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Covid-19: a puzzle with many missing pieces

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m627 (Published 19 February 2020) Cite this as: BMJ 2020;368:m627

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Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2)

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Treat the cause, calm the fire, or eradicate the source in COVID-19?

Dear Editor,

Your article on the missing pieces of the COVID-19 puzzle highlights the many aspects of the disease yet to be investigated. Beside epidemiology and pathogenesis, current therapeutic approaches, especially for those with respiratory failure, the major cause of death in COVID-19, are unsatisfactory. The mechanism for the lung injury remains to be elucidated. However, in addition to the effects from cytokine storm (CS), molecular mimicry in genetically susceptible individuals may play a part. Molecular mimicry results from the antiviral immune responses cross-reacting with some protein components in normal human cells. The detection of antiphospholipid antibodies in Covid-19 patients (1) supports the presence of this complication. The autoimmune T cells may contribute to tissue injury.

While treating the cause of COVID-19 is the ultimate goal, until an effective antiviral therapy is available, targeting the downstream effects from the infection is appropriate. One obvious downstream effect of the infection is CS, arisen from exaggerated and dysregulated immune responses. Various immunomodulatory agents such as azithromycin/hydroxychloroquine, anti-IL1, anti-IL6, and corticosteroids, aimed at inhibiting the cytokines or downregulating the immune responses, are currently being administered to these patients, both in and outside the context of clinical trials. Ruxolitinib, an inhibitor of the Jak 2 signaling pathway involved in T-cell activation, is also being studied.

Although anti-cytokine antibodies may calm some of the inflammatory processes induced by CS, the lung injuries in many patients continue to progress and lead to death. Autopsies in these patients showed that the lungs were infiltrated by CD8 cells (2). The nature of these CD8 T cells remains to be determined. However, it is possible that they are either autoimmune T cells, directed at the alveolar epithelium and induced by the dysregulated immune responses, or antiviral cytotoxic T cells that cross react with the alveolar epithelium. Eradicating these T cells, the mediator of the counter-productive immune chaos, is a logical approach. These T cells may be rapidly eradicated by extracorporal photophoresis, specific anti-T cell antibodies, or lympholytic agents. Cyclophosphamide, a widely available and inexpensive drug, is an attractive agent for this purpose. It is highly lympholytic. At doses for autoimmune diseases, including acute lung diseases, and post-haploidentical stem cell transplant, it has a good safety profile and is effective in abrogating activated T cells. If used early, cyclophosphamide could, therefore, modulate the disease course.

There are obvious theoretical risks associated with inducing immunosuppression, in the form of functional or numeric lymphopenia, in COVID-19 patients using any immunosuppressive agents. Immunosuppression may delay or prevent viral clearance. The worry about viral clearance has further been compounded by the association between lymphopenia and severity of COVID-19 (3). Lymphoid hypoplasia has also been reported in these patients (4). However, T cells from patients with less severe disease are highly activated (5). The lymphopenia and lymphoid hypoplasia are, therefore, more likely the result of uncontrolled apoptosis of the dysregulated T cells than the causes for any delay in viral clearance and ultimate fatality.

Until all convalescent patients, treated by any methods, are routinely retested for viral persistence, the clinical implications of delayed viral clearance are currently unknown. Although delay in viral clearance may be important for public health purposes, two observations suggest that it may not be the pre-requisite for health in most individuals, provided dysregulated immune responses do not occur. First, many patients with COVID-19 are asymptomatic. Second, some Korean patients who recovered from the infection continued to test positive for the virus.

In conclusion, another piece for the COVID-19 puzzle in terms of therapy may be the pool of dysregulated T cells. In the absence of an effective antiviral therapy, the dysregulated T cells may be a therapeutic target for immunomodulatory agents such as cyclophosphamide.

References
1. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med. 2020 Apr 8. doi: 10.1056/NEJMc2007575. [Epub ahead of print].
2. Fox R, Akmatbekov A, Harbert J, et al. Pulmonary and cardiac Pathology in COVID -19; the first autopsy series from New Orleans. medRxiv. doi: 10.1101/2020.04.06.20050575
3. Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020; 5: 33.
4. Yao X, Li T, He Z, et al. A pathological report of three COVID⁃19 cases by minimally invasive autopsies. Chin J Pathol. 2020; 49: 411-418.
5. Xu Z, Shi L, Wang Y, Zhang J, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8: 420-422.

Seah H Lim MD PhD
Division of Hematology and Oncology
Department of Medicine
New York Medical College
Valhalla, New York, USA
email: seah.lim@wmchealth.org

Jason Gonsky MD PhD
Division of Hematology and Oncology
Department of Medicine
SUNY Downstate Health Sciences University
Brooklyn, New York, USA

Oleg Epelbaum MD
Division of Pulmonary, Critical Care and Sleep Medicine
Department of Medicine
New York Medical College
Valhalla, New York, USA

Peter Gillette MD
Division of Hematology and Oncology
Department of Medicine
SUNY Downstate Health Sciences University
Brooklyn, New York, USA

Competing interests: No competing interests

21 April 2020
Seah H Lim
Professor of Medicine and Director of Hematology
Jason Gonsky MD PhD, Oleg Epelbaum MD, and Peter Gillette MD
New York Medical College
19 Bradhurst Avenue, Suite 2575S, Hawthorne, New York 10532