Early-life exposure to humidifier disinfectant determines the prognosis of lung function in children

Humidifier disinfectants (HD), as household chemicals, have been used to prevent microbial growth in humidifier water tanks since 1994 in South Korea and contain various concentrations of chemicals, including oligoethoxyethyl-guanidinium chloride (PGH), polyhexamethylene-guanidine phosphate (PHMG), and chloromethylisothiazol/methyl-isothiazol (CMIT/MIT). These chemicals have been widely used in either industrial or various consumer products, including cosmetics, as biocides [1, 2]. However, HD inhalation from a humidifier’s aerosolizer was finally identified as a respiratory toxicant [3, 4] after an epidemic outbreak of idiopathic childhood interstitial lung disease (chILD) characterized by spontaneous air leak, rapid progression, and high mortality among immunocompetent children in South Korea in 2006 [5, 6]. Thereby, the novel forms of HD associated lung injury (HDLI) were defined in 2011, and HDLI has been added in the chILD classification of exposure-related ILD, worldwide [7, 8]. HD use in early-life was also recently found to independently increase the risk of childhood asthma [9].

Many chemical airborne exposures are associated with a decrement in lung function in adults, including in cases of large man-made disasters, such as the 1984 Bhopal Union Carbide methyl isocyanate gas release, the 2005 chlorine gas release from the Graniteville train accident, and current 2006 epidemic HD exposure (Additional file 1: Table S1). HD inhalation causing HDLI has been found to be characterized by restrictive lung defect in adults [10, 11]. Despite the associations observed in HDLI adults, the potential effects and the long-term consequences of HDLI children on lung function have not been explored, although children’s lungs are more susceptible to airborne exposures than those of adults [12, 13]. Even in case of the other chemical-related fatalities, no study on lung function in children has been reported. This continues to be a significant public health issue because there is no reference on chemical-related health crises of children, although thousands of toxic chemicals are used worldwide. Therefore, the characteristics of lung function and the presence of associated risk factors after HD inhalation are important in determining whether lung function can improve in the future in HDLI children. Furthermore, most studies in adults about chemical inhalants have been quantified by spirometric indexes, whereas less is known about diffusing capacity of the lung for carbon monoxide (DLco), which is important to evaluate the alteration of small airways after chemical exposure. Study of changes in DLco over time is useful to follow the course of disease [14].

Therefore, we investigated the effect of inhalation exposure to HD on lung function using both spirometry and DLco. In addition, we studied the long-term prognosis during childhood, which suggested the lung function phenotype and exposure characteristics associated with the phenotype.

Lung function including FVC, FEV₁, DLco, and corrected DLco were markedly decreased in HDLI survivors compared with controls in the cross-sectional study. In the longitudinal assessment, FVC was found to be consistently low despite being within the normal range, and the corrected DLco was found to have no normalization over 80% with increasing age, although no apparent difference was seen in final growth between HDLI survivors and controls. Children with exposure within the first year of life have been associated with persistently low lung function, suggesting a critical period related to airborne chemicals. Notably, initial exposure age under 1 year increased the hazard risk of persistent decrement in corrected DLco adjusted for height and weight at DLco performance, HD type, and total months of use. These findings suggest that we may consider prolonged decrement in corrected DLco as a valuable marker of lung involvement in children with a history of HD exposure. Furthermore, persistent abnormalities with corrected DLco are also associated with higher intensity HD exposure during sleep and close distance between the bed and the humidifier. As most subjects were exposed during sleep, the difference in airborne disinfectant exposure intensity during sleep is believed to be significant.

To the best of our knowledge, this analysis is the first to address lung function impairment and the phenotype-associated sensitive window in relation to HD inhalation exposure in children with a combination of case–control and cohort designs. In addition, we confirmed the first longitudinal lung impairment in children by chemical inhalants and may provide guidance on evaluating lung injury caused by chemical inhalation.

Many recent studies have reported that environmental exposure in early-life affects the long-term prognosis of respiratory disease during childhood [28, 29]. Furthermore, identification of the critical exposure window can suggest more effective interventions for lung development during childhood [30‐32]. The present study has addressed these concerns using the association between lung function and the use of household chemical disinfectant. This study highlights the need for further evaluation and continued follow-up of pulmonary function in children with chemical inhalation during the critical period, regardless of the duration following the exposure.

The mechanism by which HD exposure affects prolonged decrement in lung function, especially corrected DLco among children who are exposed within the first year of life, remains unknown. Possibilities include that HDs were dissolved in water and then dispersed into the air by the humidifier’s aerosolizer, and the nano-sized particles allowed them to easily reach the distal airways causing lung injury. HDLI with pathologic findings such as bronchiolar destruction and obliteration, centrilobular alveolar damage, and remodeling by inflammatory may support the above-mentioned evidence [10, 11]. Respiratory inhalational toxicants including irritant gases or sensitizers have also been investigated to cause acute inhalation injury by tissue asphyxiation including inhibition of mitochondrial electron transport and oxygen use or direct airway cellular injury [33]. Additionally, in the first 2 years of life, the alveolar volume increases with age and somatic growth [24]. High density and close exposure to HD during sleep within the first year of life causes accelerated lung injury and disruption of alveolar development, resulting in lower corrected DLco. As the bronchioles, alveolar ducts, and alveolus functionally mature at approximately 2 years of age, alterations in these tissues could result in inappropriate distal lung development, resulting in restrictive lung disease. An additional explanation of the association between lung function in children and HD exposure in the first year of life [34] is that infants may spend more time at home and may be at a high risk because they take in more of the contaminant than adults relative to their body size, and have particularly vulnerable physiologies, as the minute ventilation per pound in an infant is significantly greater than that of an adult [35]. Particularly, children breath 50% more air per kg of weight compared to adults, and their habits are conducive to greater exposures [36]. As an infant’s room is in a relatively confined space, and infants cannot change positions by themselves during sleep, this can result in considerable cumulative exposure during sleep and association between corrected DLco and HD exposure intensity during sleep than the usual HD exposure intensity in our study. These results are consistent with those of a previous report on impulse oscillometry abnormality in HD-exposed children [37]. Further investigation is required to identify the pathophysiological mechanisms of this association.

Furthermore, a high proportion of children with a history of fetal exposure to HD showed persistent decrement in lung function, although without statistical significance, due to the small sample size. The placenta plays a role in exchanging foreign molecules between the maternal and fetal circulations, suggesting that HD may cause developmental toxicity in the fetuses [38]. Future studies are required to investigate whether HD chemicals cross the placenta and accumulate in the fetal tissues.

To date, no longitudinal research on DLco in children has investigated the pathophysiology of chemical airborne lung injury. DLco is an outcome of particular interest, as exposure related lung function in asymptomatic children without a chronic respiratory disease because exposure to respiratory irritants is known to cause small airway disease and affect transfer capability [39]. Impairment recovery of corrected DLco in HD-exposed children, and association between exposure characteristics and the corrected DLco outcome in our study may support the above-mentioned evidence. These findings suggest that the corrected DLco seems to be more sensitive for detecting lung damage as one of the alternative biomarkers of children with HDLI and as a long-lasting indicator in lung injury after exposure to HD in children. As approximately 30% of young Korean children were exposed to HD, although without any obvious clinical or radiologic findings, this reflects the importance of corrected DLco in the detection of latent respiratory effects in children [40]. The measurement of DLco in children is under investigation, with no generally available apparatus, and we may be unable to detect potential lung damage in many children. Therefore, in cases of absence of risk factors (including chronic respiratory disease), other than the exposure to HD in early-life, the persistent decrement in corrected DLco in Korean school children may imply an adverse impact of HD exposure on the lung function.

The strengths of the present study are that this is a well-characterized, relatively large HDLI cohort study. The PFT result was also provided by highly skilled leaders using a fixed standard operating procedure in a pediatric pulmonology laboratory. Second, the study participants are purely control subjects, in which there was no exposure to HD compared other studies about exposure to air pollution and other household chemicals. Furthermore, as a lower prevalence of chronic respiratory conditions, including smoking history, was reported in children than in adults, HDLI survivors were considered to be a pure disease group. Therefore, we may suggest adequate data to make conclusions about the HD exposure-lung function relationship.

We are aware that this study has limitations. First, we did not perform spirometry in the event because of too young children and severely affected patients (expired or not performed), and thus we cannot determine whether for some patients there was an even more severe immediate decrease in lung function and subsequent incomplete recovery. This may have resulted in a weaker exposure-response relationship. Second, there could be a risk of recall bias because most characteristics on disinfectant use were obtained from a direct questionnaire given to the study subjects. However, it is fairly reliable, considering that previous studies have already reported HDLI characteristics using this exposure data [15, 23]. Third, we could not explore the effects of exposure from adolescence to young adulthood, and the long-term clinical significance with respect to lung function is still unknown. Considering the lung growth prognosis of children exposed to HD, a longer follow-up is required to investigate whether children with HDLI with an early exposure will catch up in lung growth to peak lung function in adolescence and adulthood or will continue to have a decline in lung function [41].

In conclusion, HD inhalation exposure within the first year of life may constitute a risk to respiratory health not only in terms of HDLI, but also as a long-term impact resulting in decreased lung function in children. Although the disease-specific biomarkers remain unclear, periodic evaluation of the children using PFTs will provide a unique opportunity to follow disease progression and to identify alternative diagnostic markers for children with HDLI.