Immune responses and pathogenesis of COVID-19
The immunological pathogenicity of COVID-19 is complex and may be associated with the virulence of SARS-CoV-2 and the lack of the temporal coordination between innate and adaptive immune responsces126-128. Other mechanisms such as pre-existing immunity to SARS-CoV-2, super-antigens and autoimmunity have been also suggested to participate in the immune responses to this virus129. Adaptive responses to SARS-CoV-2 develop mainly to the spike protein. It is postulated that SARS-CoV-2 RNA is sensed by toll-like receptor (TLR)-3/7/8 and activates innate immune pathways130,131. SARS-CoV-2 replication induced a delayed type I IFN response in lung epithelial cells, which is regulated by melanoma differentiation-associated gene 5 (MDA5)132. Activation of NLRP3 inflammasomes participates in the pathophysiology of COVID-19 and is associated with the severity of this disease133. Type I IFN-mediated antiviral responses and activation of both CD4+Th1 and CD8+ cytotoxic T lymphocytes result in viral clearance in SARS-CoV-2-infected subjects with mild symptoms134. Impairment in the number and function of dendritic cells may also lead to dysregulation in innate and adaptive immunity including antiviral response129,135. The insufficient antiviral response136, or autoantibodies against type I IFNs137,138, combined with the system inflammation induced by a large number of immune cells and resident tissue cells, may contribute to the cytokine storm in severe disease131.
Virus-specific IgM and IgA can be detected in the acute phase followed by an increase in virus-specific IgG at a later stage of COVID-19129. More severe COVID-19 patients were associated with higher anti-RBD IgA and IgG antibody responses when compared to those not hospitalized or asymptomatic. No deaths were reported in patients with higher a IgG antibody index (NT50/IgG> 100)139. Dupilumab (anti-IL-4/13 Rα) used in atopic dermatitis (AD) patients with COVID-19 was associated with a lower IgG antibodies response140. Poor and delayed anti-SARS-CoV-2 IgM and IgG antibodies responses correlated with poor outcomes of COVID-19 in children141. A visible antibody cross-reactivity was reported to infectious bronchitis virus, a non-SARS-CoV infection and chicken aerosol vaccines particularly in highly exposed veterinarians who administered the vaccines. However, this immune cross-reactivity did not show a viral neutralizing activity and focused on non-RBD antibodies, which substantially differ between SARS-CoV-2 and non-SARS-CoVs142. Activated inflammatory caspases can induce pyroptosis which may partly contribute to lymphopenia in COVID-19, and the caspases inhibitors have been suggested to be potential therapeutics for severe and long COVID-19143.
Mild COVID-19 patients exhibited SARS-CoV-2-specific memory B and T cells responses that display hallmarks of antiviral immunity144. The antigen-driven activation of anti-SARS-CoV-2 memory B cells persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection145. Long COVID-19 patients were characterized with over-activated innate immune cells, lacked naive T and B cells and showed persistent elevated expression of IFN-β and IFN-λ1 at 8 months after infection146. Mast cell activation may also contribute to long-term COVID-19 as evidenced by persistent mediators release147. Diverse autoantibody responses were identified in COVID-19 patients and were correlated with disease severity and duration of hospitalization 138. Preexisting and de novo autoantibodies were more frequently detected in hospitalized or severe COVID-19 patients and may play a role in post-acute sequelae of COVID-19148. Dysregulated respiratory CD8+ T cell responses were associated with impaired lung function after acute COVID-19149. In summary, poor viral clearance, persistent inflammation and autoimmunity were proposed as the major mechanisms contributing to long COVID-19125,131,150,151 (Figure 2).
MANAGEMENT of allergic diseases during THE COVID-19 pandemic
The COVID-19 pandemic has SHAPED the ways medical services are conducted in order to accommodate for the imposed lockdown and social distancing measures. Accordingly, telemedicine was adopted by many physicians to guide the treatment and follow-up of allergic patients152.
Continuation of intranasal corticosteroids (INCS) was suggested for AR patients with COVID-19 at the recommended doses153. Treatment with INCS before SARS-CoV-2 infection was associated with a lower risk of COVID-19-related hospitalization, ICU admission or death154. A systematic review assessed the use of INCS on the olfactory dysfunction of COVID-19 patients, but only identified a single study to include in the review155. The impact of INCS on the susceptibility and outcomes of COVID-19 is still inconclusive51. Oral corticosteroids, biologicals and surgical treatment should be avoided or suspended in CRS patients with SARS-CoV-2 infection51. Telemedicine was advocated to replace in-person visits for the care of CRS patients during the COVID-19 pandemic with high patient satisfaction156.
Inhaled or oral corticosteroids should be continued to for asthmatic patients without SARS-CoV-2 infection to maintain asthma control, and oral corticosteroids and biologicals should be continued to treat severe asthma exacerbations157. In the case of asthmatic patients with confirmed SARS-CoV-2 infection, the use of inhalers should be indicated over nebulizers for the delivery of aerosolized medications to avoid viral transmission via aerosol158. Current evidence suggests that treatment with biologicals targeting type 2 inflammation does not increase the risk of SARS-CoV-2 infection and COVID-19 severity159 and may have beneficial effects115. Therefore, biologicals may be continued during COVID-19 for asthmatic patients without SARS-CoV-2 infection.
AIT should be temporarily discontinued until recovery for SARS-CoV-2 positive asthmatic patients or in contact with confirmed cases of COVID-19160. AIT can be continued in SARS-CoV-2 negative confirmed patients but with a prolonged injection interval160. Switching from subcutaneous to sublingual immunotherapy may be considered for AIT during COVID-19161. Skin manifestations of COVID-19 may be similar to other viral infections and drug hypersensitivity reactions (DHRs)162,163. The diagnosis and management of DHRs induced by medications repurposed and off-label for the treatment of COVID-19 have been discussed in a few review papers162-164.
Pulmonary function tests such as spirometry should be restricted to those patients with high clinical priority and using a high-efficiency inline filter. The patients should be encouraged to perform peak expiratory flow measurement at home to reduce the possible transmission via small droplets and aerosol generated during the pulmonary function test165,166.
Many studies have focused on the impact of the COVID-19 pandemic on the status and control of allergic diseases. In asthmatic children, environmental changes, altered medical practice and medication use, changes in transportation and travel patterns, school attendance and physical activity impacted asthma control during the pandemic167. A survey revealed that the majority of the AD patients experienced AD flares with mild worsening of the disease during the COVID-19 pandemic168. Dupilumab seems to be safe and crucial for a better outcome of COVID-19 and should be continued in AD patients during the COVID-19 pandemic169. During COVID-19, AIT was initiated and continued by most physicians in patients without indications of SARS-CoV-2 infection170. In contrast, lockdown during COVID-19 resulted in decreased numbers of patients initiating AIT but without significant impact on sublingual immunotherapy171.
COVID-19 was reported to increase the incidence of acute urticaria172 and disease activity of chronic urticaria in males but not females, which may be associated with loss of omalizumab efficacy173. Single-cell sequencing and proteomic analysis revealed that the cytokine storm associated with severe COVID-19 may promote the activation of monocytes/macrophages and cytotoxic CD8+ T cells, which may be involved in the development of maculopapular drug rash associated with COVID-19174.
COVID-19 vaccines
Natural SARS-CoV-2 infection does not establish a strong antibody response that can prevent reinfection175. COVID-19 vaccines offer promising protective immunity against SARS-CoV-2 infection. Two groups of vaccines are available for the global vaccination strategy of COVID-19. The classic group includes subunit, inactivated, live-attenuated and virus-like particle vaccines; novel approaches include RNA-based vaccines which deliver RNA coding target viral proteins into human cells176. Two mRNA -based vaccines, BNT162b2 and Moderna mRNA vaccines were approved with emergency use or conditioned marked authorization by the USA, European Union and other countries’ governmental agencies. Phase III clinical trials and real-world data suggested that COVID-19 vaccines have dramatically reduced severe COVID-19 cases177 and excess mortality due to COVID-19 (Figure 3), although breakthrough infection in fully vaccinated individuals is not uncommon178.