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infection with [SARS-CoV-2]?” said David Avigan,
MD, a hematologist-oncologist and immunotherapy
expert at the Beth Israel Deaconess Medical
Center in Boston and a professor of medicine at
Harvard Medical School.
How the immune system responds to a SARS-
CoV-2 infection is among the major questions
clinicians and researchers must answer to identify
appropriate and effective therapies, develop
a long-lasting, successful vaccine, and better treat
patients with COVID-19. To understand the infection’s
effects on the immune system and inflammation,
ASH Clinical News spoke with Dr. Avigan
and other clinicians and researchers who are treating
and analyzing the immune response in patients
with COVID-19.
Which Came First?
“When we talk about lymphopenia among patients
with COVID-19, most studies have shown that
it’s predominantly the T lymphocytes that are
depleted,” explained Irini Sereti, MD, Chief of
the HIV Pathogenesis Section of the Laboratory
of Immunoregulation at the National Institute of
Allergy and Infection Diseases. “Some studies also
show that natural killer cells or B cells are somewhat
depleted in severe infection as well.”
But the extent of lymphocyte depletion that
is caused by the viral infection is not fully understood,
she added, as some of the patients with
coronavirus who were analyzed were receiving
corticosteroids and other medications that can
affect circulating lymphocyte numbers.
“Only about 2% of the lymphocytes are represented
in the peripheral blood, so we may be missing
much of the picture of what is going on in the
body when we only sample the blood,” Dr. Sereti
said. “What we can say from the data so far is that
there is a significant degree of lymphopenia, especially
in patients with more severe disease, that is
primarily affecting the T cells,” she added.
Cezmi Akdis, MD, a medical researcher and
immunologist at the University of Zurich and
the director of the Swiss Institute for Allergy and
Asthma Research, agreed. The T lymphocytes
could be decreased if the bone marrow is suppressed
during a cytokine storm or if they home
to the lungs in patients with pneumonia. If a
patient already has a decreased lymphocyte count,
he explained, a high viral dose could prevent the
immune system from clearing the virus efficiently,
resulting in severe disease. In this case, the levels
of T cells are too low to clear the virus and can
result in a cytokine storm and inflammation, eventually
leading to tissue damage.
However, both physicians acknowledged that
the medical community does not have a definitive
answer about what causes lymphopenia in patients
infected with SARS-CoV-2.
“Most experts suspect that there is some direct
effect of the viral infection on lymphocytes,” said
Dr. Avigan. “The lymphopenia could also be a manifestation
of the inflammatory footprint that the
virus causes.”
“ One question is whether
the lymphopenia is
induced by COVID-19 and
is a parameter of the
severity of the infection,
or are patients who are
lymphopenic particularly
susceptible to a severe
infection with [SARS-
CoV-2].”
—David Avigan, MD
SARS-CoV-2, a cytopathic virus, can induce
injury and the death of those cells infected with
the virus, resulting in pyroptosis, a type of proinflammatory
programmed cell death that is linked
to vascular leakage. 5,6 Scientists hypothesize that
the pyroptosis may trigger the inflammatory
response seen in some patients with coronavirus.
Lisa F. P. Ng, PhD, a viral immunologist at the
Singapore Immunology Network of the Agency for
Science, Technology and Research, and colleagues
recently conducted a review on immunity and
inflammation seen with COVID-19 that referred
to a 2005 study on SARS caused by the SARS
coronavirus (SARS-CoV). 7 The authors determined
that SARS coronavirus particles and its RNA could
be found in T cells as well as other immune cells
such as monocytes and macrophages. The work
suggested that SARS-CoV and possibly SARS-
CoV-2 could directly infect immune cells; the
infection may result in direct killing of lymphocytes
and immune system dysfunction.
“The T lymphocytes are dying, disappearing
rapidly in some patients with COVID-19,” said Dr.
Akdis. “This has also been observed with other coronavirus
infections – SARS and Middle East respiratory
syndrome – and appears to be due to pyroptosis,
although we don’t understand the mechanism yet.”
Hypoxia-induced lymphocyte death also possibly
occurs, according to Dr. Sereti, another process
linked to inflammatory cytokines that are detrimental
to the T lymphocyte population.
Understanding the ways lymphocytes are
depleted in individuals infected with the novel
coronavirus is vital, particularly if the lymphopenia
could be targeted using novel or existing drugs,
the experts told ASH Clinical News.
Lymphopenia as a Biomarker?
Regardless of how the lymphocyte population
is depleted, many published studies show that
among patients with COVID-19, lymphopenia correlates
with a greater disease severity.
“In our experience at Beth Israel, we noticed
that patients who have a more compromised
immune system may have a harder time with this
infection,” said Dr. Avigan. “We certainly had initial
concerns about patients with hematologic
malignancies because they had what was felt to
be a higher susceptibility to this infection and the
potential for greater severity of COVID-19 due to
immunosuppression,” he continued.
Recent reports from China and the U.S. estimate
that patients with cancer are three to five
times more likely to develop severe COVID-19,
and, among patients with hematologic malignancies,
case fatality rates have reached up to 37%. 8
In particular, prolonged lymphopenia lasting
for several days – but not acute transient lymphopenia
that is observed at initial presentation but
quickly resolves – may be an important prognostic
factor to identify patients likely to develop severe
COVID-19 disease, according to Dr. Sereti.
“Lymphopenia may have clinical utility as a
marker to stratify patients by disease severity,”
said Dr. Avigan.
Dr. Akdis agreed. He and colleagues at the
Zhongnan Hospital of Wuhan University in China
analyzed 289 patients hospitalized with COVID-19
10 ASH Clinical News July 2020 Bonus Mid-Year Edition