Environmental Exposure Factors Research Articles

Mother's smoking habits affects IL10 methylation but not asthma in Ecuadorian children.

To identify polymorphisms and methylation profiles in the IL10 gene associated with asthma in children aged 5 to 11. A case-control study was conducted with asthmatic and non-asthmatic children aged 5 to 11 years in Cuenca-Ecuador. Data on allergic diseases and risk factors were collected through a questionnaire for parents. Atopy was measured by skin prick test (SPT) to relevant aeroallergens. Three IL10 single nucleotide polymorphisms were evaluated in all participants, and methylation analysis was performed in 54 participants. Association between risk factors, allergic diseases and genetic factors were estimated using multivariate logistic regression. The results of polymorphisms showed no differences between cases and controls when comparing the SNPs rs3024495, rs3024496, rs1800896 allelic and genotypic frequencies. In the methylation analysis, no differences in the IL10 methylation profile were found between cases and controls; however, the multivariate analysis showed an association between the mother's smoking habits and the IL10 methylation profile. Smoking habit could be essential as an environmental exposure factor in regulating gene expression in children with asthma.

[Research progress on the mechanism of pyroptosis in airway epithelial barrier injury in asthma].

Pyroptosis is a novel form of programmed cell death mediated by cleavage of Gasdermin family proteins by activated caspases, which plays an important role in the control of acute and chronic diseases. Asthma is a chronic inflammatory airway disease with varying degrees of airflow obstruction. The airway epithelial barrier plays an important role in initiating host defenses and controlling immune responses. Accumulating evidence suggests that pyroptosis is involved in the impairment of airway epithelial barrier function and abnormal immune regulation in asthma. This article aims to review the latest regulatory mechanism of pyroptosis involved in airway epithelial barrier injury in asthma under various environmental exposure factors, and to provide a new method for targeted therapy of asthma.

Maternal smoking during pregnancy increases the risk of gut microbiome-associated childhood overweight and obesity

ABSTRACT Childhood obesity is linked to maternal smoking during pregnancy. Gut microbiota may partially mediate this association and could be potential targets for intervention; however, its role is understudied. We included 1,592 infants from the Canadian Healthy Infants Longitudinal Development Cohort. Data on environmental exposure and lifestyle factors were collected prenatally and throughout the first three years. Weight outcomes were measured at one and three years of age. Stool samples collected at 3 and 12 months were analyzed by sequencing the V4 region of 16S rRNA to profile microbial compositions and magnetic resonance spectroscopy to quantify the metabolites. We showed that quitting smoking during pregnancy did not lower the risk of offspring being overweight. However, exclusive breastfeeding until the third month of age may alleviate these risks. We also reported that maternal smoking during pregnancy significantly increased Firmicutes abundance and diversity. We further revealed that Firmicutes diversity mediates the elevated risk of childhood overweight and obesity linked to maternal prenatal smoking. This effect possibly occurs through excessive microbial butyrate production. These findings add to the evidence that women should quit smoking before their pregnancies to prevent microbiome-mediated childhood overweight and obesity risk, and indicate the potential obesogenic role of excessive butyrate production in early life.

Association study of S100A9 gene polymorphisms with Parkinson's disease risk and age of disease onset.

Intestinal inflammation is associated with several neurodegenerative diseases, including Parkinson's disease (PD). Intestinal inflammation is also closely related to genetic and environmental factors. S100 calcium-binding protein A9 (S100A9) is also thought to be genetically associated with intestinal inflammation and PD risk. This study investigated the association between S100A9 gene polymorphisms and PD risk and age of disease onset. This study used a case-control method and included 242 PD patients and 242 healthy participants. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed. S100A9 expression in the serum of the patients and controls was detected using reverse transcription‑quantitative PCR (RT-qPCR). The CC genotype and C allele of the rs3014866 polymorphism in S100A9 had significantly higher distribution in PD patients. The recessive and dominant models demonstrated that the patients carrying the rs3014866 C allele had a significantly increased risk of developing PD as compared with patients homozygous for the TT genotype. The generalized linear model results demonstrated that rs3014866 was associated with the age of disease onset independent of environmental exposure factors (smoking and toxins). Furthermore, the S100A9 mRNA transcription level in the patients' serum was significantly higher than that of the controls. Moreover, the serum of patients with the CC genotype had higher S100A9 expression levels. The results combined the relationship between S100A9 and PD susceptibility and age of disease onset. The findings might suggest new ideas for PD clinical diagnosis and treatment.

Paternal Age Matters: Association with Sperm Criteria's- Spermatozoa DNA Integrity and Methylation Profile.

Advanced age has been reported to negatively affect sperm parameters and spermatozoa DNA integrity. A decline in sperm criteria was also associated with altered epigenetic marks such as DNA methylation with a potential downstream impact on in vitro fertilization success and clinical outcomes. The aim of the present retrospective study was to clarify the association between advanced paternal age (APA) and sperm parameters, DNA integrity and DNA methylation profile. A total of 671 patients consulting for infertility underwent sperm analysis, sperm DNA integrity assessment and methylation level measurement. The principal finding was that individuals over 40 years of age exhibit a significant increase in DNA fragmentation levels compared to the younger group (15% versus 9%, respectively, p = 0.04). However, there was no significant difference in DNA decondensation and sperm parameters in association with APA. In addition, a drop in the global methylation level was also found in men over 40 years (6% in the young group versus 2% in the old group, p = 0.03). As a conclusion, men over 40 years are at higher risk of elevated sperm DNA fragmentation and lower methylation level. Based on these observations, it is recommended that the assessment of sperm DNA fragmentation should be taken into consideration particularly after the age of 40. Our findings support the idea that paternal age is a crucial factor that should not be neglected during fertility evaluation and treatment since it is associated with epigenetics changes in sperm. Although the underlying mechanism remains to be clarified, we believe that environmental and professional exposure factors are likely involved in the process.

Association between Chronic Environmental Lead (Pb) Exposure and Cytokines in Males and Females of Reproductive Age from Kabwe, Zambia.

Lead (Pb) poisoning remains a great public health challenge globally known to induce a wide range of ailments in both children and adults. The current study investigated the association of chronic environmental Pb exposure and immunomodulatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) in adult males and females living in Kabwe, Zambia. The standard human cytokine/chemokine Milliplex assay was used to quantify plasma cytokines from four groups categorized as low (<10 μg/dL) and high (>10 μg/dL) blood lead level (BLL) groups, namely, low BLL female (n = 47; BLL = 3.76 μg/dL), low BLL Male (n = 43; BLL = 4.13 μg/dL), high BLL female (n = 21; BLL = 23.5 μg/dL), and high BLL male (n = 18; BLL = 23.7 μg/dL), respectively. The low BLL group was associated with increased TNF-α levels, and the high BLL group was associated with reduced TNF-α levels in female subjects. No associations between BLL and the levels of IL-8 and TNF-α cytokines were observed in either females or males, respectively. A negative correlation between BLL and TNF-α was found in female subjects, suggesting that an increase in BLL accompanied by a reduction in TNF-α. The reduced levels of circulating TNF-α in female subjects suggest that chronic Pb exposure could predispose females to immune and inflammation-related disorders than their male counterparts. Further studies are recommended to ascertain the impact of chronic Pb exposure on immunomodulatory cytokines, especially in females.

Effects of various environments on epigenetic settings and chromosomal damage

Air pollution is a dominant environmental exposure factor with significant health consequences. Unexpectedly, research in a heavily polluted region of the Czech Republic, with traditional heavy industry, revealed repeatedly the lowest frequency of micronuclei in the season with the highest concentrations of air pollutants including carcinogenic benzo[a]pyrene (B[a]P). Molecular findings have been collected for more than 10 years from various locations of the Czech Republic, with differing quality of ambient air. Preliminary conclusions have suggested adaptation of the population from the polluted locality (Ostrava, Moravian-Silesian Region (MSR)) to chronic air pollution exposure. In this study we utilize the previous findings and, for the first time, investigate micronuclei (MN) frequency by type: (i) centromere positive (CEN+) MN, representing chromosomal losses, and (ii) centromere negative (CEN-) MN representing chromosomal breaks. As previous results indicated differences between populations in the expression of XRCC5, a gene involved in the non-homologous end-joining (NHEJ) repair pathway, possible variations in epigenetic settings in this gene were also investigated. This new research was conducted in two seasons in the groups from two localities with different air quality levels (Ostrava (OS) and Prague (PG)). The obtained new results show significantly lower frequencies of chromosomal breaks in the OS subjects, related to the highest air pollution levels (p < 0.001). In contrast, chromosomal losses were comparable between both groups. In addition, significantly lower DNA methylation was found in 14.3% of the analyzed CpG loci of XRCC5 in the population from OS. In conclusion, the epigenetic adaptation (hypomethylation) in XRCC5 involved in the NHEJ repair pathway in the population from the polluted region, was suggested as a reason for the reduced level of chromosomal breaks. Further research is needed to explore the additional mechanisms, including genetic adaptation.

Machine learning approaches to predict age from accelerometer records of physical activity at biobank scale.

Physical activity improves quality of life and protects against age-related diseases. With age, physical activity tends to decrease, increasing vulnerability to disease in the elderly. In the following, we trained a neural network to predict age from 115,456 one week-long 100Hz wrist accelerometer recordings from the UK Biobank (mean absolute error = 3.7±0.2 years), using a variety of data structures to capture the complexity of real-world activity. We achieved this performance by preprocessing the raw frequency data as 2,271 scalar features, 113 time series, and four images. We defined accelerated aging for a participant as being predicted older than one's actual age and identified both genetic and environmental exposure factors associated with the new phenotype. We performed a genome wide association on the accelerated aging phenotypes to estimate its heritability (h_g2 = 12.3±0.9%) and identified ten single nucleotide polymorphisms in close proximity to genes in a histone and olfactory cluster on chromosome six (e.g HIST1H1C, OR5V1). Similarly, we identified biomarkers (e.g blood pressure), clinical phenotypes (e.g chest pain), diseases (e.g hypertension), environmental (e.g smoking), and socioeconomic (e.g income and education) variables associated with accelerated aging. Physical activity-derived biological age is a complex phenotype associated with both genetic and non-genetic factors.

Expert systems for diagnostics of infectious diseases in cattle

Expert systems designed to identify diseases in cattle may use a variety of sources of information such as clinical data, signs of disease, medical history, laboratory results, environmental exposure and other relevant factors. They can be developed based on rules, heuristics, or machine learning, using a large amount of data to train the model. The expert system may provide the veterinarian with a list of possible diagnoses, ranked by probability, based on the data provided. She may also recommend further investigations or tests for a more accurate diagnosis. The developed expert system for veterinary medicine provides a wide range of functions and capabilities to support the work of veterinarians and processing data on the incidence of cattle.

Design and Implementation of Taizhou Integrated Prostate Screening.

A community-based prostate cancer screening program was conducted to assess the morbidity and associated factors for prostate cancer among the subpopulation of men aged ≥50 years in Taizhou, China. Taizhou Integrated Prostate Screening (TIPS) is a large, observational, population-based study of prostate cancer screening data based on serum prostate-specific antigen (PSA) concentrations. A pilot census of all male residents aged 50 years or older was conducted in Luqiao District, one of the field sites of the TIPS cohort in the city of Taizhou, Zhejiang. The interviewer-administered questionnaire evaluated demographic characteristics and environmental exposure factors. A total of 1,806 out of 3,516 participants completed the questionnaire. The overall prevalence of PSA ≥4 ng/mL was 11.5%, and included participants at low risk (9.2%), moderate risk (1.7%), and high risk (0.6%). Participants aged 60-69, 70-79, and ≥80 years had a 2.7-fold, 4.2-fold, and 6.5-fold higher risk of elevated PSA, respectively, in comparison with those aged 50 to 59 years (p < .001). Eighteen patients were diagnosed with prostate cancer, of whom 11 (61.1%) underwent radical surgery. This community-based PSA screening program indicated the results for early detection of prostate cancer among men aged ≥50 years. Early screening and appropriate clinical therapy for the management of prostate cancer are essential in this subpopulation.

Targeting the lncMST-EPRS/HSP90AB1 complex as novel therapeutic strategy for T-2 toxin-induced growth retardation

Growth retardation is a global public health problem that is highly prevalent especially in low-and middle-income countries, which is closely related to the consumption of grains contaminated with T-2 toxin, a risk for human and animal health. However, the possible targets that can relieve T-2 toxin-induced growth retardation still need to be explored. In the present study, T-2 toxin was used as an environmental exposure factor to induce growth retardation and further explore the regulatory role of lncRNA in growth retardation. The present study systematically characterised the expression profiles of lncRNAs and identified a lncRNA lncMST that is related to growth retardation in T-2 toxin-administered rats. Functionally, lncMST could alleviate cell cycle arrest and apoptosis in T-2 toxin-treated GH3 cells. Mechanistically, lncMST, serve as an inducible chaperone RNA, involved in the paradigm “Chemical-induced stress related growth retardation”, through recruiting the EPRS/HSP90AB1 complex to increase HDAC6 expression, thus further alleviating T-2 toxin-induced growth retardation. These findings for the first time demonstrate that the probable therapeutic relationship between lncMST and growth retardation, providing an explanation and therapeutic targets for the pathogenesis of growth retardation.

Research progress of precision nursing

<p indent="0mm">With the rapid development of modern biotechnology, such as multi-omics and bioinformatics, precision nursing (PN) has become the forefront of nursing research recently. With a focus on individualized health, PN fully considers interactions between individual genes, environmental exposure, living habits, and other factors. It also explores the occurrence mechanism and regulation path of health problems, which is important to promote nursing theory and technological innovation and further improve human health. This review introduced the origin, definition, and development of PN and sorted out the research frontiers of PN in symptom science, health management, clinical nursing decision-making, and innovation. We also emphasize the future development of PN from the aspects of systematic planning of research direction, strengthening the construction of support platforms, increasing personnel training, and improving management standards to provide a reference for promoting new developments in the field of nursing.

Identification of genetic variants of the IL-22 gene in association with an altered risk of COPD susceptibility.

The incidence of chronic obstructive pulmonary disease (COPD) is related to the interaction between environmental exposure and genetic factors. Far more than 15% of smokers eventually develop COPD. In addition to smoking, genetic susceptibility may be another factor in the development of COPD. IL‐22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis. Here, we conducted a case–control study to evaluate the association between IL‐22 tag‐single nucleotide polymorphisms (SNPs) and COPD risk. Four tag‐SNPs (rs2227478, rs2227481, rs2227484 and rs2227485) were identified according to linkage disequilibrium (LD) analysis in 30 healthy controls. A total of 513 COPD cases and 504 controls were recruited to perform an association study between these four tag‐SNPs and COPD risk. We found that the “C” allele of rs2227478T>C and the “T” allele of rs2227481C>T were obviously related to decreased COPD susceptibility. Genetic model analysis showed that rs2227478T>C and rs2227481C>T were significantly associated with a decreased risk of COPD under dominant models after adjusting for the above factors. In the recessive model, rs2227485T>C was obviously associated with decreased COPD risk. Our data showed that only rs2227485T>C was associated with a decreased COPD risk after Bonferroni correction. The eQTL analysis showed that rs2227485T>C was significantly associated with IL‐22 expression. The pGL4‐rs2227485‐C gene reporter had a higher promoter activity than pGL4‐rs2227485‐T. In our study, rs2227485T>C, located in the promoter region of IL‐22, was associated with a decreased risk of COPD and increased IL‐22 promoter activity, suggesting that this variant might modulate COPD susceptibility.

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders.

As the risk of harmful environmental exposure is increasing, it is important to find suitable targets for the diagnosis and treatment of the diseases caused. Isocitrate dehydrogenase 2 (IDH2) is an enzyme located in the mitochondria; it plays an important role in numerous cell processes, including maintaining redox homeostasis, participating in the tricarboxylic acid cycle and indirectly taking part in the transmission of the oxidative respiratory chain. IDH2 mutations promote progression in acute myeloid leukemia, glioma and other diseases. The present review mainly summarizes the role and mechanism of IDH2 with regard to the biological effects, such as the mitophagy and apoptosis of animal or human cells, caused by environmental pollution such as radiation, heavy metals and other environmental exposure factors. The possible mechanisms of these biological effects are described in terms of IDH2 expression, reduced nicotine adenine dinucleotide phosphate content and reactive oxygen species level, among other variables. The impact of environmental pollution on human health is increasingly attracting attention. IDH2 may therefore become useful as a potential diagnostic and therapeutic target for environmental exposure-induced diseases.

The inhibition of CFTR in the descended testis of SD rats with unilateral cryptorchidism induced by di-(2-ethylhexyl) phthalate (DEHP)

Di-(2-ethylhexyl) phthalate (DEHP) is a kind of environmental endocrine disruptors (EEDs), which has been confirmed to cause serious consequences, such as cryptorchidism. Patients with unilateral cryptorchidism still had oligospermia or infertility even if they received orchidopexy before puberty. Testicular dysgenesis syndrome (TDS) attributes this kind of problems to the abnormal testicular development during the embryonic period, and considers that the environmental exposure factors during pregnancy play a major role. Therefore, for unilateral cryptorchidism, even if one testicle has dropped to scrotum, it may be exposed to these substances and cause damage. Cystic fibrosis transmembrane conduction regulator (CFTR) is very important for the maturation of male reproductive system. Previously, cryptorchidism was thought to cause abnormal expression of heat sensitive protein CFTR in testis, but the expression of CFTR in healthy side (descended side) testis was not clear. In this study, we established SD rats with unilateral cryptorchidism by exposure to DEHP (500mg/kg/day) during pregnancy, and detected the expression of CFTR and downstream signal NF-κB/COX-2/PGE2 in bilateral testis. Finally, we found that the expression of CFTR and downstream signal NF-κB/COX-2/PGE2 in the undescended testis was significantly abnormal, but the expression of them in the descended testis was also abnormal to some extent. Therefore, we speculate that in addition to high temperature will affect the expression of CFTR, there may be other factors that cause abnormal expression of CFTR induced by DEHP, and lead to abnormal male reproductive function eventually, but the specific mechanism needs to be further studied.

[Environmental pollution and allergy].

Air pollution, climate change, and the decrease of biological diversity are major threats to human health. In the past decades, an increase in allergic diseases, including asthma and rhinoconjunctivitis, has been observed. Up to 40 % of the world population may have an allergic disease, which represents a significant impact on the quality of life of those who suffer from it, and environmental pollution is one of the causes of its presentation. Air pollution causes significant morbidity and mortality in patients with inflammatory airway diseases such as allergic rhinitis, chronic rhinosinusitis, asthma, and chronic obstructive pulmonary disease. Oxidative stress in patients with respiratory diseases can induce eosinophilic inflammation in the airways, increase atopic allergic sensitization, and rise susceptibility to infections. Climate change has influenced exposure to extramural allergens and it is associated with exacerbations of respiratory diseases in the upper and lower airway. The interaction of indoor and outdoor environmental exposure and host factors can affect the development and progression of lifelong allergic diseases. The decrease of exposure to air pollutants has been associated with a favorable response in respiratory health, which is why it is necessary to implement measures that contribute to an improvement in air quality.

Elucidating the temperature exposome in Alzheimer's disease.

The etiology of Alzheimer's disease (AD) is multifaceted with both genetic and modifiable environmental exposure (exposome) factors contributing to cognitive decline. Metabolic syndrome, including insulin resistance, increases the risk for developing AD, which we have observed in AβPP/PS1 mice. We hypothesized that altering environmental temperature (eT) exposure would improve the metabolic profile of AD mice thereby alleviating cognitive deficits. Starting at 6 months of age (mild amyloid pathology and cognitive impairment), male and female AβPP/PS1, APPNL-F/NL-F , and genetic background control C57BL/6 mice were chronically housed at either 16, 23, or 30°C for 6 months. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and cognitive performance using the Morris water maze (MWM) behavioral paradigm. Plasma, hippocampal, and peripheral (adipose, hepatic, and pancreatic) samples were procured postmortem and tissue-specific markers of amyloid accumulation and metabolism were assayed. In male mice, chronic exposure to 16°C eT reduced body weight, but had no effect on metabolism nor cognition (Figure 1). Male AD mice exposed to 30°C eT had reduced body weight, improved glucose tolerance, and better performance on the MWM. Plasma concentrations of insulin-like growth factor 1 (IGF-1) and leptin were also decreased in male AD mice at 30°C eT. In female mice, chronic exposure to either eT did not alter body weight, nor cognition. However, 30°C eT improved insulin sensitivity of female C57BL/6 and AβPP/PS1 mice with an corresponding increase in IGF-1 plasma levels. Despite the known improvements on metabolic factors by increasing thermogenesis, chronic exposure to 16°C did not improve the metabolic profile of control or AD mice. Unexpectedly, 30°C eT improved the metabolic profile of male and female C57BL/6 and AβPP/PS1 mice, but cognitive performance was only improved in male mice. Work is ongoing to elucidate markers of glucose metabolism and amyloid pathology in post mortem tissue to better interpret these sexually dimorphic results. This work was supported by the National Institutes of Health (R01 AG057767, R01 AG061937), the Illinois Department of Public Health (03282005H), CARE, and the Kenneth Stark Endowment.

Spatial Distribution and Associated Risk Factors of Soil-Transmitted Helminth Infection in a Semi-urban Community in Southwest Nigeria

Parasite distribution exhibit heterogeneity within households and communities. The aim of this study is to identify the spatial distribution, clustering and associated risk factors of Soil-transmitted Helminths infection in a semi-urban area in Southwest Nigeria. Geographical information System (GIS) was used to map the town into three density areas; low, medium and high density areas. Two hundred and thirty six soil samples were obtained from the surroundings of 137 households and stool samples were collected from the inhabitant of the households. Moran index was used to analyze the spatial distribution of STH within the community. A total of 137 households were sampled for human STH and environmental soil samples from the household were analyzed. The prevalence of human STH infection was 41.7% while that of soil parasite was 27.7% within the selected household. Ascaris lumbricoides was the predominant STH infection in the community sampled with 24.1% prevalence followed by Hookworm. Spatial analysis showed that A. lumbricoides infection was significantly clustered only in the GIS mapped medium density area of Igbo-Ora (z-score 2.302, p=0.021), while hookworm infection was randomly distributed in all the GIS mapped areas of Igbo-Ora. There was a statistically significant association between human STH infection and presence of parasite in the household soil (x2 5.74, p-value 0.017). None of the risk factors evaluated was found to have significant association for the clustering pattern of infection found in the medium density area of the community. Meanwhile, factors such as; the physical presence of a popularly patronized local market in the area, lack of any visible public toilet and the use of bushes around the area by the people for defecation contribute to the reasons for the clustering of the Ascaris infection. Also, the ability of Ascaris to withstand environmental conditions than other STH parasite may contribute to the pattern observed. The differences in the pattern of distribution and associated risk factors revealed that environmental conditions and exposure factors are major determinant of STH infection.

Predicting coronavirus disease (COVID-19) outcomes in the United States early in the epidemic

By 21 October 2020, the coronavirus disease (COVID-19) epidemic in the United States (US) had infected 8.3 million people, resulting in 61,364 laboratory-confirmed hospitalizations and 222,157 deaths. Currently, policymakers are trying to better understand this epidemic, especially the human-to-human transmissibility of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in relation to social, populational, air travel related and environmental exposure factors. Our study used 50 US states’ public health surveillance datasets (January 1-April 1, 2020) to measure associations of confirmed COVID-19 cases, hospitalizations and deaths with these variables. Using the resulting associations and multivariate regression (Negative Binomial and Poisson), predicted cases, hospitalizations and deaths were generated for each US state early in the epidemic. Factors associated with a significantly increased risk of COVID-19 disease, hospitalization and death included: population density, enplanement, Black race and increased sun exposure; in addition, COVID-19 disease and hospitalization were also associated with morning humidity. Although predictions of the number of cases, hospitalizations and deaths due to COVID-19 were not accurate for every state, those states with a combination of large number of enplanements, high population density, high proportion of Black residents, high humidity or low sun exposure may expect more rapid than expected growth in the number of COVID-19 events early in the epidemic.

Respiratory syncytial virus and asthma: untying the Gordian knot

Asthma is a highly heritable disease; however, host environmental factors also influence variable susceptibility to disease development. One environmental exposure and asthma risk factor that has been the focus of decades of study is respiratory syncytial virus (RSV). A study of the hospital records of 100 children (76% of whom were infants) with bronchiolitis in the late 1950s first established a strong association between severe infection early in life and asthma, setting the stage for the association of RSV with asthma over the past 60 years to focus exclusively on RSV infections that are severe.