Pathobiological bases of asthma-COVID-19 interaction: A theoretical viewpoint

Reduced angiotensin-converting enzyme 2 (ACE) expression in asthmatic airways

ACE2, a close homologue of ACE, is a transmembrane protein found on the surface of lung epithelial cells. It is also expressed on the cell surface by the kidney, heart, brain, and the intestines, respectively.^[19,20] The predominant expression of the enzyme in the airways is on the sinonasal epithelium and the type 2 pneumocyte of the lungs^[21,22] with the enzyme being much concentrated on the apical aspect of the type 2 pneumocyte.^[22] Primarily, the enzyme functions to generate the angiotensin 1–7 from angiotensin II.^[23] Angiotensin II is obtained from angiotensin I by the activity of ACE2.^[23] Angiotensin 1–7 lowers blood pressure and prevents the profibrotic and hypertrophic effects of angiotensin II.^[24]

Binding of the SARS-CoV-2 through the spike protein to the extra membranous domain of the ACE2 leads to the internalization of the virus particle through endocytosis.^[25,26] The enzyme serves as receptor to both SARS-CoV-1 and SARS-CoV-2 and is indispensable for infection of pneumocytes.^[4] Variability in the expression of the ACE2 receptor on respiratory epithelium across individuals and disease states has been reported.^[5,20] Asthma modifies the expression of the ACE2 receptor on the respiratory epithelium.^[14]

ACE2 is regulated in two ways in asthma, and the direction of the regulation depends largely on the asthma endotype. The endotypes include T helper cell type 2 (Th2)-mediated atopic eosinophilic asthma, T helper cell type 17 (Th17)-mediated neutrophilic asthma, paucigranulocytic asthma, and idiopathic eosinophilic asthma ^[27] [Figure 1]. The endotypes represent the pathobiological mechanisms of asthma disease and account for its heterogeneity.^[2] In Th2 high/eosinophilic asthma, the cytokines interleukin (IL)-4 and IL-13 secreted by the innate lymphoid cell type 2 and the Th2 cell downregulate ACE2 expression. Thus, the reduced expression may deprive SARS-CoV-2 of its needed receptor for infectivity.^[28,29] We suggest that IL-13 alters ACE2 expression by increasing the activity of ADAM-17 at the apical portion of the airway epithelial cells where the ACE2 is maximally expressed [Figure 2].^[30,31] ADAM-17 enhances the shedding of ACE2 from the surface of pneumocytes.^[32] IL-13 may also act by activating protein kinase C or extracellular signal regulated kinase; these two enzymes are known to activate ADAM-17 which cleaves ACE2 from cell surface.^[29] In contrast, in Th17 high/neutrophilic asthma, the cytokine IL-17 can upregulate the expression of ACE2.^[8] Coincidentally, the predominant asthma endotype is the Th2 atopic eosinophilic asthma^[28] and this may explain why the reduced incidence of COVID-19 among patients with asthma. Furthermore, the Th2 high/eosinophilic asthma endotype is associated with eosinophilia; and elevated peripheral blood eosinophil count is regarded as good prognostic marker of COVID-19.^[33,34] Furthermore, the expression of reduced affinity ACE2 has been reported to occur due to rhinoviruses infection.^[35] As highlighted previously, rhinoviruses are linked to asthma exacerbations. Rhinoviruses induce the expression of a short isoform of ACE2 which has reduced affinity to SARS-CoV-2 spike protein thus inhibiting the entry of SARS-CoV-2 into pneumocyte.^[35]

Close

Figure 1:

Proposed pathobiologic mechanisms of interaction between asthma and COVID-19.

Export to PPT

Close

Figure 2:

Proposed effects of interleukin-13 (IL-13) on angiotensin-converting enzyme 2 (ACE-2) expression on asthmatic airways. PKC: Protein kinase C, Erf: Extracellular signal regulated kinase, ADAM-17: A disintegrin metalloprotease member 17.

Export to PPT

Anti-inflammatory and antiviral effects of corticosteroids

Corticosteroids are used in the management of bronchial asthma.^[1] The drugs counteract the allergic inflammation seen in asthma by reducing vascular permeability and hence laryngeal edema^[36] minimizing the selective trafficking of leukocytes from the peripheral blood to the lungs by downregulating the expression of the cellular adhesion molecules selectin and integrins and interfering with the maturation and survival of polymorphonuclear leukocytes.^[37-39] The relevance of corticosteroids in viral infections is incompletely understood and the available information has been contradictory. Early intravenous corticosteroids use was reported to have association with higher viral load and slower clearance of SARS-CoV infection among humans.^[40-42] Inhaled corticosteroids use in asthma is associated with higher incidence of respiratory tract infections.^[14]

The use of corticosteroids in the management of COVID-19 has had mixed reactions [Table 2].^[43-48] In addition to the pharmacology of the various corticosteroids, differences in study design, variability in disease severity, choice, and interpretation of statistical methods among others could have contributed to the variations [Table 2]. Systemic corticosteroids are found to be effective in reversing hyperinflammatory acute respiratory syndrome seen in severe COVID-19.^[49] In the UK RECOVERY trial, it was found that systemic corticosteroids (6 mg dexamethasone for 10 days) in COVID-19 patients hospitalized with severe disease and needing oxygen or respiratory/ventilatory support had reduced mortality compared to those that did not get dexamethasone.^[50] Moreover, in vitro experiments have demonstrated that corticosteroids such as ciclesonide, algestone acetophenide, budesonide, and mometasone can inhibit the replication of the Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2, respectively.^[51,52] Ciclesonide was found to act by inhibiting the non-structural protein 15 of SARS-CoV-2.^[51] Conversely, however, systemic corticosteroids such as prednisone and prednisolone, used in the management of acute exacerbations of asthma, were found to have no effect on SARS-CoV-2 replication.^[51] Many studies have identified varying effects on the use of corticosteroids in the management of asthma patients with COVID-19.^{[9,44,47,48,53]} It is hypothesized that the anti-inflammatory and antiviral effects of inhaled corticosteroids are behind the reduced severity of COVID-19 among patients with asthma.^[10] It was, however, observed that the worsening of COVID-19 following corticosteroids administration usually occurs among patients with severe asthma.^[53]

The most notable manifestation of COVID-19 is acute respiratory distress syndrome (ARDS). ARDS occurs as an indicator of severe acute lung injury (ALI). ALI is mediated by local innate inflammatory mechanisms in the airways. Activation of resident pulmonary macrophages following pneumocyte injury by SARS-CoV-2 infection leads to release of innate inflammatory cytokines such as tumor necrosis factor-alpha (TNFα), interleukin 1, 6, and macrophage inflammatory protein-α.^[54] TNFα induces microvascular endothelial activation characterized by increased expression of chemotactic molecules and procoagulant proteins. This leads to exodus of leukocytes into the alveolar spaces and thrombosis.^[4] Interstitial mononuclear cell infiltration is also seen that the monomorphs may associate in consonance with polymorphs to orchestrate an immune complex mediated injury to the lung tissue characterized by complement system activation and hemostatic aberrations.^[4,55] The polymorphs degranulate to release proteolytic enzymes, reactive oxygen and nitrogen species, and cytokines. The activity of polymorphs causes further damage to the pneumocytes and the endothelium. The microvasculature becomes leaky, leading to intra-alveolar fluid accumulation.^[56] Damage to type 2 pneumocytes impedes surfactants production thus further compromising gaseous exchange and hence the fall in the percentage saturation of oxygen and the hypoxemia.^[56] It is assumed that inhaled corticosteroids significantly counteract this vicious cycle in asthmatics by transrepression of inflammatory genes and transactivation of anti-inflammatory genes in the airways of asthmatics. As stated above, corticosteroids downregulate the migration of inflammatory cells and the release of inflammatory cytokines. Corticosteroids are lipophilic as such; they are quickly transported across the lipid bilayer of biological membranes.^[57] On entry into the cell, corticosteroids (glucocorticoids [GCs]) are quickly bound to by a glucocorticoid receptor (GR) which is chaperoned to heat shock protein 90, 70, and other proteins. The formed complex dissociates from the chaperone proteins and is translocated into the nucleus assisted by import proteins α and 13.^[58] The complex as a homodimer binds to promoter sequences (glucocorticoid response elements [GREs]) of responsive genes through the DNA-binding domain of the GR. Subsequently, recruitment of additional transcriptional cofactors leads to chromatin remodeling, RNA polymerase II binding, and gene expression.^[59] In other situations, the GRE may induce repression of the glucocorticoid responsive genes. This is usually done by monomeric GC/GR, and it happens when the activity of other transcription factors such as nuclear factor-kappa beta and activation protein one is impeded by the GC/GR transcription factor through competition for binding space in the form of composite binding or tethering.^[60,61] Through the mechanisms mentioned above, corticosteroids downregulate the expression of the following mediators: Interleukin 1β, 6, 8, 11, TNFα, granulocyte monocyte colony-stimulating factor, monocyte chemotactic protein-1, eotaxins, migration inhibitory protein-1, and regulated on activation expressed and secreted.^[58] In these ways, inhaled corticosteroids counteract neutrophil and monocyte recruitment into airways, stabilize mast cells, and prevent the secretion of histamine and late phase lipid mediators by inhibiting phospholipase A2 through lipocortin induction.^[62] It also inhibits fibroblast proliferation and collagen deposition.^[62] Most of these processes and mediators are central to the pathogenesis of COVID-19 as stated above.^[54]

As previously mentioned, the inhaled corticosteroids ciclesonide inhibits SARS-CoV-2 replication by blocking non-structural protein 15. The non-structural protein 15 is one of the 16 proteins which form the replicase machinery of SARS-CoV-2. These proteins are part of a larger protein, polyprotein 1ab which is encoded by ORF1ab of SARS-CoV-2. Non-structural protein 15 is a viral RNA modification enzyme with uridylate-specific endoribonuclease activity.^[63] However, the antiviral target of mometasone is yet to be identified.^[51] Mometasone was found to inhibit the replication of coronaviruses that have developed resistant mutation to ciclesonide; thus suggesting that mometasone has a different target from ciclesonide.^[51] Furthermore, the targets of the other inhaled corticosteroids with antiviral activity are also not known.^[51] Mometasone and possibly other inhaled corticosteroids with antiviral activity may work by targeting cellular heat shock proteins 70 and 90. Heat shock proteins are indispensable in maintenance of protein stability and cellular homeostasis. They are extensively used as chaperones to both host cell proteins and viral proteins. They protect the proteins against unfavorable conditions caused by stressors and are found in all cellular compartments, including the endoplasmic reticulum which serves as niche for SARS-CoV-2 replication.^[63,64] Coronaviruses are found to utilize heat shock protein 90 for stabilization of nucleoprotein and protection against cellular proteasomes of the host.^[65] Inhibition of HSP 90 drastically reduces MERS-CoV and SARS-CoV-2 in cell cultures.^[65] Similarly, GC receptor utilizes heat shock proteins 70 and 90 as stabilizers in the cytosol. Thus, competition for the available heat shock proteins between viral and normal proteins including the GR is inevitable. It is found that cortisol induces the downregulation of heat shock protein 70 in fish.^[66] Whether corticosteroids can alter the expression of heat shock proteins in humans is however not adequately studied. It was observed that stable binding of HSP 90 to geldanamycin disrupts glucocorticoid receptor’s stability and hence its ability to bind GC,^[67] thus suggesting that a better competitor can make HSP 90 unavailable for even the physiological routines of the cell. Therefore, through such competition, GR may inhibit SARS-CoV-2 replication. The observation that ICS do not induce HSP 90 expression in the respiratory epithelium^[68] and that serum level of HSP 90 is not altered by prednisolone administration^[69] may further support this view. However, there are contrary observations on the effects of GC on HSPs expression. Dexamethasone was reported to induce the expression of heat shock protein 72 in human cardiac myocytes in vitro.^[70]

The effects of BRMs

BRMs are used in the management of asthma that is uncontrolled at medium to high doses of inhaled corticosteroids and long-acting beta-agonist.^[71] The commonly used BRMs are cytokine and cytokine receptor antagonists.^[72,73] Only a small fraction of patients with asthma is treated using these drugs, though the guidelines on their use are increasingly being modified. The success of the therapy depends on the correct match between the biologic response modifier and the asthma endotype.^[74-77] The drugs are currently used for the management of severe atopic and eosinophilic endotypes of asthma. It is proposed that these drugs modify the manifestation of COVID-19 among asthma patient [Table 3]. The most commonly used BRMs in the management of asthma are as follows: Omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab.

Omalizumab was approved in 2003 for the management of severe to moderate asthma as an add on therapy,^[74] urticarial, and other mast cell disorders. Several case reports on the possible role of omalizumab in reducing the severity of COVID-19 have been reported. Eksu et al., 2021,^[78] and Abduelmula et al., 2021,^[79] reported no hike in COVID-19 cases among patients with asthma and patients with chronic urticaria on omalizumab. Mepolizumab and reslizumab are anti-IL-5 drugs, they are used in the management of severe eosinophilic asthma.^[72] They bind to free IL-5 thus making it unavailable for binding to eosinophils through IL-5R [Table 3]. Benralizumab is an anti-IL-5Rα antagonist which prevents downstream signal transduction by the IL-5R receptor.^[72] IL-5 stimulates eosinopoiesis and promotes survival and recruitment of eosinophils to airways.^[73] Benralizumab was used in two patients, one elderly (66 years) who did not develop severe COVID-19.^[80] Eger et al., 2020,^[81] reported more cases of severe COVID-19 among asthma patients treated mepolizumab, reslizumab, and benralizumab compared to the general Dutch population. Of these, nine patients were infected and six of them were hospitalized due to COVID-19-associated respiratory symptoms. However, most of these patients have other comorbidities such as obesity and diabetes.