Synergistic interaction of co-exposure to humidifier disinfectant chemicals CMIT/MIT and PHMG in lung injury.

A number of biocidal disinfectant chemicals are used as household products to prevent spread of pathogens. People are commonly exposed to multiple chemicals through those disinfectants. However, effects of interactions (e.g., synergism) between disinfectants on human health outcomes have been rarely studied. In this study, we aimed to investigate associations of a mixture of chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) and polyhexamethylene guanidine (PHMG), which had been used as humidifier disinfectants (HDs) in South Korea, with HD-associated lung injury (HDLI) in a Korean population (n = 4058) with HD exposure through use of HD products. Exposure to HD was retrospectively assessed by an interview-based standardized survey, and HDLI was determined by clinical assessment. After adjusting for covariates, PHMG-specific exposure indices (e.g., amount of use, indoor air concentration, and weekly exposure level) were dose-dependently associated with HDLI (their odds ratios for the comparison of third tertile versus first tertile were 1.95, 1.77, and 2.16, respectively). CMIT/MIT exposure was not observed to have a significant association with HDLI in a single chemical exposure model; however, associations between PHMG exposure and HDLI were strengthened by co-exposure to CMIT/MIT in combined chemical exposure models, where synergistic interactions between CMIT/MIT use and PHMG indices (amount of use and weekly exposure level) were observed (p-interaction in additive scale: 0.02 and 0.03, respectively). Our findings imply that adverse effects of PHMG exposure on lung injury among HD users might be worsened by co-exposure to CMIT/MIT. Given that plenty of household products contain disinfectants on global markets, epidemiological and toxicological investigations are warranted on interaction effects of co-exposure to disinfectants.

Exposures to humidifier disinfectant and various health conditions in Korean based on personal exposure assessment data of claimants for compensation.

BACKGROUND: Humidifier disinfectants (HDs) were commonly used household chemicals to prevent microbial growth in a humidifier water tank in South Korea. A growing body of evidence has indicated that its airborne exposure can induce severe lung injury. However, there has been low awareness of other health outcomes in HD users. This study aimed to evaluate health conditions appealed by claimants for compensation in relation with an increased exposure to HD. METHODS: From survey data of personal HD exposure assessment of claimants for compensation in Korea, we included a total of 4,179 subjects [cases in each dataset were defined by nine reported health conditions, i.e., pneumonia, asthma, cardiovascular disease, respiratory disease, otorhinolaryngologic disease, brain disease (including cerebrovascular disease), dermatological disease, lung cancer, and all cancers]. HD exposures was considered as the following exposure criteria: exposure duration, exposure proximity, exposure direction, chemical type, cumulative exposure time, indoor air concentration, and cumulative exposure level. Logistic regression models were used to evaluate the associations between HD exposure and health conditions. RESULTS: After adjusting for sociodemographic and health behavioral factors and other chemical exposures (households, environmental, and occupational exposures), an increase in cumulative HD exposure time was significantly associated with risks of all nine diseases (all p-trends < 0.05). An increase in HD exposure duration was associated with asthma, respiratory disease, otorhinolaryngologic disease, dermatological disease, all cancers, and lung cancer (p-trends < 0.05). Indoor HD concentration was associated with only pneumonia (p-trend = 0.015). CONCLUSIONS: Our findings suggest that cumulative exposures to airborne HD might potentially increase the risk of various reported health outcomes.

[HUMIDIFIER LUNG WITH ORGANIZING PNEUMONIA DETECTED BY BRONCHOSCOPY: A CASE REPORT].

A 58-year-old man presented with dyspnea on exertion and diffuse ground-glass opacities with mosaicism on chest computed tomography in April 201X. A transbronchial lung biopsy revealed organizing pneumonia and lymphocytic infiltration, and steroids were administered. During steroid tapering, the shortness of breath and ground-glass opacities recurred, and a transbronchial lung re-biopsy revealed organizing pneumonia without a granuloma again. Based on the clinical history, imaging features, and amount of humidifier usage, hypersensitivity pneumonitis caused by a humidifier was suspected. The inhalation challenge test was considered positive, and the diagnosis was confirmed. There have been some reports of unidentified granuloma in patients with humidifier lungs. Therefore, this case suggests that humidifier lung should be considered as a possibility even if pathological examination does not reveal granulomas and inflammatory changes such as organizing pneumonia are the only findings.

Inhalation toxicity of polyhexamethylene guanidine-phosphate in rats: A 4-week inhalation exposure and 24-week recovery period study.

Humidifier disinfectant (HD) is a causative agent of atypical lung injury reported in 2011 in South Korea, and various diseases caused by HD after exposure cessation have been reported to date. However, there is limited research on most of the reported diseases in terms of their association with HD exposure, and information on the progression of diseases caused by HD exposure is also limited. Therefore, we investigated the effects of HD inhalation on the body in rats. Rats were exposed to 0.15, 0.50, and 1.60 mg/m3 polyhexamethylene guanidine-phosphate (PHMG-p), which is the major component of HDs and most closely related to HD-associated lung injury. We conducted necropsy four times during the recovery period (0, 4, 12, and 24 weeks) and evaluated general systemic toxicities. There were significant changes in the mortality rate, body weight, and food consumption in the PHMG-p-exposed groups. Hematology revealed changes in hemoglobin level, hematocrit, red blood cell, reticulocyte, and white blood cell counts until 12 weeks of the recovery period. PHMG-p induced a delay in prothrombin time until 12 weeks of the recovery period. The aspartate aminotransferase, alanine aminotransferase, total bilirubin, and triglyceride levels were higher in the PHMG-p-exposed groups than in the control group at week 4 of the recovery period, and these parameters normalized after 12 weeks of the recovery period. Histopathological examination in PHMG-p exposed groups revealed several changes in the lungs, including the presence of alveolar macrophages, chronic inflammation, squamous metaplasia, alveolar emphysema, and pulmonary fibrosis. The severity of these symptoms was maintained or exacerbated till 24 weeks. Overall, PHMG-p inhalation can induce irreversible histological changes in the lungs and cause various types of damage throughout the body, even after exposure ends.

Health Effects Associated With Humidifier Disinfectant Use: A Systematic Review for Exploration.

BACKGROUND: It has been 10 years since the outbreak of lung disease caused by humidifier disinfectants in Korea, but the health effects have not yet been summarized. Therefore, this study aims to systematically examine the health effects of humidifier disinfectants that have been discovered so far. METHODS: All literature with humidifier disinfectants and their representative components as the main words were collected based on the web, including PubMed, Research Information Sharing Service, and government publication reports. A total of 902 studies were searched, of which 196 were selected. They were divided into four groups: published human studies (group 1), published animal and cytotoxicology studies (group 2), technical reports (group 3), and gray literature (group 4). RESULTS: Out of the 196 studies, 97 (49.5%) were published in peer-reviewed journals as original research. Group 1 consisted of 49 articles (50.5%), while group 2 consisted of 48 articles (49.5%). Overall, respiratory diseases such as humidifier disinfectant associated lung injury, interstitial lung disease, and asthma have a clear correlation, but other effects such as liver, heart, thymus, thyroid, fetal growth, metabolic abnormalities, and eyes are observed in toxicological experimental studies, but have not yet been identified in epidemiologic studies. CONCLUSION: The current level of evidence does not completely rule out the effects of humidifier disinfectants on extrapulmonary disease. Based on the toxicological evidence so far, it is required to monitor the population of humidifier disinfectant exposure continuously to see if similar damage occurs.

Review of Inhalation Health Risks Involving Chloromethylisothiazolinone (CMIT) and Methylisothiazolinone (MIT) Used as Disinfectants in Household Humidifiers.

The association between lung injury and exposure to humidifier disinfectant (HD) containing a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) has been controversial in South Korea. This study conducts a literature review in order to evaluate the likelihood of CMIT/MIT reaching the lower part of the respiratory tract and causing lung injury. A literature review focused on the inhalation risk of HD containing a mixture of CMIT and MIT. The major contents included the physicochemical properties of CMIT and MIT contained in HDs and methodological reviews on substance analysis, toxicity tests and clinical cases. HD products marketed in South Korea have been reported to contain approximately 1-2% CMIT and 0.2-0.6% MIT along with magnesium nitrate (20-25%), magnesium chloride (0.2-1.0%), and water (70-75%). The types of CMIT and MIT dispersed into the air and deposited in the respiratory tract are assumed to be either gaseous substances or nanoparticles mixed with magnesium salts. The result of the literature review including clinical cases of lung injury among CMIT/MIT HD product users, demonstrated that these chemicals likely reach the lower respiratory tract and accordingly cause lung injury. A number of humidifier disinfectant-associated lung injury cases with clinical evidence should be prioritized in risk assessment of HD containing CMIT and MIT, even though there might be insufficient evidence in all related areas, including inhalation exposure assessment studies, animal testing, and epidemiological studies.

A comprehensive study of deaths due to exposure to humidifier disinfectant in Korea: focusing on medical records, assessment of exposure to humidifier disinfectants, and causes of death.

OBJECTIVES: We aimed to determine the characteristics of the deceased victims of deaths caused by exposure to humidifier disinfectants, and present the distribution of the victims' data submitted for damage application, demographic characteristics, imaging findings, characteristics of humidifier disinfectant exposure, and distribution of the causes of death. METHODS: An integrated database of victims was established using the medical records data of 1,413 victims submitted during the application for death damage caused by exposure to humidifier disinfectants, and the demographic characteristics, medical records, imaging findings, exposure characteristics, and cause of death were examined. RESULTS: The average numbers of data submissions of each applicant for death damage were 3.0 medical use records. A total of 608 (43.0%) victims had more than one finding of acute, subacute, or chronic interstitial lung diseases. The average daily and cumulative use times of the victims were 14.40 and 24,645.81 hours, respectively, indicating greater exposure in this group than in the survivors. The humidifier disinfectants' components comprised polyhexamethylene guanidine (72.8%), chloromethylisothiazolinone/methylisothiazolinone (10.5%), other components (15.0%), and oligo-[2-(2-ethoxy)-ethoxyethyl] guanidine chloride (1.5%). The components' distribution was 67.8% for single-component use, which was higher than that in the survivors (59.8%). The distribution of the causes of death were: respiratory diseases (54.4%), neoplasms (16.8%), and circulatory diseases (6.3%). Other interstitial lung diseases (65.5%) were the most common cause of death among those who died due to respiratory diseases. CONCLUSIONS: Careful discussions of appropriate remedies should be conducted based on a comprehensive understanding of the characteristics of the deceased victims, considering their specificities and limitations.

Characteristics of the Molecular Weight of Polyhexamethylene Guanidine (PHMG) Used as a Household Humidifier Disinfectant.

(1) Background: Household humidifier disinfectant (HD) brands containing polyhexamethylene guanidine (PHMG) have been found to cause the most HD-associated lung injuries (HDLIs) in the Republic of Korea. Nevertheless, no study has attempted to characterize the potential association of the health effects, including HDLI, with the physicochemical properties of PHMG dissolved in different HD brands. This study aimed to characterize the molecular weight (MW) distribution, the number-average molecular weight (Mn), the weight-average molecular weight (Mw), and the structural types of PHMG used in HD products. (2) Methods: Quantitative measurements were made using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The Mn, Mw, and MW distributions were compared among various HD products. (3) Results: The mean Mn and Mw were 542.4 g/mol (range: 403.0-692.2 g/mol) and 560.7 g/mol (range: 424.0-714.70 g/mol), respectively. The degree of PHMG oligomerization ranged from 3 to 7. The MW distribution of PHMG indicated oligomeric compounds regardless of the HD brands. (4) Conclusions: Based on the molecular weight distribution, the average molecular weight of PHMG, and the degree of polymerization, the PHMG collected from HDLI victims could be regarded as an oligomer. PHMG, as used in household humidifiers, should not be exempted from toxic chemical registration as a polymer. Further study is necessary to examine the association of PHMG oligomeric compounds and respiratory health effects, including HDLI.

Humidifier Disinfectant Consumption and Humidifier Disinfectant-Associated Lung Injury in South Korea: A Nationwide Population-Based Study.

Humidifier disinfectant (HD) is a household biocidal product used in humidifier water tanks to prevent the growth of microorganisms. In 2011, a series of lung injury cases of unknown causes emerged in children and pregnant women who had used HD in Korea. This study investigated changes in the nationwide number of cases of humidifier disinfectant-associated lung injury (HDLI) in concordance with nationwide HD consumption using data covering the entire Korean population. More than 25 kinds of HD products were sold between 1994 and 2011. The number of diagnosed HDLI, assessed by S27.3 (other injuries of lungs) of the Korea National Health Insurance Service (NHIS) data, sharply increased by 2005, subsequently decreased after 2005, and almost disappeared after 2011 in concordance with the annual number of HD sales. The number of self-reported HDLIs, assessed using data from all suspected HDLI cases registered in the Korea Ministry of Environment, changed with the annual number of HD sales, with a delay pattern, potentially induced by the late awareness of lung injury diseases. The present study suggests that changes in the nationwide annual consumption of HD products were consistent with changes in the annual number of HDLI cases in Korea.

The Effect of 2 Humidifier Temperature Settings on Inspired Gas Temperatures and the Physiological Parameters of Preterm Infants Receiving Mechanical Ventilation Therapy.

BACKGROUND: The use of heated and humidified gas during mechanical ventilation is routine care in neonatal intensive care units. Giving gas at inadequate heat and humidity levels can affect neonatal morbidity and mortality. PURPOSE: To compare the effects of 2 humidifier temperature settings on the temperature and humidity of the inspired gas and the physiologic parameters in preterm newborns receiving mechanical ventilation. METHODS: The research was conducted in a single-group quasi-experimental design. Proximal temperature was measured using a humidity heat transmitter. The humidifier temperature was set at 38°C (temperature I) and then at 39°C (temperature II). RESULTS: The mean proximal temperatures were significantly lower than the values set in the humidifier (33.8 ± 1.20°C at temperature I, and 34.06 ± 1.30°C at temperature II, P < .001). However, the difference between the 2 proximal temperatures was not significant (P = .162). The incubator temperature was found to be effective on the proximal gas temperature (P < .05). It was found that only preterm infants in the temperature II group had a higher mean heart rate (P < .05). IMPLICATIONS FOR PRACTICE: Incubator temperatures may have an effect on inspired gas temperature in preterm infants who are mechanically ventilated and caregivers should be aware of these potentially negative effects. IMPLICATIONS FOR RESEARCH: Future studies should focus on how to measure the temperature and humidity of gas reaching infants in order to prevent heat and humidity losses.

COVID-19 and Total Laryngectomy-A Report of Two Cases.

OBJECTIVE: To date, no cases have been reported on the effects of COVID-19 in laryngectomees. CASE PRESENTATION: We herein presented two clinical cases of laryngectomized patients affected by COVID-19, detailing their clinical course and complications. DISCUSSION: In our experience, permanent tracheostomy did not significantly affect the choice of treatment. However, dedicated devices and repeated tracheal toilettes may be needed to deal with oxygen-therapy-related tracheal crusting. CONCLUSION: In conclusion, laryngectomees should be considered a vulnerable population that may be at risk for worse outcomes of COVID-19 due to anatomical changes in their airways. The role of the ENT specialist is to guide airway management and inform the support-staff regarding specific needs of these patients.

Comparison of Long Term Follow-up Chest CT Imaging in Adult and Pediatric Patients with Humidifier Disinfectant-related Lung Injury.

BACKGROUND: To compare the chest computed tomography (CT) images of children and adults in families with clusters of humidifier disinfectant-related lung injury (HDLI) after cessation of exposure to humidifier disinfectant (HD). METHODS: We reviewed medical records of 19 families with 43 patients (21 adults, 22 children) among families, which had at least one adult and one child with HDLI. Each family was exposed to the same HD exposure environment. RESULTS: In adults, centrilobular nodules were predominant (95.2%) in chronic HDLI findings after cessation of exposure to HD, however, in children, normal pattern was most prevalent on chest CT (45.5%), followed by centrilobular nodule (36.4%), bizarre lung cysts (36.4%), and reticulation (13.6%). CONCLUSION: Unlike the known chronic HDLI finding of adults, centrilobular nodules were only present in 36.4% of children. The frequency of bizarre lung cysts were significantly greater in children than that in adults after cessation of similar exposure to HD. Thus, bizarre lung cysts may be useful as another novel finding of chronic HDLI in children who have no history of pulmonary infection or other perinatal disorder such as hyaline membrane disease or other interstitial lung disease.

Characteristics of Exposure to Chloromethylisothiazolinone (CMIT) and Methylisothiazolinone (MIT) among Humidifier Disinfectant-Associated Lung Injury (HDLI) Patients in South Korea.

This study aimed to quantify both chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) dissolved in different product brands and to characterize the exposure to these chemicals among humidifier disinfectant-associated lung injury (HDLI) patients. Both CMIT and MIT dissolved in different humidifier disinfectant (HD) products were quantified using gas chromatography-mass spectrometry. The inhalation level of CMIT and MIT was estimated based on HD-associated factors as reported by HDLI patients. A total of eleven HD products marketed until the end of 2011 were found to contain CMIT and/or MIT. The level of combined CMIT and/or MIT dissolved in these HD products ranged from 12 to 353 ppm. The level varied among HD products and the year of manufacture. The average inhalation levels were estimated to be 7.5, 4.1, and 3.2 µg/m3 for the definite, probable, and possible groups, respectively. If probable and possible groups were collapsed together, the inhalation level of the collapsed group was significantly different from that of the definite group (p < 0.001). All HDLI patients responded as having used HD not only while sleeping, but also as having a humidifier treated with HD within close proximity every day in insufficiently ventilated spaces. These HD use characteristics of patients may be directly/indirectly linked to the HDLI development.

Kathon Induces Fibrotic Inflammation in Lungs: The First Animal Study Revealing a Causal Relationship between Humidifier Disinfectant Exposure and Eosinophil and Th2-Mediated Fibrosis Induction.

Currently available toxicity data on humidifier disinfectants are primarily limited to polyhexamethylene guanidine phosphate-induced lung fibrosis. We, therefore, investigated whether the sterilizer component Kathon, which is a mixture of chloromethylisothiazolinone and methylisothiazolinone, induces fibrotic lung injury following direct lung exposure in an animal model. Mice were intratracheally instilled with either the vehicle or Kathon. Differential cell counts, cytokine analysis, and histological analysis of lung tissue were then performed to characterize the injury features, and we investigated whether Kathon altered fibrosis-related gene expression in lung tissues via RNA-Seq and bioinformatics. Cell counting showed that Kathon exposure increased the proportion of macrophages, eosinophils, and neutrophils. Moreover, T helper 2 (Th2) cytokine levels in the bronchoalveolar lavage were significantly increased in the Kathon groups. Histopathological analysis revealed increased perivascular/alveolar inflammation, eosinophilic cells, mucous cell hyperplasia, and pulmonary fibrosis following Kathon exposure. Additionally, Kathon exposure modulated the expression of genes related to fibrotic inflammation, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, extracellular signal regulated kinase (ERK)1 and ERK2 cascade, extracellular matrix (ECM)-receptor interaction pathway, transforming growth factor beta receptor signaling pathway, cellular response to tumor necrosis factor, and collagen fibril organization. Our results suggest that Kathon exposure is associated with fibrotic lung injury via a Th2-dependent pathway and is thus a possible risk factor for fibrosis.

Characteristics of a new respiratory syndrome associated with the use of a humidifier disinfectant: humidifier disinfectant-related respiratory syndrome (HDRS).

OBJECTIVES: The purpose of this study was to characterize a new respiratory syndrome associated with exposure to a humidifier disinfectant (HD) in South Korea that is distinct from the well-known HD-related lung injury (HDLI). The authors identified this condition in 24 study subjects who were family members of patients with definite or probable HDLI (referred to as index cases), and were exposed to HD in the same room as the index cases. MATERIAL AND METHODS: The authors reviewed medical records of 236 family members in 110 families who were exposed to HD in the same rooms and residences as the index cases. RESULTS: They identified 24 family members who were exposed to HD in the same rooms and residences as the index cases, and who developed respiratory disorders that were distinct from HDLI. The clinical signs and symptoms of these individuals were in the upper respiratory tract, such as allergic rhinitis and croup, or in the lower respiratory tract, such as bronchitis and pneumonia. The diffusing capacity of the lung fordetermicarbon monoxide was reduced in 9 of 12 children (data not available for 1 child), and in 4 of 5 adults (data not available for 6 adults). The percent forced vital capacity and forced expiratory volume in one second/forced vital capacity ratios were within the normal ranges in most patients. The computed tomography findings, which mostly indicated non-specific inflammation, were inconsistent with the radiological diagnostic criteria for HDLI, but were abnormal in 8 of 11 adults, and in 2 of 13 children. CONCLUSIONS: The authors propose a new condition, i.e., HD-related respiratory syndrome (HDRS), which is characterized by mild to moderate or atypical respiratory symptoms and signs, and is related to HD exposure, but is distinct from HDLI. The recognition of HDRS may provide a basis for understanding the natural history of HD-related respiratory problems, and for capturing the whole spectrum of HD-related clinical manifestations in the respiratory tract. Int J Occup Med Environ Health. 2020;33(6):829-39.

Properties of Polyhexamethylene Guanidine (PHMG) Associated with Fatal Lung Injury in Korea.

The use of humidifier disinfectant (HD) has been determined to be associated with lung injuries (HDLI) in Korea. Although HD brands containing polyhexamethylene guanidine (PHMG) oligomers have been found to cause more HDLI compared to brands containing other disinfectants, the physicochemical properties of PHMG have been poorly defined. We aimed to quantify the PHMG dissolved in HD brands, characterize the number-average (Mn) and weight-average (Mw) molecular masses, and identify the polymerization degree of PHMG. Analysis of the PHMG oligomers was performed using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) operated in positive-ion reflectron mode. Eight brands of HD containing PHMG were identified. The PHMG concentrations in these brands ranged from 160 to 37,200 ppm (mean = 3100.9 ppm). Concentration was a significant variable among and within HD brands. The degree of PHMG oligomerization fell within the range of two to four. The averages of Mn and Mw were 517.2 g/mol (range: 422-613 g/mol) and 537.3 g/mol (range: 441.0-678.0 g/mol), respectively. Based on the average molecular weight and the degree of polymerization, the PHMG examined here could be regarded as oligomers, which may be associated with the highest proportion of HDLI being caused by PHMG.

Integration of transcriptomics, proteomics and metabolomics identifies biomarkers for pulmonary injury by polyhexamethylene guanidine phosphate (PHMG-p), a humidifier disinfectant, in rats.

Polyhexamethylene guanidine phosphate (PHMG-p) was used as a humidifier disinfectant in Korea. PHMG induced severe pulmonary fibrosis in Koreans. The objective of this study was to elucidate mechanism of pulmonary toxicity caused by PHMG-p in rats using multi-omics analysis. Wistar rats were intratracheally instilled with PHMG-p by single (1.5 mg/kg) administration or 4-week (0.1 mg/kg, 2 times/week) repeated administration. Histopathologic examination was performed with hematoxylin and eosin staining. Alveolar macrophage aggregation and granulomatous inflammation were observed in rats treated with single dose of PHMG-p. Pulmonary fibrosis, chronic inflammation, bronchiol-alveolar fibrosis, and metaplasia of squamous cell were observed in repeated dose group. Next generation sequencing (NGS) was performed for transcriptome profiling after mRNA isolation from bronchiol-alveoli. Bronchiol-alveoli proteomic profiling was performed using an Orbitrap Q-exactive mass spectrometer. Serum and urinary metabolites were determined using 1H-NMR. Among 418 differentially expressed genes (DEGs) and 67 differentially expressed proteins (DEPs), changes of 16 mRNA levels were significantly correlated with changes of their protein levels in both single and repeated dose groups. Remarkable biological processes represented by both DEGs and DEPs were defense response, inflammatory response, response to stress, and immune response. Arginase 1 (Arg1) and lipocalin 2 (Lcn2) were identified to be major regulators for PHMG-p-induced pulmonary toxicity based on merged analysis using DEGs and DEPs. In metabolomics study, 52 metabolites (VIP > 0.5) were determined in serum and urine of single and repeated-dose groups. Glutamate and choline were selected as major metabolites. They were found to be major factors affecting inflammatory response in association with DEGs and DEPs. Arg1 and Lcn2 were suggested to be major gene and protein related to pulmonary damage by PHMG-p while serum or urinary glutamate and choline were endogenous metabolites related to pulmonary damage by PHMG-p.

Effectiveness of chest physiotherapy and pulmonary rehabilitation in patients with non-cystic fibrosis bronchiectasis: a narrative review.

Respiratory physiotherapy and rehabilitation are important therapeutic options in non-cystic fibrosis bronchiectasis (NCFB). The aims of this review of clinical trials were to evaluate the safety and the effects on physiologic and clinical outcomes of airway clearance techniques (ACTs) and rehabilitation in NCFB patients, in comparison to usual care. The search was performed on March 2018 by using PubMed and PeDro databases. 33 studies were selected. The use of ACTs for NCFB were effective in increasing sputum volume although no benefit in quality of life (QoL) or pulmonary exacerbations were observed. There were no differences in effectiveness between the several techniques used. Humidification and saline inhalation were able to aid airway clearance. Hypertonic solution (HS) was more effective than isotonic solutions (IS) in improving expectoration and sputum viscosity. Pulmonary rehabilitation (PR) was found to be associated with short term benefits in exercise capacity, dyspnea and fatigue. Exercise training seems to improve quality of life and lower exacerbation rate, but long-term data are not available. Further studies are necessary to identify the most feasible long-term outcomes such as QoL and exacerbation rate.

NOTCH1 Pathway is Involved in Polyhexamethylene Guanidine-Induced Humidifier Disinfectant Lung Injuries.

An outbreak of fatal humidifier disinfectant lung injuries (HDLI) occurred in Korea. Human studies on mechanisms underlying HDLI have yet to be conducted. This study aimed to investigate methylation changes and their potential role in HDLI after exposure to HDs containing polyhexamethylene guanidine-phosphate. DNA methylation analysis was performed in blood samples from 10 children with HDLI and 10 healthy children using Infinium Human MethylationEPIC BeadChip. Transcriptome analysis was performed using lung tissues from 5 children with HDLI and 5 controls. Compared to healthy controls, 92 hypo-methylated and 79 hyper-methylated CpG sites were identified in children with HDLI at the statistical significance level of |Δß|>0.2 and p<0.05. NOTCH1 was identified as a candidate network hub gene in cases. NOTCH1 transcripts significantly increased in lung tissues from HDLI cases compared to unexposed controls (p=0.05). NOTCH1 may play an important role in pulmonary fibrosis of HDLI.