NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal-Hreidarsson syndrome.

Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal-Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.

Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Relationship between gender and survival in a real-life cohort of patients with COPD.

BACKGROUND: Although COPD affects both men and women, its prevalence is increasing more rapidly in women. Disease outcomes appear different among women with more frequent dyspnea and anxiety or depression but whether this translates into a different prognosis remains to be determined. Our aim was to assess whether the greater clinical impact of COPD in women was associated with differences in 3-year mortality rates. METHODS: In the French Initiatives BPCO real-world cohort, 177 women were matched up to 458 menon age (within 5-year intervals) and FEV1 (within 5% predicted intervals). 3-year mortality rate and survival were analyzed. Univariate and multivariate logistic regression analyses were performed. RESULTS: For a given age and level of airflow obstruction, women with COPD had more severe dyspnea, lower BMI, and were more likely to exhibit anxiety. Nevertheless, three-year mortality rate was comparable among men and women, respectively 11.2 and 10.8%. In a multivariate model, the only factors significantly associated with mortality were dyspnea and malnutrition but not gender. CONCLUSION: Although women with COPD experience higher levels of dyspnea and anxiety than men at comparable levels of age and FEV1, these differences do not translate into variations in 3-year mortality rates. TRIAL REGISTRATION: 04-479.

Exposure to Cypress Pollens and Subsequent Symptoms: A Panel Study.

OBJECTIVE: The objective of this panel study was to document the relationship between exposure to cypress pollen and allergic symptoms. METHODS: The study group included 47 patients with allergy to cypress pollen who completed a daily diary and a weekly evaluation of quality of life (QoL) during the cypress pollen season. Different patients were included in three consecutive pollen seasons: 2014-2015, 2015-2016, and 2016-2017. Daily cypress pollen counts were obtained from the National Aerobiological Network. Air pollution and meteorological data were recorded on a daily basis. The pollen-symptoms relationship was quantified by calculating odds ratios for an increase of 1 log of grains of pollen/m3, taking into account potential confounding factors. The QoL score was expressed with a beta coefficient that increased with 1 grain of pollen/m3. RESULTS: There was a marked increase in rhinitis and ocular symptoms during the pollen season, with a plateau effect at high levels of exposure, but no relationship with bronchial symptoms. The QoL score had a linear and significant relationship with the cypress pollen count. We did not detect any threshold level. CONCLUSION: This panel study demonstrated a significant association between exposure to cypress pollens and allergic symptoms, with a plateau effect for high exposures.

Climate and Allergic Sensitization to Airborne Allergens in the General Population: Data from the French Six Cities Study.

BACKGROUND: The results of international epidemiological surveys show large geographical variations in skin test reactivity but do not provide a rationale for such variations. OBJECTIVE: To assess the relationship between climate and allergic sensitization in schoolchildren. METHODS: In the present study, we analyzed data from a multicenter, epidemiological survey that included 6,461 schoolchildren, aged 9-11 years, living in 6 French cities scattered around France. The protocol also included a battery of skin prick tests to common airborne allergens. The crude prevalence of sensitization to each allergen was estimated for each city and then adjusted for potential confounding factors. This analysis was repeated for monosensitization and for allergens grouped into 2 categories: indoor allergens, i.e., house dust mite (HDM), cat, and cockroach allergens, and outdoor allergens, i.e., birch pollen, grass pollen, and Alternaria. We also grouped cities according to their location on the coast, i.e., Marseille and Bordeaux, or inland, i.e., Créteil, Clermont-Ferrand, Reims, and Strasbourg. RESULTS: A difference in prevalence of sensitization to each airborne allergen or allergens grouped into indoor and outdoor categories was found between cities, even after adjusting for potential confounding factors. Also, a higher prevalence of sensitization to HDM, cat dander, and, broadly speaking, indoor allergens, was found in children living on the coast than in those living inland, whereas they showed a lower prevalence of sensitization to birch pollen. Between-city differences in the prevalence of monosensitization were also statistically significant. Children living in coastal cities had a higher rate of monosensitization to indoor allergens and a lower prevalence of sensitization to birch pollen. The higher prevalence of allergic sensitization in children from coastal cities is most likely due to climatic conditions, such as proximity from sea and humidity. Differences in sensitization to birch allergens could be due to differential exposure to these pollen. CONCLUSION: These results indicate a role of environmental exposure in sensitization to perennial as well as seasonal allergens.

Changes in body mass index during childhood and risk of various asthma phenotypes: a retrospective analysis.

BACKGROUND: It is known that asthma is related to obesity but also to small birthweight. The objective of this study was to clarify this issue by assessing the putative relationship between the changes in corpulence between birth and childhood as assessed by body mass index (BMI) and asthma phenotypes. METHODS: The following status in corpulence was assessed in 7781 schoolchildren using quartile of BMI at birth and at around 10 (9-11 years): underweight at birth and at around 10, underweight at birth and overweight at around 10, overweight at birth and underweight at around 10, overweight at birth and at around 10, and the reference group constituted by all the other children in whom corpulence changes were not extreme. Determination of asthma phenotypes (allergic, non-allergic, and exercise-induced asthma) was based on a clinical examination including skin prick tests, an exercise challenge test, and a questionnaire. RESULTS: The risk of allergic asthma was higher in children with persistent underweight, children with persistent overweight, and children becoming markedly more corpulent. In boys, the risk of allergic asthma was significantly higher for the less corpulent children at birth, regardless of whether they remained so or become overweight. In girls, the risk of allergic asthma was significantly higher in those with persistent overweight. There were no significant associations between BMI changes and non-allergic and exercise-induced asthma. CONCLUSIONS: We observed that some extreme changes in BMI, persistent underweight, and persistent overweight in childhood increased the risk of allergic asthma.

Prevalence and association of asthma and allergic sensitization with dietary factors in schoolchildren: data from the french six cities study.

BACKGROUND: The prevalence of asthma and allergy has recently risen among children. This increase in prevalence might be related to various factors, particularly diet. The aim of this study is to assess the prevalence and association of asthma and allergic sensitization with dietary factors in the French Six Cities Study. METHODS: Cross-sectional studies were performed among 7432 schoolchildren aged 9-11 years in Bordeaux, Clermont-Ferrand, Créteil, Marseille, Reims, and Strasbourg. Parental questionnaires, based on the International Study on Asthma and Allergies in Childhood (ISAAC), were used to collect information on allergic diseases and potential exposure factors including a food frequency questionnaire to evaluate dietary habits. Skin prick testing to common allergens for allergic sensitization and bronchial hyper-responsiveness (BHR) testing to exercise were performed. Confounders control was performed with multiple logistic regressions. RESULTS: Asthma symptoms, asthma and allergic sensitization were more prevalent in boys than in girls and were more prevalent in the South than in the North of France. After adjustment for confounders, fruit juice intake was associated with a low prevalence of lifetime asthma (ORa [95 % CI]; 0.73 [0.56-0.97]), butter intake was positively associated with atopic wheeze (1.48 [1.07-2.05]) and having lunch at the canteen 1-2 times/week compared to never or occasionally was associated with a lower prevalence of past year wheeze (0.71 [0.52-0.96]), lifetime asthma (0.76 [0.60-0.96]) and allergic sensitization (0.80 [0.67-0.95]). Meat intake was inversely related to past year wheeze among atopic children (0.68 [0.50-0.98]) while fast food consumption and butter intake were associated with an increase prevalence of asthma (2.39 [1.47-3.93] and 1.51 [1.17-2.00] respectively). Fish intake was associated with a lower prevalence of asthma among non-atopic children (0.61 [0.43-0.87]. None of the dietary factors was associated with BHR. CONCLUSIONS: Diet is associated with wheeze, asthma and allergic sensitization but not with BHR in children. These results provide further evidence that adherence to a healthy diet including fruits, meat and fish seems to have a protective effect on asthma and allergy in childhood. However, prospective and experimental studies are needed to provide causal evidence concerning the effect of diet on asthma and atopy.

Impact of gender on COPD expression in a real-life cohort.

Reports regarding gender-related differences in COPD expression have provided conflicting results. In the French Initiatives BPCO real-world cohort, which contained 688 patients (146 women) when data were extracted, women were matched with men (1:3 ratio: n = 107:275) on age (5-year intervals) and FEV1 (5% predicted intervals) and comparisons were performed using univariate logistic regressions. For a given age and level of airflow obstruction, women with COPD had higher BOD scores due to more pronounced dyspnea and lower BMI, suggesting worse prognosis, and were more likely to exhibit anxiety, suggesting the need for specific assessment and care.

Effects of airborne birch pollen levels on clinical symptoms of seasonal allergic rhinoconjunctivitis.

BACKGROUND: Most panel studies focusing on rhinitis and conjunctivitis symptoms and birch pollen have been performed on a linear basis and have not included air pollution and meteorological variables as potential confounders. The objective of this panel study was to assess the relationship between symptoms of seasonal allergic rhinoconjunctivitis and daily airborne birch pollen concentrations, checking with adequate statistical tools the shapes of concentration-response curves and controlling for confounders. METHODS: The severity of rhinitis, conjunctivitis, and bronchial symptoms was recorded daily in March and April 2010 (3,311 person-days) in 61 seasonal allergic rhinoconjunctivitis patients sensitized to birch. Data were analyzed with generalized additive and generalized estimating equation models to quantify the effects of birch pollens. RESULTS: The relationship between birch pollen and the percentage of patients with nasal, ocular and bronchial symptoms was linear until birch daily average concentrations of, respectively, 110, 70, and 70 grains/m(3); it reached a plateau thereafter. For an increase of 10 grains/m(3), the OR (95% CI) for nasal, ocular, and bronchial symptoms were, respectively, 1.07 (1.03-1.12), 1.17 (1.08-1.27), and 1.12 (1.03-1.21). At the beginning of the season, no nasal or ocular symptoms were observed below a threshold of 30 grains/m(3). CONCLUSIONS: Adequate modeling regression shows that the clinical response to natural exposure to birch pollen in sensitized patients varies during Betula pollen season, with a threshold at the beginning of the season, while over the whole season the relationship is linear for nasal, ocular, and bronchial symptoms up to a saturation point, followed by a plateau.

Association of chronic nasal symptoms with dyspnoea and quality-of-life impairment in chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Previous studies suggested that chronic nasal symptoms (CNS) are frequent in chronic obstructive pulmonary disease (COPD) subjects, but their contribution to dyspnoea and quality-of-life (QoL) impairment is not clearly established. METHODS: Data from the French COPD cohort 'Initiatives bronchopneumopathie chronique obstructive' were analyzed to assess the frequency of CNS (rhinorrhea, obstruction, anosmia) in COPD patients and analyze their impact and associated risk factors. Univariate and multivariate analyses were performed to assess the relationship between CNS with sociodemographic and anthropometric characteristics, risk factors, respiratory symptoms, spirometry, QoL (Saint George's respiratory questionnaire (SGRQ)), dyspnoea (modified Medical Research Council (mMRC) scale), mood disorders (Hospital Anxiety and Depression Scale (HADS)), number of exacerbations and comorbid conditions. RESULTS: CNS were reported by 115 of 274 COPD subjects (42%). Among them, rhinorrhea and nasal obstruction were reported by 62% and 43%, respectively. In multivariate analysis, COPD patients with CNS had higher SGRQ total scores, corresponding to worse QoL (P = 0.01), while no independent association was found with exacerbations, lung function and HADS. Among SGRQ domains, an independent association was found with the activity score (P = 0.007). When SGRQ score was forced out of the model to avoid redundancy, mMRC score was independently associated with CNS (P = 0.01). Among risk factors, cumulative smoking, hay fever and atopic dermatitis but not occupational exposures were independently associated with CNS. CONCLUSIONS: In this group of COPD subjects, CNS were frequently observed and associated with dyspnoea and poorer QoL. CNS should be systematically assessed and could be a potential target in the management of COPD.

Relationships between molds and asthma suggesting non-allergic mechanisms. A rural-urban comparison.

BACKGROUND: A fungal index, based on specific microbial volatile organic compounds (MVOCs) emission, was employed and related to asthma in children from rural and urban dwellings after stratification on the children atopic status. METHODS: A nested case-control design was used to draw, from 2 cross-sectional surveys, 20 asthmatics and 26 controls living in urban areas, and 24 asthmatics and 25 controls in rural areas. MVOCs levels were assessed in the living-room during one week; during that week, children performed clinical tests and their parents were invited to fill in a questionnaire on respiratory health. RESULTS: According to the objective fungal index, 70.5% of cases and 49.0% of controls were exposed to molds. More children with current asthma had experienced mold exposure in their homes (OR=3.38, 95% CI (1.16; 9.90)), especially amongst children living in rural areas. Atopic status modified this association: exposure to molds was found to be related to current asthma only in non-atopic children (OR=10.42, 95% CI (2.42; 44.81)). Among urban -dwelling children that could be screened at hospital, asthmatic children living in contaminated dwellings had a higher proportion of blood neutrophils and a lower FEV1 (forced expiratory volume in 1 second) than non-exposed ones. CONCLUSION: Our findings based on an objective assessment of MVOCs suggest adverse respiratory effects of molds. Our results suggest that when looking at the aetiology of non-atopic asthma, mold exposure should be systematically assessed.

Association between occupational exposure and the clinical characteristics of COPD.

BACKGROUND: The contribution of occupational exposures to COPD and their interaction with cigarette smoking on clinical pattern of COPD remain underappreciated. The aim of this study was to explore the contribution of occupational exposures on clinical pattern of COPD. METHODS: Cross-sectional data from a multicenter tertiary care cohort of 591 smokers or ex-smokers with COPD (median FEV1 49%) were analyzed. Self-reported exposure to vapor, dust, gas or fumes (VDGF) at any time during the entire career was recorded. RESULTS: VDGF exposure was reported in 209 (35%) subjects aged 31 to 88 years. Several features were significantly associated with VDGF exposure: age (median 68 versus 64 years, p < 0.001), male gender (90% vs 76%; p < 0.0001), reported work-related respiratory disability (86% vs 7%, p < 0.001), current wheezing (71% vs 61%, p = 0.03) and hay fever (15.5% vs 8.5%, p < 0.01). In contrast, current and cumulative smoking was less (p = 0.01) despite similar severity of airflow obstruction. CONCLUSION: In this patient series of COPD patients, subjects exposed to VDGF were older male patients who reported more work-related respiratory disability, more asthma-like symptoms and atopy, suggesting that, even in smokers or ex-smokers with COPD, occupational exposures are associated with distinct patients characteristics.

Outdoor Mold and Respiratory Health: State of Science of Epidemiological Studies.

BACKGROUND: Fungal spores are the predominant biological particulates in outdoor air. However, in contrast to pollens or outdoor air pollution, little is known about their respiratory health risks. OBJECTIVES: The objectives were to conduct the first review of epidemiological studies on the short- and long-term effects of outdoor mold exposure on respiratory health in children and adults. METHODS: Health outcomes included asthma, lung function, and rhinitis. Cross-sectional and longitudinal epidemiological studies using quantitative measures of outdoor mold exposure (optical microscopy, culture-based methods) were selected, providing that important confounding factors including temporal trends or meteorological factors were accounted for. A systematic literature search was performed up to June 2020, leading to the selection of 37 publications. RESULTS: Most studies were longitudinal and investigated short-term effects. There is evidence of an association between outdoor fungal exposure and an increase in asthma exacerbation among children for total spores, 2 phyla (ascomycetes, basidiomycetes), and 2 taxa (Cladosporium, Alternaria). A few studies also suggested an association for Coprinus, Ganoderma, Aspergillus-Penicillium, Botrytis, and Epicoccum in children, but this needs to be confirmed. Some studies reported mold associations with rhinitis, lung function, and among adults, but these were few in number or inconsistent. DISCUSSION: Further ecological studies in different regions that measure exposure to all taxa over several years are required to better understand their impact on rhinitis, asthma exacerbations and lung function. Larger panel studies are necessary to identify threshold effects in susceptible individuals. Finally, further research should assess the long-term effects of outdoor mold.

Retrospective Study of the Upsurge of Enterovirus D68 Clade D1 among Adults (2014-2018).

Enterovirus D68 (EV-D68) has emerged as an agent of epidemic respiratory illness and acute flaccid myelitis in the paediatric population but data are lacking in adult patients. We performed a 4.5-year single-centre retrospective study of all patients who tested positive for EV-D68 and analysed full-length EV-D68 genomes of the predominant clades B3 and D1. Between 1 June 2014, and 31 December 2018, 73 of the 11,365 patients investigated for respiratory pathogens tested positive for EV-D68, of whom 20 (27%) were adults (median age 53.7 years [IQR 34.0-65.7]) and 53 (73%) were children (median age 1.9 years [IQR 0.2-4.0]). The proportion of adults increased from 12% in 2014 to 48% in 2018 (p = 0.01). All adults had an underlying comorbidity factor, including chronic lung disease in 12 (60%), diabetes mellitus in six (30%), and chronic heart disease in five (25%). Clade D1 infected a higher proportion of adults than clades B3 and B2 (p = 0.001). Clade D1 was more divergent than clade B3: 5 of 19 amino acid changes in the capsid proteins were located in putative antigenic sites. Adult patients with underlying conditions are more likely to present with severe complications associated with EV-D68, notably the emergent clade D1.

Burden and Characteristics of Severe Chronic Hypoxemia in a Real-World Cohort of Subjects with COPD.

BACKGROUND: Chronic respiratory failure may occur as a consequence of chronic obstructive pulmonary disease (COPD) and is associated with significant morbidity and mortality. Hypoxemia is determined by underlying disease characteristics and comorbidities. Severe hypoxemia is typically only found in subjects with severe airflow obstruction (FEV1<50% predicted). However, how hypoxemia relates to disease characteristics is not fully understood. METHODS: In the French Initiatives BPCO real-life cohort, arterial blood gases were routinely collected in most patients. Relationships between severe hypoxemia, defined by a Pa02<60 mmHg (8 kPa) and clinical/lung function features, comorbidities and mortality were assessed. In subjects with severe hypoxemia, clinical characteristics and comorbidities were compared between those with non-severe versus severe airflow limitation. Classification and regression trees (CART) were used to define clinically relevant subgroups (phenotypes). RESULTS: Arterial blood gases were available from 887 subjects, of which 146 (16%) exhibited severe hypoxemia. Compared to subjects with a PaO2≥60 mmHg, the severe hypoxemia group exhibited higher mMRC dyspnea score, lower FEV1, higher RV and RV/TLC, more impaired quality of life, lower 6-minute walking distance, less frequent history of asthma, more frequent diabetes and higher 3-year mortality rate (14% versus 8%, p=0.026). Compared to subjects with Pa02<60 mmHg and FEV1<50% (n=115, 13%), those with severe hypoxemia but FEV1≥50% predicted (n=31) were older, had higher BMI, less hyperinflation, better quality of life and a higher rate of diabetes (29% versus 13%, p=0.02). Severe hypoxemia was better related to CART-defined phenotypes than to GOLD ABCD classification. CONCLUSION: In this cohort of stable COPD subjects, severe hypoxemia was associated with worse prognosis and more severe symptoms, airflow limitation and hyperinflation. Compared to subjects with severe hypoxemia and severe airflow limitation, subjects with severe hypoxemia despite non-severe airflow limitation were older, had higher BMI and more diagnosed diabetes. TRIAL REGISTRATION: 04-479.

Air pollution and increased levels of fractional exhaled nitric oxide in children with no history of airway damage.

Air pollution is associated with a wide range of adverse respiratory events. In order to study the mechanism associated with these effects, the relationships between fractional exhaled nitric oxide (FeNO), a potential marker of airway inflammation, and exposure to air pollution were examined in schoolchildren. FeNO was measured in 104 children (34 asthmatics and 70 non-asthmatics) drawn from the general population simultaneously with air pollution assessments (fine particles with an aerodiameter under 2.5 microm, nitrogen dioxide, acetaldehyde, and formaldehyde, with pumps and passive samplers) in schoolyards and classrooms. Asthmatics exhaled more FeNO than non-asthmatics. FeNO levels were significantly elevated in both asthmatic and non-asthmatic children exposed to high concentrations of formaldehyde, acetaldehyde, and PM(2.5). Differences between high versus low exposure in non-asthmatics resulted in an FeNO increase ranging from 45% for indoor acetaldehyde to 62% for indoor PM(2.5). Stronger associations were found in non-asthmatic children who were atopic, suggesting that atopic children may be more sensitive to air pollution than non-atopic children. Exposure to air pollution may lead to airway inflammation, as measured by FeNO, in schoolchildren. These associations occur even in children with no history of airway damage and seem to be enhanced in atopic subjects.

[Long-term exposure to urban air pollution measured through a dispersion model and the risk of asthma and allergy in children]. / Exposition a long terme a la pollution urbaine evaluée par un modèle de dispersion et risque d'asthme et d'allergie chez l'enfant.

The impact of chronic urban air pollution on asthma and allergy remains controversial, probably because exposure is difficult to evaluate. In this cross-sectional epidemiological survey of 9- to 11-year-old children living in six French towns, levels of air pollution were estimated by using dispersion models that take into account background air pollution levels along with traffic density, topography and meteorological conditions. We estimated three-year exposure, in the school environment, to benzene, volatile organic compounds, SO2, particles less than 10 microns in diameter (PM10), nitrous oxides (NO2 and NOx) and CO, which are the main urban air pollutants. Several health indicators were gathered by means of a questionnaire, a physical examination, skin prick testing, and measurement of peak-flow variations following an exercise test. Among the nearly 5000 children who had been living in the survey area for at least three years, the 12-month and cumulative prevalence rates of asthma and exercise-induced hyper-reactivity correlated with estimated levels of benzene, SO2, PM10, NOx and CO. The 12-month and cumulative prevalence rates of atopic dermatitis correlated with estimated benzene, PM10, NO2, NOx and CO levels. Pollen sensitization correlated with benzene and PM10 levels, and the cumulative prevalence of allergic rhinitis correlated with the PM10 level. These associations remained statistically significant among children who had spent their entire lives in the same community.