14 March 2022

Casselbrant A, Fedorowski A, Frantz S, Engström G, Wollmer P, Hamrefors V. Common physiologic and proteomic biomarkers in pulmonary and coronary artery disease. PLoS One. 2022 Mar 9;17(3):e0264376. doi: 10.1371/journal.pone.0264376. PMID: 35263363

Kor CT, Li YR, Lin PR, Lin SH, Wang BY, Lin CH. Explainable Machine Learning Model for Predicting First-Time Acute Exacerbation in Patients with Chronic Obstructive Pulmonary Disease. J Pers Med. 2022 Feb 7;12(2):228. doi: 10.3390/jpm12020228. PMID: 35207716; PMCID: PMC8879653.

Liang H, Zhi H, Ye W, Wang Z, Liang J, Yi F, Kong X, Jiang M, Chen R, Lai K. Risk factors of chronic cough in China: a systematic review and meta-analysis. Expert Rev Respir Med. 2022 Mar 10. doi: 10.1080/17476348.2022.2049759. Epub ahead of print. PMID: 35271782.
Objectives: Risk factors of chronic cough in China have not been systematically analyzed and we hypothesized that risk factors of chronic cough might have distinct characteristics in China. Hence, we performed this meta-analysis focusing on the potential risk factors of chronic cough in China.
Methods: We searched 7 databases for studies published before May 8, 2021. This systematic review was performed in accordance with the PRISMA checklist.
Results: A total of 33 eligible articles were identified and included in this systematic review, and 28 studies were included in the meta-analysis. Our results showed that allergy (OR: 3.72; 95% CI: 1.85-7.47), nasal/sinusitis diseases (OR: 3.56; 95% CI: 2.02-6.29), family history of allergy (OR = 1.74; 95% CI: 1.59-1.90), family history of chronic respiratory diseases (OR = 1.67; 95% CI: 1.47-1.91), exposure to pollutants (OR = 1.60; 95% CI: 1.26-2.04), passive smoking (OR = 1.44; 95% CI: 1.32-1.57), and exposure to pets (OR = 1.37; 95% CI: 1.18-1.58) were risk factors for chronic cough in China.
Conclusions: Our study indicated some potential risk factors of chronic cough in China, which provides useful epidemiological information for managing chronic cough in China and is worthy as a reference for future global investigations

Xiao T, Wijnant SRA, van der Velpen I, Terzikhan N, Lahousse L, Ikram MK, Vernooij MW, Brusselle GG, Ikram MA. Lung function impairment in relation to cognition and vascular brain lesions: the Rotterdam Study. J Neurol. 2022 Mar 10. doi: 10.1007/s00415-022-11027-9. Epub ahead of print. PMID: 35267082.
Objective: To investigate the association of chronic obstructive pulmonary disease (COPD) and Preserved Ratio Impaired Spirometry (PRISm) with cognitive performance and presence of vascular brain lesions (VBL).
Methods: We determined both cross-sectional and longitudinal association of lung function impairment with cognition, as well as cross-sectional association of lung function impairment with VBL, in the general population. Between 2009 and 2014 we included 3,941 participants from the Rotterdam Study with spirometry tests, brain MRI scans and cognition tests, of whom 1815 had follow-up data on cognition.
Results: Our finding indicated that cross-sectionally, participants with PRISm or COPD GOLD2-4 had a worse global cognitive performance. We did not find differences in cognition over time between those with normal spirometry versus those with lung function impairment. In addition, PRISm and COPD GOLD2-4 were associated with a higher prevalence of lacunar infarcts compared to normal spirometry.
Conclusions: This study suggests that persons with COPD GOLD2-4 or restrictive lung function, defined as PRISm, are characterized by poorer global cognitive function and a higher prevalence of lacunar infarcts.

Antwi GO, Rhodes DL. Association between E-cigarette use and chronic obstructive pulmonary disease in non-asthmatic adults in the USA. J Public Health (Oxf). 2022 Mar 7;44(1):158-164. doi: 10.1093/pubmed/fdaa229. PMID: 33348361.
Background: Concern about the health impacts of e-cigarette use is growing; however, limited research exists regarding potential long-term health effects of this behavior. This study explored the relationship between e-cigarette use and COPD in a sample of US adults.
Methods: A secondary data analysis using data from the 2018 Behavioral Risk Factor Surveillance Survey in the USA was computed to examine associations between e-cigarette use and COPD controlling for conventional cigarette smoking status, past month leisure physical activity and demographic characteristics including age, sex, education, race, marital status and body mass index.
Results: Significant associations between e-cigarette use and COPD among former combustible cigarette smokers and those who reported never using combustible cigarettes were found. Compared with never e-cigarette users, the odds of having COPD were significantly greater for daily e-cigarette users (OR = 1.53; 95% CI: 1.11-2.03), occasional users (OR = 1.43, 95% CI: 1.13-1.80) and former users (OR = 1.46 95% CI: 1.28-1.67).
Conclusions: Findings from this study indicate a potential link between e-cigarette use and COPD. Further research to explore the potential effects of e-cigarette on COPD is recommended.

Ian R Reid, Emma O Billington Drug therapy for osteoporosis in older adults. Lancet 2022; 399: 1080–92
The goal of osteoporosis management is to prevent fractures. Several pharmacological agents are available to lower fracture risk, either by reducing bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used anti-resorptives, reducing bone turnover markers to low premenopausal concentrations and reducing fracture rates (vertebral by 50–70%, non-vertebral by 20–30%, and hip by ~40%). Bisphosphonates bind avidly to bone mineral and have an offset of effect measured in months to years. Long term, continuous use of oral bisphosphonates is usually interspersed with drug holidays of 1–2 years, to minimise the risk of atypical femoral fractures. Denosumab is a monoclonal antibody against RANKL that potently inhibits osteoclast development and activity. Denosumab is administered by subcutaneous injection every 6 months. Anti-fracture effects of denosumab are similar to those of the bisphosphonates, but there is a pronounced loss of anti-resorptive effect from 7 months after the last injection, which can result in clusters of rebound vertebral fractures. Two classes of anabolic drugs are now available to stimulate bone formation. Teriparatide and abaloparatide both target the parathyroid hormone-1 receptor, and are given by daily subcutaneous injection for up to 2 years. Romosozumab is an anti-sclerostin monoclonal antibody that stimulates bone formation and inhibits resorption. Romosozumab is given as monthly subcutaneous injections for 1 year. Head-to-head studies suggest that anabolic agents have greater anti-fracture efficacy and produce larger increases in bone density than anti-resorptive drugs. The effects of anabolic agents are transient, so transition to anti-resorptive drugs is required. The optimal strategy for cycling anabolics, anti-resorptives, and off-treatment periods remains to be determined.

Helen K. Reddel, MB, BS, PhDa,*, Eric D. Bateman, MB, ChB, MDb,*, Michael Schatz, MD, MSc, Jerry A. Krishnan, MD, PhDd, and Michelle M. Cloutier, MDe A Practical Guide to Implementing SMART in Asthma Management. J Allergy Clin Immunol Pract 2022;10:S31-S8)

Achten NB, van Rossum AMC, Bacharier LB, Fitzpatrick AM, Hartert TV. Long-Term Respiratory Consequences of Early-Life Respiratory Viral Infections: A Pragmatic Approach to Fundamental Questions. J Allergy Clin Immunol Pract. 2021 Dec 20:S2213-2198(21)01367-2. doi: 10.1016/j.jaip.2021.12.005. Epub ahead of print. PMID: 34942383.

Jackson DJ. Rhinovirus Infections and Their Roles in Asthma: Etiology and Exacerbations. (J Allergy Clin Immunol Pract 2022;10:673-81

Fizpatrick A AND Busse WW. Perspectives in Respiratory Infections and the Lung. J Allergy Clin Immunol Pract 2022;10:694-6.

Griesel M, Wagner C, Mikolajewska A, Stegemann M, Fichtner F, Metzendorf MI, Nair AA, Daniel J, Fischer AL, Skoetz N. Inhaled corticosteroids for the treatment of COVID-19. Cochrane Database Syst Rev. 2022 Mar 9;3:CD015125. doi: 10.1002/14651858.CD015125. PMID: 35262185.
Background: Inhaled corticosteroids are well established for the long-term treatment of inflammatory respiratory diseases such as asthma or chronic obstructive pulmonary disease. They have been investigated for the treatment of coronavirus disease 2019 (COVID-19). The anti-inflammatory action of inhaled corticosteroids might have the potential to reduce the risk of severe illness resulting from hyperinflammation in COVID-19.
Objectives: To assess whether inhaled corticosteroids are effective and safe in the treatment of COVID-19; and to maintain the currency of the evidence, using a living systematic review approach.
Search methods: We searched the Cochrane COVID-19 Study Register (which includes CENTRAL, PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 7 October 2021.
Selection criteria: We included randomised controlled trials (RCTs) evaluating inhaled corticosteroids for COVID-19, irrespective of disease severity, age, sex, or ethnicity. We included the following interventions: any type or dose of inhaled corticosteroids. We included the following comparison: inhaled corticosteroids plus standard care versus standard care (with or without placebo). We excluded studies examining nasal or topical steroids.
Data collection and analysis: We followed standard Cochrane methodology. For risk of bias assessment, we used the Cochrane RoB 2 tool. We rated the certainty of evidence using the GRADE approach for the outcomes of mortality, admission to hospital or death, symptom resolution, time to symptom resolution, serious adverse events, adverse events, and infections.
Main results: Inhaled corticosteroids plus standard care versus standard care (with/without placebo) People with a confirmed diagnosis of moderate-to-severe COVID-19 We found no studies that included people with a confirmed diagnosis of moderate-to-severe COVID-19. People with a confirmed diagnosis of asymptomatic SARS-CoV-2 infection or mild COVID-19 We included three RCTs allocating 3607 participants, of whom 2490 had confirmed mild COVID-19. We analysed a subset of the total number of participants recruited to the studies (2171, 52% female) as some trials had a platform design where not all participants were allocated to treatment groups simultaneously. The included studies were community-based, recruiting people who were able to use inhaler devices to deliver steroids and relied on remote assessment and self-reporting of outcomes. Most people were older than 50 years and had co-morbidities such as hypertension, lung disease, or diabetes. The studies were conducted in high-income countries prior to wide-scale vaccination programmes. A total of 1057 participants were analysed in the inhaled corticosteroid arm (budesonide: 860 participants; ciclesonide: 197 participants), and 1075 participants in the control arm. No studies included people with asymptomatic SARS-CoV-2 infection. With respect to the following outcomes, inhaled corticosteroids compared to standard care: – may result in little to no difference in all-cause mortality (at up to day 30) (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.22 to 1.67; 2132 participants; low-certainty evidence). In absolute terms, this means that for every nine deaths per 1000 people not receiving inhaled corticosteroids, there were six deaths per 1000 people who did receive the intervention (95% CI 2 to 16 per 1000 people); – probably reduces admission to hospital or death (at up to 30 days) (RR 0.72, 95% CI 0.51 to 0.99; 2025 participants; moderate-certainty evidence); – probably increases resolution of all initial symptoms at day 14 (RR 1.19, 95% CI 1.09 to 1.30; 1986 participants; moderate-certainty evidence); – may reduce the duration to symptom resolution (at up to day 30) (by -4.00 days, 95% CI -6.22 to -1.78 less than control group rate of 12 days; 139 participants; low-certainty evidence); – the evidence is very uncertain about the effect on serious adverse events (during study period) (RR 0.51, 95% CI 0.09 to 2.76; 1586 participants; very low-certainty evidence); – may result in little to no difference in adverse events (at up to day 30) (RR 0.78, 95% CI 0.47 to 1.31; 400 participants; low-certainty evidence); – may result in little to no difference in infections (during study period) (RR 0.88, 95% CI 0.30 to 2.58; 400 participants; low-certainty evidence). As studies did not report outcomes for subgroups (e.g. age, ethnicity, sex), we did not perform subgroup analyses.
Authors’ conclusions: In people with confirmed COVID-19 and mild symptoms who are able to use inhaler devices, we found moderate-certainty evidence that inhaled corticosteroids probably reduce the combined endpoint of admission to hospital or death and increase the resolution of all initial symptoms at day 14. Low-certainty evidence suggests that corticosteroids make little to no difference in all-cause mortality up to day 30 and may decrease the duration to symptom resolution. We do not know whether inhaled corticosteroids increase or decrease serious adverse events due to heterogeneity in the way they were reported across the studies. There is low-certainty evidence that inhaled corticosteroids may decrease infections. The evidence we identified came from studies in high-income settings using budesonide and ciclesonide prior to vaccination roll-outs. We identified a lack of evidence concerning quality of life assessments, serious adverse events, and people with asymptomatic infection or with moderate-to-severe COVID-19. The 10 ongoing and four completed, unpublished RCTs that we identified in trial registries address similar settings and research questions as in the current body of evidence. We expect to incorporate the findings of these studies in future versions of this review. We monitor newly published results of RCTs on inhaled corticosteroids on a weekly basis and will update the review when the evidence or our certainty in the evidence changes

Molina MF, Okoniewski W, Puranik S, Aujla S, Celedón JC, Larkin A, Forno E. Severe asthma in children: description of a large multidisciplinary clinical cohort. Pediatr Pulmonol. 2022 Mar 9. doi: 10.1002/ppul.25887. Epub ahead of print. PMID: 35261210.
Background: Children with severe asthma have substantial morbidity and healthcare utilization. Pediatric severe asthma is a heterogeneous disease, and a multidisciplinary approach can improve the diagnosis and management of these children.
Methods: We reviewed the electronic health records for patients seen in the Severe Asthma Clinic (SAC) at UPMC Children’s Hospital of Pittsburgh between August 2012 and October 2019.
Results: Of the 110 patients in whom we extracted data, 46% were female, 48% were Black/African American, and 41% had ≥1 admission to the pediatric intensive care unit (PICU) for asthma. Compared to patients without a PICU admission, those with ≥1 PICU admission were more likely to be non-White (64.4% vs 41.5%, P=0.031) and more atopic (eosinophil count geometric mean= 673 vs 319 cells/mm3 , P=0.002; total IgE geometric mean=754 vs 303 KU/L, P=0.003), and to have lower pre-bronchodilator FEV1 (58.6% [±18.1%] vs 69.9% [±18.7%], P=0.002) and elevated FeNO (60% vs 22%, P=0.02). In this cohort, 84% of patients were prescribed high-dose ICS/LABA and 36% were on biologics. Following enrollment in the SAC, severe exacerbations decreased from 3.2/year to 2.2/year (P<0.0001); compared to the year prior to joining the SAC, in the following year the group had 106 fewer severe exacerbations.
Conclusions: This large cohort of children with severe asthma had a high level of morbidity and healthcare utilization. Patients with a history of PICU admissions for asthma were more likely to be non-White and highly atopic, and to have lower lung function. Our data supports a positive impact of a multidisciplinary clinic on patients with severe childhood asthma. This article is protected by copyright. All rights reserved

Antonio Buendía J, Patiño DG. Fluticasone furoate plus vilanterol in patients with moderate persistent asthma: a cost-utility analysis. J Asthma. 2022 Mar 9:1-9. doi: 10.1080/02770903.2022.2051547. Epub ahead of print. PMID: 35261332.
Background: In recent years, the combination of fluticasone furoate and vilanterol (FF/VI) has emerged as an alternative therapy, since it is administered every 24 h, in contrast to other ICS/LABAs such as fluticasone propionate plus salmeterol (FP/Salm), which requires administration every 12 hrs. Concerns have arisen over whether the benefit generated by FF/VI justifies the additional costs it involves over FP/Salm. This study aimed at assessing the health and economic consequences of FF/VI in patients with moderate-severe persistent asthma.
Methods: A probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with persistent asthma. Total costs and QALYs for FF/VI and FP/Salm were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000.
Results: We estimated a gain of 16.8 and 10.7 QALYs per patient per year on FF/VI and FP/Salm, respectively. At the same time, we observed a difference of US$216 in total discounted cost per person-year on FF/VI with respect to FP/Salm. The incremental cost-effectiveness ratio (ICER) of FF/VI was USD $70 per QALY with respect to FP/Salm. In the deterministic and probabilistic sensitivity analyses, our base-case results were robust to variations in all assumptions and parameters.
Conclusion: FF/VI is more cost-effective than FP/Salm. The evidence supports using FF/VI therapy in Colombia, and the study should be replicated in other middle-income countries.

Phinyo P, Wongsa C, Sompornrattanaphan M, Thongngarm T. As-needed versus regular intranasal corticosteroid for allergic rhinitis: A systematic review and meta-analysis. Asian Pac J Allergy Immunol. 2022 Mar 12. doi: 10.12932/AP-091121-1269. Epub ahead of print. PMID: 35278059.
Background: Daily intranasal corticosteroid (INCS) is recommended for treating allergic rhinitis (AR). Nevertheless, patients are generally not adherent and use it on-demand. The data on the efficacy of as-needed INCS was insufficient.
Objective: We conducted a systematic review and meta-analysis to assess the efficacy of as-needed INCS compared with regular use for AR.
Methods: We searched PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) until May 2021. A pairwise meta-analysis used a random-effects model to estimate the pooled standardized mean difference (SMD). The primary outcome was the total nasal symptom score (TNSS) changes from baseline at 4 and 6 weeks. Secondary outcomes were the changes of individual nasal symptom score and quality-of-life (QoL) score.
Results: We identified five eligible RCTs with a total of 436 patients with AR. Only four studies had adequate data for quantitative synthesis. The TNSS changes of as-needed INCS were not significantly different from the regular use at both 4 (SMD 0.23 [95%CI: -0.14 to 0.60], p = 0.230) and 6 weeks (SMD 0.21 [95%CI: -0.02 to 0.44], p = 0.080). Most of the changes of individual nasal symptom scores and QoL scores were not significantly different between the two regimens. At 50% or more INCS dose of regular use, as-needed and regular INCS provided a similar efficacy. The treatment effect was, however, less sustained with as-needed INCS.

Ilaria Baiardini, PhDa,b, Salvatore Fasola, PhDc, Stefania La Grutta, MDc, Elisa Trucco, MDa, Giorgio Walter Canonica, MDb,d, and Fulvio Braido, MDaRhinitis and Asthma Patient Perspective (RAPP): Clinical Utility and Predictive Value. (J Allergy Clin Immunol Pract 2022;10:846-52)

Rodrigues Sousa S, Tenda A, Farinha I, Carvalho A, Chaves Loureiro C. Home administration of biological treatment in severe asthma in real-life experience: impact on asthma control and quality of life. Eur Ann Allergy Clin Immunol. 2022 Mar 10. doi: 10.23822/EurAnnACI.1764-1489.248. Epub ahead of print. PMID: 35261225.
Introduction. Several biological agents for the treatment of severe asthma have been approved for self-administration on an outpatient basis in the last years. However, data on the impact of home administration in outcomes such as asthma control and quality of life in real-life settings are sparse. Being this knowledge crucial for clinical practice, this study aimed to assess asthma control and quality of life in patients who transitioned from day hospital administration of biological therapy to home administration. Methods. A single-center prospective analysis of 33 patients treated with biologics for severe asthma, who switched from hospital to home treatment was performed. Asthma Control Test (ACT), Control of Allergic Rhinitis and Asthma Test (CARAT), Asthma Life Quality (ALQ) and the number of exacerbations were assessed 3 months before and 3 and 6 months after of home-use. Results. ACT and CARAT did not show statistical differences comparing to the baseline values (21.8 ± 2.7 and 23.8 ± 5.5) within 3 months (22.1 ± 2.4, p = 0.609; 23.2 ± 5.3, p = 0.572) or 6 months (23.4 ± 0.9, p = 0.553; 23.7 ± 6.2, p = 0.149) of home administration. Also, ALQ score did not show meaningful variations between baseline (9.5 ± 3.2) and after 3 months (11.2 ± 4.4, p = 0.275) and 6 months (10.3 ± 3.8, p = 0.209) of home-use. Regarding asthma exacerbations, we did not record a significant difference comparing to the baseline values of 3 months/patient exacerbations (0.2 ± 0.4) and after 3 months (0.2 ± 0.5, p = 0.786) or 6 months (0.2 ± 0.4, p = 1.000) of change in modality treatment. There was no cases of anaphylaxis or other serious adverse effects in those patients treated at home. Conclusions. Transition of day hospital administration of biologic treatment for severe asthma to home administration did not lead to any deterioration of asthma control or quality of life. Our results emphasized the efficacy and safety of home administration of biologic treatment and provide support on changing the paradigm of the administration of biological treatment in severe asthma.

Eide JG, Wu J, Stevens WW, Bai J, Hou S, Huang J, Rosenberg J, Utz P, Shintani-Smith S, Conley D, Welch K, Kern R, Hulse KE, Peters AT, Grammer LC, Zhao M, Lindholm P, Schleimer R, Tan BK. Antiphospholipid Antibodies are Elevated and Functionally Active in Chronic Rhinosinusitis with Nasal Polyps. Clin Exp Allergy. 2022 Mar 6. doi: 10.1111/cea.14120. Epub ahead of print. PMID: 35253284.
Background: Polyps from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) contain increased levels of autoreactive antibodies, B cells, and fibrin deposition. Anti-phospholipid antibodies (APA) are autoantibodies known to cause thrombosis but have not been implicated in chronic rhinosinusitis (CRS).
Objective: To compare APA levels (anti-cardiolipin, anti-phosphatidylethanolamine (anti-PE), and anti-β2 -glycoprotein (anti-B2GP)) in nasal polyp (NP) tissue with tissue from control and CRS without nasal polyp (CRSsNP) patients, we tested whether NP antibodies affect coagulation, and correlate APAs with anti-dsDNA IgG and markers of coagulation.
Methods: Patient specimens were assayed for APA IgG, anti-dsDNA IgG, and thrombin-anti-thrombin (TaT) complex by ELISA. Antibodies from a subset of specimens were tested for modified activated partial thromboplastin time (aPTT) measured on an optical-mechanical coagulometer.
Results: Anti-cardiolipin IgG in NP was 5-fold higher than control tissue (p<0.0001). NP antibodies prolonged aPTT compared to control tissue antibodies at 400 μg/mL (36.7 sec vs 33.8 sec, p=0.024) and 600 μg/mL (40.9 sec vs 34.7 sec, p=0.0037). Anti-PE IgG antibodies were increased in NP (p=0.027), but anti-B2GP IgG was not significantly higher (p=0.084). All APAs correlated with anti-dsDNA IgG levels, which were also elevated (R=0.77, 0.71, and 0.54, respectively, for anti-cardiolipin, anti-PE, and anti-B2GP; all p<0.001), but only anti-cardiolipin (R=0.50, p=0.0185) and anti-PE (R=0.45, p=0.037) correlated with TaT complex levels.
Conclusions: APA IgG antibodies are increased in NP and correlate with autoreactive tissue antibodies. NP antibodies have in vitro anti-coagulant activity similar to those observed in anti-phospholipid syndrome, suggesting that they may have pro-coagulant effects in polyp tissue.

Rossi CM et al. Adult anaphylaxis: A state-of-the-art review. Eur J Intern Med 2022, March 8 , in press.
Anaphylaxis is the most severe among acute allergic diseases and potentially life threatening. Despite its increasing frequency and related burden, it remains often underdiagnosed and improperly managed. Its multisystemic involvement, protean clinical manifestations and its rapid onset are contributory factors. In recent years new acquisitions have shed light into its pathogenesis pathways (and related biomarkers), triggers, factors increasing its severity, along with peculiar clinical manifestations. These breakthrough discoveries have contributed to phenotyping and endotyping this disease, possibly paving the way to a personalized approach which is not available at present. Moreover, to disseminate awareness and standardize diagnostic criteria and management practices, several guidelines and consensus reports, albeit mainly intended for specialist care, have been issued. We here discuss the latest issues in the field of anaphylaxis from the perspective of the emergency and/or internal medicine physician, so to improve its early recognition and treatment in the acute setting and favor allergology referral to implement therapeutical and preventive strategies, such as allergen identification in unclear cases and desensitizing t