccinated group than in the nonvaccinated group during the first 3 years (at 12 months, 2.8% vs 3.0%; at 24 months, 4.1% vs 5.6%; at 36 months, 4.9% vs 6.3%). Later in life, this tendency was reversed and differences achieved statistical significance at ages 5 and 7 (at 60 months, 13.0% vs 9.6%, P = .006; at 72 months, 13.1% vs 11.8%; at 84 months, 16.4% vs 12.3%, P = .002).
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A subpopulation of 492 children was tuberculin skin tested at 7 years of age. Fifty-eight of 492 children (11.8%) were BCG-vaccinated. BCG-vaccinated and nonvaccinated children did not differ significantly with regard to gender, atopic manifestation of mother or father, duration of breastfeeding, mean indoor allergen exposure (cat and mite), number of siblings, common childhood infections, and vaccinations during early childhood (data not shown).
Three hundred sixty-seven of 492 children (74.6%) showed no DTH to
tuberculin and 58 of 492 (11.8%) showed a reaction with an average
diameter 5 mm. The diameter was significantly larger among
BCG-vaccinated than nonvaccinated children (4.1 ± .8 mm vs
1.1 ± .2 mm; P < .001). However, among those who
showed a reaction with an average diameter 5 mm, only 18 were
BCG-vaccinated.
At 7 years of age, DTH to tuberculin did not significantly differ
between 48 children with and 442 children without atopic dermatitis
(1.8 ± .6 mm vs 1.5 ± .2 mm; P = .977),
between 29 children with and 461 children without recurrent wheeze
(.9 ± .4 mm vs 1.5 ± .2 mm; P = .312),
between 36 children with and 454 children without allergic rhinitis
(1.5 ± .5 mm vs 1.5 ± .2 mm; P = .793), or
between 84 children with 1 or more of these conditions and 406 children
without any of these conditions (1.5 ± 0.4 mm vs 1.5 ± 0.2 mm; P = .607). No significant differences were found in
the BCG-vaccinated and nonvaccinated subpopulations (data not shown).
Compared with children with a DHT 5 mm, children with a smaller DTH
had similar rates of atopic dermatitis (10.3% vs 9.7%;
P = 1.000), recurrent wheeze (3.4% vs 6.3%;
P = .559), allergic rhinitis (8.6% vs 7.2%;
P = .600), or any of these manifestations (15.5% vs
17.4%; P = .869). Children with a PPD 10 mm did not differ statistically significant from those with a diameter below regarding atopic sensitization or clinical manifestations of atopy (data not shown).
Total IgE was measured in 454 of the PPD skin-tested children. The DTH
diameter correlates very poorly with total IgE at 7 years of age
(rs = 0.022; Fig
4), similarly in the 55 BCG-vaccinated
(rs = 0.021) and the 399 nonvaccinated
children (rs = 0.015). Children with a
DTH 5 mm were found to have similar total serum IgE values in
comparison with children who showed a lower DTH (153.4 ± 39.9 kU/L vs 141.9 ± 19.3 kU/L; P = .966).
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DTH does not differ significantly between 184 children sensitized to
common airborne or nutritive allergens at their seventh birthday and
278 nonsensitized children (1.4 ± .3 mm vs 1.5 ± 0.2 mm;
P = .177). Also, DTH was found not to be significantly different between sensitized and nonsensitized children of the BCG-vaccinated or nonvaccinated subpopulation (data not shown). Among
55 children with a DTH 5 mm, the rate of sensitization to common
airborne or nutritive allergens was nonsignificantly lower than among
those 407 children with a smaller diameter (36.4% vs 40.3%;
P = .680).
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DISCUSSION |
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Methods
Results
Discussion
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Our results do not support the hypothesis that BCG vaccination in early infancy is associated with a subsequently decreased risk of atopic sensitization or of clinical manifestations of atopic disease in general. Given the good comparability of the BCG-vaccinated group and the nonvaccinated group, some transient tendencies in favor of BCG-vaccinated children that were observed early in life may actually be related to the difference in the BCG vaccination status. It could be speculated that a BCG-induced shift of the cytokine environment toward a Th1-type pattern contributed to those transient differences and that later in life additional environmental influences override an initial BCG effect. However, in this study the observed differences mostly failed to be significant. They may be stronger in even larger patient samples.
Several factors may have contributed to what could be regarded as conflicting evidence between the Japanese and the European BCG studies. First, the vaccine strains and doses used differ. The BCG Tokyo strain 172 used in the Japanese study differs biochemically from the Copenhagen strain used in the Swedish and our study.18,19 Differences in the immunogenicity of different strains have been described,20 but to our knowledge no direct comparison of the Danish and Japanese strain is presently available. The Japanese vaccine is administered in a 10-fold higher dose to achieve comparable indurations evoked by the Copenhagen strain 1331.7 Therefore, vaccine and dose differences could have been contributed to a stronger influence of BCG vaccination on development of elevated IgE levels and atopic disease.
Second, genetic and environmental differences between Japanese and European children cannot be ruled out as a possible cause for a greater susceptibility to BCG immunization.
Third, an immunity skewed toward the Th2-type cytokine pattern at the cost of Th1-type cytokines is a characteristic of being atopic. The cutaneous induration expected in children infected with mycobacteria on testing with tuberculin is a Th1-dependent type I allergic reaction. Thus, the decreased tuberculin skin reactions in atopics documented in the Japanese study may represent a marker of atopy rather than pointing toward BCG as a cause of being nonatopic. Reactivity to mycobacterial antigens has been shown to be reduced in Finnish allergic children.21 A similar phenomenon has been demonstrated in atopic pertussis-vaccinated children who respond with a smaller induration than do nonatopic children.22 Similarly, an inverse relation of total serum IgE levels and in vitro lymphoproliferative responses to tetanus toxoid was found in diphtheria-pertussis-tetanus-vaccinated children.23 In our study, however, clinical and serologic indicators of atopy were not significantly different between children with positive and negative PPD skin tests and the correlation of total serum IgE and DTH was close to zero (Fig 4). In accordance with these results, a lack of correlation between tuberculin skin test reactivity and atopy has been found among adult Norwegians who had been BCG-vaccinated at the age of 14 years.12
Finally, although Shirakawa et al24 claimed that a fixed
determination of atopy and diminished tuberculin responses by genetic factors is unlikely because of intraindividually changed tuberculin responses from positive to negative and vice versa over time, environmental mycobacterial infections known to be more common at lower
latitudes may have coinfluenced tuberculin responses and development of
atopy by continuously stimulating Th1-like clones. It would be
interesting to see how these children shifting from positive to
negative tuberculin response behave toward IgE and atopy over time.
Moreover, a high proportion of children with DTH responses 40 mm
would also be consistent with a Mycobacterium tuberculosis-infected subpopulation within the Japanese sample. Epidemiologically compared, populations of countries with high tuberculosis notification rates tend to have lower prevalences of
wheeze and asthma.8 Thus, mycobacterial infection by
respiration route may be more effective in inhibiting the development
of allergic airway disease.
There is a theoretical chance that other vaccines than BCG or infections stimulated a Th1-type immune response in the children of our cohort that could have buffered any additional differences derived from the BCG vaccination that were seen in the Japanese study. However, in this study, other common childhood vaccines and infections were not a major confounder (Table 1).
Th2-skewed cytokine milieu seems to be part of the regular prenatal development of the immune system,25 but it can be exaggerated and prolonged postnatally in genetically predisposed individuals.26-29 It has been suggested that the immune system of individuals at risk be skewed more toward a Th1 response to prevent atopy. This seems to be possible with mycobacteria in murine models.5,6,30 However, based on available data in children a possible preventive effect of a single early BCG vaccination against atopy in later life is at best controversial and no imperative to reintroduce BCG vaccination in regions with low prevalence of tuberculosis. In contrast, prokaryotic DNA fragments are a promising Th1-stimulating agent.31 Because autoimmune diseases such as insulin-dependent diabetes mellitus are Th1-associated and because a shift toward Th2-type protects the fetus in pregnancy,32,33 caution should prevail when immunization strategies are being considered to shift the cytokine balance from atopy.
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ACKNOWLEDGMENT |
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This work was supported by Grant 01GC9702 from the German Ministry of Research and Technology (BMFT).
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FOOTNOTES |
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Deceased.
Received for publication Jul 18, 2000; accepted Oct 18, 2000.
Reprint requests to (C.G.) Charité Campus Virchow, Children's Hospital, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: christoph.grueber{at}charite.de
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ABBREVIATIONS |
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Th, T helper cell; BCG, bacille Calmette-Guérin; PPD, purified protein derivative; IgE, immunoglobulin E; DTH, delayed-type hypersensitivity.
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Pediatrics (ISSN 0031 4005). Copyright ©2001 by the American Academy of Pediatrics
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