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Respiratory syncytial virus (RSV) infects nearly all infants in their first year of life and is the leading cause of hospitalization for infants younger than 1 year of age in the United States. Historically, the only option for RSV prevention was palivizumab. However, not all infants are eligible for palivizumab, it requires multiple doses per RSV season, and it is costly. In July 2023, the U.S. Food and Drug Administration approved nirsevimab for the prevention of RSV-associated lower respiratory tract infections for all infants. Nirsevimab inhibits RSV from fusing to cellular membranes and thereby neutralizes the virus in the body. Nirsevimab is expected to significantly reduce the health and economic burdens of RSV. This article provides an overview of nirsevimab, potential adverse effects, and implications for nursing practice., (Copyright © 2023 AWHONN. Published by Elsevier Inc. All rights reserved.)

Background: India is facing a burdensome public health challenge due to air pollution, with a particularly high burden of acute respiratory infections (ARI) among children. To address this issue, our study aims to evaluate the association between exposure to fine particulate matter (PM 2.5 ) and ARI incidence in young children in India., Materials and Methods: Our study used PM 2.5 data provided by the Atmospheric Composition Analysis Group at Washington University to assess the association between PM 2.5 exposure and ARI incidence in 223,375 children sampled from the 2019-2021 Demographic Health Survey in India. We employed the generalized estimating equation and reported odds ratios and 95% confidence intervals for a 10 µg/m 3 increase in PM 2.5 and quartiles of PM 2.5 exposure., Results: Each 10 µg/m 3 increase in PM 2.5 levels was associated with an increased odds of ARI (OR: 1.23, 95% CI: 1.19-1.27). A change from the first quartile of PM 2.5 (2.5-34.4 µg/m 3 ) to the second quartile (34.5-51.5 µg/m 3 ) of PM 2.5 was associated with a two-fold change (OR: 2.06, 95% CI: 1.60-2.66) in the odds of developing ARI. Similarly, comparing the first quartile to the fourth quartile of PM 2.5 exposure (78.3-128.9 µg/m 3 ) resulted in an over four-fold increase in the odds of ARI (OR: 4.45, 95% CI: 3.37-5.87)., Conclusion: Mitigation efforts must be continued implementing higher restrictions in India and to bring new interventions to ensure safe levels of air for reducing the burden of disease and mortality associated with air pollution in India., (© 2024. The Author(s).)

Introduction: Lower respiratory tract infections are amongst the main causes for hospital/intensive care unit admissions and antimicrobial prescriptions. In order to reduce antimicrobial pressure, antibiotic administration could be optimized through procalcitonin-based algorithms., Areas Covered: In this review, we discuss the performances of procalcitonin for the diagnosis and the management of community-acquired and ventilator-associated pneumonia. We provide up-to-date evidence and deliver clear messages regarding the purpose of procalcitonin to reduce unnecessary antimicrobial exposure., Expert Opinion: Antimicrobial pressure and resulting antimicrobial resistances are a major public health issue as well as a daily struggle in the management of patients with severe infectious diseases, especially in intensive care units where antibiotic exposure is high. Procalcitonin-guided antibiotic administration has proven its efficacy in reducing unnecessary antibiotic use in lower respiratory tract infections without excess in mortality, hospital length of stay or disease relapse. Procalcitonin-guided algorithms should be implemented in wards taking care of patients with severe infections. However, procalcitonin performances are different regarding the setting of the infection (community versus hospital-acquired infections) the antibiotic management (start or termination of antibiotic) as well as patient's condition (immunosuppressed or in shock) and we encourage the physicians to be aware of these limitations.

The annual burden of severe acute respiratory infection (SARI) is enormous, and environmental factors may have a vital role in respiratory infections. This study aimed to investigate the potential effects of the atmospheric environment on SARI. A time-series analysis was performed on the relationship between atmospheric environment and 136,989 SARI cases by distributed lag non-linear model. Wind speed, PM 10 , PM 2.5 , O 3, and CO exhibited differential effects at a range of lag times or exposure ranges. Air pressure, temperature, and diurnal temperature range showed risk effects in the full range. The lag effect of high pollution was stronger, appeared earlier, and lasted longer than that of low pollution. Most environmental factors had a certain non-linear lag relationship with SARI. Low wind speed and high air pollution may be increasing risk factors for SARI.

Airborne particulate matter (PM) pollution, as a leading environmental health risk, causes millions of premature deaths globally every year. Lower respiratory infection (LRI) is a sensitive response to short-term exposure to outdoor PM pollution. The airborne transmission of etiological agents of LRI, as an important pathway for infection and morbidity, bridges the public health issues of air quality and pathogen infectivity, virulence, resistance, and others. Enormous efforts are underway to identify common pathogens and substances that are etiological agents for LRI and to understand the underlying toxicological and clinical basis of health effects by identifying mechanistic pathways. Seasonal variations and geographical disparities in the survival and infectivity of LRI pathogens are unsolved mysteries. Weather conditions in geographical areas may have a key effect, but also potentially connect LRI with short-term increases in ambient air PM pollution. Statistical associations show that short-term elevations in fine and coarse PM lead to increases in respiratory infections, but the causative agents could be chemical or microbiological and be present individually or in mixtures, and the interactions between chemical and microbiological agents remain undefined. Further investigations on high-resolution monitoring of airborne pathogens in relation to PM pollution for an integrated exposure-response assessment and mechanistic study are warranted. Improving our understanding of the spatiotemporal features of pathogenic bioaerosols and air pollutants and translating scientific evidence into effective policies is vital to reducing the health risks and devastating death toll from PM pollution., (© 2021. The Author(s).)

Air pollution levels across the globe continue to rise despite government regulations. The increase in global air pollution levels drives detrimental human health effects, including 7 million premature deaths every year. Many of these deaths are attributable to increased incidence of respiratory infections. Considering the COVID-19 pandemic, an unprecedented public health crisis that has claimed the lives of over 6.5 million people globally, respiratory infections as a driver of human mortality is a pressing concern. Therefore, it is more important than ever to understand the relationship between air pollution and respiratory infections so that public health measures can be implemented to ameliorate further morbidity and mortality. This article aims to review the current epidemiologic and basic science research on interactions between air pollution exposure and respiratory infections. The first section will present epidemiologic studies organized by pathogen, followed by a review of basic science research investigating the mechanisms of infection, and then conclude with a discussion of areas that require future investigation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Contemporary data on infections after intensive chemotherapy for acute myeloid leukemia (AML) are scarce. Cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone ("CLAG-M") may result in higher remission rates than standard-dose cytarabine plus anthracycline ("7 + 3") but may result in more infections. We compared moderate to severe infections occurring up to 90 days after the first induction cycle for AML or other high-grade myeloid neoplasms in patients receiving CLAG-M for newly diagnosed (n = 196) or relapsed/refractory disease (n = 131) or 7 + 3 for newly diagnosed disease (n = 115). For newly diagnosed disease, microbiologically documented infections were more frequent after CLAG-M compared to 7 + 3 (adjusted rate ratio, 1.65 [95% CI, 1.06-2.58]; P = 0.03), with a cumulative incidence of 27.8% and 16.5% by day 90, respectively. Patients receiving CLAG-M for relapsed/refractory disease had the highest cumulative incidence of 50.7%. Bacterial bloodstream infections were the most frequent followed by respiratory tract infections. Among 29 patients (7%) who died, infection was a primary or contributing cause of death in 59%. These data indicate that infections continue to cause substantial morbidity in patients treated for AML, especially those treated for relapsed/refractory disease, and are more common with newer, more myelosuppressive regimens such as CLAG-M. Improved strategies for infection prevention are needed., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

With a remarkable increase in industrialization among fast-developing countries, air pollution is rising at an alarming rate and has become a public health concern. The study aims to examine the effect of air pollution on patient's hospital visits for respiratory diseases, particularly Acute Respiratory Infections (ARI). Outpatient hospital visits, air pollution and meteorological parameters were collected from March 2018 to October 2021. Eight machine learning algorithms (Random Forest model, K-Nearest Neighbors regression model, Linear regression model, LASSO regression model, Decision Tree Regressor, Support Vector Regression, X.G. Boost and Deep Neural Network with 5-layers) were applied for the analysis of daily air pollutants and outpatient visits for ARI. The evaluation was done by using 5-cross-fold confirmations. The data was randomly divided into test and training data sets at a scale of 1:2, respectively. Results show that among the studied eight machine learning models, the Random Forest model has given the best performance with R 2 = 0.606, 0.608 without lag and 1-day lag respectively on ARI patients and R 2 = 0.872, 0.871 without lag and 1-day lag respectively on total patients. All eight models did not perform well with the lag effect on the ARI patient dataset but performed better on the total patient dataset. Thus, the study did not find any significant association between ARI patients and ambient air pollution due to the intermittent availability of data during the COVID-19 period. This study gives insight into developing machine learning programs for risk prediction that can be used to predict analytics for several other diseases apart from ARI, such as heart disease and other respiratory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As a destructive and economic disaster in the world, drought shows an increasing trend under the continuous global climate change and adverse health effects have been reported. The interactive effects between drought and air pollutants, which may also be harmful to respiratory systems, remain to be discussed. We built the generalized additive model (GAM) and distributed lag nonlinear model (DLNM) to estimate the effects of drought and air pollutants on daily upper respiratory infections (URTI) outpatient visits among children under 6 in three cities of Gansu province. The Standardized Precipitation Index (SPI) based on monthly precipitation (SPI-1) was used as an indicator of drought. A non-stratified model was established to explore the interaction effect of SPI-1 and air pollutants. We illustrated the number of daily pediatric URTI outpatient visits increased with the decrease in SPI-1. The interactive effects between air pollutants and the number of daily pediatric URTIs were significant. According to the non-stratified model, we revealed highly polluted and drought environments had the most significant impact on URTI in children. The occurrence of drought and air pollutants increased URTI in children and exhibited a significant interactive effect.

Air pollution is a crucial risk factor for respiratory infection. However, the relationships between air pollution and respiratory infection based on pathogen detection are scarcely explored in the available literature. We detected respiratory infections through patient-based bacterial culture in sputum, obtained hourly data of all six pollutants (PM 2.5 , PM 10 , SO 2 , NO, CO, and O 3 ) from four air quality monitoring stations, and assessed the relationships of air pollutants and respiratory bacterial infection and multi-drug-resistant bacteria. Air pollution remains a challenge for Mianyang, China, especially PM 2.5 and PM 10 , and there are seasonal differences; pollution is the heaviest in winter and the lowest in summer. A total of 4237 pathogenic bacteria were detected, and the positive rate of multi-drug-resistant bacteria was 0.38%. Similar seasonal differences were found with respect to respiratory infection. In a single-pollutant model, all pollutants were significantly associated with respiratory bacterial infection, but only O 3 was significantly associated with multi-drug-resistant bacteria. In multi-pollutant models (adjusted for one pollutant), the relationships of air pollutants with respiratory bacterial infection remained significant, while PM 2.5 , PM 10 , and O 3 were significantly associated with the risk of infection with multi-drug-resistant bacteria. When adjusted for other five pollutants, only O 3 was significantly associated with respiratory bacterial infection and the risk of infection with multi-drug-resistant bacteria, showing that O 3 is an independent risk factor for respiratory bacterial infection and infection with multi-drug-resistant bacteria. In summary, this study highlights the adverse effects of air pollution on respiratory infection and the risk of infection with multi-drug-resistant bacteria, which may provide a basis for the formulation of environmental policy to prevent respiratory infections., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

To examine the short-term association between gaseous air pollutants (CO, NO 2 , SO 2 , and O 3 ) and all-cause respiratory disease, acute upper respiratory infections (AURIs) as well as acute lower respiratory infections (ALRIs) among children, we conducted the study from 25 major cities in China. Hospitalization records of children aged 0-18 years due to all-cause respiratory diseases (889,926), AURIs (97,858), and ALRIs (642,154) from 2016 to 2019 were extracted. Concentrations of CO, NO 2 , SO 2 , and O 3 were averaged across monitoring stations. Generalized additive models were used to estimate the associations between gaseous air pollutants and daily hospitalizations for all-cause respiratory disease, AURIs, and ALRIs. The meta-analysis was used to combine the city-specific estimates. A 10 mg/m 3 increase in CO at lag01, and a 10 μg/m 3 increase in NO 2 , SO 2 , and O 3 at lag01 were associated with 1.65% (95%CI, 0.41-2.91), 0.54% (95%CI, 0.30-0.79), 0.60% (95%CI, 0.22-0.99), and 0.23% (95%CI, 0.06-0.39) increase of hospitalizations due to all-cause respiratory disease, respectively. For the disease subtype, O 3 only had adverse effects on AURIs, CO and SO 2 mainly on ALRIs, and NO 2 on both AURIs and ALRIs. Children aged 4-6years were more vulnerable to the effects of CO and NO 2 , but those aged <1year were more susceptible to SO 2 and O 3 . Besides, the O 3 effect was stronger in the warm season than in the cold season. The study indicated that short-term exposure to CO, NO 2 , SO 2, and O 3 was associated with increased hospitalization for pediatric respiratory disease, and the association may vary by position of the respiratory tract, age, and season., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: While the relationship between outdoor particulate matter (PM) and lower respiratory tract infections in children and adolescents is accepted, we know little about the impacts of outdoor PM on the risk of developing or aggravating upper respiratory tract infections (URTIs)., Methods: We aimed to review the literature examining the relationship between outdoor PM exposure and URTIs in children and adolescents. A systematic search of EMBASE, MEDLINE, PubMed, Scopus, CINAHL and Web of Science databases was undertaken on April 3, 2020 and October 27, 2021. Comparable short-term studies of time-series or case-crossover designs were pooled in meta-analyses using random-effects models, while the remainder of studies were combined in a narrative analysis. Quality, risk of bias and level of evidence for health effects were appraised using a combination of emerging frameworks in environmental health., Results: Out of 1366 articles identified, 34 were included in the systematic review and 16 of these were included in meta-analyses. Both PM 2.5 and PM 10 levels were associated with hospital presentations for URTIs (PM 2.5 : RR = 1.010, 95%CI = 1.007-1.014; PM 10 : RR = 1.016, 95%CI = 1.011-1.021) in the meta-analyses. Narrative analysis found unequivocally that total suspended particulates were associated with URTIs, but mixed results were found for PM 2.5 and PM 10 in both younger and older children., Conclusion: This study found some evidence of associations between PM and URTIs in children and adolescents, the relationship strength increased with PM 10 . However, the number of studies was limited and heterogeneity was considerable, thus there is a need for further studies, especially studies assessing long-term exposure and comparing sources., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Infants are often hospitalized because of lower respiratory tract infections, and overuse of antibiotics to treat such infections has led to severe problems. Herbal medicines may be more effective and safer than antibiotics. Mahaenggamseok-tang is a common herbal medicine in Asia, but the evidence for its effectiveness in lower respiratory tract infection treatment is insufficient. This review assesses the efficacy of Mahaenggamseok-tang in treating lower respiratory tract infections., Methods: The study used Chinese, English, and Korean databases, as well as one Japanese database. All included studies were randomized controlled trials comparing Mahaenggamseok-tang with medication to treat lower respiratory tract infections. Studies using Mahaenggamseok-tang plus Western medicine were also included. Standardized mean difference (SMD), risk ratio (RR) with 95% confidence interval (CI), and risk of bias were analyzed using Review Manager 5.4 software. The GRADEpro website was used to assess the reviews., Results: Seventeen randomized controlled trials with a total of 1993 participants were included in the meta-analysis. All studies compared the Mahaenggamseok-tang plus Western medicine group to the Western medicine only group. Meta-analysis showed that Mahaenggamseok-tang affected total effective rate (risk ratio: 1.20, 95% confidence interval [CI]: 1.10-1.31, P < .001), cough disappearance time (SMD: -1.62, 95% CI: -2.30 to -0.95, P < .001), fever disappearance time (SMD: -2.04, 95% CI: -2.87 to -1.21, P < .001), abnormal lung sound disappearance time (SMD: -1.68, 95% CI: -2.43 to -0.93, P < .001), Creactive protein (SMD: -3.18, 95% CI: -4.36 to -1.99, P < .001), procalcitonin (SMD: -5.04, 95% CI: -9.20 to -0.88, P < .05), tumor necrosis factor-α (SMD: -0.84, 95% CI: -1.46 to -0.23, P < .01), IgE (SMD: -2.69, 95% CI: -2.91 to -2.47, P < .001), and adverse events (risk ratio: 0.44, 95% CI: 0.29-0.68, P < .001), but not interleukin-6 (SMD: -1.59, 95% CI: -3.48 to 0.30, P>.05)., Discussion: Mahaenggamseok-tang plus Western medicine is more effective and safer than Western medicine alone for treating lower respiratory tract infections. However, the included randomized controlled trials were not randomized well; therefore, better randomized randomized controlled trials are needed to make significant recommendations.PROSPERO registration number: CRD42020165698., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Short-term exposures to air pollutants such as particulate matter (PM) have been associated with increased risk for symptoms of acute respiratory infections (ARIs). Less well understood is how long-term exposures to fine PM (PM2.5) might increase risk of ARIs and their symptoms. This research uses georeferenced Demographic Health Survey (DHS) data from Kenya (2014) along with a remote sensing based raster of PM2.5 concentrations to test associations between PM2.5 exposure and ARI symptoms in children for up to 12 monthly lags. Methods: Predicted PM2.5 concentrations were extracted from raster of monthly averages for latitude/longitude locations of survey clusters. These data and other environmental and demographic data were used in a logistic regression model of ARI symptoms within a distributed lag nonlinear modeling framework (DLNM) to test lag associations of PM2.5 exposure with binary presence/absence of ARI symptoms in the previous two weeks. Results: Out of 7036 children under five for whom data were available, 46.8% reported ARI symptoms in the previous two weeks. Exposure to PM2.5 within the same month and as an average for the previous 12 months was 18.31 and 22.1 µg/m3, respectively, far in excess of guidelines set by the World Health Organization. One-year average PM2.5 exposure was higher for children who experienced ARI symptoms compared with children who did not (22.4 vs. 21.8 µg/m3, p < 0.0001.) Logistic regression models using the DLNM framework indicated that while PM exposure was not significantly associated with ARI symptoms for early lags, exposure to high concentrations of PM2.5 (90th percentile) was associated with elevated odds for ARI symptoms along a gradient of lag exposure time even when controlling for age, sex, types of cooking fuels, and precipitation. Conclusions: Long-term exposure to high concentrations of PM2.5 may increase risk for acute respiratory problems in small children. However, more work should be carried out to increase capacity to accurately measure air pollutants in emerging economies such as Kenya.

Background: There is growing evidence to suggest that exposure to a high concentration of nitrogen dioxide (NO 2 ) can lead to a higher incidence of Acute Respiratory Infections (ARIs) in children; however, such an association remains understudied in Sub-Saharan Africa due to the limited availability of exposure data. This study explored this association by using the satellite-detected tropospheric NO 2 concentrations measured by Sentinel-5 Precursor and ARI symptoms in children under age five collected in the Demographic and Health Survey (DHS) in Senegal., Methods: We matched the daily tropospheric NO 2 exposure with the individual ARI symptoms according to the DHS survey clusters spatially and temporally and conducted a logistic regression analysis to estimate the association of exposure to NO 2 with ARI symptoms in two preceding weeks., Results: We observed a positive association between exposure to continuous levels of NO 2 and ARI symptoms after adjusting for confounders (OR 1.27 per 10 mol/m 2 , 95% CI: 1.06 - 1.52). When the association was further examined by quartile exposure categories, the 4th quartile category was positively associated with symptoms of ARI after adjusting for confounders (OR 1.71, 95% CI: 1.08-2.69). This suggests that exposure to certain high levels of NO 2 is associated with the increased risk of children having symptoms of ARI in Senegal., Conclusions: This study highlights the need for increased research on the effects of ambient NO 2 exposure in Africa as well as the need for more robust, ground-based air monitoring in the region. For a country like Senegal, where more than 90% of the population lives in areas that do not meet the national air quality standards, it is urgently required to implement air pollution prevention efforts to protect children from the health hazards of air pollution., (© 2022. The Author(s).)

(1) Background: vitamin A deficiency (VAD) is highly prevalent in children living in poor conditions. It has been suggested that vitamin A supplementation (VAS) may reduce the risk of acute respiratory tract infections (ARTI). Our study provides updates on the effects of oral VAS (alone) in children on ARTI and further explores the effect on interesting subgroups. (2) Methods: eight databases were systematically searched from their inception until 5 July 2021. The assessments of inclusion criteria, extraction of data, and data synthesis were carried out independently by two reviewers. (3) Results: a total of 26 randomized trials involving 50,944 participants fulfilled the inclusion criteria. There was no significant association of VAS with the incidence of ARTI compared with the placebo (RR 1.03, 95% CI 0.92 to 1.15). Subgroup analyses showed that VAS higher than WHO recommendations increased the incidence of ARTI by 13% (RR 1.13, 95% CI 1.07 to 1.20), and in the high-dose intervention group, the incidence rate among well-nourished children rose by 66% (RR 1.66, 95% CI 1.30 to 2.11). (4) Conclusions: no more beneficial effects were seen with VAS in children in the prevention or recovery of acute respiratory infections. Excessive VAS may increase the incidence of ARTI in children with normal nutritional status.

Little is known on respiratory effects of indoor chemicals in the tropics. We investigated associations between asthma and respiratory infections in Malaysian students and chemical exposure at home and at school. Moreover, we investigated differences in home environment between the three main ethnic groups in Malaysia (Malay, Chinese, Indian). Totally, 462 students from 8 junior high schools in Johor Bahru participated (96% participation rate). The students answered a questionnaire on health and home environment. Climate, carbon dioxide (CO 2 ), volatile organic compounds (VOC), formaldehyde and nitrogen dioxide (NO 2 ) were measured inside and outside the schools. Multilevel logistic regression was applied to study associations between exposure and health. Totally 4.8% were smokers, 10.3% had wheeze, 9.3% current asthma, and had 18.8% any respiratory infection in the past 3 months. Malay students had more dampness or mould (p < 0.001), more environmental tobacco smoke (ETS) (p < 0.001) and more cats (p < 0.001) at home as compared to Chinese or Indian students. Wheeze was associated with ethnicity (p = 0.02; lower in Indian), atopy (p = 0.002), current smoking (p = 0.02) and recent indoor painting at home (p = 0.03). Current asthma was associated with ethnicity (p = 0.001; lower in Chinese) and para-dichlorobenzene in classroom air (p = 0.008). Respiratory infections were related to atopy (p = 0.002), ethylbenzene (p = 0.02) and para-dichlorobenzene (p = 0.01) in classroom air. Para-dichlorobenzene is used in Asia against insects. In conclusion, chemical emissions from recent indoor painting at home can increase the risk of wheeze. In schools, para-dichlorobenzene can increase the risk of current asthma and respiratory infections while ethylbenzene can increase the risk of respiratory infections., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Respiratory tract infections (RTIs) and interstitial lung disease (ILD) secondary to interleukin (IL) 12/23 or IL-23 antagonists have been reported in autoimmune diseases., Objective: To assess the risk of RTIs and noninfectious ILD with these drugs., Methods: We conducted a systematic review and meta-analysis of randomized controlled trials. Risk of RTIs and noninfectious ILD was compared to placebo by Mantel-Haenszel risk difference. We divided RTIs into upper RTIs (URTI), viral URTIs, and lower RTIs (LRTIs) including infectious pneumonia. Noninfectious ILD included ILD, eosinophilic pneumonia, and pneumonitis., Results: We identified 54 randomized controlled trials including 10,907 patients with 6 IL-12/23 or IL-23 antagonists and 5175 patients with placebo. These drugs significantly increased the risk of RTIs (Mantel-Haenszel risk difference, 0.019; 95% confidence interval, 0.005-0.033; P = .007), which was attributed to URTIs, but not viral URTIs or LRTIs. There was no significant difference in infectious pneumonia and noninfectious ILD between 2 groups., Limitations: Because of the rarity of infectious pneumonia and ILD, sensitivity analysis was required., Conclusions: The use of IL-12/23 or IL-23 antagonists for autoimmune diseases increased the risk of URTIs, but not viral URTIs, LRTIs, and noninfectious ILD., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Inhaled corticosteroids (ICS) are the mainstay of asthma treatment, but evidence suggests a link between ICS usage and increased rates of respiratory infections. We assessed the composition of the asthmatic airways microbiome in asthma patients taking low and high dose ICS and the stability of the microbiome over a 2 week period., Methods: We prospectively recruited 55 individuals with asthma. Of these, 22 were on low-dose ICS and 33 on high-dose ICS (16 on budesonide, 17 on fluticasone propionate). Sputum from each subject underwent DNA extraction, amplification and 16S rRNA gene sequencing of the bacterial component of the microbiome. 19 subjects returned for further sputum induction after 24 h and 2 weeks., Results: A total of 5,615,037 sequencing reads revealed 167 bacterial taxa in the asthmatic airway samples, with the most abundant being Streptococcus spp. No significant differences in sputum bacterial load or overall community composition were seen between the low- and high-dose ICS groups. However, Streptococcus spp. showed significantly higher relative abundance in subjects taking low-dose ICS (p = 0.002). Haemophilus parainfluenzae was significantly more abundant in subjects on high-dose fluticasone propionate than those on high-dose budesonide (p = 0.047). There were no statistically significant changes in microbiota composition over a 2-week period., Discussion: Whilst no significant differences were observed between the low- and high-dose ICS groups, increased abundance of the potential pathogen H. parainfluenzae was observed in patients taking high-dose fluticasone propionate compared to those taking high-dose budesonide. The microbiota were stable over fourteen days, providing novel evidence of the established community of bacteria in the asthmatic airways., Clinical Trial Registration: ClinicalTrials.gov NCT02671773., Competing Interests: Prof Harrison reports that this investigator-initiated study was funded by an unrestricted research grant from AstraZeneca and personal fees and non-financial support from AstraZeneca, personal fees from Vectura, non-financial support from Teva, non-financial support from NAPP, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Importance: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies., Objective: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy., Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study., Interventions: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed., Main Outcomes and Measures: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16., Results: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis., Conclusions and Relevance: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD., Trial Registration: ClinicalTrials.gov Identifier: NCT03733301.

Treatment with immune-checkpoint inhibitors (ICIs) has shown efficacy against a variety of cancer types. The use of anti PD-1, anti PD-L1, and anti CTLA-4 antibodies is rapidly expanding. The side effects of ICIs are very different from conventional cytocidal anticancer and molecular target drugs, and may extend to the digestive organs, respiratory organs, thyroid gland, pituitary gland, skin, and others. Although the details of these adverse events are becoming increasingly apparent, much is unknown regarding the effects and adverse events related to infections. This review focuses specifically on the impact of ICIs on respiratory infections. The impact of ICIs on pathogens varies depending on the significance of the role of T-cell immunity in the immune response to the specific pathogen, as well as the different modes of infection (i.e., acute or chronic), although the impact of ICIs on the clinical outcome of infections in humans has not yet been well studied. Enhanced clearance of many pathogens has been shown because immune checkpoint inhibition activates T cells. In contrast, reactivation of tuberculosis associated with ICI use has been reported, and therefore caution is warranted. In COVID-19 pneumonia, ICI administration may lead to exacerbation; however, it is also possible that ICI may be used for the treatment of COVID-19. It has also been shown that ICI has potential in the treatment of intractable filamentous fungal infections. Therefore, expanded clinical applications are expected., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: We aimed to assess the association between inhaled corticosteroids (ICSs) and the risk of upper respiratory tract infection (URTI) in patients with chronic obstructive pulmonary disease (COPD)., Methods: PubMed, Embase, Cochrane Library and Clinical Trials.gov were searched from inception to October 2019. Randomized controlled trials (RCTs) of any ICSs vs control for COPD with reporting of URTI as an adverse event were included. The study was registered with PROSPERO prospectively (#CRD42020153134)., Results: Seventeen RCTs (20,478 patients) were included. ICSs significantly increased the risk of URTI in COPD patients (RR, 1.13; 95% CI 1.03-1.24; P = 0.01; heterogeneity: I 2  = 7%). Futher subgroup analyses suggested that short-term use of ICSs increased the risk of URTI (RR, 1.29; 95% CI 1.06-1.56; P = 0.01; heterogeneity: I 2  = 14%) but not for long-term use (RR, 1.08; 95% CI 0.97-1.2; P = 0.14; heterogeneity: I 2  = 0%). Short-term use of high-dose fluticasone increased the risk of URTI (RR, 1.33; 95% CI 1.03-1.71; P = 0.03; heterogeneity: I 2  = 0%) but not for long-term use (RR, 1.12; 95% CI 0.97-1.29; P = 0.13; heterogeneity: I 2  = 50%). Medium-dose (RR, 0.97; 95% CI 0.71-1.32; P = 0.84; heterogeneity: I 2  = 0%) and low-dose (RR, 1.39; 95% CI 0.92-2.1; P = 0.12; heterogeneity: I 2  = 30%) fluticasone did not increase the risk of URTI regardless of duration. Neither mometasone (RR, 1.05; 95% CI 0.87-1.26; P = 0.61; heterogeneity: I 2  = 0%) nor budesonide (RR, 1.08; 95% CI 0.77-1.5; P = 0.67; heterogeneity: I 2  = 46%) increased the risk of URTI, regardless of dosage or duration., Conclusions: Long-term use of ICSs does not increase the risk of URTI in patients with COPD. Short-term use of high-dose fluticasone increases the risk of URTI in patients with COPD, but not mometasone or budesonide.

Background: Glecaprevir-pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data for glecaprevir-pibrentasvir in non-Japanese Asian patients have been minimal. The aim of these studies was to assess the efficacy and safety of glecaprevir-pibrentasvir in treatment-naive and treatment-experienced Asian patients with chronic HCV genotype 1-6 infection without cirrhosis (VOYAGE-1) and with compensated cirrhosis (VOYAGE-2)., Methods: We did two phase 3 studies in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection. VOYAGE-1 was a randomised, double-blind, placebo-controlled study that recruited patients without cirrhosis at 47 sites across China, South Korea, and Singapore. Randomisation was 2:1 with a fixed block size of three and stratified by geographical region and HCV genotype. Investigators, study site personnel, the study sponsor, and patients were masked to treatment allocation. VOYAGE-2 was a single-arm, open-label study that recruited patients with compensated cirrhosis at 34 sites across China and South Korea. Glecaprevir (300 mg) and pibrentasvir (120 mg) or placebo (VOYAGE-1, 2:1 ratio), administered as three tablets daily, was given for 8 weeks in patients without cirrhosis and for 12 weeks in those with cirrhosis (and for 16 weeks in treatment-experienced patients with genotype 3). The primary efficacy endpoint was the proportion of patients with a sustained virological response, defined as HCV RNA below the lower limit of quantification 12 weeks after the last dose of glecaprevir-pibrentasvir. We analysed efficacy and safety in all patients who received at least one dose of the study drug. These trials are registered with ClinicalTrials.gov, NCT03222583 (VOYAGE-1) and NCT03235349 (VOYAGE-2); both trials have been completed. This Article reports the results of the primary analysis for each study, undertaken when all patients who received glecaprevir-pibrentasvir (during the double-blind period in VOYAGE-1) had been followed up for 12 weeks following their last dose of study drug. Data from the double-blind period for placebo patients in VOYAGE-1 are also summarised., Findings: Between Oct 4, 2017, and April 20, 2018, 546 patients with chronic HCV without cirrhosis were randomly assigned to treatment (363 to glecaprevir-pibrentasvir, 183 to placebo) in VOYAGE-1. One patient withdrew consent and did not receive treatment with glecaprevir-pibrentasvir. 352 of 362 patients who received glecaprevir-pibrentasvir achieved SVR12 (97·2% [95% CI 95·5-98·9]). Of 160 patients with compensated cirrhosis who were enrolled in VOYAGE-2 between Sept 29, 2017, and June 14, 2018, 159 of 160 achieved SVR12 (99·4%, 95% CI 98·2-100·0). 20 patients with HCV genotype 3b across both trials received glecaprevir-pibrentasvir; six of these patients were among the 11 patients who did not achieve SVR12. Upper respiratory tract infection was the most common adverse event (35 [10%] of 362 receiving glecaprevir-pibrentasvir and 18 [10%] of 183 receiving placebo in VOYAGE-1; 19 [12%] of 160 in VOYAGE-2). For patients receiving glecaprevir-pibrentasvir, serious adverse events occurred in three (<1%) of 362 patients in VOYAGE-1 and five (3%) of 160 patients in VOYAGE-2. Grade 3-4 adverse events in patients receiving glecaprevir-pibrentasvir occurred in five (1%) of 362 patients in VOYAGE-1 and six (4%) of 160 patients in VOYAGE-2; each type of event was experienced by at most one patient within a study. One patient with cirrhosis discontinued study drug because of an adverse event., Interpretation: Glecaprevir-pibrentasvir showed high efficacy and an acceptable safety profile in these studies although responses were less common in the few patients with HCV genotype 3b. The results support the use of glecaprevir-pibrentasvir in these Asian populations., Funding: AbbVie., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Lower respiratory tract infections (LRTI) in early life, including pneumonia, bronchitis and bronchiolitis, can lead to decreased lung function, persistent lung damage and increased susceptibility to various respiratory diseases such as asthma. In-utero exposure to particulate matter (PM) during pregnancy may disrupt biological mechanisms that regulate fetal growth, maturation and development. We aimed to estimate the association between intrauterine exposure to PM of size < 2.5 μm in diameter (PM 2.5 ) and incidence of LRTIs during the first year of life., Methods: A retrospective population-based cohort study in a population of mothers and infants born in Soroka University Medical Center (SUMC) in the years 2004-2012. All infants < 1 year old that were hospitalized due to LRTIs were included. The main exposure assessment was based on a hybrid model incorporating daily satellite-based predictions at 1 km 2 spatial resolution. Data from monitoring stations was used for imputation of main exposure and other pollutants. Levels of environmental exposures were assigned to subjects based on their residential addresses and averaged for each trimester. Analysis was conducted by a multivariable generalized estimating equation (GEE) Poisson regression. Data was analyzed separately for the two main ethnic groups in the region, Jewish and Arab-Bedouin., Results: The study cohort included 57,331 deliveries that met the inclusion criteria. Overall, 1871 hospitalizations of infants < 1 year old due to pneumonia or bronchiolitis were documented. In a multivariable analysis, intrauterine exposure to high levels of PM 2.5 (> 24 μg/m 3 ) in the first and second trimesters was found to be adversely associated with LRTIs in the Arab-Bedouin population (1st trimester, RR = 1.31, CI 95% 1.08-1.60; 2nd trimester: RR = 1.34, CI 95% 1.09-1.66)., Conclusion: Intrauterine exposure to high levels of PM 2.5 is associated with a higher risk of hospitalizations due to lower respiratory tract infections in Arab-Bedouin infants.

Objective: Acute respiratory infections (ARI) are the leading causes of neonatal and child mortality. Despite several national efforts to reduce the incidence of mortality among children, India is one of the largest contributors to under-five mortality in the world. In this study, we examined the effects of indoor pollution on ARI among under-five children in India., Methods: A cross-sectional study was carried using nationally representative data from the 2015-2016 National Family Health Survey (NFHS-4). This study is based on 247,743 living children under the age of five years. Bivariate and multivariate analyses were performed to assess the impact of indoor air pollution on children's ARI., Results: Almost two-thirds of households (65.2%) used biomass fuels for cooking, 54.9% of households had a separate kitchen, and 47.2% of households had a smoker. About 2.7% of children suffered from ARI in the past two weeks preceding the survey. The use of biomass fuels (OR [odds ratio]: 1.10, 95% CI: 1.01-1.20), households having no separate kitchen (OR: 1.22, 95% CI: 1.14-1.30), and smoking behavior of household members (OR: 1.06, 95% CI: 1.00-1.12) were associated with greater risk of ARI among under-five children even after adjusting for age of child, sex of child, birth order, maternal age, maternal education, caste, religion, wealth quintile, any HH members suffer from tuberculosis (TB), and household crowding. Furthermore, the results revealed that the combined effects of biomass fuels and households without separate kitchen increased the likelihood of children's ARI by 36% (Adjusted OR: 1.35, 95% CI: 1.21-1.51)., Conclusion: The findings of this study suggest policy interventions to reduce the exposure of indoor air pollution, particularly among the impoverished groups. The government should ensure cleaner fuels for cooking, such as LPG and electricity, to minimize the risk of respiratory diseases among children., Competing Interests: The authors have declared that no competing interests exist.

Background: Management of moderate-to-severe atopic dermatitis (AD) commonly requires long-term treatment., Objective: The aim of this study was to report the safety and efficacy of dupilumab treatment for up to 3 years in adults with moderate-to-severe AD., Methods: This ongoing, multicenter, open-label extension study (LIBERTY AD OLE; NCT01949311) assessed dupilumab treatment in adults previously enrolled in dupilumab trials. Patients received dupilumab 300 mg weekly up to 148 weeks. The primary outcome was safety., Results: Of 2677 patients enrolled and treated, 347 reached week 148. Mean self-reported drug compliance was 98.2%. Safety data were consistent with previously reported trials (270.1 adverse events [AEs]/100 patient-years; 6.9 serious AEs/100 patient-years) and the known dupilumab safety profile. Common AEs (≥ 5% of patients) included nasopharyngitis, AD, upper respiratory tract infection, conjunctivitis, headache, oral herpes, and injection-site reactions. AD signs and symptoms showed sustained improvements during treatment with mean (standard deviation, mean percentage change from parent study baseline) Eczema Area and Severity Index 1.4 (3.2, - 95.4%) and weekly Pruritus Numerical Rating Scale 2.2 (1.8, - 65.4%) at week 148., Limitations: No control arm; fewer patients at later time points; regimen different from the approved 300 mg every 2 weeks dose., Conclusion: These safety and efficacy results support dupilumab as a continuous long-term treatment for adults with moderate-to-severe AD., Trial Registration: ClinicalTrials.gov: NCT01949311. Dupilumab provides favorable safety and sustained efficacy for up to 3 years in an open-label study of adults with moderate-to-severe atopic dermatitis (MP4  139831 kb).

Background: Prednisolone dosing regimen based on body surface area (BSA) or body weight (BW) in managing uncomplicated nephrotic syndrome (NS) has been a matter of controversy., Methods: In this parallel-arm randomized clinical trial, 60 children with uncomplicated NS in relapse were randomized to receive either of two regimens. Children of BW cohort received prednisolone (2 mg/kg/day) till remission (or 6 weeks for first episode); followed by 1.5 mg/kg on alternate days for 4 weeks (or 6 weeks for first episode). Children randomized for BSA cohort received prednisolone (60 mg/m 2 /day) till remission (or 6 week for first episode); followed by 40 mg/m 2 on alternate days for 4 weeks (or 6 weeks for first episode). The primary endpoint was 6-month relapse-free survival in the intention-to-treat population (clinical trial registry of India CTRI/2015/03/005655)., Results: The 6-month relapse-free survival rates were similar for both BSA cohort 73.33% (22/30) and BW cohort 70% (21/30) (p = 1, OR 0.19, 95% CI 0.07-0.52). Requirement of cumulative steroid to achieve initial remission (96.1 ± 57.8 vs 63.58 ± 40.2 mg/kg, p = 0.014) and over 6-month study period (104.34 ± 50.82 vs 73.88 ± 42.95 mg/kg, p = 0.015) were significantly higher in BSA cohort in comparison to BW cohort. However, time taken in achieving remission during enrolment episode in both BSA and BW groups was comparable (7 ± 1.7 vs 6.9 ± 1.4 days, p = 0.81). While both treatments were well tolerated, the number of adverse events was one and half times as common in the BSA group than BW group (37 vs. 22 events)., Conclusions: In treating children with uncomplicated NS, both BSA and BW regimens were equally effective in achieving initial remission and maintaining disease remission. Due to fewer adverse events and lesser cumulative steroid exposure with BW based regimen, it may be considered as better option over BSA regimen., Clinical Trial Registry Name: Clinical Trial Registry of India (CTRI/2015/03/005655).

We present a case of tendon rupture and subcutaneous bleeding after administration of gemifloxacin for the treatment of lower respiratory tract infection. Fluoroquinolone-induced tendinopathy is a rare but increasingly acknowledged adverse effect of this group of antibiotics. Most of the cases occur in the Achilles tendon and can lead to tendon rupture. Possible predisposing risk factors include steroid use, patients with renal failure or kidney transplantation, old age and being an athlete.

Background: Treatment with tenofovir disoproxil fumarate has been associated with renal toxicity or reductions in bone mineral density, or both, in some patients with chronic hepatitis B virus (HBV) infection. Tenofovir alafenamide is a tenofovir prodrug with high intrahepatic concentrations of active drug and reduced systemic tenofovir exposures compared with tenofovir disoproxil fumarate. In patients with chronic HBV, tenofovir alafenamide has shown efficacy non-inferior to that of tenofovir disoproxil fumarate with improved renal and bone safety. With this non-inferiority study, we aimed to evaluate the efficacy and safety of tenofovir alafenamide in patients with HBV infection switching from tenofovir disoproxil fumarate who are virally suppressed., Methods: Patients with chronic HBV infection who had been receiving tenofovir disoproxil fumarate for 48 weeks or more and who had HBV DNA less than the lower limit of quantification (LLOQ) for at least 12 weeks were recruited to this randomised, multicentre, double-blind, phase 3 non-inferiority study. Patients were randomly assigned in a 1:1 ratio to receive tenofovir alafenamide 25 mg once a day or to continue tenofovir disoproxil fumarate 300 mg once a day. The primary efficacy endpoint was loss of virological control, defined as the proportion of patients who received at least one dose of study drug who had HBV DNA of at least 20 IU/mL at week 48 by the modified US Food and Drug Administration (FDA) snapshot algorithm. Key safety endpoints were changes in hip and spine bone mineral density, estimated creatinine clearance by Cockcroft-Gault, and markers of bone turnover and renal tubular function. The study was powered for non-inferiority in efficacy of tenofovir alafenamide versus tenofovir disoproxil fumarate with a 4% margin. Investigators and patients were unaware of treatment allocation and on-treatment results. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02979613., Findings: Participants in this study were enrolled between Dec 29, 2016, and Oct 20, 2017. 541 patients were screened and 490 patients were randomly assigned to switch to tenofovir alafenamide or to stay on tenofovir disoproxil fumarate. Two patients assigned to receive tenofovir alafenamide did not receive treatment; thus the full analysis set for efficacy and safety analyses consisted of 243 patients in the tenofovir alafenamide group and 245 in the tenofovir disoproxil fumarate group. At week 48, one patient from each treatment group (both <1%) had HBV DNA of at least 20 IU/mL (difference in proportion 0·0%, 95% CI -1·9 to 2·0), thereby showing non-inferior efficacy of tenofovir alafenamide to tenofovir disoproxil fumarate. Patients who received tenofovir alafenamide had significantly increased bone mineral density at hip (mean change 0·66% [SD 2·08] vs -0·51% [SD 1·91]; difference in least square means 1·17% [95% CI 0·80 to 1·54; p<0·0001]) and at spine (mean change 1·74% [3·46] vs -0·11% [3·13]; difference in least square means 1·85% [1·24 to 2·46; p<0·0001]), creatinine clearance by Cockcroft-Gault relative to tenofovir disoproxil fumarate (median change 0·94 mL/min [IQR -4·47 to 6·24] vs -2·74 mL/min [-7·89 to 1·88]; p <0·0001), and improved markers of bone turnover and tubular function at week 48. The most common treatment-emergent adverse events were upper respiratory tract infection (18 [7%] of 243 patients in the tenofovir alafenamide group and 16 [7%] of 245 patients in the tenofovir disoproxil fumarate group) and nasopharyngitis (13 [5%] of 243 patients in the tenofovir alafenamide group and 12 [5%] of 245 patients in the tenofovir disoproxil fumarate group). The incidence of grade 3 and above adverse events and serious adverse events was low and similar between groups. No viral resistance was observed in patients who qualified for viral sequencing., Interpretation: These findings suggest that tenofovir alafenamide can be substituted for tenofovir disoproxil fumarate in patients with HBV infection for improved safety without a loss of efficacy., Funding: Gilead Sciences., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pulmonary infections (PIs) are a major complication of patients with myelodysplastic syndromes (MDS). We retrospectively evaluated 234 MDS patients treated with azacytidine (AZA). The total number of AZA cycles was 2886 (median 8 cycles per patient). There were 111 episodes of PI (3.8% of AZA cycles) in 81 patients (34.6%). PIs were considered of fungal origin in 27 cases (24.3%), associated to bacteremia in 11 cases (9.9%), to influenza infection in two cases (1.8%) and of unknown origin in the remaining 71 cases (64.0%). Forty-five PI episodes were documented in cycles 1 to 4 of AZA (5.1% of 875 cycles) and the remaining 66 episodes beyond the fourth cycle (3.2% of 2011 cycles) (P = .017). Overall, a fungal PI was documented in 13/875 (1.5%) cycles 1 to 4 and in 13/2011 (0.6%) cycles beyond the fourth cycle (P = .001). A baseline chronic pulmonary disease was significantly associated to a higher risk of severe PIs. In the survival analysis, cases of PI in patients who progressed to acute leukemia (PAL) were excluded, in view of the predominant influence of PAL on the outcome of the patients. A PI unrelated to PAL documented during the first 4 AZA cycles was an independent factor predicting lower survival (OR, 2.13; 95% CI, 1.37-3.33; P = .001). In conclusion, PIs are common in MDS patients receiving AZA, in particular during the first cycles of treatment and are associated with an unfavorable outcome. The results of our study raise the issue of the need of a tailored infection prevention strategy., (© 2019 John Wiley & Sons Ltd.)

Objective: Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions., Methods: Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed., Results: 2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time., Conclusion: The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: The predisposition of cigarette smokers for the development of respiratory infections, including influenza, have been well documented. As well, those exposed to side stream smoke are prone to viral and bacterial infections of the respiratory tract., Aim: The study aimed to evaluate whether the prevalence of smoking parents is higher among children with respiratory tract infections, including influenza, in comparison to the general population., Material and Methods: Observational, cohort study. The authors surveyed a cohort of patients and their families, hospitalized in the Paediatric University Hospital in Warsaw during 2018 influenza season. Patients were diagnosed with influenza (using PCR) or other respiratory tract infections. A questionnaire on smoking habits was performed., Results: Overall, 72 patients were included in the study, median age 2 years and 9 months (IQR: 1.4 - 7.2), influenza was diagnosed in 43% (n= 31) of patients. The percentage of regularly smoking parents in the whole cohort amounted to 33.3% (44 of 132) and was statistically significantly higher (p < 0.05) than in the general population (22.7%), whereas in the subgroup with influenza and non-influenza infections it reached 32.2% and 34.2%, respectively., Conclusions: The prevalence of smoking parents of children with acute respiratory tract infections is higher than in the general population: exposing children to tobacco smoke is one of the risk factors for acquiring influenza and others respiratory tract infections. Quitting smoking can decrease the risk of infectious diseases., (© National Institute of Public Health – National Institute of Hygiene.)

Ambient particulate matter is a public health concern. We aimed (1) to estimate national and provincial long-term exposure of Iranians to ambient particulate matter (PM) < 2.5 μm (PM 2.5 ) from 1990 to 2016, and (2) to estimate the national and provincial burden of disease attributable to PM 2.5 in Iran. We used all available ground measurements of PM < 10 μm (PM 10 ) (used to estimate PM 2.5 ) from 91 monitoring stations. We estimated the annual mean exposure to PM 2.5 for all Iranian population from 1990 to 2016 through a multi-stage modeling process. By applying comparative risk assessment methodology and using life table for years of life lost (YLL), we estimated the mortality and YLL attributable to PM 2.5 for five outcomes. The predicted provincial annual mean PM 2.5 concentrations range was between 21.7 μg/m 3 (UI: 19.03-24.9) and 35.4 μg/m 3 (UI: 31.4-39.4) from 1990 to 2016. We estimated in 2016, about 41,000 deaths (95% uncertainty interval [UI] 35634, 47014) and about 3,000,000 YLL (95% UI: 2632101, 3389342) attributable to the long-term exposure to PM 2.5 in Iran. Ischemic heart disease was the leading cause of mortality by 31,363 deaths (95% UI: 27520, 35258), followed by stroke (7012 (5999, 8062) deaths), lower respiratory infection (1210 (912, 1519) deaths), chronic obstructive pulmonary disease (1019 (715, 1328) deaths), and lung cancer (668 (489, 848) deaths). In 2016, about 43% of all PM 2.5 related mortality in Iran was, respectively, in the following provinces: Tehran (12.6%), Isfahan (9.3%), Khorasan Razavi (8.0%), Fars (6.5%), and Khozestan (6.4%). In summary, we found that the majority of Iranians were exposed to the levels of ambient particulate matter exceeding the WHO guidelines from 1990 to 2016. Further, we found that there was an increasing trend of total mortality attributed to PM 2.5 in Iran from 1990 to 2016 where the slope was higher in western provinces., (Copyright © 2019. Published by Elsevier Ltd.)

Psoriasis is a chronic inflammatory disease affecting multiple organ systems affecting approximately 2% of the population worldwide. The etiology is multifactorial etiology with multiple co-morbidities complicating the disease. Therapeutic options for patients with moderate-to-severe psoriasis have made tremendous strides since the turn of the century and biologic agents are now generally considered to be safe, efficacious and common options for these patients. However, some patients remain recalcitrant to the current treatment options. Risankizumab is a newly US FDA-approved biologic therapy that inhibits IL-23p19 subunit, which is specific to IL-23. Risankizumab has proven rapid onset, safety and efficacy in moderate-to-severe psoriasis and is currently being studied in other diseases utilizing the IL-23 pathway.

Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease. Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease. Methods: Forty-two subjects with aspirin-exacerbated respiratory disease underwent an aspirin desensitization and were placed on high-dose aspirin (1,300 mg daily). Fifteen aspirin-tolerant subjects with asthma were also placed on high-dose aspirin. Biologic specimens and clinical parameters were collected at baseline and after 8 weeks on aspirin. Urinary eicosanoids, plasma tryptase and cytokine levels, platelet-leukocyte aggregates, and granulocyte transcripts were assessed. Measurements and Main Results: Eight weeks of high-dose aspirin decreased nasal symptoms and urinary prostaglandin E metabolite ( P  < 0.05) and increased urinary leukotriene E 4 ( P  < 0.01) levels in subjects with aspirin-exacerbated respiratory disease, but not in those with aspirin-tolerant asthma. Urinary prostaglandin D 2 and thromboxane metabolites decreased in both groups. Only in subjects with aspirin-exacerbated respiratory disease, exhaled nitric oxide ( P  < 0.05), plasma tryptase ( P  < 0.01), and blood eosinophil ( P  < 0.01) and basophil ( P  < 0.01) counts increased and plasma tryptase correlated with eosinophil counts (Pearson r  = 0.514; P  < 0.01) on aspirin. After correction for eosinophil counts, aspirin-induced changes in blood granulocyte transcripts did not differ between groups. Aspirin had no effect on platelet-leukocyte aggregates, platelet activation markers, or plasma cytokines in either group. Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.

Background: Respiratory infections are among the leading causes of death and disability globally. Respirable aerosol particles released by agricultural crop-residue burning (ACRB), practised by farmers in all global regions, are potentially harmful to human health. Our objective was to estimate the health and economic costs of ACRB in northern India., Methods: The primary outcome was acute respiratory infection (ARI) from India's fourth District Level Health Survey (DLHS-4). DLHS-4 data were merged with Moderate-Resolution Imaging Spectroradiometer satellite data on fire occurrence. Mutually adjusted generalized linear models were used to generate risk ratios for risk factors of ARI. Overall disease burden due to ACRB was estimated in terms of disability-adjusted life years., Results: Seeking medical treatment for ARI in the previous 2 weeks was reported by 5050 (2%) of 252 539 persons. Living in a district with intense ACRB-the top quintile of fires per day-was associated with a 3-fold higher risk of ARI (mutually adjusted risk ratio 2.99, 95% confidence interval 2.77 to 3.23) after adjustment for socio-demographic and household factors. Children under 5 years of age were particularly susceptible (3.65, 3.06 to 4.34 in this subgroup). Additional ARI risk factors included motor-vehicle congestion (1.96, 1.72 to 2.23), open drainage (1.91, 1.73 to 2.11), cooking with biomass (1.73, 1.58 to 1.90) and living in urban areas (1.35, 1.26 to 1.44). Eliminating ACRB would avert 14.9 million disability-adjusted life years lost per year, valued at US$152.9 billion over 5 years., Conclusions: Investments to stop crop burning and offer farmers alternative crop-residue disposal solutions are likely to improve population-level respiratory health and yield major economic returns., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Fine particulate matter ≤2.5 μm (PM 2.5 ) is a prominent global public health risk factor that can cause respiratory infection by downregulating the amounts of antimicrobial proteins and peptides (AMPs). Both salivary agglutinin (SAG) and surfactant protein D (SPD) are important AMPs in respiratory mucosal fluid, providing protection against airway pathogen invasion and infection by inducing microbial aggregation and enhancing pathogen clearance. However, the relationship between PM 2.5 and these AMPs is unclear. To better understand the relationship between PM 2.5 and airway innate immune defenses, we review the respiratory antimicrobial activities of SAG and SPD, as well as the adverse effects of PM 2.5 on airway innate antimicrobial defense. We speculate there exists a dual effect between PM 2.5 and respiratory antimicrobial activity, which means that PM 2.5 suppresses respiratory antimicrobial activity through downregulating airway AMPs, while airway AMPs accelerate PM 2.5 clearance by inducing PM 2.5 microbial aggregation. We propose further research on the relationship between PM 2.5 and these AMPs., (Copyright © 2019. Published by Elsevier Ltd.)

This study aimed to estimate the number of incident cases and hospital admissions attributable to secondhand smoke (SHS) exposure at home for asthma, otitis media (OM), and lower respiratory infections (LRI) in children in Spain. The burden of respiratory disease caused by SHS exposure was estimated in terms of incident cases and hospitalized cases for asthma, OM, and LRI. Estimates were calculated using the population attributable fraction. The age-specific (0-1 year, 0-4 years, 5-11 years, and 0-11 years) prevalence of SHS exposure in children was estimated through a telephone survey performed in a representative sample of Spanish households with children in 2016. The risk estimates for all diseases were selected from international meta-analyses. The number of hospitalized cases was obtained for each disease from the Hospital Minimum Data Set provided by the Ministry of Health of Spain. Incident cases were obtained from the Global Health Data Exchange. In 2015, SHS exposure caused an estimated total of 136,403 incident cases of the following respiratory diseases: 9058 (8.5%) cases of asthma, 120,248 (8.5%) of OM, and 7097 (13.5%) of LRI in children aged 0-14 years old in Spain. Likewise, SHS exposure caused a total of 3028 hospitalized cases, with 379 (8.5%) for asthma and 167 (8.5%) for OM in children 0-11 years old, and 2482 (11.6%) for LRI in children <2 years old. The high burden of respiratory disease attributed to SHS exposure supports the need to improve protection of children against SHS exposure by extending smoke-free regulations to homes and cars., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recent studies have suggested a possible association between respiratory infection and the use of inhaled corticosteroids (ICS). We aimed to ascertain the risk of upper respiratory tract infection (URTI) with long-term inhaled corticosteroid use among patients with asthma., Methods: Through a comprehensive literature search of PubMed, Cochrane Library, EMBASE, and Google Scholar from inception to May 2018, we included randomized controlled trials of any ICS vs. a control treatment for asthma, with reporting of URTI as an adverse event. We conducted meta-analyses by the Peto approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of URTI., Results: Seventeen trials (15,336 subjects) were included. Compared with non-ICS treatment, ICSs were associated with a significantly increased risk of URTI (Peto OR, 1.24; 95% CI 1.08-1.42; I 2 = 5%, p = 0.002). Subgroup analyses were performed for different dose, both high- and low-dose ICSs were associated with a significantly increased risk of URTI (high dose: Peto OR, 1.46; 95% CI 1.05-2.03; I 2 = 0%; p = 0.03) (low dose: Peto OR, 1.20; 95% CI 1.04-1.39; I 2 = 25%; p = 0.01). Moreover, fluticasone was observed with an increased risk of URTI (Peto OR, 1.18; 95% CI 1.02-1.38; p = 0.03; heterogeneity: I 2 = 21%) but not budesonide, low-dose fluticasone treatment was associated with a significantly higher risk of URTI but not high dose., Conclusions: This study raises safety concerns about the risk of URTI associated with ICS use in patients with asthma, but it should be further investigated.

Few studies have examined the association between fine particulate matter (PM 2.5 ) and upper respiratory tract infections (URTI) in urban cities. The principal aim of the present study was to evaluate the short-term impact of PM 2.5 on the incidence of URTI in Beijing, China. Data on hospital visits due to URTI from 1 October 2010 to 30 September 2012 were obtained from the Beijing Medical Claim Data for Employees, a health insurance database. Daily PM 2.5 concentration was acquired from the embassy of the United States of America (US) located in Beijing. A generalized additive Poisson model was used to analyze the effect of PM 2.5 on hospital visits for URTI. We found that a 10 μg/m³ increase in PM 2.5 concentration was associated with 0.84% (95% CI, 0.05⁻1.64%) increase in hospital admissions for URTI at lag 0⁻3 days, but there were no significant associations with emergency room or outpatient visits. Compared to females, males were more likely to be hospitalized for URTI when the PM 2.5 level increased, but other findings did not differ by age group or gender. The study suggests that short-term variations in PM 2.5 concentrations have small but detectable impacts on hospital utilization due to URTI in adults.

Background: Our previous phase 2, open-label study of 11 infants and young children with life-threatening perinatal or infantile hypophosphatasia showed 1 year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We aimed to report the long-term outcomes over approximately 7 years of treatment., Methods: We did a prespecified, end of study, 7 year follow-up of our single-arm, open-label, phase 2 trial in which children aged 3 years or younger with life-threatening perinatal or infantile hypophosphatasia were recruited from ten hospitals (six in the USA, two in the UK, one in Canada, and one in the United Arab Emirates). Patients received asfotase alfa (1 mg/kg three times per week subcutaneously, adjusted to 3 mg/kg three times per week if required) for up to 7 years (primary treatment period plus extension phase) or until the product became commercially available; dosage adjustments were made at each visit according to changes in the patient's weight. The primary objectives of this extension study were to assess the long-term tolerability of asfotase alfa, defined as the number of patients with one or more treatment-emergent adverse events, and skeletal manifestations associated with hypophosphatasia, evaluated using the Radiographic Global Impression of Change (RGI-C) scale (-3 indicating severe worsening, and +3 complete or near-complete healing). Respiratory support, growth, and cognitive and motor functions were also evaluated. All efficacy and safety analyses were done in all patients who received any asfotase alfa (full-analysis population). This study and extension phase are registered with ClinicalTrials.gov, number NCT01205152, and EudraCT, number 2009-009369-32., Findings: 11 participants were recruited between Oct 6, 2008, and Dec 4, 2009. Ten patients completed a 6 month treatment period and entered the extension phase; nine received asfotase alfa for at least 6 years and completed the study, with four being treated for more than 7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores of at least +2 at year 6 (n=9; median score +2·0 [range 2·0-3·0]) and year 7 (n=7; median score +2·3 [2·0-3·0]). No patient who completed the study required respiratory support after year 4. Weight Z scores improved to within normal range from year 3 to study end; length or height Z scores improved but remained below normal. Age-equivalent scores on gross motor, fine motor, and cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. All 11 patients had at least one treatment-emergent adverse event. The most common adverse events were pyrexia (eight [73%] of 11 patients), upper respiratory tract infection (eight [73%]), craniosynostosis (seven [64%]), and pneumonia (seven [64%]). Serious adverse events related to asfotase alfa occurred in three (27%) patients (severe chronic hepatitis; moderate immediate post-injection reaction; and severe craniosynostosis with severe conductive deafness)., Interpretation: Patients with perinatal or infantile hypophosphatasia treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralisation. Respiratory function, growth, and cognitive and motor function also improved, and asfotase alfa was generally well tolerated., Funding: Alexion Pharmaceuticals, Inc., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ambient fine particulate matter (PM 2.5 ) is a risk factor for respiratory diseases. Previous studies suggest that PM 2.5 exposure may down-regulate airway antimicrobial proteins and peptides (AMPs), thereby accelerating airway pathogen infection. However, epidemiological research is scarce. Hence, we estimated the associations between individual PM 2.5 chronic daily intake (CDI) and the levels of the airway AMP salivary agglutinin (SAG), as well as peripheral leukocyte counts and pro-inflammatory cytokines, of preschool children in Guiyu (an e-waste area) and Haojiang (a reference area located 31.6 km to the east of Guiyu). We recruited 581 preschool children from Guiyu and Haojiang, of which 222 were included in this study for a matching design (Guiyu: n = 110 vs. Haojiang: n = 112). Air PM 2.5 pollution data was collected to calculate individual PM 2.5 CDI. The mean concentration of PM 2.5 in Guiyu was higher than in Haojiang, resulting in a higher individual PM 2.5 CDI. Concomitantly, saliva SAG levels were lower in Guiyu children (5.05 ng/mL) than in Haojiang children (8.68 ng/mL), and were negatively correlated with CDI. Additionally, peripheral counts of white blood cells, and the concentrations of interleukin-8 and tumor necrosis factor-alpha, in Guiyu children were greater than in Haojiang children, and were positively associated with CDI. Similar results were found for neutrophils and monocytes. To our knowledge, this is the first study on the relationship between PM 2.5 exposure and innate airway antimicrobial activity in children, in an e-waste area, showing that PM 2.5 pollution may weaken airway antimicrobial activity by down-regulation of saliva SAG levels, which might accelerate airway pathogen infection in children., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes., Methods: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed., Findings: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment., Interpretation: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis., Funding: Gilead Sciences., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To assess the efficacy and safety of febuxostat extended release (XR) and immediate release (IR) in patients with gout and normal or impaired renal function., Methods: This was a 3-month, phase III, multicenter, double-blind, placebo-controlled study. Patients (n = 1,790) with a history of gout and normal or impaired (mild-to-severe) renal function were randomized to receive placebo, febuxostat IR 40 or 80 mg, or febuxostat XR 40 or 80 mg once daily (1:1:1:1:1 ratio). End points included proportions of patients with a serum urate (UA) level of <5.0 mg/dl at month 3 (primary end point), a serum UA level of <6.0 mg/dl at month 3, and ≥1 gout flare requiring treatment over 3 months (secondary end points)., Results: Both febuxostat formulations led to significantly greater proportions of patients achieving a serum UA level of <5.0 mg/dl or <6.0 mg/dl at month 3 (P < 0.001 for all comparisons versus placebo). Equivalent doses of febuxostat XR and IR had similar treatment effects on serum UA level end points; however, a significantly greater proportion of patients achieved a serum UA level of <5.0 mg/dl with XR 40 mg versus IR 40 mg. Similar proportions of patients experienced ≥1 gout flare across treatment groups. Rates of treatment-emergent adverse events were low and evenly distributed between treatment arms. A preplanned subgroup analysis demonstrated that febuxostat formulations were well tolerated and generally effective on serum UA level end points (versus placebo) across all renal function subgroups., Conclusion: Both formulations of febuxostat (XR and IR) were well tolerated and effective in patients with gout and normal or impaired renal function, including patients with severe renal impairment., (© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

The introduction of biologic agents opened a new era of treatment of juvenile idiopathic arthritis (JIA) over the past decade. From clinical experience, it appears that biological agents are well tolerated overall, and serious adverse events are rare. However, such clinical studies have not been conducted in Korea. Therefore, we examined the safety profile of JIA patients with biologics in a single center in Korea. All JIA outpatients treated from April 2004 to June 2013 were enrolled and retrospectively reviewed. Pharmacy-based surveillance of adverse drug events (ADEs) was identified by recording the patient's symptoms in the medical record and suspected ADEs were additionally explored by screening laboratory test values and observing changes in medication orders. Finally, 83 patients were enrolled and experienced 109 ADEs in 52 patients. Most ADEs (99.1%) were mild to moderate in severity assessment. The total follow-up time was 328 patient-treatment years and the overall rate of ADEs was 0.33 per patient-years for etanercept. Infection including upper respiratory tract was the most common ADE and concomitant corticosteroids contributed to the risk of infections. If the dose of prednisolone increases 0.34 mg/kg/day, the probability of developing infections increases 3.29 times. Also, all 11 patients who stopped etanercept with injection site reactions were receiving a single use prefilled syringe. In our study, etanercept appears well tolerated and safe. Children affected by JIA should be carefully monitoring so as to limit the risk of ADEs during etanercept as much as possible. To gain further knowledge about risk profiles, national collaboration for the accumulation of long-term data should be encouraged in Korea., Competing Interests: The authors have delcared that no competing interests exist.

Objective: We aimed to assess risk factors for the development of severe infection in patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) receiving rituximab., Methods: 192 patients with AAV were identified. Univariate and multivariate analyses were performed to identify risk factors for severe infection following rituximab. Severe infections were classified as grade ≥3 as proposed by the Common Terminology Criteria for Adverse Events V.4.0., Results: 95 severe infections were recorded in 49 (25.52%) patients, corresponding to an event rate of 26.06 per 100 person-years. The prophylactic use of trimethoprim-sulfamethoxazole was associated with a lower frequency of severe infections (HR 0.30, 95% CI 0.13 to 0.69), while older age (HR 1.03, 95% CI 1.01 to 1.05), endobronchial involvement (HR 2.21, 95% CI 1.14 to 4.26), presence of chronic obstructive pulmonary disease (HR 6.30, 95% CI 1.08 to 36.75) and previous alemtuzumab use (HR 3.97, 95% CI 1.50 to 10.54) increased the risk. When analysis was restricted to respiratory tract infections (66.3% of all infections), endobronchial involvement (HR 4.27, 95% CI 1.81 to 10.06), severe bronchiectasis (HR 6.14, 95% CI 1.18 to 31.91), higher neutrophil count (HR 1.19, 95% CI 1.06 to 1.33) and major relapse (HR 3.07, 95% CI 1.30 to 7.23) as indication for rituximab use conferred a higher risk, while refractory disease (HR 0.25, 95% CI 0.07 to 0.90) as indication had a lower frequency of severe infections., Conclusions: We found severe infections in one quarter of patients with AAV receiving rituximab. Trimethoprim-sulfamethoxazole prophylaxis reduced the risk, while especially bronchiectasis and endobronchial involvement are risk factors for severe respiratory infections., Competing Interests: Competing interests: AK has received travel support from Roche/Genentech. DRWJ has received research grants and consulting fees from Roche/Genentech and Terumo BCT and is supported by the Cambridge Biomedical Research Centre., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)