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Sensitization to Ascaris lumbricoides and severity of childhood asthma in Costa Rica

      Background

      Little is known about sensitization (defined as a positive IgE) to helminths and disease severity in patients with asthma.

      Objectives

      To examine the relationship between sensitization (defined as a positive IgE) to Ascaris lumbricoides and measures of asthma morbidity and severity in a Costa Rican population with low prevalence of parasitic infection but high prevalence of parasitic exposure.

      Methods

      Cross-sectional study of 439 children (ages 6 to 14 years) with asthma. Linear regression and logistic regression were used for the multivariate statistical analysis.

      Results

      After adjustment for parental education and other covariates, sensitization to Ascaris lumbricoides was associated with having at least 1 positive skin test to allergens (odds ratio, 5.15; 95% CI, 2.36-11.21; P < .001), increased total serum IgE and eosinophils in peripheral blood, reductions in FEV1 and FEV1/forced vital capacity, increased airway responsiveness and bronchodilator responsiveness, and hospitalizations for asthma in the previous year (odds ratio, 3.08; 95% CI, 1.23-7.68; P = .02).

      Conclusion

      Sensitization to Ascaris lumbricoides is associated with increased severity and morbidity of asthma among children in Costa Rica. This association is likely mediated by an increased degree of atopy among children with asthma who are sensitized to Ascaris.

      Clinical implications

      In areas with a low prevalence of helminthiasis such as Costa Rica, Ascaris sensitization may be an important marker of severe atopy and disease morbidity in children with asthma.

      Key words

      Abbreviation used:

      FVC (Forced vital capacity)
      Infection with Ascaris lumbricoides is the most prevalent helminthic disease in the world,
      • Chan M.S.
      • Medley G.F.
      • Jamison D.
      • Bundy D.A.
      The evaluation of potential global morbidity attributable to intestinal nematode infections.
      affecting an estimated 1.4 billion persons.
      • Khuroo M.S.
      Ascariasis.
      Ascariasis is very common in economically deprived areas of Hispanic America
      • Lynch N.R.
      • Hagel I.
      • Perez M.
      • Di Prisco M.C.
      • Lopez R.
      • Alvarez N.
      Effect of anthelmintic treatment on the allergic reactivity of children in a tropical slum.
      • Cooper P.J.
      • Chico M.E.
      • Bland M.
      • Griffin G.E.
      • Nutman T.B.
      Allergic symptoms, atopy, and geohelminth infections in a rural area of Ecuador.
      but very rare in Costa Rica,
      Ministerio de Salud. Encuesta Nacional de Nutricion, 1996: Helmintos Intestinales.
      a prosperous Hispanic American nation. The prevalence of ascariasis in Costa Rica declined markedly between 1953 and 1996, likely because of improved hygienic conditions and widespread distribution of antihelminthic treatment by healthcare agencies.
      Ministerio de Salud. Encuesta Nacional de Nutricion, 1996: Helmintos Intestinales.

      Morales MT, Hernández BI. Frecuencia de cuatro nematodos intestinales en el Hospital Nacional de Niños. Acta Pediatr Costarric 1997;11:106-8.

      Normas de Atencion Integral de Salud, Primer Nivel de Atención.
      Among children admitted to a tertiary hospital in San José (Costa Rica's capital) in 1953, the prevalence of ascariasis was moderately high (39.5%).

      Morales MT, Hernández BI. Frecuencia de cuatro nematodos intestinales en el Hospital Nacional de Niños. Acta Pediatr Costarric 1997;11:106-8.

      In 1996, the estimated prevalence of ascariasis among children and adults in a nationwide study in Costa Rica was ∼2%.
      Ministerio de Salud. Encuesta Nacional de Nutricion, 1996: Helmintos Intestinales.
      The relation between infection with helminths such as A lumbricoides and atopy or asthma is controversial.
      • Cooper P.J.
      Intestinal worms and human allergy.
      Helminthiasis has been associated with reduced risk of atopy
      • Lynch N.R.
      • Hagel I.
      • Perez M.
      • Di Prisco M.C.
      • Lopez R.
      • Alvarez N.
      Effect of anthelmintic treatment on the allergic reactivity of children in a tropical slum.
      • Cooper P.J.
      • Chico M.E.
      • Rodrigues L.C.
      • Ordonez M.
      • Strachan D.
      • Griffin G.E.
      • et al.
      Reduced risk of atopy among school-age children infected with geohelminth parasites in a rural area of the tropics.
      and/or asthma symptoms
      • Cooper P.J.
      • Chico M.E.
      • Bland M.
      • Griffin G.E.
      • Nutman T.B.
      Allergic symptoms, atopy, and geohelminth infections in a rural area of Ecuador.
      • Scrivener S.
      • Yemaneberhan H.
      • Zebenigus M.
      • Tilahun D.
      • Girma S.
      • Ali S.
      • et al.
      Independent effects of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study.
      in areas with high prevalence of parasitic infections, but with increased risks of atopy and asthma in areas with low prevalence of parasitic infections.
      • Palmer L.J.
      • Celedon J.C.
      • Weiss S.T.
      • Wang B.
      • Fang Z.
      • Xu X.
      Ascaris lumbricoides infection is associated with increased risk of childhood asthma and atopy in rural China.
      These findings suggest that the relation among helminthiasis, atopy, and asthma is complex and influenced by host factors, timing and intensity of infection, and concurrent environmental exposures.
      Little is known about the relation between past or current exposure to A lumbricoides and disease severity in individuals with asthma,
      • Lynch N.R.
      • Palenque M.
      • Hagel I.
      • DiPrisco M.C.
      Clinical improvement of asthma after anthelminthic treatment in a tropical situation.
      particularly in areas with low prevalence of helminthic infections. We examined the association between sensitization to A lumbricoides and asthma severity among children with asthma in Costa Rica, a country with a low prevalence of ascariasis but high prevalence of asthma (∼23.7% among adolescents).
      Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee.

      Methods

       Study population

      Children who participated in this study were index cases for a genetic study of nuclear families of children with asthma in Costa Rica. From February 2001 to March 2005, short questionnaires were sent to the parents of 9054 children age 6 to 14 years who were enrolled in 95 schools in Costa Rica. Of the questionnaires distributed, 5355 (59.1%) were returned. Children were eligible for inclusion in the study if they had asthma (defined as physician-diagnosed asthma and at least 2 respiratory symptoms [wheezing, cough, or dyspnea] or a history of asthma attacks in the previous year) and high probability of having at least 6 great-grandparents born in the Central Valley of Costa Rica.
      • Escamilla M.A.
      • Spesny M.
      • Reus V.I.
      • Gallegos A.
      • Meza L.
      • Molina J.
      • et al.
      Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population.
      Of the 5355 children whose parents returned the screening questionnaires, 1947 (36.4%) had asthma. Of these 1947 children, 439 (22.5%) unrelated children were willing to participate in the study along with their parents (for whom only genotypic information was collected) and had Central Valley ancestry. There was no significant difference in sex or grade in school for children who did and did not agree to participate in the study.

       Study procedures

      Study participants completed a protocol that included a questionnaire, spirometry, allergy skin testing, measurement of serum total and allergen-specific IgE, peripheral blood eosinophil count, and (on a separate visit) assessment of airway responsiveness to methacholine. In addition, a stool specimen was examined for ova and parasites in the first 137 study participants (because helminths were not found in any instance, stool samples were not collected for the remaining study subjects). Written parental consent was obtained for participating children, for whom written assent was also obtained. The study was approved by the Institutional Review Boards of the Hospital Nacional de Niños (San José, Costa Rica) and Brigham and Women's Hospital (Boston, Mass).

       Questionnaire

      Each participant completed a slightly modified version of the questionnaire used in the Collaborative Study on the Genetics of Asthma,
      • Blumenthal M.N.
      • Banks-Schlegel S.
      • Bleecker E.R.
      • Marsh D.G.
      • Ober C.
      Collaborative studies on the genetics of asthma: National Heart, Lung and Blood Institute.
      which was translated into Spanish.

       Pulmonary function tests and bronchodilator responsiveness

      Spirometry was conducted with a Survey Tach Spirometer (Warren E. Collins, Braintree, Mass) following American Thoracic Society recommendations.
      Standardization of Spirometry, 1994 update. American Thoracic Society.
      Height was measured to the nearest half inch. Subjects were instructed to avoid use of short-acting bronchodilators for at least 4 hours before testing. Spirometric maneuvers were performed with subjects seated and wearing a noseclip. The best FEV1 and forced vital capacity (FVC) were selected for data analysis of FEV1 and FEV1/FVC. Because of a nonnormal distribution, the FEV1/FVC ratio was transformed to a log10 scale for analysis. After completing baseline spirometry, subjects were given 200 μg (2 puffs) of an albuterol metered-dose inhaler using a spacer, and spirometry was repeated after 15 minutes. For the statistical analysis, bronchodilator responsiveness was treated as a binary (positive if there was an increment of at least 12% and at least 200 mL in baseline FEV1 after administration of albuterol) and continuous (absolute difference, in milliliters, in FEV1 measurements before and after administration of albuterol) outcome.

       Methacholine challenge testing

      After completion of baseline spirometry, subjects whose FEV1 was at least 65% of predicted underwent methacholine challenge testing using a slightly modified version of the Chatham protocol.
      • Chatham M.
      • Bleecker E.R.
      • Smith P.L.
      • Rosenthal R.R.
      • Mason P.
      • Norman P.S.
      A comparison of histamine, methacholine, and exercise airway reactivity in normal and asthmatic subjects.
      The study protocol consisted of 5 breaths of saline solution followed by 1 breath of a 1 mg/mL methacholine solution, 1 and 4 breaths of a 5 mg/mL methacholine solution, and 1 breath of a 25 mg/mL methacholine solution. All inhalations, which were taken from a DeVilbiss 646 nebulizer (Sunrise Medical, Carlsbad, Calif), lasted 6 seconds and were followed by 2 seconds of breath holding. After each inhalation level, spirometry was performed at 180, 210, and 240 seconds. The test was terminated if the FEV1 declined by at least 20% from the best FEV1 value after inhalation of saline solution. For the statistical analysis, airway responsiveness was treated as a binary (positive if there was a 20% fall in baseline FEV1 with a methacholine dose ≤ 1.98 μmol) and continuous (log10-transformed dose-response slope to methacholine) outcome.

       Allergy skin testing

      Skin testing was performed according to the protocol of the International Study of Asthma and Allergies in Childhood.
      • Weiland S.K.
      • Bjorksten B.
      • Brunekreef B.
      • Cookson W.O.
      • von Mutius E.
      • Strachan D.P.
      Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II): rationale and methods.
      In addition to histamine and saline controls, the following antigens were applied to the volar surface of the forearm: Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blatella germanica, Periplaneta americana, cat dander, dog dander, mixed grass pollen, mixed tree pollen, and Alternaria tenuis. A test was considered positive if the maximum diameter of the wheal was ≥3 mm after subtraction of the maximum diameter of the negative control.

       Serum total and allergen-specific IgE and peripheral blood eosinophil count

      Serum total and allergen-specific IgE levels were determined by the UniCAP 250 system (Pharmacia & Upjohn, Kalamazoo, Mich), with samples measured in duplicate. Total serum IgE levels were transformed to a log10 scale for data analysis. Serum was assayed for IgE to 3 allergens: B germanica, D pteronyssinus, and A lumbricoides. IgEs to specific allergens were considered positive at a level ≥ 0.35 IU/mL. Eosinophil count was measured in peripheral blood by Coulter counter (Beckman Coulter, Fullerton, Calif) techniques and then transformed to a log10 scale for data analysis.

       Examination of stool specimens for ova and parasites

      Microscopic examination of wet mounts of fresh stool specimens in saline and iodine was conducted at low and high power at the Parasitology Laboratory of the Hospital Nacional de Niños in San José (Costa Rica).

       Definition of other variables

      Sociodemographic, perinatal, and familial variables considered for inclusion in the multivariate analyses were the child's sex, age, height, parental education, number of persons in the household, number of older siblings, number of children sharing a bedroom, day care in the first year of life, in utero exposure to smoking, current exposure to cigarette smoking in the household, paternal history of asthma, maternal history of asthma, paternal history of hay fever, maternal history of hay fever, and use of medications for asthma (inhaled β2-agonists [long-acting and short-acting], inhaled corticosteroids, leukotriene inhibitors, theophylline, and oral corticosteroids) in the previous year.

       Statistical analysis

      Bivariate analyses were conducted by Fisher exact tests for categorical variables and 2-tailed t tests for categorical and continuous variables. Stepwise linear or logistic regression (as appropriate) was used to study the relation between a positive IgE to A lumbricoides (heretofore referred to as sensitization to Ascaris) and the outcomes of interest (markers of allergy, spirometric measures of lung function [FEV1 and FEV1/FVC], airway responsiveness to methacholine, bronchodilator responsiveness, and asthma exacerbations [hospitalizations and emergency department visits the previous year]) while adjusting for potential confounders. All of the final multivariate models included age, sex, and parental education, as well as variables that satisfied a change-in-estimate criterion (≥10% in the risk ratio or the odds ratio) or that were significant at P < .05. In addition, height was included in all models for measures of lung function. All analyses were performed using Statistical Analysis Software version 8.2 (SAS Institute, Cary, NC).

      Results

      A comparison of selected characteristics of children who were (n = 171) and were not (n = 268) sensitized to Ascaris is presented in Tables I (for categorical variables) and II (for continuous variables). Children who were sensitized to Ascaris were more likely to be boys, to have been hospitalized for asthma in the previous year, and to have at least 1 positive skin test to allergens, a positive IgE to dust mite or cockroach, markedly increased airway responsiveness to methacholine (a 20% fall in FEV1 with a methacholine dose ≤1.98 μmol), and significant bronchodilator responsiveness (an increment of at least 12% and at least 200 mL in baseline FEV1 after administration of albuterol) than children who were not sensitized (Table I). Children who were sensitized to Ascaris were older and had greater total serum IgE, eosinophil count, bronchodilator responsiveness (as an absolute difference in FEV1 before and after administration of bronchodilator), and airway responsiveness (expressed as log10-transformed dose-response slope to methacholine) but lower FEV1/FVC than nonsensitized children (Table II). There were no significant differences in parental education, FEV1, and maternal or paternal history of asthma between children who were and were not sensitized to Ascaris (Table I, Table II).
      Table ICharacteristics of participating children
      Information missing on some subjects for airway responsiveness to methacholine ≤1.98 μmol (n = 40), bronchodilator responsiveness (n = 18), presence of a current smoker in the home (n = 2), maternal asthma (n = 1), paternal asthma (n = 5), maternal hay fever (n = 1), paternal hay fever (n = 3), and allergy skin testing (n = 2).
      with asthma in Costa Rica
      Sensitized to A lumbricoides N (%)
      Categorical variablesYes (n = 171)No (n = 268)P value for comparison
      Comparison by Fisher exact test.
      Male119 (69.6)157 (58.6).02
      Parental education
      Defined as the highest level of education of either parent.
       Less than high school87 (50.9)117 (43.7).33
       Completed high school39 (22.8)73 (27.2)
       At least some college45 (26.3)78 (29.1)
      Current smoker living in the home44 (25.7)70 (26.3).91
      Maternal asthma49 (28.7)90 (33.7).29
      Paternal asthma38 (22.5)55 (20.8).72
      Maternal hay fever52 (30.4)93 (34.8).35
      Paternal hay fever49 (28.8)74 (27.8).83
      Skin test reactivity to ≥1 allergen162 (95.3)213 (79.8)<.001
      Positive IgE to dust mite161 (94.2)173 (64.6)<.001
      Positive IgE to cockroach119 (69.6)63 (23.5)<.001
      Airway responsiveness to methacholine ≤ 1.98 μmol107 (70.4)144 (58.3).02
      Bronchodilator responsiveness
      An increase of at least 200 mL and at least 12% in FEV1 after administration of inhaled albuterol.
      32 (19.1)21 (8.3).002
      Hospitalized for asthma, last year13 (7.6)9 (3.4).07
      Emergency department visits for asthma, last year144 (84.2)212 (79.1).21
      Comparison by Fisher exact test.
      Defined as the highest level of education of either parent.
      An increase of at least 200 mL and at least 12% in FEV1 after administration of inhaled albuterol.
      § Information missing on some subjects for airway responsiveness to methacholine ≤1.98 μmol (n = 40), bronchodilator responsiveness (n = 18), presence of a current smoker in the home (n = 2), maternal asthma (n = 1), paternal asthma (n = 5), maternal hay fever (n = 1), paternal hay fever (n = 3), and allergy skin testing (n = 2).
      Table IICharacteristics of participating children
      Information missing on some subjects for the dose response slope to methacholine (n = 40), absolute bronchodilator responsiveness (n = 18), baseline FEV1 (n = 8), FEV1/FVC ratio (n = 8), height (n = 3), number of positive skin tests (n = 2), and total eosinophil count (n = 1).
      with asthma in Costa Rica
      Sensitized to A lumbricoides
      Continuous variables
      Results expressed as median (interquartile range).
      Yes (n = 171)No (n = 268)P value for comparison
      Comparison by 2-tailed t tests.
      Age (y)9.2 (8.1-10.9)8.5 (7.6-10.0).004
      Height (cm)133 (126-139)129 (123-136)0.007
      No. of persons in the family5 (4-6)5 (4-6).74
      No. of positive skin tests to allergens4 (3-5)3 (1-4)<.001
      Total serum IgE (IU/mL)870.1 (414.0-1613.0)234.4 (75.2-586.0)<.001
      Eosinophil count (cells/mL3)660.7 (450.0-970.0)475.1 (234.9-700.0)<.001
      Baseline FEV1 (L)1.76 (1.48-2.02)1.65 (1.44-1.98).28
      Baseline FEV1/FVC (%)81.3 (76.9-87.2)83.2 (79.1-87.8).03
      Absolute response to bronchodilator (mL)80.0 (10.0-170.0)60.0 (−10.0-140.0).005
      Dose-response slope to methacholine (μmol)16.2 (11.0-27.1)13.2 (4.1-23.1).006
      Results expressed as median (interquartile range).
      Comparison by 2-tailed t tests.
      Information missing on some subjects for the dose response slope to methacholine (n = 40), absolute bronchodilator responsiveness (n = 18), baseline FEV1 (n = 8), FEV1/FVC ratio (n = 8), height (n = 3), number of positive skin tests (n = 2), and total eosinophil count (n = 1).

       Skin test reactivity to allergens, serum total and allergen-specific IgE, and eosinophil count

      The results of the bivariate and multivariate analyses of the relation between sensitization to Ascaris and binary and continuous markers of allergy and eosinophilia are shown in Table III, Table IV. In bivariate analyses, sensitization to Ascaris was associated with a 5-fold increase in the odds of having ≥1 positive skin test to allergens; 9-fold and 7-fold increases in the odds of having a positive IgE to dust mite and cockroach, respectively; an increased number of positive skin tests to allergens; an increased total serum IgE level; and an increased eosinophil count. These results were not appreciably changed after adjustment for relevant covariates (model 1 in Table III, Table IV). As an example of the results of the multivariate linear regression analysis of markers of allergy and eosinophilia (as continuous outcomes), sensitization to Ascaris would predict a 127 cell/m3 increase in peripheral blood eosinophil count for a male subject of average characteristics in our study.
      Table IIISensitization to A lumbricoides and categorical measures of allergy, asthma morbidity, and asthma severity in Costa Rican children
      Odds ratio (95% CI) P value
      Adjusted
      Models 1, 2, and 3 were adjusted for age, sex, and parental education level for all outcomes. For all outcomes, model 2 was additionally adjusted for skin test reactivity to ≥1 allergen and model 3 was additionally adjusted for a positive IgE to dust mite and a positive IgE to cockroach. All models for FEV1 and FEV1/FVC were additionally adjusted for height, and all models for airway responsiveness and bronchodilator responsiveness were additionally adjusted for height and baseline FEV1.
      OutcomesUnadjustedModel 1Model 2Model 3
      Skin test reactivity to ≥1 allergen5.13 (2.38-11.09)5.15 (2.36-11.21)0.62 (0.19-1.99)
      <.001<.001.418
      Positive IgE to dust mite8.84 (4.45-17.56)8.93 (4.46-17.89)9.02 (3.65-22.31)
      <.001<.001<.001
      Positive IgE to cockroach7.45 (4.84-11.46)7.31 (4.72-11.33)6.25 (3.97-9.84)
      <.001<.001<.001
      Airway response to ≤1.98 μmol of methacholine
      Also adjusted for paternal asthma history.
      1.70 (1.11-2.62)1.61 (1.02-2.54)1.30 (0.85-2.09)0.90 (0.53-1.54)
      .016.040.285.703
      Bronchodilator responsiveness2.60 (1.44-4.69)2.60 (1.34-5.05)2.34 (1.19-4.61)3.12 (1.39-6.97)
      .002.005.014.006
      Emergency department visits for asthma in the previous year
      Also adjusted for presence of a current smoker in the home.
      1.41 (0.85-2.34)1.53 (0.91-2.58)1.35 (0.79-2.31)1.09 (0.60-1.99)
      .184.110.273.779
      Hospitalizations for asthma in the previous year
      Also adjusted for use of anti-inflammatory medications (inhaled steroids and/or leukotriene inhibitors) in the previous year.
      2.37 (0.99-5.67)3.08 (1.23-7.68)2.98 (1.16-7.65)1.97 (0.71-5.44)
      .053.016.023.191
      Models 1, 2, and 3 were adjusted for age, sex, and parental education level for all outcomes. For all outcomes, model 2 was additionally adjusted for skin test reactivity to ≥1 allergen and model 3 was additionally adjusted for a positive IgE to dust mite and a positive IgE to cockroach. All models for FEV1 and FEV1/FVC were additionally adjusted for height, and all models for airway responsiveness and bronchodilator responsiveness were additionally adjusted for height and baseline FEV1.
      Also adjusted for paternal asthma history.
      Also adjusted for presence of a current smoker in the home.
      § Also adjusted for use of anti-inflammatory medications (inhaled steroids and/or leukotriene inhibitors) in the previous year.
      Table IVSensitization to A lumbricoides and continuous measures of allergy, asthma morbidity, and asthma severity in Costa Rican children
      Coefficient estimate (95% CI) P value
      Adjusted
      Models 1, 2, and 3 were adjusted for age, sex, and parental education for all outcomes. For all outcomes, model 2 was additionally adjusted for skin test reactivity to ≥1 allergen and model 3 was additionally adjusted for a positive IgE to dust mite and a positive IgE to cockroach. All models for FEV1 and FEV1/FVC were additionally adjusted for height, and models for airway responsiveness and bronchodilator responsiveness were additionally adjusted for height and baseline FEV1.
      OutcomesUnadjustedModel 1Model 2Model 3
      Total IgE (IU/mL)
      Variable was log10-transformed before analysis.
      0.58 (0.47-0.69)0.57 (0.46-0.68)0.46 (0.36-0.56)0.24 (0.13-0.34)
      <.001<.001<.001<.001
      Eosinophil count (cells/m3)
      Variable was log10-transformed before analysis.
      0.18 (0.12-0.25)0.20 (0.13-0.26)0.14 (0.08-0.21)0.10 (0.02-0.17)
      <.001<.001<.001.011
      Number of positive skin tests
      Also adjusted for number of older siblings.
      1.08 (0.74-1.41)1.06 (0.72-1.39)0.05 (-0.26-0.35)
      <.001<.001.764
      Baseline FEV1 (L)
      Also adjusted for number of children sharing the bedroom.
      0.05 (–0.04 to 0.14)−0.06 (−0.12 to −0.01)−0.06 (−0.11 to −0.004)−0.06 (−0.12 to 0.004)
      .282.022.028.068
      Baseline FEV1/FVC (%)
      Variable was log10-transformed before analysis.
      −0.01 (−0.02 to −0.001)−0.01 (−0.01 to 0.001)−0.01 (−0.01 to 0.002)−0.002 (−0.01 to 0.01)
      .028.083.179.678
      Dose-response slope to methacholine (μmol)0.15 (0.04-0.26)0.15 (0.04-0.25)0.08 (–0.03 to 0.19)−0.008 (−0.13 to 0.11)
      .006.009.163.898
      Absolute response to bronchodilator (mL)
      Also adjusted for use of inhaled corticosteroids.
      40.49 (12.45-68.53)27.17 (0.28-54.07)21.54 (–6.00 to 49.08)26.46 (–4.11 to 57.03)
      .005.048.125.090
      Models 1, 2, and 3 were adjusted for age, sex, and parental education for all outcomes. For all outcomes, model 2 was additionally adjusted for skin test reactivity to ≥1 allergen and model 3 was additionally adjusted for a positive IgE to dust mite and a positive IgE to cockroach. All models for FEV1 and FEV1/FVC were additionally adjusted for height, and models for airway responsiveness and bronchodilator responsiveness were additionally adjusted for height and baseline FEV1.
      Variable was log10-transformed before analysis.
      Also adjusted for number of older siblings.
      § Also adjusted for number of children sharing the bedroom.
      Also adjusted for use of inhaled corticosteroids.

       Spirometric measures of lung function, airway responsiveness, and bronchodilator responsiveness

      The results of the bivariate and multivariate analyses of the relation between sensitization to Ascaris and binary and continuous indicators of lung function, airway responsiveness to methacholine, and bronchodilator responsiveness are shown in Table III, Table IV. Sensitization to Ascaris was associated with a 1.6-fold increase in the odds of having markedly increased airway responsiveness (a 20% fall in FEV1 with a methacholine dose ≤1.98 μmol) and a 2.6-fold increase in the odds of having significant bronchodilator responsiveness (an increment of at least 12% and at least 200 mL in baseline FEV1 after administration of albuterol; model 1 in Table III). In addition, sensitization to Ascaris was significantly associated with increased airway responsiveness (expressed as log10-transformed dose-response slope to methacholine) and a reduction in FEV1, and nonsignificantly associated with increased bronchodilator responsiveness (as an absolute difference in FEV1 before and after administration of bronchodilator) and a reduced FEV1/FVC (model 1 in Table IV).

       Asthma exacerbations

      Table III shows the results of the analysis of the relation between sensitization to Ascaris and asthma exacerbations in the previous year. Sensitization to Ascaris was associated with a 1.4-fold increase in the odds of at least 1 visit to the emergency department for asthma in the previous year; these results were not appreciably changed after adjustment for relevant covariates (results for neither the bivariate nor the multivariate analysis reached statistical significance). Sensitization to Ascaris was also associated with a 2.4-fold increase in the odds of having at least 1 hospitalization for asthma in the previous year. After adjustment for use of anti-inflammatory medications (inhaled steroids and/or leukotriene inhibitors), sensitization to Ascaris was associated with a 3-fold increase in the odds of having at least 1 hospitalization for asthma in the previous year.

       Exploratory analyses

      To examine whether atopy explains the observed association between sensitization to Ascaris and measures of asthma morbidity and severity, we repeated the multivariate analysis after adjustment for skin test reactivity to ≥1 aeroallergen. In that analysis, there was only a change in the association between sensitization to Ascaris and airway responsiveness, which was appreciably attenuated (model 2 in Table III, Table IV). We also repeated the analysis after adjustment for positive IgE to dust mite and/or cockroach. In that analysis, sensitization to Ascaris was still significantly associated with increased total serum IgE, increased eosinophil count, and bronchodilator responsiveness (as a binary variable; model 3 in Table III, Table IV).
      Sensitization to each of 2 common allergens (dust mite and cockroach) was associated with various measures of asthma severity and asthma morbidity (Table V, Table VI), suggesting that sensitization to allergens other than Ascaris is associated with disease severity in Costa Rican children with asthma.
      Table VSensitization to D pteronyssinus and B germanica and categorical measures of allergy, asthma morbidity, and asthma severity in Costa Rican children
      Odds ratio
      All multivariate models were adjusted for age, sex, and parental education. Models for airway responsiveness and bronchodilator responsiveness were additionally adjusted for height and baseline FEV1.
      (95% CI) P value
      OutcomesModel 1 (dust mite)Model 2 (cockroach)
      Airway responsiveness to ≤1.98 μmol of methacholine3.78 (2.29-6.23)2.32 (1.48-3.63)
      <.001<.001
      Bronchodilator responsiveness3.96 (1.33-11.57)0.98 (0.51-1.88)
      .01.95
      Emergency department visits for asthma in the previous year
      Also adjusted for presence of a current smoker in the home.
      2.04 (1.19-3.50)1.84 (1.09-3.11)
      .01.02
      Hospitalizations for asthma in the previous year
      Also adjusted for use of anti-inflammatory medications (inhaled steroids or leukotriene inhibitors) in the previous year.
      7.39 (0.97-56.62)2.59 (1.02-6.18)
      .05.05
      All multivariate models were adjusted for age, sex, and parental education. Models for airway responsiveness and bronchodilator responsiveness were additionally adjusted for height and baseline FEV1.
      Also adjusted for presence of a current smoker in the home.
      Also adjusted for use of anti-inflammatory medications (inhaled steroids or leukotriene inhibitors) in the previous year.
      Table VISensitization to D pteronyssinus and B germanica and continuous measures of allergy, asthma morbidity, and asthma severity in Costa Rican children
      Coefficient estimate
      All models were adjusted for age, sex, and parental education. Models for FEV1 and FEV1/FVC were additionally adjusted for height, and models for airway responsiveness and bronchodilator responsiveness were adjusted for height and baseline FEV1.
      (95% CI) P value
      OutcomesModel 1 (dust mite)Model 2 (cockroach)
      Total IgE (IU/mL)
      Variable was log10-transformed before analysis.
      0.84 (0.72-0.96)0.64 (0.54-0.75)
      <.001<.001
      Eosinophil count (cells/m3)
      Variable was log10-transformed before analysis.
      0.35 (0.28-0.43)0.16 (0.09-0.23)
      <.001<.001
      Baseline FEV1 (L)
      Also adjusted for number of children sharing the bedroom.
      −0.03 (−0.09 to 0.03)−0.03 (−0.09 to 0.02)
      .31.19
      Baseline FEV1/FVC (%)
      Variable was log10-transformed before analysis.
      −0.01 (−0.02 to −0.002)−0.01 (−0.02 to 0.001)
      .01.02
      Dose-response slope to methacholine (μmol)
      Variable was log10-transformed before analysis.
      0.38 (0.26-0.50)0.21 (0.11-0.32)
      <.001<.001
      Absolute response to bronchodilator (mL)
      Also adjusted for use of inhaled corticosteroids.
      39.27 (8.83-69.72)−0.29 (−26.89 to 26.30)
      .01.98
      All models were adjusted for age, sex, and parental education. Models for FEV1 and FEV1/FVC were additionally adjusted for height, and models for airway responsiveness and bronchodilator responsiveness were adjusted for height and baseline FEV1.
      Variable was log10-transformed before analysis.
      Also adjusted for number of children sharing the bedroom.
      § Also adjusted for use of inhaled corticosteroids.

      Discussion

      To our knowledge, this is the first report of an association between sensitization to A lumbricoides and increased asthma morbidity. Among children with asthma in Costa Rica, sensitization to Ascaris was associated with increased odds of allergic sensitization, increased levels of total serum IgE and eosinophils in peripheral blood, increased airway responsiveness and bronchodilator responsiveness, reduced lung function, and hospitalizations for asthma in the previous year.
      Studies of children not selected on the basis of asthma in Brazil,
      • Camara A.A.
      • Silva J.M.
      • Ferriani V.P.
      • Tobias K.R.
      • Macedo I.S.
      • Padovani M.A.
      • et al.
      Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.
      Germany,
      • Dold S.
      • Heinrich J.
      • Wichmann H.E.
      • Wjst M.
      Ascaris-specific IgE and allergic sensitization in a cohort of school children in the former East Germany.
      and South Africa
      • Obihara C.C.
      • Beyers N.
      • Gie R.P.
      • Hoekstra M.O.
      • Fincham J.E.
      • Marais B.J.
      • et al.
      Respiratory atopic disease, Ascaris-immunoglobulin E and tuberculin testing in urban South African children.
      have reported that sensitization to Ascaris is associated with current wheeze,
      • Camara A.A.
      • Silva J.M.
      • Ferriani V.P.
      • Tobias K.R.
      • Macedo I.S.
      • Padovani M.A.
      • et al.
      Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.
      increased total serum IgE levels,
      • Dold S.
      • Heinrich J.
      • Wichmann H.E.
      • Wjst M.
      Ascaris-specific IgE and allergic sensitization in a cohort of school children in the former East Germany.
      higher prevalence of asthma and hay fever (by parental report),
      • Dold S.
      • Heinrich J.
      • Wichmann H.E.
      • Wjst M.
      Ascaris-specific IgE and allergic sensitization in a cohort of school children in the former East Germany.
      atopic asthma,
      • Obihara C.C.
      • Beyers N.
      • Gie R.P.
      • Hoekstra M.O.
      • Fincham J.E.
      • Marais B.J.
      • et al.
      Respiratory atopic disease, Ascaris-immunoglobulin E and tuberculin testing in urban South African children.
      atopic airway responsiveness,
      • Obihara C.C.
      • Beyers N.
      • Gie R.P.
      • Hoekstra M.O.
      • Fincham J.E.
      • Marais B.J.
      • et al.
      Respiratory atopic disease, Ascaris-immunoglobulin E and tuberculin testing in urban South African children.
      and increased odds of sensitization to ≥1 aeroallergen.
      • Dold S.
      • Heinrich J.
      • Wichmann H.E.
      • Wjst M.
      Ascaris-specific IgE and allergic sensitization in a cohort of school children in the former East Germany.
      • Obihara C.C.
      • Beyers N.
      • Gie R.P.
      • Hoekstra M.O.
      • Fincham J.E.
      • Marais B.J.
      • et al.
      Respiratory atopic disease, Ascaris-immunoglobulin E and tuberculin testing in urban South African children.
      Those studies were limited by small sample size,
      • Camara A.A.
      • Silva J.M.
      • Ferriani V.P.
      • Tobias K.R.
      • Macedo I.S.
      • Padovani M.A.
      • et al.
      Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.
      limited information on socioeconomic status,
      • Camara A.A.
      • Silva J.M.
      • Ferriani V.P.
      • Tobias K.R.
      • Macedo I.S.
      • Padovani M.A.
      • et al.
      Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.
      lack of data on the prevalence of helminthiasis in the source population,
      • Camara A.A.
      • Silva J.M.
      • Ferriani V.P.
      • Tobias K.R.
      • Macedo I.S.
      • Padovani M.A.
      • et al.
      Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.
      nonexamination of stool specimens for helminths,
      • Camara A.A.
      • Silva J.M.
      • Ferriani V.P.
      • Tobias K.R.
      • Macedo I.S.
      • Padovani M.A.
      • et al.
      Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.
      • Dold S.
      • Heinrich J.
      • Wichmann H.E.
      • Wjst M.
      Ascaris-specific IgE and allergic sensitization in a cohort of school children in the former East Germany.
      and absent
      • Camara A.A.
      • Silva J.M.
      • Ferriani V.P.
      • Tobias K.R.
      • Macedo I.S.
      • Padovani M.A.
      • et al.
      Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.
      • Dold S.
      • Heinrich J.
      • Wichmann H.E.
      • Wjst M.
      Ascaris-specific IgE and allergic sensitization in a cohort of school children in the former East Germany.
      or limited
      • Obihara C.C.
      • Beyers N.
      • Gie R.P.
      • Hoekstra M.O.
      • Fincham J.E.
      • Marais B.J.
      • et al.
      Respiratory atopic disease, Ascaris-immunoglobulin E and tuberculin testing in urban South African children.
      assessment of lung function or airway responsiveness. Among 39 children with asthma in an area with high prevalence of helminthiasis (Coche Island, Venezuela), unblinded antihelminthic treatment for 1 year resulted in a 2-year reduction in asthma attacks and medication use but no significant change in pulmonary function or frequency of sensitization to Ascaris.
      • Lynch N.R.
      • Palenque M.
      • Hagel I.
      • DiPrisco M.C.
      Clinical improvement of asthma after anthelminthic treatment in a tropical situation.
      Together with findings from previous studies in children not selected on the basis of a diagnosis of asthma,
      • Camara A.A.
      • Silva J.M.
      • Ferriani V.P.
      • Tobias K.R.
      • Macedo I.S.
      • Padovani M.A.
      • et al.
      Risk factors for wheezing in a subtropical environment: role of respiratory viruses and allergen sensitization.
      • Dold S.
      • Heinrich J.
      • Wichmann H.E.
      • Wjst M.
      Ascaris-specific IgE and allergic sensitization in a cohort of school children in the former East Germany.
      our results suggest that the observed association between sensitization to Ascaris and indicators of asthma severity (eg, increased airway responsiveness) and asthma morbidity (eg, asthma exacerbations) is likely mediated by an increased degree of atopy in children who are sensitized to Ascaris. In support of this hypothesis, the observed association between sensitization to Ascaris and airway responsiveness was attenuated and became nonstatistically significant after adjustment for having a positive skin to at least 1 of the common allergens in Costa Rica
      • Soto-Quiros M.E.
      • Stahl A.
      • Calderon O.
      • Sanchez C.
      • Hanson L.A.
      • Belin L.
      Guanine, mite, and cockroach allergens in Costa Rican homes.
      (model 2 in Table III, Table IV). However, sensitization to Ascaris was significantly associated with other measures of asthma morbidity and asthma severity, suggesting that sensitization to or cross-reactivity with other allergens is not the sole explanation for the observed findings. Although analytical adjustment for a positive IgE to dust mite and/or cockroach may be overly conservative because of strong collinearity among measured IgEs, sensitization to Ascaris remained significantly associated with increased total serum IgE, increased eosinophil count, and bronchodilator responsiveness (as a binary outcome) after such adjustment (model 3 in Table III, Table IV). The latter finding is interesting in light of a reported association between polymorphisms in the gene for the B2-adrenergic receptor (ADRB2) and intensity of helminthic infection.
      • Ramsay C.E.
      • Hayden C.M.
      • Tiller K.J.
      • Burton P.R.
      • Hagel I.
      • Palenque M.
      • et al.
      Association of polymorphisms in the beta2-adrenoreceptor gene with higher levels of parasitic infection.
      Because of the cross-sectional design of our study, we cannot establish causality for the increased degree of atopy among children sensitized to Ascaris. A plausible explanation for our findings is that children with asthma and severe atopy (which is associated with increased asthma severity and morbidity)
      • Siroux V.
      • Oryszczyn M.P.
      • Paty E.
      • Kauffmann F.
      • Pison C.
      • Vervloet D.
      • et al.
      Relationships of allergic sensitization, total immunoglobulin E and blood eosinophils to asthma severity in children of the EGEA Study.
      • Ponsonby A.L.
      • Gatenby P.
      • Glasgow N.
      • Mullins R.
      • McDonald T.
      • Hurwitz M.
      Which clinical subgroups within the spectrum of child asthma are attributable to atopy?.
      • Carroll W.D.
      • Lenney W.
      • Child F.
      • Strange R.C.
      • Jones P.W.
      • Whyte M.K.
      • et al.
      Asthma severity and atopy: how clear is the relationship?.
      have enhanced immune responses against A lumbricoides and may thus be protected from infection with this helminth.
      • Lynch N.R.
      • Hagel I.A.
      • Palenque M.E.
      • Di Prisco M.C.
      • Escudero J.E.
      • Corao L.A.
      • et al.
      Relationship between helminthic infection and IgE response in atopic and nonatopic children in a tropical environment.
      • Cooper P.J.
      The potential impact of early exposures to geohelminth infections on the development of atopy.
      Among Venezuelan children living in 2 areas with high prevalence of ascariasis (51% to 57%), a group with high prevalence of atopy (80%) had higher levels of specific IgE to Ascaris but a lower intensity of Ascaris infection than a group with a low prevalence of atopy (20%).
      • Lynch N.R.
      • Hagel I.A.
      • Palenque M.E.
      • Di Prisco M.C.
      • Escudero J.E.
      • Corao L.A.
      • et al.
      Relationship between helminthic infection and IgE response in atopic and nonatopic children in a tropical environment.
      More recently, Cooper et al
      • Cooper P.J.
      • Chico M.E.
      • Sandoval C.
      • Nutman T.B.
      Atopic phenotype is an important determinant of immunoglobulin E-mediated inflammation and expression of T helper cell type 2 cytokines to ascaris antigens in children exposed to ascariasis.
      demonstrated that atopic children had higher levels of TH2 cytokines (IL-4 and IL-5) and greater histamine release in response to Ascaris antigens than nonatopic children. Although sensitization to Ascaris could also be a result of cross-reactivity between proteins present in Ascaris, dust mite, and cockroach (eg, tropomyosin)
      • Fernandes J.
      • Reshef A.
      • Patton L.
      • Ayuso R.
      • Reese G.
      • Lehrer S.B.
      Immunoglobulin E antibody reactivity to the major shrimp allergen, tropomyosin, in unexposed Orthodox Jews.
      in children with severe atopy, this remains unproven.
      • Bernardini R.
      • Mistrello G.
      • Novembre E.
      • Roncarolo D.
      • Zanotta S.
      • Lombardi E.
      • et al.
      Cross-reactivity between IgE-binding proteins from Anisakis simplex and Dermatophagoides pteronyssinus.
      Cross-reactivity is unlikely to be the sole explanation for our results because 213 (56.8%) of the 375 participating children who had at least 1 positive skin test to allergens and significant subsets of children who had a positive IgE to either dust mite (51.8%) or cockroach (34.6%) were not sensitized to Ascaris (Table I). Furthermore, 8 (12.9%) of the 62 participating children who had no positive skin tests to allergens were sensitized to Ascaris, suggesting that although most children who are sensitized to Ascaris are highly atopic (43.7%), sensitization to Ascaris may occur in the absence of sensitization to common aeroallergens. Furthermore, results of recent genome-wide linkage analyses of allergy phenotypes in large families of Costa Rican children with asthma suggest that having a positive IgE to Ascaris is under distinct genetic regulation from having a positive IgE to either B germanica or D pteronyssinus (J. C. Celedón, personal communication, August 2006).
      An alternative explanation for our results is that previous removal of immunoregulatory influences by helminthic infection (eg, stimulation of T-regulatory cells)
      • Cooper P.J.
      Intestinal worms and human allergy.
      • Maizels R.M.
      • Yazdanbakhsh M.
      Immune regulation by helminth parasites: cellular and molecular mechanisms.
      in susceptible children leads to more severe atopy and thus increased asthma severity and morbidity. Although a recent large randomized trial of antihelminthic therapy in Ecuador did not show an increased prevalence of atopy in the year after treatment,
      • Cooper P.J.
      • Chico M.E.
      • Vaca M.G.
      • Moncayo A.L.
      • Bland J.M.
      • Mafla E.
      • et al.
      Effect of albendazole treatments on the prevalence of atopy in children living in communities endemic for geohelminth parasites: a cluster-randomised trial.
      reversible suppression of allergen sensitization by helminthiasis was shown in a clinical trial of antihelminthic treatment in Gabon (Africa)
      • van den Biggelaar A.H.
      • Rodrigues L.C.
      • van Ree R.
      • van der Zee J.S.
      • Hoeksma-Kruize Y.C.
      • Souverijn J.H.
      • et al.
      Long-term treatment of intestinal helminths increases mite skin-test reactivity in Gabonese schoolchildren.
      and in an uncontrolled study of antihelminthic treatment in Venezuela.
      • Lynch N.R.
      • Hagel I.
      • Perez M.
      • Di Prisco M.C.
      • Lopez R.
      • Alvarez N.
      Effect of anthelmintic treatment on the allergic reactivity of children in a tropical slum.
      The discrepant findings of the trials in Ecuador and Gabon could be explained by differences in frequency and intensity of helminthic infections, duration of follow-up, and concurrent environmental or infectious exposures.
      The current low prevalence of helminthiasis in Costa Rica is the result of improved hygienic conditions and systematic campaigns for antihelminthic treatment in a tropical country where exposure to helminths is common. Current Costa Rican national guidelines for primary care physicians recommend empiric antihelminthic treatment for all schoolchildren biannually.
      Normas de Atencion Integral de Salud, Primer Nivel de Atención.
      The low prevalence of helminthiasis in Costa Rican schoolchildren (3.4% for Ascaris, 5.6% for Trichuris, and 1.9% for Necator in 1996) was confirmed by our negative findings in the first 137 children participating in the current study.
      Ministerio de Salud. Encuesta Nacional de Nutricion, 1996: Helmintos Intestinales.
      Our finding of a high prevalence of Ascaris sensitization coupled with a low prevalence of ascariasis is consistent with a recent report from South Africa.
      • Obihara C.C.
      • Beyers N.
      • Gie R.P.
      • Hoekstra M.O.
      • Fincham J.E.
      • Marais B.J.
      • et al.
      Respiratory atopic disease, Ascaris-immunoglobulin E and tuberculin testing in urban South African children.
      Sensitization to Ascaris may result from past or current exposure to Ascaris and other helminths.
      • Turner K.J.
      • Fisher E.H.
      • McWilliam A.S.
      Homology between roundworm (Ascaris) and hookworm (N. americanus) antigens detected by human IgE antibodies.
      • Revoltella R.
      • Jayakar S.D.
      • Tinelli M.
      • Scaglia M.
      • Peracino A.
      • Desmarais J.C.
      • et al.
      Parasite-reactive serum IgE antibodies in African populations: relation to intestinal parasite load.
      The ability to generate IgE in response to Ascaris may be a more important predictor of asthma severity than other markers of past infectious exposure, because Ascaris-specific IgG does not appear to be strongly associated with asthma.
      • Karadag B.
      • Ege M.
      • Bradley J.E.
      • Braun-Fahrlander C.
      • Riedler J.
      • Nowak D.
      • et al.
      The role of parasitic infections in atopic diseases in rural schoolchildren.
      Levels of IgE specific for Ascaris may rise in the first year after antihelminthic treatment,
      • Lynch N.R.
      • Palenque M.
      • Hagel I.
      • DiPrisco M.C.
      Clinical improvement of asthma after anthelminthic treatment in a tropical situation.
      with a subsequent decline over a period of 2 to 4 years.
      • Dold S.
      • Heinrich J.
      • Wichmann H.E.
      • Wjst M.
      Ascaris-specific IgE and allergic sensitization in a cohort of school children in the former East Germany.
      Although we did not assess sensitization to other parasites, the prevalence of infection with helminths other than Ascaris (eg, Necator americanus, Strongyloides stercoralis) is very low (<0.5% for Strongyloides and 1.9% for Necator) in Costa Rican children.
      Ministerio de Salud. Encuesta Nacional de Nutricion, 1996: Helmintos Intestinales.
      Normas de Atencion Integral de Salud, Primer Nivel de Atención.
      Although infection with Trichuris trichiura is slightly more common in Costa Rican schoolchildren (3.4% vs 5.6%),
      Ministerio de Salud. Encuesta Nacional de Nutricion, 1996: Helmintos Intestinales.
      Trichuris does not have a systemic phase as part of its life cycle
      • Cooper E.
      Tropical infectious diseases.
      and has not been frequently implicated in the pathogenesis of asthma or atopy. In particular, infection with Ascaris, but not with Trichuris, was associated with asthma in a recent meta-analysis.
      • Leonardi-Bee J.
      • Pritchard D.
      • Britton J.
      Asthma and current intestinal parasite infection: systematic review and meta-analysis.
      We recognize that we cannot exclude low-grade helminthiasis in a small minority of children in the absence of serial stool examinations for ova and parasites. However, active and/or intense ascariasis is unlikely in most of the participating children given the relatively high sensitivity and specificity of a single stool examination in asymptomatic populations with low prevalence of Ascaris infection
      • Gyorkos T.W.
      • MacLean J.D.
      • Law C.G.
      Absence of significant differences in intestinal parasite prevalence estimates after examination of either one or two stool specimens.
      • Morris A.J.
      • Wilson M.L.
      • Reller L.B.
      Application of rejection criteria for stool ovum and parasite examinations.
      and results from previous nationwide surveys. Selection bias and/or residual confounding by socioeconomic status are unlikely explanations for our results. Because parents were largely unaware of the pattern of allergic sensitization of their children, entry into the study was unlikely to be affected by the presence or absence of sensitization to Ascaris. All of our analyses were adjusted for level of parental education, and other variables potentially associated with low socioeconomic status (eg, crowding, cigarette smoking) were considered for inclusion in our final multivariate models. In addition, extreme gradations in household income and/or access to health care would not be expected among Costa Rican children attending public schools (Costa Ricans enjoy universal access to health care).
      In summary, we found a strong association between sensitization to A lumbricoides and increased asthma severity and asthma morbidity in a country with a low prevalence of helminthiasis. This association is likely mediated by an increased degree of atopy among children with asthma who are sensitized to Ascaris. Longitudinal studies are needed to determine whether this finding is a result of removal of helminthic suppression of atopy in children with asthma who received anthelminthic treatment and/or increased protection against helminthic infection in children with asthma and severe atopy. Regardless of the mechanisms for our findings, sensitization to Ascaris appears to be an important marker of severe atopy, increased disease morbidity, and increased disease severity in children with asthma.
      We thank the participating families for their collaboration, the members of our field team in Costa Rica (Ligia Sanabria, Jenny Vega, Marvin Corrales, Adriana Gonzalez, Raquel Boza, Joaquín Acuña, Laura Rojas, Ana Castillo, Gabriela Ivankovich, Marcia Solano, Herminia Solano, and Heliberto Mena), and Ms Jaylyn Olivo for editorial assistance.

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