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\begin{document}

\title{Comment on Matricardi PM et al.: The first, holistic immunological model
of COVID-19: implications for prevention, diagnosis, and public health
measures}



\author[1]{Antonio Mirijello}%
\author[1]{Maria D'Errico}%
\author[1]{Antonella La Marca}%
\author[1]{Pamela Piscitelli}%
\author[1]{Salvatore De Cosmo}%
\affil[1]{IRCCS Ospedale Casa Sollievo della Sofferenza}%


\vspace{-1em}



  
  \date{June 12, 2024}


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\textbf{Comment on Matricardi PM et al.: The first, holistic
immunological model of COVID-19: implications for prevention, diagnosis,
and public health measures}

TO THE EDITOR:

We read with great interest the review article by Matricardi and
colleagues \textbf{{[}1{]}} depicting mechanisms of disease for COVID-19
and analyzing both viral and host factors influencing its course. We
particularly agree with Authors on the pivotal role of innate immunity
in the very early phase of disease, being crucial for the subsequent
evolution. Most known weapons of innate immune system are represented by
natural antibodies, non-specific antimicrobial proteins, interferons,
cytokines and cellular elements (i.e. natural killer
cells).\textbf{{[}1{]}} However, innate immunity could be influenced by
other, still underrecognized, factors.

At present, a solid proof of evidence is available on the ability of
vitamin D in modulating immune response.\textbf{{[}2{]}} Most of data
are available from the field of bacterial infections and
sepsis,\textbf{{[}3{]}} being low vitamin D levels associated with a
higher risk of infection and mortality.\textbf{{[}4{]}}

In addition, vitamin D could play a role against viruses by maintaining
physical barriers (i.e. tight junctions, gap junctions, etc.), enhancing
natural immunity (i.e. production of cathelicidin, defensins, etc.) and
modulating adaptive immune response (i.e. modulation of TH1/TH2 response
and inflammation).\textbf{{[}5{]}} On this connection, emerging data
support the role of vitamin D supplementation in reducing the risk and
severity of influenza.\textbf{{[}5{]}} Both influenza and COVID-19 show
their maximum spread in winter season and the highest severity in
elderly people. Reduced vitamin D levels could represent a possible
pathophysiological explanation, among others, in both
cases.\textbf{{[}5,6{]}} With this regard, it has been hypothesized that
variations in vitamin D status across countries and latitudes could, at
least in part, explain variations of mortality from
COVID-19.\textbf{{[}6,7{]}}

However, at present the exact vitamin D status among COVID-19 patients
is unknown.\textbf{{[}7{]}} Moreover, the role and mechanisms of vitamin
D in the treatment of COVID-19 are still unexplored and several
interventional trials are ongoing. Should these hypotheses be confirmed,
universal vitamin D supplementation would represent a possible and
inexpensive strategy to enhance natural immunity against COVID-19.

Antonio Mirijello, MD

Maria Maddalena D'Errico, MD

Antonella Lamarca, MD

Pamela Piscitelli, MD

Salvatore De Cosmo, MD

Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza
Hospital, San Giovanni Rotondo, Italy

\textbf{REFERENCES}

\begin{enumerate}
\tightlist
\item
  Matricardi PM, Dal Negro RW, Nisini R. The first, holistic
  immunological model of COVID-19: implications for prevention,
  diagnosis, and public health measures. Pediatr Allergy Immunol 2020
  May 2. doi: 10.1111/pai.13271.
\item
  Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives
  on the regulation of innate and adaptive immunity. Nat Clin Pract
  Endocrinol Metab 2008;4:80-90.
\item
  Mirijello A, Tosoni A, Zaccone V, Impagnatiello M, Passaro G, Vallone
  CV, et al. MEDS score and vitamin D status are independent predictors
  of mortality in a cohort of Internal Medicine patients with
  microbiological identified sepsis. Eur Rev Med Pharmacol Sci
  2019;23:4033-4043.
\item
  Li Y, Ding S. Serum 25-Hydroxyvitamin D and the risk of mortality in
  adult patients with Sepsis: a meta-analysis. BMC Infect Dis
  2020;20:189.
\item
  Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL,
  et al. Evidence that Vitamin D Supplementation Could Reduce Risk of
  Influenza and COVID-19 Infections and Deaths. Nutrients 2020;12. pii:
  E988. doi: 10.3390/nu12040988.
\item
  Marik PE, Kory P, Varon J. Does vitamin D status impact mortality from
  SARS-CoV-2 infection? Med Drug Discov 2020 Apr 29:100041. doi:
  10.1016/j.medidd.2020.100041.
\item
  Silberstein M. Vitamin D: A simpler alternative to tocilizumab for
  trial in COVID-19? Med Hypotheses 2020;140:109767. doi:
  10.1016/j.mehy.2020.109767.
\end{enumerate}

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