INTRODUCTION
One of the most impressive aspects of SARS-CoV-2 infection is the broad spectrum of consequences that may vary from a complete absence of symptoms (asymptomatic infection) to a mild upper airways disease to pneumonia whose severity may range from benign to fatal (1). The most severe complication of the infection by SARS-CoV-2 is the acute respiratory distress syndrome (ARDS) which may lead to mechanical ventilation and ICU admission and is often fatal. The most frequent sign of evolution towards respiratory failure or ARDS is dyspnea associated with decreased oxygenation. The median time from the onset of symptoms to dyspnea is 8 days (2), and the unfavorable evolution occurs about 10-15 days after the onset the first signs and symptoms of the infection (3).
Since SARS-CoV-2 is a new virus, the first-line early defense against it is the innate immunity, before the adaptive response occurs. Innate immunity is based on both humoral and cellular elements, including Natural Killer cells and gamma/delta T cells that kill infected cells, thus limiting viral invasion, and secrete cytokines that cause inflammation and stimulate the adaptive immune response. Most severe cases of Covid-19, frequently leading to the death of affected patients, are characterized by the activation of two major biological cascades: the so-called “IL-6 cytokine storm” and a disseminated intravascular cascade in the lung. The mechanisms leading to these events are still incompletely defined, but their coincidence with the rise of the adaptive response suggests that the immune response per se, particularly the adaptive one, may play a role. In effect, Covid-19 patients with agammaglobulinemia recovered without experiencing lung complications (4). Thus, the type of immune response rather than the virus itself seems to lead to the inflammatory events observed in the most severe Covid-19 cases.
Atopic status is the genetic predisposition to produce a Type 2 immune response to environmental antigens that are harmless for non-atopic subjects. Type 2 immunity is characterized by the differentiation of naïve T CD4+ cells towards Th2 effector cells, which is followed by IgE production, eosinophilia, and mast cell activation. Type 2 immune response relies on some keystone cytokines, including interleukin (IL) 4, IL-5, IL-9, and IL-13 (5, 6). IL-4 induces the differentiation of naïve Th0 cells to Th2 cells, which in turn induce the isotype switching to IgE production. In infection, the Th2 immune response counteracts the microbicidal Th1 response, which could limit the tissue damage induced by Th1-mediated inflammation (7). In a study on experimental Coronavirus 229E infection of the upper airways carried out in healthy volunteers, atopy appeared to be associated with a more severe rhinitis score, suggesting a less efficient anti-virus response (8). Another recent, important finding is the reduced expression of ACE2, the SARS-CoV-2 receptor, in atopic subjects, which could be associated with reduced susceptibility to the virus (9).
Since it seems that the immune response itself, rather than the virus, leads to those catastrophic inflammatory events occurring in the most severe Covid-19 cases, we hypothesized that atopic subjects infected by SARS-CoV-2 might have a milder clinical course than non-atopic subjects, and tested this hypothesis in a large cohort of hospitalized Covid-19 patients.