The Association between Humidifier disinfectant exposure and allergic diseases in Children

Abstract

Introduction: Humidifier disinfectants (HDs) have been associated with respiratory diseases such as interstitial lung disease and asthma (AS). However, limited research exists on the impact of HD exposure on overall allergic diseases. This study investigates the association between HD exposure and the incidence and aggravation of allergic diseases, as well as potential alterations in the typical progression of allergic comorbidities, we so called "allergic march." Material and Methods: We established a cohort of 1,655 children born between 2002 and 2012 who were registered as HD damage claimants. Allergic diseases were identified using matched National Health Insurance Service claim data, with follow-up until 119 months of age. To better capture changes in disease incidence and aggravation over time, exposure status was classified into three groups: 'pre-exposure', 'during exposure', and 'post-exposure'. A time-dependent Cox model assessed the incidence of allergic disease, and multilevel interrupted time series analysis assessed aggravation, as our longitudinal data included repeated measurements over time, allowing us to effectively capture changes in exposure status and their impacts. All analyses examined interactions with atopic dermatitis(AD) to assess whether impact on allergic march. Subgroup analyses of PHMG-P and CMIT/MIT exposure were performed to explore differences in mechanisms. Introduction: Humidifier disinfectants (HDs) have been associated with respiratory diseases such as interstitial lung disease and asthma (AS). However, limited research exists on the impact of HD exposure on overall allergic diseases. This study investigates the association between HD exposure and the incidence and aggravation of allergic diseases, as well as potential alterations in the typical progression of allergic comorbidities, so called "allergic march." Material and Methods: I established a cohort of 1,655 children born between 2002 and 2012 who were registered as HD damage claimants. Allergic diseases were identified using matched National Health Insurance Service claim data, with follow-up until 119 months of age. To better capture changes in disease incidence and aggravation over time, exposure status was classified into three groups: 'pre-exposure', 'during exposure', and 'post-exposure'. A time-dependent Cox model assessed the incidence of allergic disease, and multilevel interrupted time series analysis assessed aggravation, as my longitudinal data included repeated measurements over time, allowing me to effectively capture changes in exposure status and their impacts. All analyses examined interactions with atopic dermatitis(AD) to assess whether impact on allergic march. Subgroup analyses of PHMG/PGH and CMIT/MIT exposure were performed to explore differences in mechanisms. Results: The cumulative incidence of AS, allergic rhinitis (AR), and AD was 67.9%, 71.1%, and 27.2%, respectively. In time-dependent Cox PH, during exposure significantly increased the incidence of AS (adjusted hazard ratio [aHR] 2.126, 95% confidence interval [CI] 1.681–2.688) and AR (aHR 1.671, 95% CI 1.250–2.234) compared to pre-exposure. In post-exposure, the incidence of AS and AR remained elevated (aHR 1.794, 95% CI 1.359–2.368, and aHR 1.559, 95% CI 1.135–2.141, respectively), while AD demonstrated no significant association. In multilevel ITS, during exposure, the level of the monthly number of office visits for AS and AR increased (adjusted utilization rate ratio [aURR] 1.218, 95% CI 1.051–1.410; aURR 1.143, 95%CI 1.031-1.279). In post-exposure, the level of the monthly number of office visits for AS and AR increased (aURR 1.171, 95% CI 1.011–1.356; aURR 1.148, 95% CI 1.031–1.279) then the slope of the monthly number of office visits for AS and AR decreased (aURR 0.849, 95% CI 0.754–0.956; aURR 0.815, 95% CI 0.755–0.880). HD exposure also independently increased both the incidence and monthly office visits for AS and AR, no significant interaction with AD. The results of the subgroup analysis were consistent with these findings, with no suggestion mechanistic differences between the two subgroups. Conclusion: HD exposure was associated with a significant increase in both the incidence and aggravation of AS and AR, independent of the allergic march, with no differences observed among HD types. Further studies are needed to better understand the mechanisms underlying allergic diseases related to HD exposure, including the role of different HD types. Additionally, further research on exposed populations is necessary to address selection bias and overcome limitations due to the small sample size Conclusion: HD exposure was associated with a significant increase in both the incidence and aggravation of AS and AR, independent of the allergic march, with no differences observed among HD types. Further studies are needed to better understand the mechanisms underlying allergic diseases related to HD exposure, including the role of different HD types. Additionally, further research on exposed populations is necessary to address selection bias and overcome limitations due to the small sample size.

서론: 가습기 살균제는 간질성 폐질환과 천식과 같은 호흡기 질환과 연관되어 있지만, 가습기 살균제 노출이 전체적인 알레르기 질환에 미치는 영향에 대한 연구는 제한적이다. 본 연구는 가습기 살균제 노출과 알레르기 질환의 발생 및 악화 간의 연관성을 조사하고, 가습기 살균제 노출이 흔히 “알레르기 행진”이라 불리는 알레르기 동반 질환의 자연 경과를 변경시키는지 평가하고자 한다. 방법: 2002년에서 2012년 사이에 태어나 가습기 살균제 피해자로 신고된 1,655명의 소아를 대상으로 코호트를 구성하였다. 알레르기 질환은 국민건강보험공단 청구 데이터를 이용해 확인하였으며, 120개월까지 추적 관찰을 진행하였다. 질병 발생 및 악화의 변화를 더 잘 파악하기 위해 노출 상태는 ‘노출 전’, ‘노출 중’, ‘노출 후’ 세 그룹으로 분류하였다. 알레르기 질환 발생은 시간 의존적 콕스 모델을 사용하여 분석하였고, 악화는 반복 측정 데이터를 활용해 다수준 단절 시계열 분석으로 평가하였다. 모든 분석에서는 아토피 피부염의 상호작용을 평가하였다. 또한 PHMG/PGH 및 CMIT/MIT에 대한 하위 그룹 분석을 통해 기전의 차이를 탐색하였다. 결과: 천식, 알레르기 비염, 아토피 피부염의 누적 발생률은 각각 67.9%, 71.1%, 27.2%로 나타났다. 시간 의존적 콕스 모델에서, 노출 중 천식(조정 위험비 [aHR] 2.126, 95% 신뢰구간 [CI] 1.681–2.688)과 알레르기 비염(aHR 1.671, 95% CI 1.250–2.234)의 발생이 유의하게 증가한 반면, 아토피 피부염은 유의한 연관성을 보이지 않았다. 노출 후에도 천식(aHR 1.794, 95% CI 1.359–2.368)과 알레르기 비염(aHR 1.559, 95% CI 1.135–2.141)의 발생률은 여전히 높았다. 다수준 단절 시계열 분석에서 AS와 AR의 월별 외래 방문 횟수는 노출 전과 비교하여, 노출 중에 각각 증가하였으며(aURR 1.218, 95% CI 1.051–1.410; aURR 1.143, 95% CI 1.031–1.279), 노출 후에도 증가가 관찰되었다(aURR 1.171, 95% CI 1.011–1.356; aURR 1.143, 95% CI 1.024–1.275). 그러나 노출 후 천식과 알레르기 비염의 월별 외래 방문 횟수 경향은 감소하였다 (aURR 0.849, 95% CI 0.754–0.956; aURR 0.815, 95% CI 0.755–0.880). 가습기 살균제 노출은 천식과 알레르기 비염의 발생 및 월별 외래 방문 횟수를 독립적으로 증가시켰으나, 아토피 피부염과의 유의한 상호작용은 관찰되지 않았다. 하위 그룹 분석에서도 이와 일관된 결과가 나타났으며, 두 그룹 간 기전의 차이는 관찰되지 않았다.