SPOTLIGHT
to identify risk factors for severity and mortality.
According to Dr. Akdis, the preliminary analysis
revealed that a continuing increase of leukocyte
and neutrophil counts, sustained lymphopenia,
progressing decrease in platelet counts, and a high
neutrophil-to-lymphocyte ratio were associated
with in-hospital death. 9
A study from the Beijing Ditan Hospital in
China, available as a preprint, prospectively analyzed
61 patients with SARS-CoV-2 admitted to
the hospital in January 2020 for prognostic factors
of severe COVID-19 illness.10 As with Dr. Akdis’
analysis, these researchers also identified a high
neutrophil-to-lymphocyte ratio as an independent
risk factor for severe illness. Older age (>50 years)
and a neutrophil-to-lymphocyte ratio of ≥3.13
were associated with severe COVID-19 illness. The
study authors recommended that patients with
these factors have rapid access to the intensive
care unit at a hospital.
Timing and quality of the immune response
appear to be important for the course of disease
and its severity.
“The timing for development of the naturalizing
antibody response is likely a decisive factor for
the body’s ability to clear the infection,” said Dr.
Akdis. “If the response is too slow, the lymphopenia
ensues and there could be little chance for developing
a robust neutralizing antibody response.
The helper and cytotoxic T cells are getting lost
and there is no help for antibody production.”
“What we don’t fully understand is whether
the inability to respond to the viral infection is a
consequence of the lymphopenia in patients with
COVID-19,” said Dr. Avigan. “Does the lymphopenia
prevent an individual from mounting a robust
antibody response, for example? There are many
studies ongoing to understand what roles different
parts of the immune system – the cellular and
humoral components – play in creating protection
and effective responses to fight the virus.”
Dr. Sereti and her NIH colleagues are currently
conducting such a study, collecting samples
from patients at various stages of their disease
to capture what the immune system looks like in
response to a coronavirus infection. They hope to
figure out a comprehensive picture of individual
immune responses to the virus. “Comparing the
immune profiles of the elderly, who generally have
weaker lymphocytes, with the immune profiles of
children, for example, could provide particularly
good clues because we know that children generally
have mild disease,” she explained.
Thus far, study results suggest that lymphopenia
may be a useful prognostic marker, but
additional prospective studies are needed to validate
these results. “If there is viral-mediated
inflammation, the lymphocyte depletion may be
an initial step in this cascade and, in that way,
lymphopenia may be an early marker to help guide
clinical care to try to prevent further damaging
inflammation,” said Dr. Avigan.
Treating Viral Infection and Lymphopenia
While researchers try to understand why lymphopenia
develops in patients with COVID-19,
clinicians are learning which treatments are
appropriate for which patients – and when. Therapeutic
options for which there is some evidence of
efficacy include antiviral drugs such as remdesivir
and anti-inflammatory drugs such as low-dose
dexamethasone.
In late June, scientists at the University of
Oxford in the U.K. announced results from the
RECOVERY study, which compared a range of
possible treatments with usual care among 2,104
patients hospitalized with COVID-19. The commonly
used corticosteroid dexamethasone reduced
deaths by one-third among ventilated patients
(rate ratio [RR] = 0.65; 95% CI 0.48-0.88; p=0.0003)
and by one-fifth in patients receiving only oxygen
(RR=0.80; 95% CI 0.67-0.96; p=0.0021), compared
with usual care. 11
“It appears that the immune response to the
virus is what is killing the tissues, not the virus
itself,” Dr. Akdis commented. “If we can suppress
the dysregulated immune response and inflammation,
then patients can get better before being
admitted to the intensive care unit or requiring
ventilation.”
Drs. Sereti and Avigan concurred. “At the point
when there is severe inflammation, or when the
trajectory goes toward severe inflammation, it
makes sense to suppress the immune response,”
Dr. Sereti said.
In contrast, experts hypothesize that immune
stimulation could be effective during earlier stages
of the disease. One such therapeutic option being
explored in clinical trials is interleukin-7 (IL-7), a
cytokine required for the development of T lymphocytes.
According to Dr. Sereti, IL-7 should also
be considered in combination with a vaccine, as a
booster of a vaccine response – especially in older
patients, who are more likely to have a weaker
immune response to some vaccines. 12
For a disease that only emerged in December
2019, the worldwide clinical and scientific community
has learned a lot about the pathophysiology
of a SARS-CoV-2 infection and how to care for
patients with severe manifestations of COVID-19.
However, there is still much to be learned.
“What is the best timing and sequence of therapies
and whether there are patients for whom
anti-inflammatory treatment would exacerbate
their disease – we don’t know,” Dr. Sereti said.
“Again, the question about COVID-19–related
lymphopenia is whether it is a measure of an individual’s
immune competence, which speaks to
whether they can fight off the virus, or is it a surrogate
for a certain kind of inflammation?” said Dr.
Avigan. The explanation may be complicated. “We
may find that the answer is different for different
individuals.” —By Anna Azvolinsky
References
1. Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and
moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620-2629.
2. Zhao Q, Meng M, Kumar R, et al. Lymphopenia is associated with severe
coronavirus disease 2019 (COVID-19) infections: A systemic review and metaanalysis.
Int J Infect Dis. 2020;96:131-135.
3. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019
in China. N Engl J Med. 2020;382:1708-1720.
4. Brown RAC, Barnard J, Harris-Skillman E, et al. Lymphocytopaenia is associated
with severe SARS-CoV-2 disease: a systematic review and meta-analysis of
clinical data. medRxiv preprint. April 17, 2020.
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COVID-19 patients. Authorea. 2020 June 8.
10. Liu J, Liu Y, Xiang P, et al. Neutrophil-to-lymphocyte ratio predicts severe
illness patients with 2019 novel coronavirus in the early stage. medRxiv
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11. University of Oxford press release. Low-cost dexamethasone reduces death by
up to one third in hospitalised patients with severe respiratory complications
of COVID-19.” Accessed June 16, 2020, from https://www.recoverytrial.net/
news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-inhospitalised-patients-with-severe-respiratory-complications-of-covid-19.
12. ClinicalTrials.gov. InterLeukin-7 (CYT107) to Improve Clinical Outcomes
in Lymphopenic pAtients With COVID-19 Infection UK Cohort (ILIAD-7-
UK). Accessed June 25, 2020, from https://clinicaltrials.gov/ct2/show/
NCT04379076.
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