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\begin{document}

\title{COVID-19, air pollution and population density}



\author[1]{Silvana Fiorito}%
\author[1]{Marzia Soligo}%
\author[2]{Ya-dong Gao}%
\author[3]{Ismail Ogulur}%
\author[3]{Cezmi Akdis}%
\author[1]{Sergio Bonini}%
\affil[1]{Consiglio Nazionale delle Ricerche}%
\affil[2]{Zhongnan Hospital of Wuhan University}%
\affil[3]{Universitat Zurich Schweizerisches Institut fur Allergie- und Asthmaforschung}%


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  \date{May 18, 2024}


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\textbf{Reply to: ``COVID-19 pandemic and environment: not only air
pollution''. M.Carminati et al.}

\textbf{COVID-19, air pollution and population density}

Dear Editor,

We fully agree with Carminati and co-workers that air pollution is not
the only determinant influencing the incidence and severity of COVID-19.
Individual severity factors have been intensively studied and
reported\textsuperscript{1}. Nevertheless, the review of our data (data
not shown) allows us to confirm that the death rate, even after adjusted
for population density, was higher in the regions of northern as
compared to that of southern Italy\textsuperscript{2}.

More than the geographical population density, it has been suggested
that, in addition to other variables mentioned in our paper, the
population density in confined spaces, such as homes and working places,
may influence the virus spread\textsuperscript{2,3}. However, the high
population density in confined spaces existing in some southern cities,
where many people live in small houses, was still associated with a
lower mortality rate compared to that of northern
cities\textsuperscript{2}.

Therefore, we still think that environmental air pollution represents a
major factor in influencing COVID-19 burden and mortality. Certainly,
although not shown by data collected in the three cities considered by
Carminati and co-workers, the level of air pollutants in northern
Italian cities has unanimously been reported to be significantly higher
than that in southern Italian cities.

On the other hand, the objective of our work was not to confirm the role
of air pollution in COVID-19 -- documented by several studies worldwide-
but to suggest a mechanism through which an epithelial damage -- also
caused by other offending agents and common in other ``epithelial
barrier diseases'' -- may result in the immune changes typically
associated with severe COVID-19\textsuperscript{4}. In accordance with
the epithelial barrier hypothesis, it was recently reported that
bacterial DNA passage to circulation, a marker of epithelial barrier
leakiness in the gut, has been shown to be linked to severe
COVID-19\textsuperscript{5}.

Moreover, although recent studies suggest that even a short-term
exposure to pollutants is associated with SARS CoV-2
infection\textsuperscript{3}, chronic exposure has a more relevant role
in influencing incidence and severity of COVID-19 than actual values of
pollutants during the pandemic, possibly influenced by the reduced
vehicle traffic and industrial emissions.

References

\selectlanguage{ngerman}\emph{1. Gao YD, Ding M, Dong X, Zhang JJ, Kursat Azkur A, Azkur D, Gan
H, Sun YL, Fu W, Li W, Liang HL, Cao YY, Yan Q, Cao C, Gao HY, Brüggen
MC, van de Veen W, Sokolowska M, Akdis M, Akdis CA. Risk factors for
severe and critically ill COVID-19 patients: A review. Allergy. 2021
Feb;76(2):428-455. doi: 10.1111/all.14657.}

\emph{2. Fiorito S, Soligo M, Gao Y, Ogulur I, Akdis C, Bonini S. Is
epithelial barrier hypothesis the key to understanding the higher
incidence and excess mortality during COVID-19 pandemic? The case of
Northern Italy. Allergy. 2022;77:1408--1417 doi: 10.1111/all.15239}

\emph{3. Yu Z, Bellander T; Bergström A, Dillner J, et al. and the BAMSE
COVID-19 Study Group. Association of Short-term Air Pollution Exposure
With SARS-CoV-2 Infection Among Young Adults in Sweden.}

\emph{JAMA Network Open \textbar{} Public Health 2022;5(4) :e228109.
doi:10.1001/jamanetworkopen.2022.8109 (Reprinted) April 20, 2022 1/12}

\emph{4. Akdis CA. Does the epithelial barrier hypothesis explain the
increase in allergy, autoimmunity and other chronic conditions? Nat Rev
Immunol. 2021 Nov;21(11):739-751. doi: 10.1038/s41577-021-00538-7.}

\emph{5. Lunjani N, Albrich WC, Suh N, Barda B, Finnegan LA, Dam SA,
Walter J, Sadlier C, Horgan M, O'Toole PW, O'Mahony L. Higher levels of
bacterial DNA in serum associate with severe and fatal COVID-19.
Allergy. 2022 Apr;77(4):1312-1314. doi: 10.1111/all.15218.}

*Silvana Fiorito\textsuperscript{1,} Marzia Soligo\textsuperscript{1},
Yadong Gao\textsuperscript{2}, Ismail Ogulur\textsuperscript{3}, Cezmi
A. Akdis\textsuperscript{3}, Sergio Bonini\textsuperscript{1}

\emph{1. Institute of Translational Pharmacology, Italian National
Research Council, Rome, Italy}

\emph{2. Department of Allergology, Zhongnan Hospital of Wuhan
University, Wuhan, China}

\emph{3. Swiss Institute of Allergy and Asthma Research (SIAF),
University of Zurich, Davos, Switzerland}

\emph{*Corresponding author}

\emph{silvana.fiorito@ift.cnr.it}

\emph{Disclosure of potential conflicts of interest: CA has received
research grants from the Swiss National Science Foundation, European
Union (EU CURE), Novartis Research Institutes (Basel, Switzerland),
Stanford University (Redwood City, Calif), and SciBase (Stockholm,
Sweden); he is the Co-Chair for EAACI Guidelines on Environmental
Science in Allergic diseases and Asthma, and serves on the Advisory
Boards of Sanofi/Regeneron, Novartis, GlaxoSmithKline, and SciBase, and
is the Editor-in-Chief of Allergy. SB is consultant for Lallemand Pharma
and DSMB member for some COVID-19 vaccines and monoclonal antibodies}

\emph{Author contribution statement: SF, SB and CA made substantial
contributions to the conception and design, analysis and interpretation
of data; they have been equally involved in drafting the manuscript,
writing and revising it critically for the intellectual content. MS, YG
and IO contributed equally to the elaboration of the graphic part, to
the bibliographic research and to the revision of the manuscript.}

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