COVID-19 severity appears to be reduced in spring/summer.

BACKGROUND: because of different human behaviours, SARS-CoV-2 spread may be lower in spring/summer. On the contrary, it is not clearly known whether the clinical course/severity of hospitalized patients infected by SARS-CoV-2 can be different in the various seasons.. OBJECTIVES: to understand whether there were differences in severity of COVID-19 in patients who had contracted the infection in winter versus those infected in spring/summer. DESIGN: observational retrospective cohort study. SETTING AND PARTICIPANTS: from the administrative database of the SARS-CoV-2 surveillance system and that of hospital discharge, a cohort of patients (8,221, 653 of which were hospitalized) who tested positive to the RT-PCR test for SARS-CoV-2 between 01.12.2020 and 31.07.2021 in the Grosseto province (Tuscany Region, Central Italy) was selected and analysed. MAIN OUTCOME MEASURES: hospitalization rate and length, continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) use, Intensive Care Unite (ICU) admissions, intra-hospital mortality and PaO2/FiO2 values were measured and compared between subjects infected in winter and those who developed COVID-19 in spring/summer. Viral load (cycle threshold, Ct), vitamin D, serum ferritin, IL-6, procalcitonin, D-dimer, and C-reactive protein measured in the two periods were also compared. RESULTS: in the considered months, the hospitalization rate among 8,221 patients with COVID-19 was 8%: 370 (8.5%) individuals were hospitalized in winter and 283 (7,3%; p=0.31) in spring/summer; 62 (16.8%), 88 (23.8%), and 63 (17%) in winter and 28 (9.9%), 40 (14.1%), and 36 (12.7%) in spring/summer were admitted in ICU (p=0.01), used CPAP/NIV (p=0.002) and died (p=0.13), respectively. Hospitalization days were 14.5±11.6 in winter and 10.3±8.84 in spring/summer (p=0.001), while minimum PaO2/FiO2, measured during hospital stays was 123.2±38.6 in spring/summer and 112.6±40.8 in winter (p=0.054). Multivariate analysis (adjusted for all confounding factors) also confirmed reduced risks of having ICU admissions (0.53; 95%CI 0.32;0.88; p=0.01) and of using CPAP/NIV (0.48; 95%CI 0.32;0.75; p=0.001) in spring/summer when compared to winter. Hospitalization days and minimum PaO2/FiO2 were also lower in spring/summer (ß= -3.9; 95%CI -5.5;-2.2; p=0.001) and winter (ß= -17; 95%CI -0.93;35; p=0.06), respectively. The adjusted hazard ratio of mortality in winter, obtained with a Cox model, was higher of about 38% compared to spring/summer. No Ct values (viral load) differences were found either in winter (19.45±6.18) or spring/summer (20.3±6.7; p=0.343). IL-6, ferritin, procalcitonin, D-dimer were similar. Conversely, CRP was lower whereas vitamin D was higher in the warmer seasons. CONCLUSIONS: COVID-19 may be less severe during spring/summer in hospitalized patients. This does not seem to be influenced by different SARS-CoV-2 viral load in the different periods considered. C-reactive protein was found to be lower whereas vitamin D higher in the warmer months. It can be hypothesized that higher levels of vitamin D in spring/summer, compared to winter, may be associated to a positive modulation of COVID-19 induced inflammation with a possible disease severity reduction during spring/summer.

Sex differences in excessive oral corticosteroid exposure in poor adherent adult asthmatics overusing short-acting ß-2 agonists.

BACKGROUND: We know that excessive short-acting ß2-agonists (SABA) use in asthma may be associated to high exacerbation risks. We studied whether such excessive SABA consumption is connected with different higher oral corticosteroid (OC) prescriptions in the two sexes. METHODS: In our prescribing database, we searched subjects aged 18-40 years that were prescribed at least one SABA package/year and/or at least two ICS or two ICS/LABA boxes/year to identify asthmatics. Their OC prescriptions/year were also examined. Subjects were divided into 4 groups according to SABA packages/year prescribed (0, 1-2,3-6 and ≥7), considering sexes separately. RESULTS: Individuals recruited were 9,102. Subjects with at least one OC prescription were higher in each group and were females (P<0.001). The OC packages/year number was also more elevated in women especially those with >7 SABA prescriptions/year (0.96 in males vs. 2.64 in females, P<0.001). 94.7%/93.6% males/females, who never used SABA, took at least one ICS/LABA (mean 5.84/5.48 packages/year), while the subject percentage adhering to ICS/LABA dropped to 28-47% (mean 0.94-3.82 packages/year) in those who used SABA (P<0.001). Higher SABA prescriptions were associated with an increasing OC dispensation (ß=0.057, P<0.0001). We observed also a greater risk of using >3 OC packages/year in subjects with 3-6 (OR: 2.98 [95% CI: 2.19-4.06], P<0.001) and ≥7 (OR: 3.49 [95% CI: 2.39-5.10], P<0.001) SABA prescriptions compared to those that never used SABA. Besides, we found that using ICS (OR:0.51 [95% CI: 0.35-0.75], P<0.001) or ICS/LABA (OR:0.07 [95% CI: 0.05-0.09], P<0.001) may significantly reduce SABA prescriptions. CONCLUSIONS: Poor adherence to maintenance treatment appears to associated with excessive SABA prescriptions that may lead to a higher OC consumption particularly noticeable in women.

Should a prescription database be used to search uncontrolled severe asthmatics?

INTRODUCTION: Many uncontrolled severe asthmatics are not on biologic therapy. We hypothesized that using a prescription database could help us identify them. MATERIAL AND METHODS: 3,309 patients who received at least one Montelukast prescription in 2019 were extracted from our prescription database. Number of packages/year, types and dosages of ICS, LABA, ICS/LABA, LAMA and monoclonal antibodies were considered for each patient. In our analysis, for subjects that took > 7 packages of ICS/LABA + LTRA +/- LAMA (high adherent) the number of oral corticosteroids (OC) packets prescribed for each of them was also looked upon. RESULTS: Patients that took ICS/LABA or ICS/LABA + LAMA continuously with high ICS doses were 188 (25.6%) and 117 (39.3%) respectively (total: 305 - 29.5%). Among them, 58 (30.9%) and 53 (45.3%) (total: 111 - 36.4%) were prescribed more than 2 OC packages. Whereas, 21 (11.2%) and 24 (20.5%) patients (total: 45 - 14.75%) received at least 4 OC package prescriptions. CONCLUSION: Approximately 36% of patients in continuous step-4/5 of GINA guidelines treatment may have severe uncontrolled asthma (overusing OC) which needed biologic treatment. In our opinion, a prescription archiving database may be a tool that can help us identify such uncontrolled asthma patients.

Which LABA/LAMA should be chosen in COPD patients in real life?

BACKGROUND: Given COPD heterogeneity, we do not know if some LABA/LAMAs are more suitable for some COPD phenotypes. This real-life database study aimed to evaluate retrospectively the 4 LABA/LAMA effectiveness and highlight possible specificities that could better guide us in choosing the right LABA/LAMA to be used. METHODS: We searched for subjects (1,779) adherent to umeclidinium/vilanterol (UM/VI), indacaterol/glycopyrronium (IND/GLY), aclidinium/formoterol (ACLI/FOR) and tiotropium/olodaterol (TIO/OLO) treatments in our prescribing/dispensing database. Prescriptions for systemic corticosteroids (SC), antibiotics and salbutamol during one year of LABA/LAMA treatment were analyzed. RESULTS: A better adherence was found in individuals taking IND/GLY (10.42 ± 1.86 packages/year) compared with UM/VI (10.09 ± 1.9; p = 0.008), ACLI/FOR (9.8 ± 1.8; p = 0.001) and TIO/OLO (10.1 ± 2.1; p = 0.047). The number of patients that were prescribed at least one package of SC/year and their package numbers/year were similar in males/females, across age groups and in "non-frequent exacerbators" with the 4 LABA/LAMAs. More SC were taken by frequent exacerbators, whereas fewer SC/antibiotic packages were prescribed to subjects aged >80 years with all treatments. In patients treated with ACLI/FOR or TIO/OLO, lower risks to having antibiotic prescriptions were observed when UM/VI (0.698[0.516-0.945] and 0.696[0.491-0.985; p = 0.020 and p = 0.041) and IND/GLY (0.597[0.445-0.802] and 0.595[0.423-0.836]; p = 0.001 and p = 0.003) were considered as landmarks. Lower risks for salbutamol prescriptions were detected with UM/VI (0.678[0.480-0.958]; p = 0.027) and TIO/OLO (0.585[0.365-0.937]; p = 0.026) when ACLI/FOR was used as a reference. CONCLUSION: According to our retrospective database study, each LABA/LAMA could have a specific efficacy profile in COPD that might be considered for personalized therapy. However, head-to-head targeted trials aimed to assess the impact of different LABA/LAMAs on COPD are needed to confirm/disprove such results.

Spontaneous abdominal bleeding associated with SARS-CoV-2 infection: causality or coincidence?

Authors present 6 cases of abdominal bleeding associated with COVID-19, representing 1.35% of all hospitalized COVID-19 patients and hypothesize that there could be, although not very frequently, a relationship between SARS-CoV2 and bleeding. They excluded a side effect of the low molecular weight heparin therapy that all patients underwent during the course of the disease or other possible causes. Alterations of the coagulation state or a weakness of the vascular wall due toa presumed endotheliitis SARS-CoV-2 infection induced, are hypothesized by the authors. Investigation and follow-up for possible hemorrhagic problems in patients with COVID-19 is recommended. In particular, clinicians should be vigilant about retroperitoneal hemorrhage in COVID-19 patients. In addition to the fact that these patients are being treated with anticoagulants, anemia and abdominal pain are the signs that should lead us to suspect this type of haemorrhage. More studies are needed to understand if COVID-19 can be directly associated with bleeding. (www.actabiomedica.it)

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Can the response to Omalizumab be influenced by treatment duration? A real-life study.

OBJECTIVE: It is unknown whether Omalizumab effectiveness changes over the course of time. Our retrospective real-life study tried to analyze whether Omalizumab response may be influenced by treatment duration. METHODS: 340 severe asthmatics treated with Omalizumab for different periods of time were recruited. They were subdivided into 4 groups according to the Omalizumab treatment length: <12, between 12 and 24, between 24 and 60 and >60 months. Omalizumab treatment results (FEV1, exacerbations, ACT, SABA use, asthma control levels, medications used e and ICS doses) were compared. RESULTS: ACT, exacerbations, GINA control levels, ICS doses and SABA use were similar in all groups with different Omalizumab treatment durations. Using a linear regression model, corrected for all confounding variables, a higher significant positive increase in FEV1% in subjects treated for 12-24 (ß = 9.49; p = 0.034) or 24-60 months (ß = 8.56; p = 0.043) was found when compared with subjects treated for a shorter period. Treatment duration was positively associated with a step down of the other associated therapies (OR: 1.013; p = 0.019). This association was more relevant (OR: 4.167; p = 0.005) when we considered Omalizumab treatment duration >60 months compared to the shorter therapy. In particular, the percentage of subjects that were taking Montelukast, LABAs and oral corticosteroids was lower in the group treated with Omalizumab for a longer period of time. CONCLUSION: In real-life, the positive Omalizumab response remained stable for over 60 months. Long term Omalizumab treatment may lead to a discontinuation of some associated medications and to a slowing down of FEV1 decline.

Smoking and Obesity Increase Airway Hyperesponsiveness Risk in the Elderly.

OBJECTIVE: of our study was assessing whether smoking and obesity might affect airways hyperresponsiveness (AHR) differently in younger and older subjects and whether this influence might be due to their different impacts on baseline lung function values at different ages. METHODS: 3,903 consecutive adult subjects with normal lung function (1,920 males; mean age 35.1±16.2; median FEV1:97.3% of predicted [interquartile range (IQR):89.7-105.2] and FEV1/FVC: 84.6% of predicted [IQR:79.8-89.2]), having performed a methacholine test, were considered. They were subdivided into three groups according to age (18-39, 40-64 and ≥ 65 years) and into different sub-groups according to body mass index (BMI) and smoking habits, considering two AHR level cut-offs (PD20≤ 1600 µg and PD20≤ 800 µg). RESULTS: PD20 was significantly lower (p<0.004) in obese subjects aged 18-39 years, in comparison to older patients. Smoking was an AHR risk factor for subjects aged 40-64 and especially for those aged >65 (OR: 12.786 [IQR: 1.450-112.753]; p<0.0001). Obesity caused an AHR risk only in older subjects (>65 years) (OR: 3.120 [IQR: 1.144-8.509]; p<0.0001). FEV1/FVC and FEF25-75% decreased progressively (p<0.001) with age in subjects with different weights/smoking habits. No reductions with age were observed in FEV1% and FVC% except for a significant FVC% decrease in older smokers compared to older non-smokers. CONCLUSION: Smoking determined a progressively increasing AHR risk reaching its peak in the elderly. In younger obese individuals, AHR was higher than in obese elderly, whereas obesity was a higher AHR risk factor only in subjects aged >65 years. A small airway age-related reduction may cause the increased smoking/obesity induced AHR risk in older people.