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.