Challenges in asthma management during COVID-19 pandemics
The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing Coronavirus Disease 2019 (COVID-19) pandemics led to the worldwide emergency affecting the life of more than 21 million people (status for 14.08.2020). It also raised a vigorous discussion in the research community, whether or not asthma should be classified as a COVID-19 risk factor. Reports regarding asthma prevalence among COVID-19 patients are inconsistent, varying from 0.9% in Wuhan to 17% in the US. 185 Wang et al. exclude asthma as a factor influencing COVID-19. Their statement is supported by the data from Avdeev et al. and Zhang et al. 186,187 Both groups did not observe the increase in the prevalence of bronchial asthma or COPD among patients with COVID-19. 186,187 Additionally, experts from 43 countries around the world in ARIA-EAACI statement185, as well as a recent publication from Carli et al.188 rule out asthma as a risk factor for COVID-19, while another group advocates asthma as a COVID-19 risk factor based on the impaired antiviral responses that may predispose asthmatic patients to severe COVID-19 manifestations. 189 Indeed, the United Kingdom reported increased asthma-related deaths in non-COVID-19 patients.190 The US Center for Disease Control and Prevention proposed that moderate to severe asthma should be considered a risk for severe COVID-19 manifestations.185Additionally, a recent study from Zhu et al. (n=492 768) demonstrated inflammatory phenotype of underlying asthma as a crucial factor for COVID-19 risk assessment. They showed, that nonallergic, but not allergic asthma predisposes patients to COVID-19. Due to the reported discrepancies, available data should be interpreted with caution.191
Data are still unclear as the COVID-19 population included in the studies is skewed towards older and hospitalized patients with predisposing comorbidities (such as hypertension, obesity, or diabetes) which are strong confounders.185,186 As gender, smoking status, ethnicity, lifestyle and genetic background can influence COVID-19 outcomes, these factors should be carefully investigated. 185,192 Age seems especially significant, as childhood and adolescent asthma does not seem to be a hazard for COVID-19. 192 This may be related to reduced prevalence of comorbidities, lack of smoking, or boosted immune system due to recent vaccinations.192
Allergic responses accompanying asthma are hypothesized to play a protective role in the course of COVID-19. Eosinopenia (decreased frequencies of eosinophils in the blood) is a biomarker of severity and poor prognosis for COVID-19 patients.192 Eosinophils respond to viral infections by releasing cytotoxic proteins, reactive oxygen species, and type 1 cytokines.192 Therefore, they play a supportive role in fighting the infection. Allergic patients present eosinophilia (increased frequencies of eosinophils in the blood) and could have an advantage for the eosinophil-dependent antiviral responses.192 Notably, in the cohort from Licari et al. allergic children had significantly higher frequencies of eosinophils in the blood, when compared to COVID-19 pediatric patients.192
Receptor ACE2 and serine protease TMPRSS2 mediates SARS-CoV-2 entry into host cells.193-195 CD147, CD26, ANPEP, ENPEP, or DC-SIGN are other receptors, proven or potentially involved in COVID-19 pathogenesis.193 Radzikowska, Ding et al. demonstrated that ACE2 and TMPRSS2 are expressed only in the epithelial tissues, whereas CD147 and its interaction partners are present in both – epithelial tissues and immune cells. 196 The expression of several SARS-CoV-2 receptors seems to be different in asthma patients (increased: TMPRSS2 , CD44 , ITGA6 ,NFATC2 , NME1 , APOD ; decreased: ACE2 ,ACE , MCT4 , APH1A , S100A9 , NOD2 ). These finding were partially confirmed by others.185,197 There is growing evidence that allergic type 2 inflammation (mainly IL-13) decreases ACE2 and increase TMPRSS2 expression.185,197 Additionally, ACE2 is an interferon-induced gene.197 Impaired/delayed interferon responses observed in asthma patients, usually a foe, may play a protective role during SARS-CoV-2 infection and result in a subsequent decrease of an ACE2. 197 Carli et al. suggested that the altered interferon responses and the type 2 immunity signature in asthmatic patients downregulates the late phase hyper inflammation and consequently decrease tissue damage in the lungs which might be beneficial in allergic asthma during COVID-19.188
Asthma management in the times of COVID-19 pandemics presented a challenge due to the overlap of the respiratory symptoms induced by asthma or by SARS-CoV-2 and by reduced face-to-face appointments and risky pulmonary function testing generating aerosols (Figure 4).185,190,198-202 If possible, a video examination and attentive observation of the patient may help in proper diagnosis.190,203 Fever, persistent dry cough, flu-like symptoms, and lack of wheeze can indicate COVID-19 over asthma exacerbation.190 Severe asthma exacerbation leads to the hospitalization, which exposes asthmatics to unnecessary risk of being infected with SARS-CoV-2. 192 Steroid therapy in asthmatic patients in times of COVID-19 pandemics should be continued as clinically indicated.186,189,190,197,200 Additionally, ICS use can be beneficial during COVID-19 as it restores the impaired antiviral responses in asthma, subsequently leading to less severe manifestations.189 ICS suppresses coronavirus replication and decreases the ACE2/TMPRSS2 expression.197 However, ICS treatment can cause SARS-CoV-2 nebulization and its spread to the lower airways and surrounding surfaces.192 Therefore the use of a spacer is encouraged.192 On the other hand, the use of OCS was linked with a risk of severe COVID-19 manifestations (including death).185 If good asthma control in patients cannot be maintained, the introduction of azithromycin prophylaxis can be considered. 189 Azithromycin reduces asthma exacerbations in patients, probably by augmenting IFN-β and IFN-λ responses, a subsequent decrease in viral replication, and reduced inflammatory response. 189,197 Azithromycin interferes with the CD147 receptor and decrease its downstream signals after viral (rhinovirus) infections.197 COVID-19 in high endemic HDM environment may affect antiviral immune responses. In a study by Akbarshahi et al. the authors hypothesized that HDM may adversely affect viral stimulus-induced antiviral interferon response. To test the hypothesis, they investigated the effects of HDM exposure in both human bronchial epithelial cells and a mouse model of asthma exacerbation. They observed that toll-like receptor-3 is the main target involved in reducing the antiviral response by HDM.204
Lommatzsch et al. reported the safety of Omalizumab in an 52-year-old severe allergic asthmatic patient with SARS-CoV-2 infection.205 During the SARS-CoV-2 infection, the patient did not report any asthma exacerbation and maintained proper asthma control. A mild manifestation of COVID-19 observed in this study, was related to either i) allergic endotype of underlying asthma, ii) ongoing omalizumab treatment, or iii) both.205However, this observation needs further confirmation in the bigger patients’ population. Furthermore, Omalizumab decreases the duration of rhinovirus infections and virus-related exacerbations.189,197 It can be hypothesized that anti-IgE therapy protects also during SARS-CoV-2 infection. Experts suggest that immunomodulatory biological treatment strategies should continue in SARS-CoV-2-negative asthmatic individuals in times of pandemics.185,192,197 However, due to possible immunosuppressive effects, they should be suspended in patients which developed COVID-19, until disease resolution.185,192
In summary, available data suggest, asthma is not a risk factor for the development of severe forms of COVID-19. Yet, COVID-19 can be a severe disease in already damaged lungs of chronic asthma, particularly, ACOS and COPD patients. More evidence is needed to fully understand the impact of asthma and asthma therapies on the prevalence and the course of COVID-19. More data are required from controlled clinical trials. Meanwhile, considering the current emergency, asthmatic patients should avoid SARS-CoV-2 infection and should receive the SARS-CoV-2 vaccine with priority, as recommended for the influenza and the pneumococcal vaccine. In the present situation, prevention and proper asthma control, including continuation of the background controller treatment, is the most efficacious way to assure the safety of asthma patients.206