The association of airway hyperresponsiveness and tuberculin responses

BACKGROUND: The balance between the two subsets of T cell is pivotal for allergic sensitization.Objective: We conducted a cross-sectional study of 486 children vaccinated with bacillus Calmette-Guérin (BCG), aged 10-13 years, to evaluate whether tuberculin responses may contribute to airway hyperresponsiveness (AHR). METHODS: Tuberculin skin test, allergic skin test, and methacholine challenge test were done. The methacholine concentration causing a 20% fall (PC20) in forced expiratory volume in 1 second (FEV1) was used as a threshold of AHR. Atopy was defined as a reaction showing a mean wheal size of > or = 3 mm to one or more allergens on skin prick test (SPT). Two tuberculin units of polysorbate-stabilized purified protein derivatives (PPD) were injected intradermally into the volar surface of the forearm. Reactions were read at 48-72 h as the transverse diameter in millimeters of induration. RESULTS: Of the children in the study, 12.3% (60/486) had PPD induration; 7.8% (38/486) of children had PPD induration of greater than 10 mm. The PPD induration size was 10.5 +/- 1.03 mm (confidence interval (CI) 7.19-12.33) in atopic children and 11.2 +/- 0.76 mm (CI 7.89-13.1) in nonatopic children. The differences of PPD induration diameter between the two groups were not significant. There was no difference of log PC20 between PPD induration > or = 10 mm and < 10 mm (0.13 +/- 0.18 vs. 0.42 +/- 0.05). The difference of log PC20 between positive and negative tuberculin response was not significant. Children with atopy had lower log PC20 than those without atopy (0.16 +/- 0.07 vs. 0.51 +/- 0.05, P = 0.001). After adjusting for sex, age, height, weight, tuberculin response, atopy was associated with AHR in multivariate analyses (odds ratio = 1.895, CI 1.285-2.505, P = 0.002). CONCLUSION: These data suggested that a tuberculin response due to mycobacterial infection status have no effect on AHR in schoolchildren.     

The atopy trait in hypersensitivity to nonsteroidal anti-inflammatory drugs

The prevalence of atopy was evaluated in two groups of subjects with hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAID):

• 1)

  78 patients with aspirin-induced asthma (AIA) confirmed by oral or bronchial provocation challenges
• 2)

  42 subjects with hypersensitivity to pyrazolone drugs (case history and positive skin tests to noramidopyrine/aminophenazone) who tolerated aspirin well.

Fifty sex- and age-matched persons from an unselected general population, with no hypersensitivity to NSAID, formed the control group. Atopy was estimated from the results of the following clinical and biologic parameters:

• 1)

  personal and family history of atopic diseases
• 2)

  skin prick tests with 16 aeroallergens
• 3)

  serum levels of specific IgE to five aeroallergens
• 4)

  total serum IgE level.

Different definitions of atopy were used, consisting of constellations of two or three of the above-mentioned features. The results of the study revealed that the prevalence of atopy varied according to the criteria used for its definition. Irrespective of the definition used, a similar distribution of atopy was observed in both groups of patients with hypersensitivity to NSAID. Atopy was more frequent in either group of patients with intolerance of NSAID than in the control group. Thus, atopy is related to adverse drug reactions to NSAID.     

The association between birth size and atopy in young North-European adults

BACKGROUND: There is evidence that atopic disorders may begin in intra-uterine life; however, studies of birth characteristics and atopy show conflicting results. METHODS: We wanted to investigate the association of birth weight and head circumference with serum total or specific IgE, allergic rhinitis or eczema while addressing the influence of demographic and geographical factors. In this historic prospective cohort study, data were collected from birth records for 1683 men and women born in 1947-1973, from six Nordic-Baltic populations participating in the European Community Respiratory Health Survey. Blood tests for the measurement of serum total and specific IgE were available for 1494 subjects. In multiple regression analyses, adjustments were made for birth length, gender, age, study centre, adult body mass index, level of education, parental and adult smoking. RESULTS There was no association of birth weight (n=1230) and head circumference (n=285) with serum total IgE, specific IgE antibodies, allergic rhinitis or eczema. There were neither significant interactions by gender or age, nor heterogeneity between the study centres in the analyses of birth weight and adult atopy. CONCLUSION: Birth size was not associated with atopy among adults in this large Nordic-Baltic population study.     

Atopic allergy and delayed type hypersensitivity in Estonian children

BACKGROUND: A shift in the balance ofT helper (Th) cell subsets towards a polarized Th2 population is generally accepted to occur in atopic disease, however, both Th1 and Th2 disorders have increased over the past decades in Western communities. OBJECTIVE: The aim of our study was to investigate delayed type hypersensitivity (DTH) response in atopic and non-atopic children in a population with a low prevalence of allergic disorders. METHODS: Skin prick tests (SPT) were performed with fresh egg white and extracts of five inhalant allergens, i.e. cat, dog, house dust mite (Dermatophagoides pteronyssinus), birch and timothy, and DTH response was evaluated by Multitest CMI in 72 Estonian 4- to 6-year-old children. RESULTS: The frequency of response to diphtheria was significantly increased in SPT-positive children (55% vs. 26%, chi2 = 5.5; P = 0.038). The induration to diphtheria (2.4 +/- 0.5 vs. 0.9 +/- 0.2 mm; P = 0.004), and tetanus (3.5 +/- 0.6 vs. 2.1 +/- 0.3 mm; P = 0.025) was significantly greater in the SPT-positive children. The cumulative size of induration in the positive DTH tests was significantly greater in the SPT-positive children (9.0 +/- 1.2 vs. 5.2 +/- 0.6 mm, P = 0.01). CONCLUSION: In this group of children our findings do not support the hypothesis of an immune deviation with decreased Th1 and increased Th2 responses leading to atopic disease, but rather a process of immune modulation whereby both Th1 and Th2 responses are increased in atopic subjects.     

The association between infant feeding practices and subsequent atopy among children with a family history of asthma

BACKGROUND: Although longer duration of breastfeeding and later introduction of solid foods are both recommended for the prevention of asthma and allergic disease, evidence to support these recommendations is controversial. OBJECTIVE: To examine the relation between infant feeding practices and the risk of asthma and allergic disease at age 5 years. METHODS: A cohort of children with a family history of asthma in Sydney, Australia, was followed from birth to age 5 years. Data on infant feeding practices and on early manifestations of eczema were collected prospectively. The presence of eczema, asthma and atopy (positive allergen skin prick tests) were determined at age 5 years. RESULTS: In 516 children evaluated at age 5 years, there was no significant association between the duration of breastfeeding or timing of introduction of solid foods and protection against asthma or other allergic disease, after adjustment for confounding factors. However, breastfeeding for 6 months or more and introduction of solid foods after 3 months were both associated with an increased risk of atopy at age 5 years (P=0.02 and 0.01, respectively). There was no significant association between the presence of eczema at 4 weeks and at 3 months and continued breastfeeding beyond those times. CONCLUSION: Longer duration of breastfeeding and later introduction of solid foods did not prevent the onset of asthma, eczema or atopy by age 5 years.     

Hepatitis B immunization and hepatocellular carcinoma: The Gambia Hepatitis Intervention Study

The Gambia Hepatitis Intervention Study (GHIS) was initiated by the International Agency for Research on Cancer (IARC) in 1986. It consisted of a randomized trial in the Gambian population, aiming to evaluate the protection provided by HBV vaccination administered during the first year of life against primary infection, the development of chronic carriage, and primary liver cancer. The results, reported at 9 years from the introduction of the vaccine as conferring a high degree of protection (83% against primary infection and 95% against chronic carriage), are briefly discussed. It is expected that HBV vaccination will result in a reduction of mortality from hepatocellular carcinoma, the most frequent cancer in males in sub-Sahara Africa.     

Severe respiratory syncytial virus infection in early life is associated with increased type 2 cytokine production in Gambian children

BACKGROUND: Severe respiratory syncytial virus (RSV) infection in early childhood has been associated with subsequent wheezing and atopy. The aim of this study was to test if severe RSV infection in early life was associated with an increase in type 2 cytokine production and atopy in Gambian children 5 years later. METHODS: A cohort of children with severe RSV infection during the first year of life ('cases', n = 66) and without ('controls', n = 122) was followed-up at 5 years of age. Immediate hypersensitivity to common allergens, airway reactivity, serum IgE concentration and the production of IFN-gamma, IL-5 and IL-13 by lymphocytes activated in vitro with RSV F-G or control antigens was determined. RESULTS: After adjustment for confounders, cases produced significantly higher concentrations of IL-13 in response to RSV F-G and of IL-5 and IL-13 in response to tuberculin. Cases were more likely to have presented with a wheezy lower respiratory tract infection in the first 3 years of life (adjusted odds ratio = 9.9; 95% CI 1.6-61.0), but not thereafter. Cases and controls had similar skin response to allergens, airway reactivity and serum IgE concentrations. CONCLUSION: Severe RSV infection in early life is associated with a higher production of type 2 cytokines in Gambian children at 5 years of age. However this does not appear to result in increased risk of atopy or clinical allergy at that age.     

Exposure to endotoxin or other bacterial components might protect against the development of atopy

BACKGROUND: Several recent studies have shown that growing up on a farm confers significant protection against the development of atopy. These findings point particularly towards the importance of exposure to stable dust and farm animals. It has furthermore been reported that endotoxin, an intrinsic part of the outer membrane of gram negative bacteria, is abundant in environments where livestock and poultry is kept. The aim of this study was therefore to measure the level of environmental endotoxin exposure in homes of farmers' children, children with regular contact to livestock and control children with no contact to farm animals. METHODS: Eighty-four farming and nonfarming families were identified in rural areas in Southern Germany and Switzerland. Samples of settled and airborne dust were collected in stables, and of settled dust indoors from kitchen floors and the children's mattresses. Endotoxin concentrations were determined by a kinetic Limulus assay. RESULTS: Endotoxin concentrations were highest in stables of farming families, but were also significantly higher indoors in dust from kitchen floors (143 EU/mg vs 39 EU/mg, P < 0.001) and children's mattresses (49479 EU/m2 vs 9383 EU/m2, P < 0.001) as compared to control children from nonfarming families. In addition, endotoxin levels were also significantly higher in mattresses and dust from kitchen floors in households where children had regular contact to farm animals (38.6 EU/mg and 23340 EU/m2, respectively) as compared to control subjects. CONCLUSION: We propose that the level of environmental exposure to endotoxin and other bacterial wall components is an important protective determinant for the development of atopic diseases in childhood.     

The association between atopy and asthma in a semirural area of Tanzania (East Africa)

BACKGROUND: Atopy is consistently associated with asthma, except in a study in Africa. We assessed the association between atopy and asthma in women from a semirural area of Tanzania (East Africa). METHODS: All pregnant women delivering at the district hospital during a 1-year period were recruited (n = 658, 60.6% of those selected). Asthma was investigated by a standard questionnaire and atopy by specific IgE (immunoglobulin E) antibodies to Dermatophagoides pteronyssinus (Der p 1) and cockroach. RESULTS: The prevalence of wheezing chest was 10.7%; of asthma, 3.5%. Levels of specific IgE of >0.35 kU/l (73%) and high levels of total IgE (62% higher than 1000 kU/l) were highly prevalent. Specific IgE antibody levels in sera were not associated with asthma (3.8% of women with negative specific IgE to any antigen had asthma in comparison to 4.0% of women with positive specific IgE; odds ratio [OR] = 1.06, 0.35-3.22). Total IgE was not different between women with asthma and women without asthma (P=0.36). CONCLUSIONS: In tropical regions, the association between allergy and asthma is complex, and specific IgE reactivity to environmental allergens may not be related to asthma.     

Risk factors for atopy among school children in a rural area of Latin America

BACKGROUND: Infection with common childhood infectious diseases including geohelminth infections may provide protection against the development of atopy and allergic disease. Few studies have investigated risk factors for atopy among children living in rural areas of Latin America. OBJECTIVE: To identify risk factors associated with atopy among school-age children in a rural area of Latin America. METHODS: Analytic cross-sectional study of school-age children conducted in seven rural schools in Pichincha Province in Ecuador. Detailed risk factor information was obtained by questionnaire, stool samples were collected for identification of geohelminth parasites, and Mantoux testing was performed to determine tuberculin sensitization. RESULTS: A total of 1002 children from seven rural schools were recruited. The prevalence of geohelminth infections was high (70.1% were infected with at least one geohelminth parasite) and the prevalence of allergic sensitization was high (20.0% had evidence of aeroallergen sensitization). Factors associated with significant protection against atopy in multivariate analyses were the presence of overcrowding in the child's home, low socio-economic level, and infection with geohelminth parasites, and the protective effects of the three factors were statistically independent. CONCLUSION: Low socio-economic level, overcrowding and geohelminth infection, are independently protective against atopy among school-age children living in a rural area of Latin America.     

Early BCG vaccination and reduction in atopy in Guinea-Bissau

BACKGROUND: It has been proposed that certain viral and bacterial infections in early childhood may prevent allergic sensitization, by inducing Th1-type immune responses. This has led to speculation that mycobacterial vaccines might, through their Th1-stimulating properties, also protect against atopy. OBJECTIVE: To investigate whether the prevalence of atopy is lower in children who have been vaccinated with BCG in infancy than in children who have not been vaccinated. METHODS: We measured skin test reactivity to three allergens (Dermatophagoides pteronyssinus, D. farinae and cockroach) in 400 children, aged 3-14 years, as part of a follow-up study to examine the immune sequelae of measles in an urban area of Bissau, the capital of Guinea-Bissau in west Africa. Information on childhood vaccinations, including BCG in infancy, was available from child records. Of these children, 271 had been vaccinated with BCG (according to records) and 53 had not been vaccinated (no record and no BCG scar). Atopy was defined in two ways, according to the presence of any allergen reaction > or = 2 mm and any reaction > or = 3 mm. RESULTS: Of the children who had received BCG vaccine, 57 (21%) were atopic (any reaction > or = 2 mm), compared with 21 (40%) of the unvaccinated children [odds ratio, after controlling for potential confounding factors, 0.19 (95% CI 0.06-0.59)]. When atopy was defined using the 3-mm criterion, the reduction in atopy associated with BCG was greater the earlier the age at vaccination, and the largest reduction was seen in children vaccinated in the first week of life. CONCLUSION: BCG vaccination given early in infancy may prevent the development of atopy in African children.     

Asthma, allergic rhinitis and atopic eczema in Finnish children and adolescents

The parents of 3649 Finnish children and adolescents were interviewed in 1980 to evaluate the prevalence of bronchial asthma, allergic rhinitis and atopic dermatitis. The same group was interviewed 6 years later to determine the incidence of new cases of bronchial asthma in the 1980s. Age- and sex-matched samples were taken from three areas, southern, eastern and northern Finland to allow assessment of possible regional differences in prevalences and incidences. The prevalences of atopic eczema, allergic rhinitis and asthma were 1.7%, 6.0% and 4.3%, respectively. These figures are similar to those found in previous studies in Scandinavia and Finland over 10 years ago. The prevalence of atopy was highest (6.4%) in southern Finland, which is the most urbanized area of our country. The prevalence of asthma was highest (3.3%) in northern Finland. This is still low when compared with the incidences in other European countries. THe prevalences of asthma and atopy were lowest in eastern Finland which is the most agrarian area. The incidence of asthma was 1.5 cases/1000 individuals/year, but regional differences were shown.     

Histological and immunopathological studies of delayed hypersensitivity reaction to tuberculin in mice

At 4 to 6 weeks after intravenous infection with 2 X 10(4) CFU of dispersed Mycobacterium bovis bacilli (BCG), C3H/HeNCrIBR and C57BL/6NCrIBR mice exhibited a strong reaction to purified protein derivatives, as evaluated by the increase in footpad swelling at both 24 and 48 h after local antigenic challenge. However, histological studies of the footpad skin demonstrated a prominent perivascular infiltration with polymorphonuclear cells at 6 and 24 h after purified protein derivative challenge, whereas mononuclear cells represented the majority of infiltrating cells only at 48 h. An immunopathological study of the footpad skin showed granular deposits of immunoglobulins and complement in vascular walls and perivascular tissues at 6 and 24 h. These results demonstrate that the footpad swelling observed 24 h after the antigenic challenge is caused by an Arthus-type reaction, whereas that caused by cell-mediated immunity appears at 48 h. Hence, delayed hypersensitivity must be evaluated at 48 and not 24 h after challenge.     

Enhanced expression of type 1 procollagen and transforming growth factor-beta in tuberculin induced delayed type hypersensitivity.

AIMS--Tissue fibrosis is a common and serious consequence of chronic inflammation. The mechanism linking these two processes is poorly understood. The present study has utilised a human in vivo model of a delayed type hypersensitivity (DTH) reaction, the tuberculin Heaf reaction, induced by intradermal tuberculin in BCG immunised subjects, to dissect the relation between these two processes. METHODS--Punch skin biopsy specimens were obtained on day 5, day 13 and six to 16 weeks following the tuberculin Heaf test in 18 subjects with grade 3 or 4 responses. Skin biopsy specimens from six subjects served as controls. The specimens were examined using immunohistochemical staining for type 1 procollagen and transforming growth factor-beta (TGF-beta), as well as in situ hybridisation for type 1 procollagen messenger RNA (mRNA). RESULTS--Immunohistochemical analysis revealed increased deposition of TGF-beta in tissue matrix in the biopsy specimens obtained on day 5 following the tuberculin Heaf test. There was also extensive type 1 procollagen staining in the biopsy specimens obtained as early as day 5. Procollagen-1 staining was maximal on day 13, and was present in biopsy specimens from tuberculin Heaf test sites up to eight weeks after the tuberculin inoculation. The type 1 procollagen was localised within cells surrounding areas of inflammatory infiltrate and in perivascular tissues. The presence of new collagen formation was confirmed by in situ hybridisation using oligonucleotide probes for type 1 procollagen mRNA in cells in sections from biopsy specimens obtained on day 13. CONCLUSIONS--These data from a human in vivo model of a DTH response indicate that the immune response is intimately associated with an increase in the production of growth factors and the initiation of a fibrotic response.     

Lack of evidence of a significant association between HLA-DR, DQ and DP genotypes and atopy in families with HDM allergy

Background HLA class II genetic polymorphism has been variably implicated in susceptibility to specific immune responsiveness to house dust mite (HDM) allergens, and may also influence the development of atopy. Objective In order to assess accurately the influence of HLA alleles in the atopic immune response, we typed 22 families selected from 131 previously obtained randomly selected families (i.e. without regard to atopy or asthma), chosen on the basis of two or more members having skin prick reactivity to HDM. Methods Each individual was fully typed for HLA-DRB1, DQA1, DQB1 and DPB1 class II alleles using a combination of sequence-specific oligonucleotide probes (SSOP) and sequence-specific primer (SSP) polymerase chain reaction (PCR) typing and direct sequencing. Results Using appropriate statistical tests, no significant allelic associations were found between any DRBl, DQB1 or DPBl alleles and atopy or skin prick reactivity to Dermataphagoides pteronyssinus (Der p) or D. farinae (Der f). However, positive associations were found between DQA 1*0301 and skin prick reactivity to Der f (P= 0.009) and atopy (P= 0.027). Sib-pair analysis revealed no significant sharing of alleles between affected sib pairs for any of the phenotypes studied. Conclusion These results fail to confirm a previously reported association between the DRB1*04 and 07 haplotypes and atopy, and suggest that HLA class II restriction does not play a major role in the development of the IgE response to domestic house dust mite allergens in the British population.     

A differing pattern of association between dietary fish and allergen-specific subgroups of atopy

BACKGROUND: We examined the role of fish intake in the development of atopic disease with particular reference to the possibility of differential effects on allergen-specific subgroups of sensitization. METHODS: The exposure of interest was parental report of fish intake by children aged 8 years at the 1997 Childhood Allergy and Respiratory Health Study (n = 499). The outcomes of interest were subgroups of atopy: house dust mite (HDM)-pure sensitization [a positive skin-prick test (SPT) > or = 2 mm to Der p or Der f only], ryegrass-pure sensitization (a positive SPT > or = 2 mm to ryegrass only); asthma and hay fever by allergen-specific sensitization. RESULTS: A significant association between fish intake and ryegrass-pure [adjusted odds ratio (AOR) 0.37 (0.15-0.90)] but not HDM-pure sensitization [AOR 0.87 (0.36-2.13)] was found. Fish consumption significantly decreased the risk for ryegrass-pure sensitization in comparison with HDM-pure sensitization [AOR 0.20 (0.05-0.79)]. CONCLUSIONS: We have demonstrated a differential effect of fish intake for sensitization to different aeroallergens. This may be due to the different timing of allergen exposure during early life. Further investigation of the causes of atopic disease should take into account allergen-specific subgroups.     

Which factors explain the lower prevalence of atopy amongst farmers' children?

BACKGROUND: The inverse association between farming and atopy in children has been attributed to microbial exposure, especially through livestock. Very little is known about other potential explanatory factors. OBJECTIVE: To explore potential differences in lifestyle and environmental factors between farmer and non-farmer families, and whether these factors could explain the association between farming and childhood atopy. METHODS: A cross-sectional study, including 366 farmers' and 344 non-farmers' children in eastern Finland. Information regarding exposure and background characteristics was gathered by a written questionnaire. Atopy was defined as having one or more positive skin prick test reactions (> 3 mm) against the six common aeroallergens. RESULTS: Regardless of the current farming type, atopy was less frequent among the farmers' children than the non-farmers' children (aOR 0.56, 95% CI 0.40-0.78). Remarkable differences were seen in many lifestyle factors (including diet) between the farmer and non-farmer families, but only a few of the explored factors were associated with atopy. The frequency of current livestock contacts seemed to have an inverse, dose-dependent association with atopy (aOR 0.46, 95% CI 0.22-0.97 for daily vs. no contact). Having lived on a dairy farm in infancy (aOR 0.51, 95% CI 0.28-0.93), or having had cats or dogs in infancy (aOR 0.60, 95% CI 0.42-0.85), decreased the risk of atopy at school age. The inverse association between farming and atopy was not explained by the sociodemographic factors, or by differences in conventional risk factors of atopy. Animal contacts explained partially, but not completely, the association. CONCLUSION: Higher frequency of animal contacts is one factor, but probably not the only one, explaining the inverse association of farming and atopy in children. The importance of early life exposures may have recently been over-emphasized, and current exposures discounted, when studying the risk factors of childhood atopy.