Seasonal Patients Research Articles

Racial, biological sex, and geographic disparities of venous thromboembolism in the United States, 2016 to 2019

BackgroundVenous thromboembolism (VTE) stands as the leading cause of preventable death within hospitals in the United States. Although there have been some studies investigating the incidence rates of VTE, there has yet to be a large-scale study elucidating disparities in sex, race, income, region, and seasons in patients with VTE. The goal of this study was to report the disparities in race, sex, income, region, and seasons in patients with VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT), in hospitalized patients from 2016 to 2019. MethodsWe used the United States National Inpatients Sample database to identify inpatients diagnosed with PE, DVT, and PE and DVT from 2016 to 2019. The inpatient incidence per thousand was calculated for sex and race using the weighted sample model. The regional and monthly incidence of DVT and PE per thousand inpatients and risk of incidence were calculated. Patients' characteristics including hospital type, bed size, median length of stay, median total charges, and mortality were also collected. ResultsWe examined 455,111 cases of VTE, 177,410 cases of DVT, 189,271 cases of PE, and 88,430 cases of both DVT and PE combined. Over the study period, we observed a statistically significant trend among PE hospitalization incidences. There was a strong and positive correlation between DVT and PE inpatients. Black inpatients had the highest cumulative incidence of hospitalizations in all cohorts with 10.36 per 1000 in PE and 9.1 per 1000 in DVT. Asian and Pacific Islander inpatients had the lowest cumulative incidence with 4.42 per 1000 in PE and 4.28 per 1000 in DVT. Females showed the lowest cumulative incidence with 7.47 per 1000 in PE and 6.53 per 1000 in DVT. The Mountain region was the highest among PE hospitalizations with 9.62 per 1000. For DVT, the Middle Atlantic region was the highest at 8.65 per 1000. The in-hospital mortality rate was the highest among the PE hospitalizations at 7.3%. Also, the trend analysis showed significant increases among all groups. ConclusionsOver the study period (2016-2019), we report the racial, biological sex, and geographical disparities from the National Inpatient Sample database, highlighting that Black inpatients had the highest incidence of PE and DVT, whereas Asian/Pacific Islander inpatients had the lowest incidences of PE and DVT. Moreover, women had a lower incidence compared with men. The observed regional variations indicated that the incidence of PE was highest in the Mountain region, whereas the incidence of DVT was lowest in the Middle Atlantic region. There was an increase in the mortality of inpatients diagnosed with VTE reflecting the growing burden of this condition in the US health care system.

Methylation-driven mechanisms of allergic rhinitis during pollen and non-pollen seasons using integrated bioinformatics analysis.

Allergic rhinitis (AR) is a widespread allergic airway disease that results from a complex interplay between genetic and environmental factors and affects approximately 10%-40% of the global population. Pollen is a common allergen, and exposure to pollen can cause epigenetic changes. However, the mechanism underlying pollen-induced DNA methylation changes and their potential effects on the allergic march are still unclear. The purpose of this study was to explore the methylation-driven mechanisms of AR during the pollen and non-pollen seasons using bioinformatics analysis and to investigate their relationship with asthma. We downloaded DNA methylation and gene expression data from the GEO database (GSE50387: GSE50222, GSE50101) and identified differentially methylated positions (DMPs) and differentially expressed genes (DEGs) during the pollen and non-pollen seasons using the CHAMP and limma packages. Through correlation analysis, we identified methylation-driven genes and performed pathway enrichment analysis to annotate their functions. We incorporated external data on AR combined with asthma (GSE101720) for analysis to identify key CpGs that promote the transformation of AR to asthma. We also utilized external data on olive pollen allergy (GSE54522) for analysis to validate the methylation-driven genes. Weighted correlation network analysis (WGCNA) was employed to identify gene modules significantly correlated with pollen allergy. We extracted genes related to the key methylation-driven gene ZNF667-AS1 from the significant module and performed pathway intelligent clustering using KOBAS-i. We also utilized gene set enrichment analysis to explore the potential function of ZNF667-AS1. We identified 20 and 24 CpG-Gene pairings during the pollen and non-pollen seasons. After incorporating external data from GSE101720, we found that ZNF667-AS1 is a key gene that may facilitate the transformation of AR into asthma during the pollen season. This finding was further validated in another external dataset, GSE54522, which is associated with pollen allergy. WGCNA identified 17 modules, among which the blue module showed significant correlation with allergies. ZNF667-AS1 was located in the blue module. We performed pathway analysis on the genes correlated with ZNF667-AS1 extracted from the blue module and identified a prominent cluster of pathways in the KOBAS-i results, including Toll-like receptor (TLR) family, MyD88, MAPK, and oxidative stress. Gene set enrichment analysis around cg05508084 (paired with ZNF667-AS1) also indicated its potential involvement in initiating and modulating allergic inflammation from the perspective of TLR and MAPK signaling. We identified methylation-driven genes and their related pathways during the pollen and non-pollen seasons in patients with AR and identified key CpGs that promote the transformation of AR into asthma due to pollen exposure. This study provides new insights into the underlying molecular mechanisms of the transformation of AR to asthma.

Efficacy and safety of stapokibart (CM310) in uncontrolled seasonal allergic rhinitis (MERAK): an investigator-initiated, placebo-controlled, randomised, double-blind, phase 2 trial

There is no trial to assess the benefits of periodically using biologics during the pollen season in patients with uncontrolled seasonal allergic rhinitis (SAR), who have moderate-to-severe symptoms even after standard-of-care. This trial aimed to evaluate the efficacy and safety of the add-on administration of stapokibart, a humanised monoclonal antibody that targets interleukin-4 receptor alpha, in patients with uncontrolled SAR. In this investigator-initiated, randomised, double-blind, placebo-controlled trial, eligible patients received either stapokibart 600-300mg weekly (QW), every 2 weeks (Q2W), or placebo QW for 4 weeks. All patients were given mometasone furoate nasal spray and loratadine throughout the trial. The primary endpoint was the mean change from baseline in daily reflective total nasal symptom score (rTNSS) during 2-week treatment. Secondary efficacy outcomes included: the mean change from baseline in daily rTNSS during 4-week treatment; the mean changes and the mean percentage changes from baseline during 2-week and 4-week treatment in 1) daily rTNSS and reflective total ocular symptom score (rTOSS), 2) morning (AM)/evening (PM) rTNSS and rTOSS, 3) AM instantaneous total nasal symptom score (iTNSS) and instantaneous total ocular symptom score (iTOSS), 4) individual nasal and ocular symptoms; the change from baseline in Rhinoconjunctivitis Quality of-Life Questionnaire score during 4-week treatment. Exploratory endpoints included the change of prespecified markers related to type 2 inflammation pre- and post-treatment. Safety, immunogenicity, and pharmacokinetics were also evaluated. This study is registered with www.clinicaltrials.gov (NCT05470647). Between August 17, 2022, and December 28, 2022, 92 patients with uncontrolled SAR were enrolled from 4 centres in China and randomly assigned to receive stapokibart 600-300mg QW (n=31), stapokibart 600-300mg Q2W (n=30), or placebo QW (n=31), of whom 86 (93%) completed the study. Both stapokibart Q2W and QW did not significantly improve mean change from baseline in daily rTNSS compared with placebo in 2 weeks. The least-squares (LS) mean differences (97.5% confidence interval [CI]) compared with placebo were-1.0 (-2.3, 0.2) in stapokibart Q2W group (p=0.065) and-0.2 (-1.5, 1.0) in stapokibart QW group (p=0.67). For the secondary outcomes, compared with placebo, stapokibart Q2W presented significant improvements in the mean percentage change from baseline in daily rTNSS in 2 weeks (LS mean difference-12.9%, 95% CI-25.3%,-0.4%, p=0.043), as well as AM iTNSS over 2 weeks (LS mean difference-17.4%, 95% CI-31.0%,-3.8%, p=0.013) and 4 weeks (LS mean difference-15.4%, 95% CI-29.0%,-1.9%, p=0.026). Additionally, the nasal congestion score was significantly lower in stapokibart Q2W than placebo during 2-week (LS mean difference-0.4, 95% CI-0.7,-0.1, p=0.014) and 4-week (LS mean difference-0.4, 95% CI-0.7,-0.04, p=0.028) treatment. Treatment-emergent adverse events (TEAEs) occurred in 48% (15/31), 33% (10/30), and 61% (19/31) of patients receiving stapokibart QW, Q2W, and placebo, respectively. Most reported TEAEs were sinus bradycardia, hyperlipidaemia, and blood uric acid increased. In this phase 2 trial, both stapokibart regimens had an acceptable safety and tolerability profile but did not significantly improve daily rTNSS in patients with uncontrolled SAR. The efficacy of stapokibart in patients with uncontrolled SAR is being further investigated in ongoing phase 3 trials (clinicaltrials.gov, NCT05908032). Ministry of Science and Technology of the People's Republic of China; Ministry of Education of the People's Republic of China; National Natural Science Foundation of China; Chinese Academy of Medical Sciences.

Relationship between platelet-related parameters and new-onset atrial fibrillation after coronary bypass surgery.

Inflammation plays a key role in the pathogenesis of postoperative atrial fibrillation after coronary artery bypass graft surgery. In this study, we aimed to investigate the changes in mean platelet volume and platelet values during the spring and autumn seasons in patients who underwent isolated coronary artery bypass graft surgery and the possible effect of these occurrences on postoperative atrial fibrillation. Consecutive patients who underwent elective isolated coronary bypass surgery at our clinic in the spring and autumn months, between August 2020 and July 2022, were retrospectively included in this study. Variables were evaluated according to the spring and autumn seasons. Patients who did not develop in-hospital postoperative atrial fibrillation were identified as Group 1, and those who did constituted Group 2. A total of 622 patients were included in the study. The patients were divided into two groups: those who were operated on in the spring (n=277, median age=62 years, male gender ratio=77.3%) and those who were operated on in the autumn (n=345, median age=61 years, male gender ratio=81.4%). There was no statistically significant difference between the patients operated on in both seasons in terms of age, gender, hypertension rates, and the frequency of chronic obstructive pulmonary disease. In multivariate analysis, being over 70 years old (OR: 1.934, 95% confidence interval (CI) 1.489-2.995, p<0.001), having a left ventricular ejection fraction below 30% (OR: 1.550, 95%CI 1.190-2.236, p=0.012), and having chronic obstructive pulmonary disease (OR: 1.663, 95%CI 1.339-2.191, p<0.001) were found to be independent predictors in predicting the development of postoperative atrial fibrillation. In this study, we first demonstrated that mean platelet volume and platelet mass index values were higher in patients in the autumn months. Additionally, for the first time in the literature, we showed that there is a significant relationship between platelet mass index value and the development of postoperative atrial fibrillation in patients who underwent isolated coronary artery bypass graft.

Impact of dupilumab across seasons in patients with type 2, uncontrolled, moderate-to-severe asthma

BackgroundSeasonal variability could influence asthma exacerbations. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation. In the 52-week QUEST study (NCT02414854), add-on dupilumab every 2 weeks vs placebo significantly reduced exacerbations and improved prebronchodilator forced expiratory volume in 1 second in patients with uncontrolled, moderate-to-severe asthma. TRAVERSE (NCT02134028), the open-label QUEST extension study, enrolled patients with moderate-to-severe asthma to investigate long-term safety and efficacy of dupilumab, including patients who previously received placebo that initiated dupilumab therapy. ObjectiveTo investigate long-term dupilumab efficacy in reducing exacerbations across yearly seasons in patients with type 2 inflammatory asthma with and without clinical evidence of allergic asthma. MethodsUnadjusted annualized exacerbation rate and proportions of patients experiencing severe asthma exacerbations are reported by month and season and for both hemispheres. ResultsThe proportion of patients with type 2 asthma experiencing 1 or more severe asthma exacerbations during QUEST was 20.8% vs 10.0% in spring, 18.2% vs 7.3% in summer, 22.2% vs 12.6% in autumn, and 26.4% vs 12.0% in winter, for placebo- vs dupilumab-treated patients, respectively; P was less than .001 for placebo vs dupilumab in all seasons. Reductions in the proportion of patients experiencing severe exacerbations across seasons in subgroups with and without evidence of allergic asthma were similar to the overall type 2 population. Reductions in severe exacerbations observed during QUEST were sustained during TRAVERSE, up to 96 weeks across both hemispheres. ConclusionDupilumab reduced asthma exacerbations, with no difference in the reduction between seasons, in patients with type 2 inflammation, with and without evidence of allergic asthma. Trial RegistrationClinicalTrials.gov Identifiers: NCT02414854, NCT02134028.

Are there more acute cardiac hospitalizations in winter in patients with systemic sclerosis? An analysis from the National Inpatient Sample

Objective: Cold-induced transient myocardial ischemia has been described in patients with systemic sclerosis. The clinical impact of cold exposure in systemic sclerosis patients with acute cardiac conditions is unknown. We compared the seasonal variation of acute cardiac hospitalizations in patients with and without systemic sclerosis. Methods: We performed a retrospective cross-sectional study using the National Inpatient Sample from 2016 to 2019. The primary outcome was acute cardiac hospitalization primarily due to heart failure, acute myocardial infarction, or cardiac arrhythmias. We compared the proportion of acute cardiac hospitalizations in each season in patients with and without systemic sclerosis. We also performed a subgroup analysis by US geographic region (Northeast, Midwest, South, West). Results: There were a total of 10,118,002 acute cardiac hospitalizations over the 4-year study period. Compared to those without systemic sclerosis, patients with systemic sclerosis who were hospitalized for acute cardiac care were younger (mean age 67 ± 13 vs 70 ± 14 years, p &lt; 0.01), a greater proportion were female (82% vs 45%, p &lt; 0.01), and a smaller proportion were Caucasian (68% vs 71%, p &lt; 0.01). There was a lesser proportion of traditional cardiovascular risk factors in systemic sclerosis compared to non-systemic sclerosis patients. There was no significant difference in the proportion of winter admissions between systemic sclerosis and non-systemic sclerosis patients for total acute cardiac hospitalizations (26.4% vs 25.9%, p = 0.51), heart failure (27.0% vs 26.5%, p = 0.64), acute myocardial infarction (26.9% vs 25.5%, p = 0.50), or arrhythmias (24.3% vs 25.0%, p = 0.68). The results were consistent across all four US geographic regions. Conclusion: Our study did not support that patients with systemic sclerosis had a disproportionally higher risk of acute cardiac hospitalization in winter compared to the general population. We found that systemic sclerosis patients hospitalized for acute cardiac care had a lower burden of traditional cardiovascular risk factors than their non-systemic sclerosis counterparts.

Tezepelumab reduces exacerbations across all seasons in patients with severe, uncontrolled asthma (NAVIGATOR)

BackgroundAsthma exacerbation frequencies vary throughout the year owing to seasonal triggers. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) vs placebo in patients with severe, uncontrolled asthma. ObjectiveTo evaluate the effect of tezepelumab on asthma exacerbations across all seasons in NAVIGATOR patients (post hoc). MethodsNAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. AAER over 52 weeks was assessed by season. Data from patients in the Southern Hemisphere were transformed to align with Northern Hemisphere seasons. ResultsTezepelumab reduced the AAER vs placebo by 63% (95% confidence interval [CI], 52-72) in winter, 46% (95% CI, 26-61) in spring, 62% (95% CI, 48-73) in summer, and 54% (95% CI, 41-64) in fall. In matched climates, during the spring allergy season (March 1 to June 15) and ragweed allergy season (September), tezepelumab reduced the AAER vs placebo in patients with seasonal allergy by 59% (95% CI, 29-77) and 70% (95% CI, 33-87), respectively. In patients with perennial allergy and in those with seasonal allergy, tezepelumab reduced the AAER vs placebo across all seasons. ConclusionTezepelumab reduced exacerbations across all seasons vs placebo in patients with severe, uncontrolled asthma, including patients with seasonal and perennial allergies. These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma. Trial RegistrationClinicalTrials.gov Identifier: NCT03347279 (https://clinicaltrials.gov/ct2/show/NCT03347279)

Tezepelumab Reduces Exacerbations Across All Seasons In Patients With Severe, Uncontrolled Asthma With Seasonal Allergy: Results From The Phase 3 NAVIGATOR Study

Exposure to seasonal allergens may contribute to spatiotemporal variations in asthma exacerbations. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab, reduced the annualized asthma exacerbation rate (AAER) versus placebo in patients with severe, uncontrolled asthma, across all seasons. This post hoc analysis evaluated the effect of tezepelumab on seasonal asthma exacerbations.

Seasonality of month of birth in patients with autoimmune endocrine diseases: A systematic review

BackgroundExposure to seasonal environmental factors during gestation or early in the postnatal period could influence the development of autoimmunity, determining a seasonality in the month of birth (MOB). There are studies evaluating this potential seasonality in patients with type 1 diabetes (T1D), autoimmune thyroid diseases (AITD), and Addison's disease (ADD), but results have been controversial. MethodsSystematic review according to PRISMA guidelines, using PubMed, Web of Science and WorldCat databases (2005–2020) of studies that explored the association between the seasonality of the MOB and T1D, AITD and ADD. Information on sex and age, location, methodology and internal quality, seasonal patterns, hypotheses and other factors proposed to explain seasonality were extracted. Differences in season and month of birth were further discussed. ResultsThe initial search retrieved 300 articles, and after further screening, 11 articles fulfilled inclusion criteria and were finally selected and reviewed. 73% found a seasonal pattern and 64% showed birth peaks in spring and/or summer. Hashimoto's thyroiditis and women exhibited a higher seasonality. Ultraviolet radiation, Vitamin D levels and viral infections were identified as influencing factors. ConclusionsThe effect of certain seasonal factors during foetal development, reflected by the seasonal differences in the MOB, could contribute to the development of endocrine autoimmune diseases in predisposed patients. Further research is needed to elucidate the mechanisms underlying the observed seasonality.

Seasonal variation of cytomegalovirus disease in kidney transplant recipients.

Studies conducted in the northern United States found cytomegalovirus (CMV) disease after liver transplantation follows a seasonal pattern, with increased incidence in fall and winter. This has not been evaluated in kidney transplant recipients. Improved understanding of CMV seasonality may help guide use of preventative therapies. We evaluated adult patients receiving a kidney transplant at our center in Wisconsin from January 1, 1995 to December 31, 2018. CMV event was defined as quantifiable viral replication with clinical signs or symptoms suspicious for CMV per current consensus recommendations. Seasons were divided as follows: winter (December-February), spring (March-May), summer (June-August), and fall (September-November). The primary objective was to evaluate the annual distribution of CMV disease and determine whether this differed by season. There were 6151 kidney transplants in the study period. A total of 913 patients had 1492 episodes of CMV. Median time from transplant to first detection was 5.51 months (interquartile range [IQR] 2.87-11.7). The observed overall incidence exceeded the expected incidence in winter (+.7%), spring (+5.5%), and fall (+3.4%) and was less than expected in summer (-9.5%) (p=.18). The incidence of CMV during summer, however, was 21% less than expected (p=.001) in recipients who were CMV positive (R+) at the time of transplantation. No such difference was observed in CMV negative recipients (R-; p=.58). CMV after kidney transplant appears to be less common during the summer season in patients who were R+ at transplant but does not follow seasonal variation in R-. Reasons for this are unclear but are likely related to CMV-specific cell-mediated immunity. These findings may have clinical implications, particularly the use of non-pharmacologic strategies to improve response to antiviral therapy.

Safety of subcutaneous allergen immunotherapy.

Subcutaneous allergen immunotherapy (SCIT) is a unique treatment option for managing patients with allergic rhinitis, asthma, atopic dermatitis, and stinging insect allergy. Although systemic reactions to allergen injections are rare, near-fatal, and fatal anaphylactic reactions can occur. Patients with asthma are at greatest risk for more severe reactions as are those with previous systemic reactions. Treating allergists should institute best clinical practices to prevent and manage severe systemic reactions to SCIT, including the following: (1) prescreening patients with asthma for recent increases in asthma symptoms, (2) not prescribing SCIT to patients with severe and uncontrolled asthma, (3) instituting clinic protocols to prevent dosing errors, (4) considering modifying allergen doses during peak allergy seasons in patients at high risk, (5) instituting measures that require all patients on SCIT to be observed for at least 30 minutes after injections, and (6) regular training of all clinical staff in the recognition and expeditious treatment of anaphylaxis.

Omalizumab in the severe exacerbations of seasonal allergic rhinitis

BACKGROUND: According to the Federal Clinical Guidelines, patients with severe persistent allergic rhinitis and/or severe exacerbation who failed to respond to third-line pharmacotherapy (antihistamines, leukotriene receptor antagonists, nasal corticosteroids) are advised to consider the administration of omalizumab. However, there is a lack of practical recommendations guiding the regimens and duration of the omalizumab therapy in the severe exacerbation of seasonal allergic rhinitis.&#x0D; AIMS: To assess the efficacy of omalizumab additional therapy in patients with severe exacerbation of allergic rhinitis during the pollen season, and to determine the optimal regimen and duration of treatment.&#x0D; MATERIALS AND METHODS: This is an open observational uncontrolled prospective single-center study. 10 adult patients with severe exacerbation of seasonal allergic rhinitis due to birch pollen were selected for the study. All of them received the third-line of therapy according to Federal Clinical Guidelines and had absence or incomplete control: Total nasal symptom score 2. All of them were treated with omalizumab. The dose and regime were prescribed according to instructions that took into account the overall IgE level, as well as the patients weight. Daily symptom diaries and the need for rescue medication levels were evaluated. The primary endpoint had a decrease in the Combined Medical and Symptom Score mean.&#x0D; RESULTS: The additional omalizumab treatment improved allergic rhinitis control for all patients and also reduced the rescue medication (TNSS 1.8 [95% CI 1.562.04]; р 0.001, and CMSS 2.12 [95% CI 1.742.5]; р 0.001, by the end of 1 week after the first omalizumab injection; TNSS 2.53 [95% CI 2.053.01]; р 0.0001, and CMSS 5.22 [95% CI 4.745.7]; р 0.001, by the end of four weeks, respectively). It was noted that the omalizumab effect realization occurs for some time (37 days). Due to short-season pollen for birch (12 months), the duration of treatment in our study did not exceed one month, so we managed to achieve complete control over the symptoms in all patients by the omalizumab with a small multiplicity of injections (12 injections). No adverse events were registered during the study.&#x0D; CONCLUSION: Omalizumab additional therapy in patients with severe exacerbation of allergic rhinitis allows control of all symptoms. Taking into account the mechanism of its action, omalizumab should be administered at least a week before the expected pollen season in patients with severe exacerbation (according to the previous seasons) who did not complete their allergen-specific immunotherapy on time, and continue therapy till the end of the pollen season.

Seasonality of month of birth in patients with autoimmune endocrine diseases: A systematic review

BackgroundExposure to seasonal environmental factors during gestation or early in the postnatal period could influence the development of autoimmunity, determining a seasonality in the month of birth (MOB). There are studies evaluating this potential seasonality in patients with type 1 diabetes (T1D), autoimmune thyroid diseases (AITD), and Addison's disease (ADD), but results have been controversial. MethodsSystematic review according to PRISMA guidelines, using PubMed, Web of Science and WorldCat databases (2005–2020) of studies that explored the association between the seasonality of the MOB and T1D, AITD and ADD. Information on sex and age, location, methodology and internal quality, seasonal patterns, hypotheses and other factors proposed to explain seasonality were extracted. Differences in season and month of birth were further discussed. ResultsThe initial search retrieved 300 articles, and after further screening, 11 articles fulfilled inclusion criteria and were finally selected and reviewed. 73% found a seasonal pattern and 64% showed birth peaks in spring and/or summer. Hashimoto's thyroiditis and women exhibited a higher seasonality. Ultraviolet radiation, Vitamin D levels and viral infections were identified as influencing factors. ConclusionsThe effect of certain seasonal factors during foetal development, reflected by the seasonal differences in the MOB, could contribute to the development of endocrine autoimmune diseases in predisposed patients. Further research is needed to elucidate the mechanisms underlying the observed seasonality.

Tezepelumab Reduces Exacerbations Across All Seasons in Patients with Severe, Uncontrolled Asthma: Results from the Phase 3 NAVIGATOR Study

Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin (TSLP). The phase 3 NAVIGATOR study (NCT03347279) investigated the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Seasonal variations in the frequency of asthma exacerbations can occur owing to the presence of different exacerbation triggers (e.g. allergens and viruses) during different seasons. This prespecified exploratory analysis evaluated the effect of tezepelumab on asthma exacerbations across all seasons in patients from NAVIGATOR.

Association between the Arylalkylamine N-Acetyltransferase (AANAT) Gene and Seasonality in Patients with Bipolar Disorder.

Objective Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD. Methods We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway. Results Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality. Conclusion This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.

Tezepelumab Reduces Exacerbations Across All Seasons in Patients with Severe, Uncontrolled Asthma: A Post Hoc Analysis of the PATHWAY Phase 2b Study.

IntroductionTezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in airway inflammation in asthma, from binding to its heterodimeric receptor. In the PATHWAY phase 2b study, tezepelumab significantly reduced exacerbation rates compared with placebo in adults with severe, uncontrolled asthma, irrespective of baseline disease characteristics.ObjectiveTo evaluate the effect of tezepelumab on asthma exacerbations on a seasonal basis.MethodsThis was a post hoc analysis of the PATHWAY study (NCT02054130). Adults (N=550) with severe, uncontrolled asthma were randomized 1:1:1:1 to receive subcutaneous tezepelumab 70 mg every 4 weeks (Q4W), 210 mg Q4W or 280 mg every 2 weeks (Q2W), or placebo Q2W, for 52 weeks. The annualized asthma exacerbation rate (AAER), total number of days with an exacerbation, proportion of patients with at least one exacerbation or 0, 1 or ≥2 exacerbations, and proportion of patients experiencing an exacerbation per day were evaluated by season and over the year, by treatment in the overall study population and in subgroups according to baseline blood eosinophil count (≥300 cells/µL or <300 cells/µL) or atopic asthma status (fluoro-enzyme immunoassay [FEIA]+ or FEIA−).ResultsSeasonal variations in exacerbation rates were found, with peaks observed in fall and winter, and greater variations in patients with high blood eosinophil counts (≥300 cells/µL). Tezepelumab treatment consistently reduced exacerbation rates across all seasons compared with placebo. Furthermore, there was a trend, which was not significant, toward a reduction in the total number of days with exacerbations and in the proportion of patients with exacerbations during each season in patients treated with tezepelumab compared with those who received placebo, irrespective of blood eosinophil count or atopic asthma status.ConclusionTezepelumab reduced exacerbations across all seasons, irrespective of evaluated baseline disease characteristics. These data support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma.

1496. Aspergillosis Complicating Severe Respiratory Syncytial Virus (RSV) in ICU Patients: A Retrospective Cohort Study

BackgroundThere are recent reports that identify severe influenza pneumonia as an independent risk factor for the development of invasive pulmonary aspergillosis (IPA), even in patients without immunocompromise. We aimed to understand the incidence of IPA as well as other coinfections over multiple seasons in patients with RSV pneumonia in the intensive care unit (ICU).MethodsA retrospective cohort study was conducted in a single center in Chicago. Data was collected over 9 seasons (January 2009-March 2018) from adult patients admitted to the ICU at a large urban tertiary care center with severe RSV pneumonia. Patients were included if they had a positive RSV PCR test, older than 18 years, admitted to the ICU with acute respiratory failure, and had pulmonary infiltrates on imaging. IPA was defined per both the EORTC/MSG criteria as well as the revised AspICU criteria (Schauwvlieghe et al). Descriptive statistics were calculated. In univariable analysis, we compared categorical variables by Fisher’s exact test and Chi-square test, continuous variables by Wilcoxon Rank Sum where appropriate.ResultsOf 224 patients admitted to the ICU with RSV (median ICU LoS 10.5 d), IPA was diagnosed in 8 (3.5%). Patients diagnosed with IPA had an increased LoS in the hospital (23.7 days vs. 11.6 days, p=0.01). Although the mortality was numerically higher (3, 37.5% vs 26, 17.9%) this was statistically not significant). History of hematological malignancy, stem cell transplant, and neutropenia were significant factors in the development of IPA. Those with lung disease had significantly lower rates of IPA. All patients with IPA were treated with voriconazole. Other coinfections among RSV-infected ICU patients included bacterial (21, 13.7%), viral (10, 6.5%), and non-IPA fungal (13, 8.5%) pathogens.Baseline Characteristics and Mortality/Morbidity Patient Characteristics in Invasive Pulmonary Aspergillosis ConclusionAlthough IPA is relatively uncommon in patients admitted to the ICU with severe RSV pneumonia, patients with IPA had significant increased LOS and tended to have underlying host factors. Other coinfections with bacterial, viral, and non-IPA fungal pathogens are common in those with severe RSV pneumonia.DisclosuresMichael G. Ison, MD MS, AlloVir (Consultant)

ASPERGILLOSIS COMPLICATING SEVERE INFLUENZA AND RSV PNEUMONIA IN ICU PATIENTS: A RETROSPECTIVE COHORT STUDY

Background: Invasive pulmonary aspergillosis (IPA) has been recognized as a complication of influenza infection even in immunocompetent patients. We aimed to understand the incidence of IPA as well as other coinfections over multiple seasons in patients with either severe influenza and RSV pneumonia in the intensive care unit (ICU), with a focus on solid organ transplant (SOT). Materials and Methods: A retrospective cohort study was conducted in a single center in Chicago. Data were collected over six seasons (January 2012 – March 2018) from adult patients admitted to the ICU at a large urban tertiary care center with severe RSV or influenza pneumonia. Patients were included if they had a positive RSV or influenza PCR test, older than 18 years, admitted to the ICU with acute respiratory failure. IPA was defined per both the EORTC/MSG criteria as well as the revised AspICU criteria.[1] Statistics were calculated with Stata 16.0 (StataCorp, TX). Results: Overall the incidence of IPA was low in patients with RSV or influenza (5.5% and 1.7%, respectively). Patients diagnosed with IPA were both predominantly of male sex in both RSV (87.5%, n=7) and influenza (83.3%, n=6) groups. The median overall length of stay was significantly longer in both RSV (23.6 +/- 4.3 d) and influenza (24.6 +/- 3.7 d) groups with IPA. Patients with RSV that developed IPA had significant mortality (62.5%, p=0.01), while patients with influenza did not (33.3%, p=0.11). In patients with SOT, IPA developed in 16.7% (n=1) of SOT patients with influenza, and 12.5% (n=1) with RSV. All SOT patients with IPA had a history of liver transplantation with comorbidities (malignancy, post-op complications) and developed bacterial coinfections. In patients with severe RSV, history of hematological malignancy and neutropenia showed trends towards the development of IPA. In contrast, those with influenza had a history of hematological malignancy (p=0.03), hematopoietic stem cell transplant (p=0.01), non-transplant related immunosuppression (p=0.01), and history of solid organ malignancy (p=0.01) as significant factors associated with IPA. Other coinfections were common with incidences of RSV and influenza groups at bacterial (27.1% v 46.7%), viral (6.9% v 11.7%), and non-aspergillosis fungal (1.3% v 13.3%).Conclusions and Discussion: The incidence of IPA was significantly lower in both RSV and influenza groups in our study (5.5% and 1.7%) than previously reported in similar studies. While RSV-infected patients with IPA had significant mortality, influenza-infected patients did not. SOT itself does not seem to be a significant factor contributing to the development of IPA in the setting of severe viral pneumonia. At the same time, malignancy and profound immunosuppression are factors strongly associated with the development of IPA. Other coinfections with bacterial, viral, and fungal pathogens are common in those with both severe RSV and influenza pneumonia. Reference: 1. Schauwvlieghe A, Rijnders BJA, Philips N, et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med 2018;6:782-92.

Immunization status in chronic obstructive pulmonary disease: A multicenter study from Turkey.

OBJECTIVE:The purpose of this study is to detect the prevalence and the factors associated with influenza and pneumococcal vaccination and outcomes of vaccination during 2013–2014 season in patients with chronic obstructive pulmonary disease (COPD) in Turkey.METHODS:This was a multicenter retrospective cohort study performed in 53 different centers in Turkey.RESULTS:During the study period, 4968 patients were included. COPD was staged as GOLD 1-2-3-4 in 9.0%, 42.8%, 35.0%, and 13.2% of the patients, respectively. Influenza vaccination rate in the previous year was 37.9%; and pneumococcus vaccination rate, at least once during in a life time, was 13.3%. Patients with older age, higher level of education, more severe COPD, and comorbidities, ex-smokers, and patients residing in urban areas had higher rates of influenza vaccination. Multivariate logistic regression analysis showed that advanced age, higher education levels, presence of comorbidities, higher COPD stages, and exacerbation rates were associated with both influenza and pneumococcal vaccination. The number of annual physician/outpatient visits and hospitalizations due to COPD exacerbation was 2.73 ± 2.85 and 0.92 ± 1.58 per year, respectively. Patients with older age, lower education levels, more severe COPD, comorbid diseases, and lower body mass index and patients who are male and are residing in rural areas and vaccinated for influenza had significantly higher rates of COPD exacerbation.CONCLUSIONS:The rates of influenza and pneumococcal vaccination in COPD patients were quite low, and the number of annual physician/outpatient visits and hospitalizations due to COPD exacerbation was high in Turkey. Advanced age, higher education levels, comorbidities, and higher COPD stages were associated with both influenza and pneumococcal vaccination.

Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study

Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis. We did a retrospective multicentre cohort study. Data were collected from adult patients with severe influenza admitted to seven ICUs across Belgium and The Netherlands during seven influenza seasons. Patients were older than 18 years, were admitted to the ICU for more than 24 h with acute respiratory failure, had pulmonary infiltrates on imaging, and a confirmed influenza infection based on a positive airway PCR test (influenza cohort). We used logistic regression analyses to determine if influenza was independently associated with invasive pulmonary aspergillosis in non-immunocompromised (ie, no European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] host factor) influenza-positive patients (influenza case group) compared with non-immunocompromised patients with severe community-acquired pneumonia who had a negative airway influenza PCR test (control group). Data were collected from patients admitted to the ICU between Jan 1, 2009, and June 30, 2016. Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU. The incidence was similar for influenza A and B. For patients with influenza who were immunocompromised, incidence of invasive pulmonary aspergillosis was as high as 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis. The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0·0001). In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5·19; 95% CI 2·63-10·26; p<0·0001), along with a higher APACHE II score, male sex, and use of corticosteroids. Influenza was identified as an independent risk factor for invasive pulmonary aspergillosis and is associated with high mortality. Future studies should assess whether a faster diagnosis or antifungal prophylaxis could improve the outcome of influenza-associated aspergillosis. None.