The bimodal SARS-CoV-2 outbreak in Italy as an effect of environmental and allergic causes

To the Editor:

We read with attention the very recent Editorial by Navel et al¹ in the latest issue of the Journal. The topic intrigued us because we are currently investigating how come Italy is cropped into 2 great coronavirus disease 2019 (COVID-19)-infected macro areas, an upstream (Northern) zone and a downstream (Central-Southern) zone, with respect to the river Po. More recent data from the Italian Ministry of Health assessed that the 7 regions in the Northern macro area account for about 79.81% of the whole severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive population. This singular circumstance fits perfectly with the observation that the Central-Southern part, downstream the Po, is completely surrounded by Mediterranean. Fundamental insights come from past studies conducted in our Academy, where the authors assessed that the Italian population in the Central-Southern part of the peninsula has a higher risk to be affected by chronic airway allergy, that is, asthmatic disease, compared with more rainy-cold Northern regions.² The peninsular part of Italy is exactly the portion of the country with only about one-fifth (21.19%) of COVID-19–positive subjects and also being endowed with the largest near-coastal environment. The latter is particularly enriched in troposphere ozone (O₃), which is a well-known risk factor for asthmatic allergy disorders, particularly during sunlight exposure in warm season.³ The role of O₃ in pulmonary physiology and airway allergy might be particularly intriguing to shed light on the progress of COVID-19, particularly in such circumstance described by the authors, that is, following a reduction in the anthropic pollutants.¹ So far, very few associations were established between SARS-CoV-2 and subjects with asthma, although it is observed that the prevalence of asthma in severe patients with COVID-19 is lower than in the general adult population.⁴ Moreover, some reports have shown that, particularly in elder subjects with hypertension-derived cardiovascular disease, the expression of angiotensin-converting enzyme 2 (ACE2) is reduced, whereas, on the contrary, in people predisposed to develop asthmatic symptoms, the expression of ACE2 was much higher and exerting a protective role against the COVID-19 exacerbation, which otherwise should lead to interstitial bilateral pneumonia and lung fibrosis.⁵ Finally, Central-Southern Italy is characterized by a higher frequency of ACE I/D polymorphism in the II allele compared with the Northern macro area, which has a prevalence in the DD allele, usually linked with a higher risk for cardiovascular disease.⁶

Although lockdown with its drastic reduction in engine exhausts has decreased airborne urban pollutants¹ such as particulate matter ≤10 μm (PM₁₀), NO₂, SO₂, CO, and O₃, the coexistence of O₃ high levels and PM₁₀ low levels is associated with a low COVID-19 incidence odds ratio (OR). Furthermore, it is well known that in Italy urban pollutants decrease from inlands to offshore and near the coastal environment and are associated with interstitial pneumonia.⁷

On the basis of several publicly available data from government’s environmental, health, and statistical institutions for the latest 3 years, we calculated that the Northern regions have an OR of 11.44 (95% CI, 10.707-12.238) for COVID-19 incidence risk in subjects living in inland areas with PM₁₀ levels of greater than or equal to 40 μg/m³ and NO₂ levels of greater than or equal to 40 μg/m³ for at least 3 months/y, whereas the Central-Southern regions, including major islands, have an OR of 0.97 (95% CI, 0.898-1.068) with same values in the same time course; that is, there is no relevant risk association between the onset of COVID-19 following SARS-CoV-2 infections and major urban pollutants. Furthermore, we calculated from data of the Italian Government “Institute of STATistics” (ISTAT) and the National Institute of Health that the OR of COVID-19 risk incidence in subjects with asthma living permanently in Northern inland macro area was 1.44 (95% CI, 1.395-1.488), whereas in the Central-Southern macro area (including Sardinia and Sicily), the OR was 0.76 (95% CI, 0.721-0.807). This result is in agreement with the latitude dependency in asthma prevalence in Italy and assesses that asthma is not a risk factor for COVID-19.² According to our opinion, one possible leading factor in the paradoxical bimodal distribution of COVID-19 cases in Italy, very high in the Northern part and slightly modest in the Central-Southern part, is not only the favorable genetic endowment of ACE I/D polymorphism but also the presence of environmental O₃, because ozone, besides being a nontoxic asthma trigger, is able to modulate the pulmonary microbiome, thus assessing the correct cross-talk between airway bacteria and the immune surveillance of lung physiology, whereas PM₁₀ alters this interelationship.5, 6, 7 It is possible therefore to suggest that the increasing asthma prevalence from North to South is a sign of the different impact of the troposphere ozone in Italy.

The article by Navel et al offered us the opportunity to boost current research about COVID-19 in Italy, trying to shed light on the unusual COVID-19 distribution, which might even drive the political decision about lockdown and “Fase-2”, if taking into consideration both allergy and environmental issues.