To the Editor:
We read with care and interest the original article from Ballow and Haga1 about the possible explanation for why some individuals have life-threatening COVID-19 disease whereas others have no or mild symptoms.
Because this is not the conclusive report and we appreciate the attempt to explain the peculiar reactions of some patients with COVID-19, we would like to suggest some specific ideas with a view to more targeted therapeutic interventions.
First, it is not easy to determine the relation between risk factors predisposing people to a more severe reaction to COVID-19 infection with regard to vitamin D deficiency and genetic risk factors. On the other hand, genetic alterations suggest interesting ideas with regard to multigene expression, especially on large specific chromosomes for epithelial membrane proteins in the lungs, according to recent papers on this topic.2
Second, apparent contradictions in COVID-19 mortality and morbidity in patients with common variable immune deficiency allow the authors to produce a scholarly examination of the immune imbalance and dysregulation of innate and adaptive immune responses in patients with severe COVID-19. The factors analyzed, sometimes in a correlated manner, are (1) the importance of the type I interferon pathway; (2) immune-senescence; (3) age-independent comorbidities such as hypertension, diabetes, and obesity; (4) the uncontrollable proinflammatory response in the lungs driven by macrophage-activation syndrome; (5) the T cell and subtype response; and (6) the antibody response against the viral envelope S (spike) and N (nucleocapsid) proteins.
However, before concluding that “a combination of multiple genetic and non-genetic factors contribute to an individual's unique immune response and susceptibility to SARS-CoV-2 infection,” in our opinion, it is of paramount importance to introduce the vascular endothelium into the discussion.3 Endothelial damage to various organs was also highlighted by autopsy outcomes.4
With regard to the subject of the vascular endothelium, information reported on the AB0 blood group loci that were associated with severe SARS-CoV-2 infection may find a more complete and significant interpretation in this direction, as also may be the case regarding the integrity of endothelial glycoproteins.5 , 6
Thus, we encourage an examination of these points, not to negate any of the points made but to augment and improve this thought-provoking original article, which sheds further light on why some people develop serious COVID-19 disease after infection whereas others exhibit only mild symptoms.
Footnotes
Conflicts of interest: The authors declare that they have no relevant conflicts of interest.
References
- 1.Ballow M., Haga C.L. Why do some people develop serious COVID-19 disease after infection, while others only exhibit mild symptoms? J Allergy Clin Immunol Pract. 2021;9(4):1442–1448. doi: 10.1016/j.jaip.2021.01.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Pairo-Castineira E., Clohisey S., Klaric L., Bretherick A.D., Rawlik K., Pasko D., et al. Genetic mechanisms of critical illness in Covid-19. Nature. 2021;591:92–98. doi: 10.1038/s41586-020-03065-y. [DOI] [PubMed] [Google Scholar]
- 3.Tricarico G., Zavan B., Travagli V. Clinical evidence and therapeutic treatments at the time of the coronaviruses responsible for SARS: a perspective and points of view with a focus on vascular endothelium. Coronaviruses. 2021;2:1. [Google Scholar]
- 4.Maccio U., Zinkernagel A.S., Shambat S.M., Zeng X., Cathomas G., Ruschitzka F., et al. SARS-CoV-2 leads to a small vessel endotheliitis in the heart. EBioMedicine. 2021;63:103182. doi: 10.1016/j.ebiom.2020.103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Reilly J.P., Meyer N.J., Shashaty M.G., Anderson B.J., Ittner C., Dunn T.G., et al. The ABO histo-blood group, endothelial activation, and acute respiratory distress syndrome risk in critical illness. J Clin Invest. 2021;131:e139700. doi: 10.1172/JCI139700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Sabioni L., De Lorenzo A., Lamas C., Muccillo F., Castro-Faria-Neto H.C., et al. Systemic microvascular endothelial dysfunction and disease severity in COVID-19 patients: evaluation by laser Doppler perfusion monitoring and cytokine/chemokine analysis. Microvasc Res. 2021;134 doi: 10.1016/j.mvr.2020.104119. 104119. [DOI] [PMC free article] [PubMed] [Google Scholar]