Upon entry into the host, the inhaled SARS-CoV-2 is likely to bind to epithelial cells in the nasal cavity and start replicating.11 Angiotensin-converting enzyme-2 (ACE2) is the primary receptor for both SARS-CoV-2 and SARS-CoV.11 The cellular protease TMPRSS2 also appears vital for SARS-CoV-2 cell entry.12 There is local propagation of the virus but a limited innate immune response.11 At this stage, the virus can be detected by nasal swabs and although the viral burden may be low, these individuals are infectious.11 The virus propagates and migrates down the respiratory tract along the conducting airways, and a more robust innate immune response is triggered.11 For about 80% of the infected patients, the disease will be mild and mostly restricted to the upper and conducting airway.13 This phase would be the result of the infection itself. Unfortunately, about 20% of the infected patients will progress and develop pulmonary infiltrates and some of these might develop very severe disease.13 The virus reaches the lung's gas exchange units and infects alveolar type II cells with high surface expression of ACE2 receptors. The virus rapidly disseminates through peripheral blood to other organs like the heart, kidney, liver, spleen, etc14,15 The cytokine storm generated damages the organs or may lead to ARDS or multiorgan failure in COVID-19.16-18 Human SARS-CoV-2 infection involves the innate immune response, T and B cell immunity and antiviral neutralizing antibodies.

The current severe asthma approach relies on disease phenotypes identification, but these do not necessarily relate to or give insights into the underlying pathogenetic mechanisms described by disease endotypes.19 Based on the major immune-inflammatory pathway involved, type2-high, type2-low and mixed endotypes are described for severe asthma.19

Mixed endotypes asthma / COVID-19

At the present moment, we could not find any information relating to mixed endotypes of severe asthma and COVID-19 and this is an area of particular research interest.

Fig. 1 is a summary of the main evidence about severe asthma endotypes and COVID-19 mechanisms:

Figure 1.

Summary of the main evidence about severe asthma endotypes and COVID-19 disease mechanisms. Legend: ACE2: angiotensin-converting enzyme 2 receptor; COVID-19: coronavirus disease 2019; IL: interleukin; NETs: neutrophil extracellular traps; Th1: T Helper 1 cell.

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The literature search yielded 56 records and after identifying and removing duplicates 35 articles remained. After screening for relevant titles/abstracts, 11 publications were considered to report original epidemiological data. Four of these publications were related to Severe Asthma Registries.

In the Belgian Severe Asthma Registry29 only 14 out of 676 patients (2.1%) had SARS-CoV-2 infection confirmed by a positive PCR or serology testing. These findings indicated a lower incidence than in the general population (5.1%). There was no statistically difference in COVID-19 incidence between patients treated or untreated with biologics. No deaths were attributed to COVID-19 on this cohort of severe asthma patients.

In the Severe Asthma Network in Italy (SANI)30, Heffler et al. reported an incidence of 26 confirmed or highly suspected infections out of 1504 patients (1.73%). The majority (n = 21) were under biologics: 15 on anti-IL-5 and six on anti-IgE. As previously described, due to the higher proportion of COVID-19 infections with anti-IL-5 treatments, the authors speculated about the role of these monoclonal antibodies (mAbs) in the COVID-19 course. It should be noted that this finding was not seen in the Belgian registry.29 In the Italian cohort, the related mortality was 7.7%, lower than in the general Italian population (14.5%).

In the Italian Registry of Severe Asthma (IRSA)31, a different Italian severe asthma registry, seven subjects out of 558 (1.25%) contracted COVID-19. The hospitalization rate in COVID‐19 infected patients with severe asthma was similar to the general population, and no deaths were reported. The proportion of COVID-19 in patients on biologics was 5.43% compared to 0% on subjects treated with ICS‐LABA alone, but no statistical difference was found.

Eger et al.32 found a frequency of nine out of 634 (1.4%) patients with COVID-19 among severe asthma patients on biologics in the Dutch Severe Asthma Registry RAPSODI. From these, five patients needed intensive care and one patient died. In the group of 73 patients not prescribed any biological, one (1.73%) was diagnosed with COVID-19. In this study, the proportion of COVID-19 related hospitalization, intubation, and death was 1.26% in the patients under biologics, which is a number 4.5 times higher than in the Dutch population within the same age category (0.28%). It must be considered that RAPSODI patients under biologics had a higher prevalence of obesity than the general population (30% versus 15%).

Rial J. et al.33 conducted a multicentre study in nine centres from the Spanish Severe Asthma Network. Among 545 adult severe asthma patients under biological treatment, 35 (6.4%) had COVID-19, a proportion similar to the Spanish seroprevalence (5.2%) at the time of the study. Eight patients were hospitalized and one patient died. No statistical differences were found between the frequency of COVID-19 in patients under anti-IgE (5.32%) compared to the subjects treated with anti-IL-5 (7.4%).

Table 1 presents a summary of the epidemiological data regarding COVID-19 in the European severe asthma registries and the Spanish Severe Asthma Network.

Caminati et al.34 reviewed the medical records of patients admitted to COVID-19 Units of six Italian cities (n = 2000). From the 42 asthmatic patients identified, patients on GINA 4/5 and those not adequately treated were considered at higher risk. Hauron-Diaz et al.35, in a sample of 80 severe asthma patients followed in the Allergy Service of Infanta Leonor University Hospital (Madrid, Spain), SARS-CoV-2 infection was confirmed in three (3.75%) patients. None of the patients required intensive care. Chibba et al.36 conducted a retrospective study that assessed the risk of hospitalization associated with asthma and/or inhaled corticosteroid use in patients with COVID-19. The proportion of asthmatic patients using ICS plus long-acting beta2-agonists admitted to an intensive care unit was higher (57.9%) than those using ICS alone. Kow et al.37 suggest that this finding may indicate that those with more severe disease have worse outcomes. According to the health analytics platform OpenSafely38 that covers 40% of all patients in England, severe asthma (defined as asthma with recent use of an oral corticosteroid) was associated with COVID-19 related death after adjusting for sex and age (hazard ratio: 1.13; 95%: 1.01–1.26).

Calmes D. et al.39 conducted a study to evaluate if obstructive diseases were risk factors for intensive care unit stay and death due to COVID-19. Twenty out of 57 (35%) asthmatic patients included were under a high dose of inhaled steroids, and 2 (3%) were taking oral steroids daily. In this study, inhaled and oral corticosteroid treatment were not identified as risk factors.

There are now five approved biologic agents for severe asthma: one anti-IgE – omalizumab, two anti-IL-5 - mepolizumab and reslizumab, one anti-IL-5 receptor alpha (Rα) – benralizumab - and the anti-IL-4Rα dupilumab.40

Omalizumab is a humanized monoclonal antibody that selectively binds to human IgE, preventing its high-affinity receptor.41 Regarding anti-IL-5/IL-5-R, their major effect is the reduction or depletion of tissue and peripheral blood eosinophils.41 Mepolizumab and reslizumab are humanized anti–IL-5 mAbs that bind circulating IL-5 with high affinity and prevent binding of IL-5 to its receptor.41 Benralizumab is a humanized afucosylated mAb that binds to the alpha subunit of the human IL-5Rα, specifically expressed on the surface of eosinophils and basophils.41 Dupilumab is a mAb that attaches to the alpha subunit of IL-4/13 receptors and promotes signaling after binding to the IL-4Rα subunit.41

MAbs targeting type-2 inflammation is likely to reduce the risk of COVID-19 mediated severe asthma exacerbations by reducing baseline airway inflammation and possibly through specific antiviral properties.20 Omalizumab, cross-linking IgE, would lead to lower type 1 IFN production.20 Mepolizumab, reslizumab and benralizumab, act by increasing the ratio of IFN-γ-to-IL-5 mRNA, which is associated with lower viral shedding and faster disease clearance.20 Finally, IL-4 is crucial for antibody switching to IgE, and IL-13 is a Th2 cytokine involved in airway hyperresponsiveness and remodeling; both of them are involved in susceptibility and clearance of viral infections affecting lower airways.20

Fig. 2 shows a summary of the potential main benefits of mAbs for severe asthma treatment in COVID-19:

Figure 2.

Summary of the potential main benefits of monoclonal antibodies for severe asthma treatment in COVID-19 Legend: AA: airways Ig: immunoglobulin; IFN: interferon; IL: interleukin; pDC: plasmacytoid dendritic cells.

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From another perspective, it is theoretically reasonable that mAbs targeting type-2 asthma inflammation can be associated with increased risk for COVID-19 (in terms of infection or severity). However, early reports did not show this clearly.42 Available data did not show consistently significant differences among patients treated with different mAbs in a large cohort study.42 Even though, contradictorily, in the Severe Asthma Network in Italy (SANI), patients treated with anti-IL-5 mAbs had a considerably higher proportion of SARS-CoV-2 (71%) compared to those treated with anti-IgE (29%)30 and this possible effect about increased disease severity in patients treated with biologics for type-2 inflammation has been further debated in another recent study32. Although the number of cases was too small to draw any definitive conclusions, the authors speculated that different mAbs could have specific and distinct impact on antiviral immune response, as suggested for anti-IgE as protective for other viral infections.30 Furthermore, the authors also proposed that the consequence of eosinopenia induced by anti-IL-5 agents might be a risk factor for more severe COVID-19. Currently, no large series of severe asthmatics treated with biologicals infected by COVID-19 have been published, so the ideas about the role of mAbs in modulating the risk of COVID-19 are speculations and need further evidence.30 Assuming the previously stated notion that eosinopenia associated with COVID-19 is likely to be a secondary phenomenon, this concern about biological drug-induced eosinopenia may not be relevant.25 Comprehensive and large-scale investigations are expected to elucidate further the interactions between COVID-19 and type-2 high severe asthma.

Treatment with omalizumab might protect from severe forms of COVID-1943. Omalizumab was shown to enhance antiviral immunity via downregulation of the high-affinity IgE receptor on plasmacytoid dendritic cells, essential for antiviral immune responses.43 Cases of omalizumab patients who contracted COVID-19 have been recorded, and no increased susceptibility to severe disease or asthma exacerbations was observed43,.44 The PROSE study showed that in severe asthmatics, omalizumab treatment decreases the duration of viral infections, viral shedding and the risk of respiratory viral illnesses.45 Another study indicated that omalizumab treatment augments plasmacytoid dendritic cells IFN-α responses and attenuates the FcεRIα protein expression induced by these cells, reducing the susceptibility to virus-induced asthma exacerbations.46 Besides, IL-33 levels decrease after omalizumab treatment47,48 and this interleukin is important for the production of pro-inflammatory cytokines (including IL-6, IL-1β, TNF-α, MCP-1, and prostaglandin D2).49 All this data suggests a potential effect of omalizumab on antiviral responses.8 It would be interesting to explore whether previous or concurrent use of omalizumab might have protective effects on COVID-19 infection, either on duration, severity or both.8

In those on mepolizumab therapy, a very recent publication reports the outcomes of four severe asthmatic patients with COVID-19 while receiving treatment with mepolizumab, from different centres (UK, Italy and North America).50 Only one patient (who had recognized risk factors for admission and death from COVID-19) required hospitalization and ventilatory support but recovered without evidence of long-term respiratory consequences.50 Four published case reports describe six patients contracting SARS-CoV-2 while receiving benralizumab treatment for severe eosinophilic asthma. The range of symptoms experienced by each patient varied, but all of them recovered.51-53 These reports add to the debate about whether patients with eosinophil targeting therapies might have an unaltered outcome in COVID-19. As previously mentioned, evidence of severe asthma registries still poses this into question.32 Considering the reported evidence, it is clear that more data is needed. Until then, and for the moment, in severe eosinophilic asthma the expert recommendations are to continue biologic therapy unchanged.54

Case reports of severe asthma patients under dupilumab show no association with negative impact in COVID-19.55,56 However, as previously mentioned, dupilumab will block IL-4, which is fundamental for the differentiation of Th2 by IL-6 and this might shift the balance Th1/Th2 towards Th1 and facilitate INFγ production.57 The differentiation of Th2 by IL-6 is dependent on endogenous production of IL-4 whose activity is significantly reduced by dupilumab.57 This mechanism plays a central role in the “cytokine storm” damaging lung in COVID-19 patients57 but the clinical consequences are still a matter of debate32,56 On the other hand, due to the mechanism of action of dupilumab, drug discontinuation could be associated with higher susceptibility toward infections, even if there is no evidence supporting this hypothesis regarding SARS-CoV-2.57 Considering available evidence at the moment, treatment with dupilumab should not be stopped during the COVID-19 pandemic.

Globally, in the era of COVID-19, major respiratory societies (Global Initiative for Asthma, European Respiratory Society, British Thoracic Society and American Academy of Allergy, Asthma & Immunology) recommend continuing the biologic treatment, preferably in a self-administered home program.