Abstract
Controversy persists as to whether helminth infections cause or protect against asthma and atopy. The aim of this study was to investigate the effects of helminth infection on asthma and atopy among Bangladeshi children. A total of 912 children aged 4.5 years (mean = 54.4, range = 53.5–60.8 months) participated in a cross-sectional study nested into a randomized controlled trial in Bangladesh. Ever-asthma, ever-wheezing and current wheezing were identified using the International Study of Asthma and Allergies in Childhood questionnaire. Current helminth infection was defined by the presence of helminth eggs in stools, measured by routine microscopic examination. Repeated Ascaris infection was defined by the presence of anti-Ascaris IgE ≥ 0.70 UA/ml in serum measured by the CAP-FEIA method. Atopy was defined by specific IgE to house dust mite (anti-DP IgE) ≥ 0.70 UA/ml measured by the CAP-FEIA method and/or positive skin prick test (≥ 5 mm). Anti-Ascaris IgE was significantly associated with ever asthma (odds ratio (OR) = 1.86, 95% CI: 1.14–3.04, highest vs. lowest quartile; P for trend 0.016). Anti-Ascaris IgE was also significantly associated with positive anti-DP IgE (OR = 9.89, 95% CI: 6.52–15.00, highest vs. lowest; P for trend < 0.001) and positive skin prick test (OR = 1.69, 95% CI: 1.01–2.81, highest vs. lowest, P for trend 0.076). These findings suggest that repeated Ascaris infection is a risk factor for asthma and atopy in rural Bangladeshi children. Further analysis is required to examine the mechanism of developing asthma and atopy in relation to helminth infection.
Keywords: pediatric asthma, atopy, IgE, helminth infection, Bangladesh
Introduction
Asthma and allergic diseases pose a serious public health problem in many middle and low-income countries. Asthma is a chronic inflammatory disease of the airways and one of the most common diseases of childhood. Atopy is an increased level of immunoglobulin against common allergens as well as house dust mites. Currently, asthma affects 300 million people worldwide [1]. There are estimates that lifetime prevalence of atopic dermatitis in school children in Western countries is now in the range of 10% to 20%. In the United States, the prevalence of asthma rose from 30.7 per 1000 in 1980 to 53.8 per 1000 in 1993–1994 [2]. In Western countries, serial prevalence studies have shown an increasing trend toward childhood asthma and airway hyper-responsiveness [3]. It has been established that the cause of allergic diseases is multifactorial: the main factors related to the development of allergic diseases having been identified as allergen exposure, pollutant exposure, endotoxin exposure, immunizations, diet, genetic predisposition, and exposure to parasites and viruses [4]. There is now increasing interest in whether helminth infections cause or protect against asthma and atopy. It is estimated that 2 billion people worldwide are currently infected with the intestinal parasites Ascaris lumbricoids, Trichuris trichiura, hookworm, and Strongyloides stercoralis [5]. As many as 150,000 deaths per annum (at an incidence rate of 0.015%) may be attributed to intestinal helminthiasis [6]. Previous studies mentioned the multi-dimensional relationship between helminth infections and asthma and atopy [7]. However, the association between helminth infection and childhood asthma and atopy remains controversial [8]. In the present study, we examined the effects of helminth infections on asthma and atopy among children in Bangladesh, where repeated helminth infections occur and the prevalence of asthma and atopy is increasing [9, 10].
Materials and Methods
Study area and population
This cross-sectional study was nested into a large-scale randomized clinical trial of nutrition interventions in pregnancy, namely the Maternal and Infant Nutrition Intervention in Matlab (MINIMat) Trial (trial registration: isrctn.org Identifier: ISRCTN16581394) [11]. Matlab is a rural region of Bangladesh located about 50 km southeast of the capital city of Dhaka [12]. The International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), has been running a health and demographic surveillance system (HDSS) in the area since 1966 that covers a population of about 220,000. Community health research workers visit every household on a monthly basis to update information on demographic events such as, marriage, pregnancy, birth, death and in- and out-migration, as well as to collect information on the morbidity of children below five years of age and women of childbearing age. Socioeconomic information, including education and household assets, is also recorded by periodic censuses [12]. The details of the MINIMat study have been described elsewhere [11].
Study subjects and design
The 4,436 mothers in the MINIMat trial were followed during pregnancy when data on the socioeconomic status (SES) and morbidity of mothers were collected. Information about their children’s gestational age, birth weight, birth length, head circumference and chest circumference were also collected at delivery. Out of these, a total of 3,625 singleton babies were born. A total of 2,745 children were eligible for a follow-up assessment when they reached 4.5 years of age. To reduce the burden of repeated examinations on each child in the multi-component 4.5 year follow-up study, the children were split into two groups according to the year of birth (Group A, May 2002 to April 2003; Group B May 2003 to April 2004). The study component of immunity, asthma and allergic diseases was included in the protocol using Group B children. There was no significant statistical difference between the two groups with regard to basic characteristics of age, sex and socioeconomic status.
Laboratory procedures
Stools from the participants were collected in the morning for helminth egg counts by routine microscopy examination. After the count, the numbers of eggs was categorized into low < 5/high power field (hpf), moderate 5–10/hpf and high > 10/hpf. The stools were also grouped as positive or negative according to the presence or absence of eggs. Moreover, 5 ml of venous blood was collected to measure specific IgE against Ascaris and house dust mites (Dermatophagoides pteronyssinus) in the serum. The serum samples were separated and kept at −70°C until analysis. Specific IgE levels against Ascaris and house dust mites were measured by the CAP-FEIA method (Phadia AB, Uppsala, Sweden). Both anti-Ascaris IgE and anti-DP IgE ≥ 0.70 UA/ml were evaluated according to the guidelines provided by the manufacturer. Immediate hypersensitivity reaction was determined by a skin prick test using a mite allergen (Dermatophagoides pteronyssinus) following standard procedures (Torii Pharmaceutical Co. Ltd. Tokyo, Japan). Skin reactions were recorded at 20 minutes as the average of the maximum wheel diameters. A swelling size equal to or greater than 5 mm in diameter was considered positive. Atopy was defined as IgE against dust mites ≥ 0.70 UA/ml and/or the presence of positive skin prick test.
Questionnaires
Ever asthma, ever wheezing and current wheezing were identified using the International Study on Asthma and Allergies in Childhood (ISAAC) questionnaire [13]. Ever-asthma was defined as asthma symptoms at any point in the past. Ever-wheezing was defined as wheezing symptoms at any point in the past, while current wheezing was defined as wheezing symptoms within the last 12 months. The written ISAAC questionnaires were translated into Bangla, the national and local language, following the ISAAC protocol. A trained expert in both Bangla and English translated the original ISAAC questionnaire. Then it was back-translated into English by another bilingual expert. The translated questionnaire was pretested and necessary modifications made before data collection. The ISAAC questionnaires were administered by trained interviewers.
Ethical considerations
This study was approved by the research review committees and ethical review committees of both icddr,b and Uppsala University. Written informed consent was obtained from each child’s legal guardian prior to participation in the study.
Statistical analysis
Data were categorized and analyzed using SPSS statistics version 21.0 (IBM Corporation, NY, USA). Descriptive statistics were performed for age, sex, asthma information, specific IgE, skin prick test, history of diarrhea and parasite egg counts. Values were expressed as means, standard deviation (SD), number (n) and percentage (%). Socio-economic status (SES) was estimated using a wealth index based on information about household assets and the related principal component analysis, producing a weighted score [14]. Scores were categorized into quintiles, with category 1 representing the poorest and category 5 the richest. Anti-Ascaris IgE was classified into quartiles based on the distribution of the study participants. The linear trends of association with ever-asthma, positive anti-DP IgE and positive skin prick test were tested by an ordinal variable for quartiles of anti-Ascaris IgE titre. Univariate logistic regression was performed to examine the association between anti-Ascaris IgE, A. lumbricoids egg count, T. trichiura egg count and asthma and atopy. Finally, multivariate logistic regressions were performed including the available covariates (sex, socioeconomic status, family history of asthma, history of diarrhea, and intervention trial arm) for asthma and atopy. The associations were estimated as odds ratios (ORs) together with a 95% confidence interval (95% CI). Two-sided p-values less than 0.05 were considered statistically significant.
Results
The mean age of children in this cross-sectional study was 54.4 months (range 53.5–60.8 months). Boys accounted for 52.6% of the sample. Ever-asthma was found in 18.0% of the children, current wheezing in 19.7% and ever-wheezing in 45.2%. Family history of asthma was positive for 22.0% of the children. Anti-Ascaris IgE was positive for 69.7% and anti-DP IgE was positive for 44.3%. The skin prick test with mite antigen (Dermatophagoides pteronyssinus) was positive in 15.7% of the study children (Table 1). To see the intensity of active helminth infection, we considered the details of the helminth egg counts: A. lumbricoids egg in stool was 17.4% positive, T. trichiura was 17.5% positive, hookworm was scarce at only 0.4% positive. Categorizing the egg counts as low, moderate and high, we found a low level of Ascaris eggs in 11.0% of stools, a moderate level of eggs in 5.8%, but a high level in only 0.6%. Most of the Trichuris egg counts were at a low level (16.9%), very few at a moderate level (0.6%), and none at a high level (Table 2).
Table 1.
Number of cells in pSC or aSC macrochatatete cell lineage from 0–6 h APF
| Characteristics | n | % |
|---|---|---|
| Age of the children (month) | 54.4 ± 0.7* | |
| Sex (boys) | 480 | 52.6 |
| Ever asthma | 164 | 18.0 |
| Ever wheezing | 412 | 45.2 |
| Current wheezing | 180 | 19.7 |
| Family history of asthma (positive) | 201 | 22.0 |
| Anti-Ascaris IgE (positive) | 636 | 69.7 |
| Anti-DP IgE (positive) | 404 | 44.3 |
| Mite antigen skin prick test (positive) | 139 | 15.7 |
| History of diarrhea in last 15 days (yes) | 123 | 13.5 |
| Socioeconomic status (calculated by asset score) | ||
| Poor | 148 | 16.2 |
| Below Middle | 187 | 20.5 |
| Middle | 180 | 19.7 |
| Upper Middle | 195 | 21.4 |
| Wealthy | 202 | 22.1 |
*Mean ± SD
Table 2.
Helminth egg counts of the study participants (n = 890)
| n | % | |
|---|---|---|
| A. lumbricoids eggs in stool (positive) | 155 | 17.4 |
| Low (< 5/hpf*) | 98 | 11.0 |
| Moderate (5–10/hpf) | 52 | 5.8 |
| High (> 10/hpf) | 5 | 0.6 |
| T. trichiura eggs in stool (positive) | 156 | 17.5 |
| Low (< 5/hpf) | 151 | 16.9 |
| Moderate (5–10/hpf) | 5 | 0.6 |
| High (> 10/hpf) | 0 | 0.0 |
| Hookworm eggs in stool (positive) | 4 | 0.4 |
| Few (< 5/hpf) | 3 | 0.3 |
| Moderate (5–10/hpf) | 1 | 0.1 |
| High (> 10/hpf) | 0 | 0.0 |
*High power field
Univariate logistic regression analysis revealed that anti-Ascaris IgE was significantly associated with ever-asthma (OR = 1.93, 95% CI: 1.23–2.04, highest compared with lowest quartile; P for trend 0.007) but was not associated with either current wheezing (OR = 1.40, 95% CI: 0.91–2.17; highest compared with lowest quartile) or ever-wheezing (OR = 1.04, 95% CI: 0.73–1.48; highest compared with lowest quartile). We also analyzed the relationship between ever-asthma and anti-Ascaris IgE as positive/negative and found a significant association in univariate analysis (OR = 1.49, 95% CI: 1.00–2.20) but not after adjustment in multivariate analysis (OR = 1.34, 95% CI: 0.86–2.09). A. lumbricoids and T. trichiura egg count in stools did not show any significant association with ever-asthma (OR = 0.78, 95% CI: 0.48–1.25) and (OR = 1.02, 95% CI: 0.65–1.60). In the multivariate model, after adjustment for available co-variables, anti-Ascaris IgE remained significantly associated with ever-asthma (OR = 1.86, 95% CI: 1.1–3.04, highest compared with lowest quartile; P for trend 0.016) (Table 3). We also looked for a correlation between stool egg count and anti-Ascaris IgE but did not find any such influence (P = 0.21).
Table 3.
Unadjusted and adjusted odds ratio with 95% CI interval for ever asthma with sex, stool egg count and anti-Ascaris IgE
| Ever asthma |
||||
|---|---|---|---|---|
| Yes n (%) | No n (%) | Unadjusted OR (95% CI) | Adjusted* OR (95% CI) | |
| Sex (n = 912) | ||||
| Boys | 96 (20.0) | 384 (80.0) | 1.34 (0.95–1.88) | 1.42 (0.98–2.07) |
| Girls | 68 (15.7) | 364 (84.3) | 1 | 1 |
| A .lumbricoids eggs (n = 890) | ||||
| Positive | 24 (15.4) | 132 (84.6) | 0.78 (0.48–1.25) | 0.79 (0.47–1.33) |
| Negative | 139(18.9) | 595 (81.1) | 1 | 1 |
| T. trichiura eggs (n = 890) | ||||
| Positive | 29 (18.6) | 127 (81.4) | 1.02 (0.65–1.60) | 1.19 (0.73–1.94) |
| Negative | 134(18.3) | 600 (81.7) | 1 | 1 |
| Anti-Ascaris IgE (n = 912)** | ||||
| Positive | 125(19.7) | 511 (80.3) | 1.49 (1.00–2.20) | 1.34 (0.86–2.09) |
| Negative | 39 (14.1) | 237 (85.9) | 1 | 1 |
| Anti-Ascaris IgE (n = 912) | ||||
| P for trend = 0.007 | P for trend = 0.016 | |||
| 4th quartile | 55 (24.1) | 173 (75.9) | 1.93 (1.23–3.04) | 1.86 (1.14–3.04) |
| 3rd quartile | 39 (17.2) | 188 (82.8) | 1.26 (0.78–2.04) | 1.24 (0.74–2.08) |
| 2nd quartile | 31 (17.1) | 150 (82.9) | 1.25 (0.75–2.10) | 1.18 (0.68–2.04) |
| 1st quartile | 39 (14.1) | 237 (85.9) | 1 | 1 |
*Adjusted for sex, socioeconomic status, family history of asthma, history of diarrhea and intervention trial arm
**Anti-Ascaris IgE ≥ 0.70 UA/ml considered as positive
We found that anti-Ascaris IgE was significantly associated with anti-DP IgE (OR = 9.93, 95% CI: 6.57–15.00, highest compared with lowest quartile; P for trend < 0.001) in the univariate model. After adjustment for available co-variables, the relationship between anti-Ascaris IgE and anti-DP IgE remained significant (OR = 9.89, 95% CI: 6.52–15.00, highest compared with lowest quartile; P for trend < 0.001). We analyzed the relationship between positive anti-DP IgE and anti-Ascaris IgE as positive/negative and found it to be significant both in univariate (OR = 5.34, 95% CI: 3.80–7.50) and multivariate (OR = 5.33, 95% CI: 3.77–7.53) analysis. We also found that, compared with girls, boys were significantly associated with anti-DP IgE both in univariate (OR = 1.52, 95% CI: 1.17–1.98) and multivariate analysis (OR = 1.48, 95% CI: 1.11–1.96) (Table 4).
Table 4.
Unadjusted and adjusted odds ratio with 95% CI interval for anti-DP IgE with sex, stool egg count and anti-Ascaris IgE
| Positive anti-DP IgE* |
||||
|---|---|---|---|---|
| Yes n (%) | No n (%) | Unadjusted OR (95% CI) | Adjusted** OR (95% CI) | |
| Sex (n = 912) | ||||
| Boys | 236 (49.2) | 244 (50.8) | 1.52 (1.17–1.98) | 1.48 (1.11–1.96) |
| Girls | 168 (38.9) | 264 (61.1) | 1 | 1 |
| A. lumbricoids eggs (n = 890) | ||||
| Positive | 64 (41.0) | 92 (59.0) | 0.84 (0.59–1.20) | 0.92 (0.63–1.35) |
| Negative | 332 (45.2) | 402 (54.8) | 1 | 1 |
| T. trichiura eggs (n = 890) | ||||
| Positive | 65 (41.7) | 91 (58.3) | 0.87 (0.62–1.24) | 0.96 (0.66–1.41) |
| Negative | 330 (45.0) | 404 (55.0) | 1 | 1 |
| Anti-Ascaris IgE (n = 912)*** | ||||
| Positive | 352 (55.3) | 284 (44.7) | 5.34 (3.80–7.50) | 5.33 (3.77–7.53) |
| Negative | 52 (18.8) | 224 (81.2) | 1 | 1 |
| Anti-Ascaris IgE (n = 912) | ||||
| P for trend = <0.001 | P for trend = <0.001 | |||
| 4th quartile | 159 (69.7) | 69 (30.3) | 9.93 (6.57–15.00) | 9.89 (6.52–15.00) |
| 3rd quartile | 108 (47.6) | 119 (52.4) | 3.91 (2.62–5.82) | 3.90 (2.61–5.82) |
| 2nd quartile | 85 (47.0) | 96 (53.0) | 3.81 (2.51–5.80) | 3.92 (2.57–5.99) |
| 1st quartile | 52 (18.8) | 224 (81.2) | 1 | 1 |
*Anti-DP IgE ≥ 0.70 UA/ml considered as positive
**Adjusted for sex, socioeconomic status, family history of asthma, history of diarrhea and intervention trial arm
***Anti-Ascaris IgE ≥ 0.70 UA/ml considered as positive
We further tested the association between Ascaris egg count and anti-Ascaris IgE using the skin prick test and observed that Ascaris egg count was not significant in either univariate or multivariate analysis (OR = 1.00, 95% CI: 0.62–1.61) and (OR = 1.01, 95% CI: 0.62–1.65). However, anti-Ascaris IgE was significant both in univariate (OR = 1.68, 95% CI: 1.01–2.79, highest compared with lowest quartile, P for trend 0.079) and multivariate analysis (OR = 1.69, 95% CI: 1.01–2.81, highest compared with lowest quartile, P for trend 0.076). The skin prick test was also significant when tested for an association with anti-Ascaris IgE (OR = 1.63, 95% CI: 1.06–2.50) as positive/negative (Table 5). In addition, anti-DP IgE and skin prick test had no significant association with ever-asthma (OR = 0.91, 95% CI: 0.51–1.61) and OR = 1.37, 96% CI: 0.83–2.28).
Table 5.
Unadjusted and adjusted odds ratio with 95% CI interval for skin prick test for D. pteronyssinus antigen with sex, stool egg count and anti-Ascaris IgE
| Positive skin prick test* |
||||
|---|---|---|---|---|
| Yes n (%) | No n (%) | Unadjusted OR (95% CI) | Adjusted** OR (95% CI) | |
| Sex (n = 886) | ||||
| Boys | 75 (16.2) | 389 (83.8) | 1.08 (0.75–1.55) | 1.08 (0.75–1.55) |
| Girls | 64 (15.2) | 358 (84.8) | 1 | 1 |
| A. lumbricoids eggs (n = 769) | ||||
| Positive | 11 (15.5) | 604 (84.5) | 1.00 (0.62–1.62) | 1.01 (0.62–1.65) |
| Negative | 24 (15.6) | 130 (84.4) | 1 | 1 |
| T. trichiura eggs (n = 869) | ||||
| Positive | 114 (15.9) | 603 (84.1) | 0.89 (0.55–1.47) | 0.89 (0.54–1.50) |
| Negative | 22 (14.5) | 130 (85.5) | 1 | 1 |
| Anti-Ascaris IgE (n = 886)*** | ||||
| Positive | 108 (17.5) | 510 (82.5) | 1.62 (1.05–2.48) | 1.63 (1.06–2.50) |
| Negative | 31 (11.6) | 237 (88.4) | 1 | 1 |
| Anti-Ascaris IgE (n = 886) | ||||
| P for trend = 0.079 | P for trend = 0.076 | |||
| 4th quartile | 40 (18.0) | 182 (82.0) | 1.68 (1.01–2.79) | 1.69 (1.01–2.81) |
| 3rd quartile | 35 (16.1) | 183 (83.9) | 1.46 (0.87–2.46) | 1.46 (0.89–2.46) |
| 2nd quartile | 33 (18.5) | 145 (81.5) | 1.74 (1.02–2.96) | 1.76 (1.03–2.30) |
| 1st quartile | 31 (11.6) | 237 (88.4) | 1 | 1 |
*Skin prick test ≥ 5 mm considered as positive
**Adjusted for sex, socioeconomic status, family history of asthma, history of diarrhea and intervention trial arm
***Anti-Ascaris IgE ≥ 0.70 UA/ml considered as positive
Discussion
The results of the present study implicated anti-Ascaris IgE as a possible risk factor for asthma and atopy in children. In particular, ever-asthma and atopy were positively associated with elevated serum anti-Ascaris IgE, a finding similar to that of a previous study [15]. But stool egg counts did not show any association. Elevated serum IgE due to helminthes does not necessarily indicate an active infection because it reflects both current and past infections [16, 17], suggesting that repeated Ascaris infection, rather than only the presence of infection, is a risk factor for asthma and atopy in children.
Exactly a century ago, Herrick recognized for the first time that helminth infections can trigger asthma [18]. After his work in the early 20th century, very little attention was paid to the potential links between endoparasitic infestations and asthma until the 1970s. Many authors emphasized that further evidence is needed to either support or disprove the hypothesis that parasites cause asthma and allergies. A more recent systematic review and meta-analysis of 30 cross-sectional studies found that an inverse relationship exists between asthma and geohelminths for hookworm infection and that this effect was related to infection intensity. However, A. lumbricoids appeared to increase asthma risk while T. trichiura exerted no significant effect [19], which is similar to our findings. In our study area, helminth infections are endemic but the intensity of infections is not particularly high, indicating that low intensity but continuous presence of infection might cause allergic sensitization. In our study, we found that ever-asthma was associated with Ascaris infection but not current wheezing or ever-wheezing. It is postulated that wheezing symptoms may be misinterpreted by parents. Wheezing in children is usually related to lower respiratory tract infections which are caused by common respiratory viral or bacterial infections. Asthma, on the other hand, is a more specific disease and is usually diagnosed by medical personnel.
Previous studies have provided conflicting evidence showing that helminth infection inhibits [20, 21], causes [22] or is unrelated to asthma and atopic diseases [23, 24]. The role of anti-Ascaris IgE in the development of asthma is not clear. One possible explanation for the relationship is that elevated anti-Ascaris IgE levels are associated with larval migration after re-infection, as Ascaris migrates through the lungs during maturation and causes pulmonary infiltrates of Th2 immunity and episodic airway obstruction associated with wheezing [25]. It is postulated that, due to the high prevalence of infection in this area, repeated Ascaris infections and larval migration could increase the risk of asthma symptoms. Another explanation is that anti-Ascaris IgE acts as IgE specific to common inhaled aero-antigens directly triggering mast cell activation [26]. This finding is supported by two other studies in which researchers who handled helminthes suffered from wheezing [27] and fisherman who suffered from wheezing caused by IgE-mediated hypersensitivity to common earthworms [28]. The third explanation is that the higher anti-Ascaris IgE levels in the wheezing group simply mean that atopic children produce more anti-Ascaris IgE in response to Ascaris infection [29]. Another explanation is that the human immune response to helminth infections is associated with elevated levels of IgE, tissue eosinophilia and mastocytosis and the presence of CD4+ T cells that preferentially produce IL-4, IL-5 and IL-13 [30]. Still another explanation is that parasites in the tissues stimulate a strong localized Th2 response, characterized by an eosinophil-rich inflammatory infiltrate [31].
Our study confirms the existence of an association between atopy and repeated Ascaris infections shown by anti-Ascaris IgE. The intriguing “Hygiene Theory” suggests that exposure to infection, or lack of exposure, produces the conditions necessary for the development of atopy. On the one hand, because of a lack of bacterial infections (or lack of viral infections because of immunization), lower levels of IL-12 result in decreased Th1 stimulation which allows the bias of the immune system toward Th2 to be realized. On the other hand, exposure to parasites may influence Th1 dominance [32, 33]. In 2001, the World Health Assembly passed a resolution urging member states to control the morbidity of soil–transmitted helminth infections through large-scale use of anthelmintic drugs among school-aged children in less developed countries [34]. Following that resolution, deworming medication was initiated in the study area once in every six month interval among children from two to five years old in 2004. Some earlier studies indicated that deworming may increase the IgE level, but a recent study from Cuba indicated that deworming is not a risk factor for atopic diseases [35].
We found that boys were more prone than girls to increased anti-DP IgE, which is similar to a previous report [36]. Population-based large birth cohort studies showed that total IgE and allergen-specific IgE concentrations varied by gender [36, 37]. The observation that total IgE increases more rapidly in boys than in girls during early childhood was consistent with the many previous reports of a higher prevalence of asthma among boys than girls prior to puberty [38]. These gender differences in IgE development were related to the differences in risk factors associated with asthma and differences in the prevalence of asthma between boys and girls.
In our study, the results of the skin prick test were related to anti-Ascaris IgE but not to helminth egg count. The relationship of the test results to helminth infections may depend on the intensity and chronicity of helminth infections. Thus the lack of an effect of present worm infection on skin prick test reactivity in our study and those of Palmer et al. [22] and Cooper et al. [24] might be due to the lower intensity as compared to that in which skin prick test reactivity was inversely related to helminthiases [32]. The suppression of skin prick test reactivity to aeroallergens by geohelminth infection is postulated on the basis of a biological model in which helminth infections actively inhibit allergic effector responses including immediate hypersensitivity [33]. In our study there was no association between asthma and atopy, which is similar to a previous Latin American study on children and adolescents in underprivileged populations [39], indicating that the asthma in our study area is the non-atopic type. The association between asthma and atopic sensitization increases with economic development, a trend evidenced in industrialized countries. In the ISAAC Phase II study, the population fraction of asthma attributable (PAF) to atopy measured by the skin prick test was 41% in affluent countries but only 20% in non-affluent countries among children aged 8–12 years [40]. Moreover, in the two Latin American study centers included in the ISAAC Phase II study (Pichincha Province, Ecuador and Uruguaiana, Brazil), only 11% of asthma was attributable to atopy measured by the skin prick test, while a study of children of the same age living in rural Esmeraldas Province in Ecuador showed that only 2.4% of asthma was attributable to atopy measured by the same test. The weak association between asthma and atopy in those populations could be explained by the attenuation of atopy or Th2-mediated allergic responses by environmental factors including chronic helminth infections [41].
One strength of the current cross-sectional study is the relatively large sample size, which promotes confidence in the results reported. Other strengths are the compact age group of study participants and the unique demographic and socioeconomic statuses. However, there were also several limitations to the present study. First, it was a cross-sectional study; therefore, the data did not provide direct information as to whether Ascaris infection is a cause of the development of asthma and atopy. Second, we could not do lung function tests, which provide stronger evidence for the diagnosis of asthma. Another weakness is that we used a questionnaire based on the ISAAC to diagnose wheezing and asthma. The term wheezing is often misinterpreted by parents and this may produce overestimation or underestimation of the symptoms; however, asthma is a more specific disease and usually diagnosed by medical personnel. On the other hand, the ISAAC questionnaire has been used worldwide and has reportedly provided a reliable estimation of the prevalence of asthma in children 2–6 years of age.
In conclusion, our data suggest that Ascaris infection is a risk factor for asthma and atopy in rural Bangladeshi children. Further analysis is required to examine the exact mechanism of high levels of anti-Ascaris IgE and asthma and atopic responses in countries with low-income populations, repeated helminth infections and an increasing prevalence of asthma and atopic disease.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
This study was supported by the International Centre for Diarrhoeal Disease Research, Bangladesh; the UK Medical Research Council; the Swedish Research Council; the UK Department for International Development; the Grant-in-Aid for Scientific Research of the Japan Society for the Promotion of Science (JSPS, Grant #18256005); the Child Health and Nutrition Research Initiative; Uppsala University; the US Agency for International Development under the Cooperative Agreement #388-G-00-02- 00125-00; the Australian International Development Agency; the Government of Bangladesh; the Canadian International Development Agency; The Kingdom of Saudi Arabia; the Government of the Netherlands; the Government of Sri Lanka; the Swedish International Development Cooperative Agency; and the Swiss Agency for Development and Cooperation. We are grateful to the study participants for their cooperation in the study. We thank the field team members and data management staff for their excellent work. We thank Brian K. Purdue for his revision of the English text.
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