Advances in clinical outcomes: What we have learned during the COVID-19 pandemic.

Our understanding of risk factors and interventions influencing outcomes from coronavirus disease 2019 (COVID-19) has continued to evolve, revealing advances emerging from hypotheses formed at the start of the pandemic. Epidemiologic studies have shown that asthma control, rather than a diagnosis of asthma, is a determinant of COVID-19 severity. Clinical outcomes in patients with primary immunodeficiencies, even in those with impaired cellular immunity, are variable. IL-6 has emerged as a reliable biomarker of COVID-19 severity, and large clinical trials have shown the potential for improving outcomes through inhibition of IL-6 signaling in some patients. Studies of genetic risk factors for severe COVID-19 have also revealed the importance of interferon homeostasis in the defense against severe acute respiratory syndrome coronavirus 2. Because COVID-19 vaccines constitute the primary tool for ending this pandemic, strategies have been developed to address potential allergic and immune-mediated reactions. Here, we discuss advances in our understanding of COVID-19 risk factors and outcomes within the context of allergic and immunologic mechanisms.

The relationship between human coronaviruses, asthma and allergy-An unresolved dilemma.

Human coronaviruses (HCoVs) such as HCoV-229E or OC43 are responsible for mild upper airway infections, whereas highly pathogenic HCoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, often evoke acute, heavy pneumonias. They tend to induce immune responses based on interferon and host inflammatory cytokine production and promotion of T1 immune profile. Less is known about their effect on T2-type immunity. Unlike human rhinoviruses (HRV) and Respiratory Syncytial Virus (RSV), HCoVs are not considered as a dominant risk factor of severe exacerbations of asthma, mostly T2-type chronic inflammatory disease. The relationship between coronaviruses and T2-type immunity, especially in asthma and allergy, is not well understood. This review aims to summarize currently available knowledge about the relationship of HCoVs, including novel SARS-CoV-2, with asthma and allergic inflammation.

Can Measurements of Inflammatory Biomarkers be Used to Spot Respiratory Viral Infections?

Accurate detection of human respiratory viral infections is highly topical. We investigated how strongly inflammatory biomarkers (FeNO, eosinophils, neutrophils, and cytokines in nasal lavage fluid) and lung function parameters change upon rhinovirus 16 infection, in order to explore their potential use for infection detection. To this end, within a longitudinal cohort study, healthy and mildly asthmatic volunteers were experimentally inoculated with rhinovirus 16, and time series of these parameters/biomarkers were systematically recorded and compared between the pre- and post-infection phases of the study, which lasted two months and one month, respectively. We found that the parameters'/biomarkers' ability to discriminate between the infected and the uninfected state varied over the observation time period. Consistently over time, the concentration of cytokines, in nasal lavage fluid, showed moderate to very good discrimination performance, thereby qualifying for disease progression monitoring, whereas lung function and FeNO, while quickly and non-invasively measurable using cheap portable devices (e.g., at airports), performed poorly.

Comparative Study of SARS-CoV-2, SARS-CoV-1, MERS-CoV, HCoV-229E and Influenza Host Gene Expression in Asthma: Importance of Sex, Disease Severity, and Epithelial Heterogeneity.

Epithelial characteristics underlying the differential susceptibility of chronic asthma to SARS-CoV-2 (COVID-19) and other viral infections are currently unclear. By revisiting transcriptomic data from patients with Th2 low versus Th2 high asthma, as well as mild, moderate, and severe asthmatics, we characterized the changes in expression of human coronavirus and influenza viral entry genes relative to sex, airway location, and disease endotype. We found sexual dimorphism in the expression of SARS-CoV-2-related genes ACE2, TMPRSS2, TMPRSS4, and SLC6A19. ACE2 receptor downregulation occurred specifically in females in Th2 high asthma, while proteases broadly assisting coronavirus and influenza viral entry, TMPRSS2, and TMPRSS4, were highly upregulated in both sexes. Overall, changes in SARS-CoV-2-related gene expression were specific to the Th2 high molecular endotype of asthma and different by asthma severity and airway location. The downregulation of ACE2 (COVID-19, SARS) and ANPEP (HCoV-229E) viral receptors wascorrelated with loss of club and ciliated cells in Th2 high asthma. Meanwhile, the increase in DPP4 (MERS-CoV), ST3GAL4, and ST6GAL1 (influenza) was associated with increased goblet and basal activated cells. Overall, this study elucidates sex, airway location, disease endotype, and changes in epithelial heterogeneity as potential factors underlying asthmatic susceptibility, or lack thereof, to SARS-CoV-2.

Is asthma a risk factor for coronavirus disease-2019 worse outcomes? The answer is no, but .

PURPOSE OF REVIEW: To search for evidence on whether having asthma increases the risk of poor outcomes of COVID-19 and report on recommendations on optimal asthma management in times of COVID-19. RECENT FINDINGS: Patients with asthma are neither at greater risk of becoming infected by SARS-CoV-2 nor they are at risk of complications of COVID-19 but those requiring frequent use of oral corticosteroid may be at greater risk. SUMMARY: In general, patients with asthma are not at risk of COVID-19 morbidity or mortality. On the contrary, patients with asthma may be at lower risk of hospitalizations during the COVID-19 pandemic. This may be related to asthma and its treatment, to patient's behavior, to the health system, and to collective changes in activities. It is likely that reduction in respiratory infections because of social distancing, face masks, and hand washing have a role in the reduction in asthma hospitalizations. Management of asthma in times of COVID-19 must be optimized, medication have to be used regularly and exacerbations detected early. Systemic corticosteroids may be used for control of severe asthma or severe exacerbations. Patient education on an action plan is crucial, as well as facilitating communications with the healthcare team.

Inhaled corticosteroids may have a protective effect against coronavirus infection.

BACKGROUND: Spain has been severely affected by the COVID-19 epidemic, with 195,944 persons infected and 20,453 deaths at the time of writing. Older people with respiratory or cardiac conditions are most at risk. OBJECTIVE: The aim was to compare respiratory symptoms in nursing home residents and patients with uncontrolled asthma, who are considered vulnerable to COVID-19. METHODS: We studied 134 nursing home residents and 139 patients with uncontrolled asthma, groups vulnerable to COVID-19. Demographic characteristics, clinical manifestations, outcomes, key laboratory results, and radiological images were collected from medical records. COVID-19 infection was detected by polymerase chain reaction (PCR). RESULTS: Thirteen (9.3%) patients with uncontrolled asthma, all receiving inhaled corticosteroids were infected by COVID-19. Eighty (60%) nursing home residents were infected; only 28, all of whom had received inhaled corticosteroids, had a good prognosis. CONCLUSIONS: Early treatment with inhaled corticosteroids may be helpful in COVID-19 infection. Persons with an allergy might have some protective mechanisms against coronavirus.

A review on the effect of COVID-19 in type 2 asthma and its management.

BACKGROUND: COVID-19 is considered the most critical health pandemic of 21st century. Due to extremely high transmission rate, people are more susceptible to viral infection. COVID-19 patients having chronic type-2 asthma prevails a major risk as it may aggravate the disease and morbidities. OBJECTIVE: The present review mainly focuses on correlating the influence of COVID-19 in type-2 asthmatic patients. Besides, it delineates the treatment measures and drugs that can be used to manage mild, moderate, and severe symptoms of COVID-19 in asthmatic patients, thus preventing any exacerbation. METHODS: An in-depth research was carried out from different peer-reviewed articles till September 2020 from several renowned databases like PubMed, Frontier, MEDLINE, and related websites like WHO, CDC, MOHFW, and the information was analysed and written in a simplified manner. RESULTS: The progressive results were quite conflicting as severe cases of COVID-19 shows an increase in the level of several cytokines that can augment inflammation to the bronchial tracts, worsening the asthma attacks. Contradicting to this, certain findings reveal the decrease in the severity of COVID-19 due to the elevation of T-cells in type-2 asthmatic patients, as prominent reduction of T-cell is seen in most of the COVID-19 positive patients. This helps to counteract the balance of immune responses and hence ameliorate the disease progression. CONCLUSION: Asthmatic patients must remain cautious during the COVID-19 pandemic by maintaining all the precautions to stay safe due to limited research data. Future strategies should include a better understanding of asthmatic exacerbation and its relation to COVID-19.

Asthma in a large COVID-19 cohort: Prevalence, features, and determinants of COVID-19 disease severity.

BACKGROUND: Asthma prevalence among COVID-19 patients seems to be surprisingly low. However the clinical profile of COVID-19 asthmatic patients and potential determinants of higher susceptibility/worse outcome have been scarcely investigated. We aimed to describe the prevalence and features of asthmatic patients hospitalized for COVID-19 and to explore the association between their clinical asthma profile and COVID-19 severity. METHODS: Medical records of patients admitted to COVID-Units of six Italian cities major hospitals were reviewed. Demographic and clinical data were analyzed and compared according to the COVID-19 outcome (death/need for ventilation vs discharge at home without requiring invasive procedures). RESULTS: Within the COVID-Units population (n = 2000) asthma prevalence was 2.1%. Among the asthmatics the mean age was 61.1 years and 60% were females. Around half of patients were atopic, blood eosinophilia was normal in most of patients. An asthma exacerbation in the 6 months before the Covid-Unit admittance was reported by 18% of patients. 24% suffered from GINA step 4-5 asthma, and 5% were under biologic treatment. 31% of patients were not on regular treatment and a negligible use of oral steroid was recorded. Within the worse outcome group, a prevalence of males was detected (64 vs 29%, p = 0.026); they suffered from more severe asthma (43 vs 14%, p = 0.040) and were more frequently current or former smokers (62 vs 25%, p = 0.038). CONCLUSIONS: Our report, the first including a large COVID-19 hospitalized Italian population, confirms the low prevalence of asthma. On the other side patients with GINA 4/5 asthma, and those not adequately treated, should be considered at higher risk.

COVID-19 Susceptibility in Bronchial Asthma.

BACKGROUND: Bronchial asthma has not been adequately assessed in coronavirus disease 2019 (COVID-19). Respiratory allergy is associated with significant reductions in the expression of angiotensin-converting enzyme 2 receptor, which is the entry receptor for COVID-19. OBJECTIVE: To observe COVID-19 susceptibility in patients with bronchial asthma, analyze the prevalence of asthma in a large cohort of consecutive outpatient subjects who were tested with the RT-PCR assay for COVID-19. METHODS: This was a retrospective population-based cross-sectional study using data from a large nationwide health maintenance organization in Israel. All health maintenance organization enrollees who had been tested for COVID-19 from February to June 2020 were included. Differences in demographic and clinical characteristics between the subjects with negative and positive COVID-19 RT-PCR test results and between COVID-19 RT-PCR-positive subjects with and without asthma were analyzed. RESULTS: A total of 37,469 subjects were tested for COVID-19 RT-PCR, and results for 2,266 (6.05%) of them were positive. A significantly higher proportion of smokers was observed in the COVID-19-negative group than in the COVID-19-positive group (4734 [13.45%] vs 103 [4.55%]; P < .001). Asthma was found in 153 (6.75 %) subjects of the COVID-19-positive group and in 3388 (9.62%) subjects of the COVID-19-negative group (P < .001). No significant impact of antileukotrienes, inhaled corticosteroids, and long-acting beta-blockers use was revealed on COVID-19 positivity proportions. Multiple logistic regression analysis adjusted for sex, age, smoking, and comorbidity revealed a negative association of asthma with the likelihood of being positive for COVID-19 (odds ratio, 0.71; 95% CI, 0.58-0.87; P = .001). CONCLUSIONS: We observed lower COVID-19 susceptibility in patients with preexisting asthma.

Rhinovirus and asthma: Challenges and opportunities.

Human rhinoviruses (RVs) are the primary aetiological agent of the common cold. Generally, the associated infection is mild and self-limiting, but may also be associated with bronchiolitis in infants, pneumonia in the immunocompromised and exacerbation in patients with pulmonary conditions such as asthma or chronic obstructive pulmonary disease. Viral infection accounts for as many as two thirds of asthma exacerbations in children and more than half in adults. Allergy and asthma are major risk factors for more frequent and severe RV-related illnesses. The prevalence of RV-induced wheezing will likely continue to increase given that asthma affects a significant proportion of the population, with allergic asthma accounting for the majority. Several new respiratory viruses and their subgroups have been discovered, with various degrees of relevance. This review will focus on RV infection in the context of the epidemiologic evidence, genetic variability, pathobiology, clinical studies in the context of asthma, differences with other viruses including COVID-19 and current treatment interventions.

Asthma and severe acute respiratory syndrome coronavirus 2019: current evidence and knowledge gaps.

PURPOSE OF REVIEW: Although respiratory viruses are common triggers of asthma exacerbation, it is unknown whether this also applies to infection with SARS-CoV-2. Indeed, patients with asthma and allergy appear underrepresented in large reports of COVID-19 cases worldwide. In this review, we evaluate existing literature on this topic and potential underlying mechanisms for any interrelationship between asthma and COVID-19. RECENT FINDINGS: Data from several preclinical and clinical reports suggest a lower susceptibility for COVID-19 in patients with underlying type 2 airway inflammation including asthma that may be related to a reduced expression of ACE2 and TMPRSS2 receptors for SARS-CoV-2. Corticosteroids further decrease expression of the ACE2 and TMPRSS2 receptors, hence may also have a protective effect against infection with SARS-CoV-2. In addition, some studies suggest that the reported improvement in asthma control and a reduction in asthma exacerbations during the COVID-19 pandemic may be related to improvement in adherence to controller therapy and reduced exposure to triggers, such as other respiratory viruses and air pollutants. Recent data point towards differential susceptibility for COVID-19 among asthma patients based on their phenotype and/or endotype. On the basis of existing evidence, continuation with controller therapies is recommended for all patients with asthma. For patients with severe uncontrolled asthma infected by SARS-CoV-2, adjustment of controllers and biologics should be based on a multidisciplinary decision. SUMMARY: Underrepresentation of SARS-CoV-2-infected patients with asthma and related allergic diseases may be based on potentially protective underlying mechanisms, such as type 2 airway inflammation, downregulation of ACE2/TMPRSS2 receptors, reduced exposures to triggers and improved adherence to controller medications. Although it is imperative that control should be maintained and asthma medications be continued in all patients, management of patients with severe uncontrolled asthma infected by SARS-CoV-2 including adjustment of controllers and biologics should be discussed on an individual basis.

Rhinovirus Type in Severe Bronchiolitis and the Development of Asthma.

BACKGROUND: Respiratory syncytial virus (RSV)- and rhinovirus (RV)-induced bronchiolitis are associated with an increased risk of asthma, but more detailed information is needed on virus types. OBJECTIVE: To study whether RSV or RV types are differentially associated with the future use of asthma control medication. METHODS: Over 2 consecutive winter seasons (2008-2010), we enrolled 408 children hospitalized for bronchiolitis at age less than 24 months into a prospective, 3-center, 4-year follow-up study in Finland. Virus detection was performed by real-time reverse transcription PCR from nasal wash samples. Four years later, we examined current use of asthma control medication. RESULTS: A total of 349 (86%) children completed the 4-year follow-up. At study entry, the median age was 7.5 months, and 42% had RSV, 29% RV, 2% both RSV and RV, and 27% non-RSV/-RV etiology. The children with RV-A (adjusted hazard ratio, 2.3; P = .01), RV-C (adjusted hazard ratio, 3.5; P < .001), and non-RSV/-RV (adjusted hazard ratio, 2.0; P = .004) bronchiolitis started the asthma control medication earlier than did children with RSV bronchiolitis. Four years later, 27% of patients used asthma control medication; both RV-A (adjusted odds ratio, 3.0; P = .03) and RV-C (adjusted odds ratio, 3.7; P < .001) etiology were associated with the current use of asthma medication. The highest risk was found among patients with RV-C, atopic dermatitis, and fever (adjusted odds ratio, 5.0; P = .03). CONCLUSIONS: Severe bronchiolitis caused by RV-A and RV-C was associated with earlier initiation and prolonged use of asthma control medication. The risk was especially high when bronchiolitis was associated with RV-C, atopic dermatitis, and fever.

Expression of SARS-CoV-2 entry receptors in the respiratory tract of healthy individuals, smokers and asthmatics.

SARS-CoV-2 is causing a pandemic with currently > 29 million confirmed cases and > 900,000 deaths worldwide. The locations and mechanisms of virus entry into the human respiratory tract are incompletely characterized. We analyzed publicly available RNA microarray datasets for SARS-CoV-2 entry receptors and cofactors ACE2, TMPRSS2, BSG (CD147) and FURIN. We found that ACE2 and TMPRSS2 are upregulated in the airways of smokers. In asthmatics, ACE2 tended to be downregulated in nasal epithelium, and TMPRSS2 was upregulated in the bronchi. Furthermore, respiratory epithelia were negative for ACE-2 and TMPRSS2 protein expression while positive for BSG and furin, suggesting a possible alternative entry route for SARS-CoV-2.