Deworming improves current wheeze and temporarily deteriorates atopy: longitudinal anthelminthic treatment studies in Cuban schoolchildren Wördemann Meike, Menten Joris, Junco Diaz Raquel, Menocal Heredia Lenina, Ruiz Espinosa Aniran, Gryseels Bruno, Bonet Gorbea Mariano, Polman Katja Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium National Institute of Hygiene, Epidemiology and Microbiology, Havana, Cuba Institute Pedro Kouri, Havana, Cuba Congreso Higiene y Epidemiologia, Havana, 5-9 Nov 2007 9 May 2018

Rationale Atopic diseases very common and helminth infections uncommon in developed countries, while inverse is true in many developing countries Inverse relationship helminth infections and atopic diseases? (~hygiene hypothesis) *Hygiene hypothesis: exposure to infections in early childhood reduces risk of developing allergies Helminth infections  allergy  ? Anthelminthic treatment  allergy  ? ---> scientific, clinical + PH consequences 9 May 2018

Objective Prospective intervention study Investigate the effect of deworming and intestinal helminth (re)infections (Ascaris, Trichuris, hookworm) on atopy and atopic diseases (asthma, allergic rhinitis and atopic dermatitis) 9 May 2018

Methods 440 children (4-13yrs) from randomly selected primary schools in San Juan y Martinez, Pinar del Rio Treatment follow up study six-monthly for 24 months Helminth positive children treated with anthelminthics  untreated controls* 9 May 2018

asthma (current wheeze): affirmative answer to ISAAC question CW 2 International Study of Asthma and Allergies in childhood (ISAAC) questionnaire (atopic disease): asthma (current wheeze): affirmative answer to ISAAC question CW 2 allergic rhinoconjunctivitis: affirmative answer to ISAAC question AR 2+3 (= definition Strachan) atopic dermatitis: affirmative answer to ISAAC question AD 2+3 (= definition Williams) 9 May 2018

Presence of helminth eggs of A. lumbricoides, T. trichiura, hookworm Stool examination by Kato-Katz & direct smear (intestinal helminth infection): Presence of helminth eggs of A. lumbricoides, T. trichiura, hookworm 9 May 2018

Skin prick test (atopy): Positive reaction to any of 7 international standard allergens tested (Dermatophagoides pteronyssinus, D. farinae, cat dander, mixed tree, mixed grass, Alternaria alternata, and cockroach) 9 May 2018

Statistics Repeated measures logistic regression time trend for atopic disease/atopy after treatment Transition logistic regression model  effect of helminth infection (after treatment failure or reinfection) on development/ retainment of atopic conditions 9 May 2018

Baseline data on age, sex, and helminth infection, atopy and atopic disease status for treated cohort Treated Cohort Untreated Control Group Month 6 Month 12 Month 18 Control Group Month 24 N 119 112 71 75 63 % Male 45% 44% 39% 53% 57% Age: mean (SD) 8.0 (2.0) 8.8 (2.1) 7.9 (2.1) 8.8 (2.2) 8.1 (1.9) Helminths (% positive) A. lumbricoides 46% 50% 51% 60% T. trichiura 28% 14% hookworm 25% 11% 6% 5% 16% Atopy/atopic disease (% positive) Current wheeze 31% 20% 22% Skin prick test positive 9% 15% Allergic rhinitis 18% 10% Atopic dermatitis 8% 12% 17% 4% 9 May 2018

Percentages of children with current wheeze (asthma) in treated and untreated helminth-positive children in San Juan y Martínez. Significant decrease over time in percentage of children with wheeze for treated cohort, not for untreated control groups 9 May 2018

Sign/Symptom Prevalence Frequencies and results from transition logistic regression model for asthma by helminth infection Sign/Symptom Prevalence Odds-Ratio† Helminth species in non infected children‡ in infected children‡ Estimate 95% Confidence Interval P-value Current wheeze A. lumbricoides 18.1% 30.8% 2.02 ( 0.97 , 4.22) 0.065 T. trichiura 17.4% 39.8% 3.65 ( 1.49 , 8.92) 0.006 hookworm 21.7% 17.8% 0.54 ( 0.17 , 1.77) 0.289 Any helminth 14.6% 27.5% 1.96 (1.05, 3.65) 0.033 † Odds-ratio of developing atopy/atopic diseases (for children who did not have atopy/atopic diseases at previous visit) or retaining atopy/atopic diseases (for children who had atopy/atopic diseases at previous visit) in helminth infected versus non helminth infected children. Odds-ratio, 95% confidence interval, and p-value obtained from transition logistic regression model with adjustment for time, age, gender and rural/urban location of the school. ‡ After anthelminthic treatment, i.e. children with successful treatment versus children with unsuccessful treatment or reinfection. 9 May 2018

Sign/Symptom Prevalence Frequencies and results from transition logistic regression model for asthma by helminth infection Sign/Symptom Prevalence Odds-Ratio† Helminth species in non infected children‡ in infected children‡ Estimate 95% Confidence Interval P-value Current wheeze A. lumbricoides 18.1% 30.8% 2.02 ( 0.97 , 4.22) 0.065 T. trichiura 17.4% 39.8% 3.65 ( 1.49 , 8.92) 0.006 hookworm 21.7% 17.8% 0.54 ( 0.17 , 1.77) 0.289 Any helminth 14.6% 27.5% 1.96 (1.05, 3.65) 0.033 Children who were helminth-free after treatment are less likely to develop or retain current wheeze than those who remained infected or were reinfected † Odds-ratio of developing atopy/atopic diseases (for children who did not have atopy/atopic diseases at previous visit) or retaining atopy/atopic diseases (for children who had atopy/atopic diseases at previous visit) in helminth infected versus non helminth infected children. Odds-ratio, 95% confidence interval, and p-value obtained from transition logistic regression model with adjustment for time, age, gender and rural/urban location of the school. ‡ After anthelminthic treatment, i.e. children with successful treatment versus children with unsuccessful treatment or reinfection. 9 May 2018

Sign/Symptom Prevalence Frequencies and results from transition logistic regression model for asthma by helminth infection For A. lumbricoides and T. trichiura but not for hookworm, those who remained infected or were (re)infected after treatment were more likely to develop or retain wheeze than children who cleared their infection. Sign/Symptom Prevalence Odds-Ratio† Helminth species in non infected children‡ in infected children‡ Estimate 95% Confidence Interval P-value Current wheeze A. lumbricoides 18.1% 30.8% 2.02 ( 0.97 , 4.22) 0.065 T. trichiura 17.4% 39.8% 3.65 ( 1.49 , 8.92) 0.006 hookworm 21.7% 17.8% 0.54 ( 0.17 , 1.77) 0.289 Any helminth 14.6% 27.5% 1.96 (1.05, 3.65) 0.033 † Odds-ratio of developing atopy/atopic diseases (for children who did not have atopy/atopic diseases at previous visit) or retaining atopy/atopic diseases (for children who had atopy/atopic diseases at previous visit) in helminth infected versus non helminth infected children. Odds-ratio, 95% confidence interval, and p-value obtained from transition logistic regression model with adjustment for time, age, gender and rural/urban location of the school. ‡ After anthelminthic treatment, i.e. children with successful treatment versus children with unsuccessful treatment or reinfection. 9 May 2018

Sign/Symptom Prevalence Frequencies and results from transition logistic regression model for allergic rhinitis by helminth infection Sign/Symptom Prevalence Odds-Ratio† Helminth species in non infected children‡ in infected children‡ Estimate 95% Confidence Interval P-value Allergic Rhinitis A. lumbricoides 8.9% 16.2% 2.44 ( 1.01 , 5.85) 0.053 T. trichiura 19.3% 1.95 ( 0.64 , 5.91) 0.258 hookworm 11.5% 5.5% 0.22 ( 0.03 , 1.74) 0.077 Any helminth 8.1% 13.2% 1.36 (0.63, 2.92) 0.433 (Re)infection with A. lumbricoides positively associated and with hookworm negatively associated with the development or retention of allergic rhinitis † Odds-ratio of developing atopy/atopic diseases (for children who did not have atopy/atopic diseases at previous visit) or retaining atopy/atopic diseases (for children who had atopy/atopic diseases at previous visit) in helminth infected versus non helminth infected children. Odds-ratio, 95% confidence interval, and p-value obtained from transition logistic regression model with adjustment for time, age, gender and rural/urban location of the school. ‡ After anthelminthic treatment, i.e. children with successful treatment versus children with unsuccessful treatment or reinfection. 9 May 2018

Percentages of skin prick test positive children (atopy) in treated and untreated helminth-positive children in San Juan y Martínez. Significant change over time (temporary increase followed by gradual decrease to baseline) in percentage of skin prick test positive children for treated cohort, not for untreated control groups 9 May 2018

Percentages of skin prick test positive children (atopy) in treated and untreated helminth-positive children in San Juan y Martínez. Significant change over time (temporary increase followed by gradual decrease to baseline) in percentage of skin prick test positive children for treated cohort, not for untreated control groups Early strong reaction of immune system shortly after treatment Repeated treatment  immune suppression ~ immunotherapy in allergy (repeated vaccinations with allergens)  9 May 2018

Sign/Symptom Prevalence Frequencies and results from transition logistic regression model for atopy by helminth infection Sign/Symptom Prevalence Odds-Ratio† Helminth species in non infected children‡ in infected children‡ Estimate 95% Confidence Interval P-value Skin Prick Test A. lumbricoides 20.5% 12.0% 0.77 ( 0.35 , 1.69) 0.510 T. trichiura 19.8% 12.1% 0.61 ( 0.22 , 1.66) 0.316 hookworm 18.1% 20.6% 1.56 ( 0.66 , 3.64) 0.317 Any helminth 22.3% 14.7% 0.82 (0.45, 1.48) 0.511 † Odds-ratio of developing atopy/atopic diseases (for children who did not have atopy/atopic diseases at previous visit) or retaining atopy/atopic diseases (for children who had atopy/atopic diseases at previous visit) in helminth infected versus non helminth infected children. Odds-ratio, 95% confidence interval, and p-value obtained from transition logistic regression model with adjustment for time, age, gender and rural/urban location of the school. ‡ After anthelminthic treatment, i.e. children with successful treatment versus children with unsuccessful treatment or reinfection. 9 May 2018

Sign/Symptom Prevalence Frequencies and results from transition logistic regression model for atopy by helminth infection Trend opposite to that observed for atopic diseases: (re)infection with A. lumbricoides or T. trichiura negatively associated and with hookworm positively associated with the development or retention of atopy Sign/Symptom Prevalence Odds-Ratio† Helminth species in non infected children‡ in infected children‡ Estimate 95% Confidence Interval P-value Skin Prick Test A. lumbricoides 20.5% 12.0% 0.77 ( 0.35 , 1.69) 0.510 T. trichiura 19.8% 12.1% 0.61 ( 0.22 , 1.66) 0.316 hookworm 18.1% 20.6% 1.56 ( 0.66 , 3.64) 0.317 Any helminth 22.3% 14.7% 0.82 (0.45, 1.48) 0.511 † Odds-ratio of developing atopy/atopic diseases (for children who did not have atopy/atopic diseases at previous visit) or retaining atopy/atopic diseases (for children who had atopy/atopic diseases at previous visit) in helminth infected versus non helminth infected children. Odds-ratio, 95% confidence interval, and p-value obtained from transition logistic regression model with adjustment for time, age, gender and rural/urban location of the school. ‡ After anthelminthic treatment, i.e. children with successful treatment versus children with unsuccessful treatment or reinfection. 9 May 2018

Conclusion Atopic diseases improve after anthelminthic treatment Atopy increases after deworming, but As this increase appears only temporarily, deworming of schoolchildren does not seem to be a risk factor for the development of atopy, nor for atopic disease Effects of helminth (re)infections on atopy and atopic diseases appear to be species-specific 9 May 2018

Thank you for your attention 9 May 2018