Reply.

To the Editor:

We read with considerable interest the relevant comment of Chirumbolo and Bjørklund concerning our recent Editorial. The authors discussed the complex link between the prevalence of coronavirus disease 2019 (COVID-19) in Italy and the geographic zones of a peninsula location, air pollution related to different climates, and allergic diseases of the respiratory tract. As explained by the authors, it is very intriguing that the Northern zone of the Italian peninsula (ie, north of the river Po) is more affected by COVID-19 than the Central-Southern zone, but it is a common observation in most of the affected countries around the world. The provinces around Wuhan, where the first cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were identified (ie, Henan, Hubei, Hunan, Jiangsu, and Anhui), are located in the Northern and Eastern parts of China with continental rainy-cold climates. These provinces are particularly industrialized with considerable pollution in cities, ensuring populations are heavily exposed to particulate matter (PM), ozone (O3), carbon dioxide (CO2), nitrogen dioxide (NO2), and sulfur dioxide (SO2) produced by diesel combustion. Similar to Italy and China, the North-eastern population of France is more affected by COVID-19 than the population of the Atlantic coast and Mediterranean regions. , Similar to the Italian peninsula, France could be isolated into 2 macro-area zones on both sides of the river Loire, highlighting a clear North-West/South-East line coinciding with the French Demarcation line during World War II (Fig 1 ). The populations living next to coasts with daily exposure to oceanic or Mediterranean climates seem to be less at risk of COVID-19. However, the putative link between COVID-19 and geographic zones could be associated with genetic variations in the population and explained by the importance of human exchanges around continental frontiers areas (eg, North-eastern part of France, BENELUX countries, and urban area of Ruhr). Similar to the environmental exposures affecting the incidence and decompensation of allergic diseases, COVID-19 could be affected by internal and external exposome. In crowded areas and industrialized territories exposed to hot warm season, the high levels of O3 seem to be associated with variations in epigenetic modulation. Globally, emerging data may identify air pollution as a modulator to DNA methylation (DNAm) disturbing the inflammation process, allergic diseases development, and exacerbation risk. As such, NO2 and PM exposures during pregnancy could significantly deregulate DNAm of antioxidants or anti-inflammatory genes related to the oxidative stress pathway in utero. , Interestingly, lower DNAm of IL-6 and IFN-γ genes was identified in adults exposed to PM, black carbon, and O3, involving an increase in specific immune system. The change in DNAm was often observed at specific locations within the promoter region, deregulating the expression of genetic heritage. Considering that SARS-CoV-2 infection involves a proinflammatory cytokine storm as IL-6 and IL-1β, a putative hypothesis could explain that populations exposed to chronic air pollution are associated with a different COVID-19 incidence in line with chronic epigenetic deregulation. Affecting the immune system and the inflammatory pathways, DNAm related to air pollution could explain the disparities in COVID-19 in geographic zones in which genetically predisposed populations were living in climate favoring SARS-CoV-2 distribution.

Fig 1

Repartition of SARS-CoV-2 cases in metropolitan French territory. Three levels of SARS-CoV-2 spreading, and saturation of intensive care units, that is, red for high risk, orange for moderate risk, and green for low risk. Data from Santé Publique France and Ministère des Solidarités et de la Santé—French Government.