Lymphopenia has been reported to be a common feature associated with
severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) causing
Coronavirus disease 2019 COVID-19(Chen et al., 2020; Huang et al.,
2020), similarly to what has been previously reported for SARS CoV
epidemic in 2002-2003(Chan & Chen, 2008). It’s currently well known
that both viruses belong to the same genus of beta coronaviruses and
share multiple similarities including the same ACE2 receptor to enter
the target cells, as well as an immune cross reactivity(Ou et al.,
2020). Further, SARS CoV-2 induced lymphopenia was recently described as
an effective and reliable indicator of the severity and hospitalization
in COVID-19 patients(Tan et al., 2020). Thus, if we may find a possible
hypothesis to explain the lymphopenia induced by SARS CoV, it might also
help us to explore a potential treatment for SARS CoV-2.
It was previously suggested that SARS CoV induced lymphopenia is likely
to be caused by indirect mechanisms like an increase of cortisol levels
that occurred as part of the body stress response to this severe
respiratory viral infection or by an iatrogenic effect of
glucocorticoids used to manage those patients. Further, cortisol level
was demonstrated to be significantly higher in the lymphopenic compared
with nonlymphopenic patients as well as to be significantly negatively
correlated with monocytes and suppressor CD8+ cells, B
lymphocytes and helper CD4+ cells in SARS CoV
patients(Chan & Chen, 2008; Panesar, Lam, Chan, Wong & Sung, 2004).
Interestingly, the adrenal gland was previously shown to express ACE2
receptors and SARS CoV related inflammation of various organs including
the adrenal gland have been also reported. Similarly, SARS CoV has been
demonstrated to cause architectural disruption and lymphocyte depletion
in the spleen and lymph nodes despite no or trace ACE2 expression in
examined human tissues specimens and SARS CoV has also been associated
with adrenal glands’ necrosis and infiltration of monocytes and
lymphocytes (Hamming, Timens, Bulthuis, Lely, Navis & van Goor, 2004;
Harmer, Gilbert, Borman & Clark, 2002). Relying on the previous
mechanisms related to SARS CoV, to be added to our current knowledge
that COVID-19 pathogenesis has been showed to be associated with
excessive chemokines release; a cytokine storm that has been associated
with unfavorable clinical outcomes, including some chemokines attracting
the lymphocytes and other inflammatory cells to the infected
tissues(Pedersen & Ho, 2020; Xiong et al., 2020). The author suggests
that SARS CoV-2, like SARS CoV may progressively cause, both directly
and indirectly, a fulminant inflammation in different body organs and
some of these released chemokine, and perhaps others yet to be
discovered, are well known to attract the lymphocytes to those organs
causing the lymphopenia encountered with COVID-19. More importantly, the
author suggests that this lymphopenia might be considered as a symbol
for distraction of lymphocytes to multiple organs instead of being
mainly directed to the lungs, the main target organ of COVID-19.
Interestingly, it might also be considered as another reflection to the
previously described disturbance of the homeostasis of the interferons’
immune response in COVID-19 patients(Pedersen & Ho, 2020; Sallard,
Lescure, Yazdanpanah, Mentre & Peiffer-Smadja, 2020; Zhang et al.,
2020). Noteworthy, hydroxychloroquine has been previously reported to
cause lymphopenia and increase human immunodeficiency virus, viral load
which was suggested to be only explained by a biological effect of the
drug(Paton et al., 2012) and a potential likewise relationship with SARS
CoV-2 induced lymphopenia should be carefully and thoroughly
investigated as it might reason for its recent report of
inefficacy(Magagnoli et al., 2020), especially if similar confirmatory
results are released. Moreover, acute inflammation of the adrenal glands
is increasing cortisol secretion, especially early in the COVID-19
clinical course, which is further augmenting the lymphopenia and might
complete the unfortunate vicious circle. Noteworthy, short-duration,
high-dose glucocorticoid therapy wasn’t proved effective for early acute
respiratory distress syndrome or for severe sepsis and when combined
with mineralocorticoids, they’ve only shown some benefits in some
selected critical cases classified with a poor prognosis, and moderate
doses of glucocorticoids were suggested to be beneficial only for
patients with late acute respiratory distress syndrome (Thompson, 2003).
Further, it’s been recommended for patients with rheumatic disease on
glucocorticoids therapy to use the minimum possible doses of
glucocorticoids during COVID-19 infection(Misra, Agarwal, Gasparyan &
Zimba, 2020). Thus, the author would like to agree with the clinical
recommendation against the routine use of glucocorticoids in the
management of COVID-19 and to confirm they should be only discussed to
be administered on a case by case basis(SRLF-SFAR-SFMU-GFRUP-SPILF-SPLF,
2020, April 7) and the author would like to dispute with some other
contradictory reports and encourages more colleagues to present properly
performed clinical data to end any remaining controversy(Zhang et al.,
2020). Most importantly, basing on the suggested pathogenesis of
COVID-19 described in this manuscript, the author suggests that using
anti-inflammatory drugs, other than glucocorticoids, e.g. ibuprofen
might prove beneficial for early management of COVID-19 trying to
ameliorate the suggested inflammatory process leading to lymphopenia and
immunosuppression. Similarly, this recommendation might be considered,
to be applied as early as possible during the clinical course of
COVID-19 and the author suggests it might be added to his newly
suggested nitazoxanide/azithromycin protocol for early management of
COVID-19 (Kelleni, 2020) but in a separate arm for
nitazoxanide/azithromycin/ibuprofen as well as to add it to any other
already adopted protocol for early cases of COVID-19 and compare the
results against the already used analgesic/antipyretic paracetamol. If
proved right, it would be more superior to the currently used analgesic
antipyretic paracetamol, improving the survival rate and immune response
of COVID-19 patients. The author is fully aware that his hypothesis is
contradictory to another one that has been suggested(Fang, Karakiulakis
& Roth, 2020), The author has also prepared a full paper disputing the
contradictory hypothesis and is looking for a potential peer review.
It’s noteworthy to mention that ibuprofen has been previously
hypothesized to be hazardous in another medical argument and later on it
was proved incorrect(Sodhi & Etminan, 2020) and it’s also worthwhile to
notice that some recent clinical results related to other drugs,
mentioned with ibuprofen in that contradictory hypothesis, have recently
revoked their claimed hazards(Bean et al., 2020). The main difference
here, is that we can’t wait for long time before testing a possibility
that we’ve a beneficial drug like ibuprofen that might help us in this
very depressive COVID-19 crisis, we should learn from unintended
mistakes and make sure not to be repeated, the author perhaps is doing a
mistake but this is something that would be only answered by our fellow
researchers who might consider his as well as others claims.
Conflict of interests: None.
Funding: None
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