Critical Care

Commentary Explorations

Consideration of Severe Coronavirus Disease

2019 As Viral Sepsis and Potential Use of
Immune Checkpoint Inhibitors
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Zekaver Odabasi, MD1; Ismail Cinel, MD, PhD2

Abstract: Taking into consideration the multisystemic clinical and treatment options for coronavirus disease 2019 (COVID-19), but
autopsy findings in “severe” coronavirus disease 2019 patients, viral there are still many unsolved aspects. Most of the patients infected
sepsis would be a more accurate term to describe the whole clinical with SARS-CoV-2 usually have a mild to moderate illness, but
picture. The most significant pathophysiological components of this depending on the viral load, immune system, underlying comor-
picture are intense cytokine release, prolonged inflammation, immu- bid diseases, or currently unknown factors, approximately 5% of
nosuppression with T cell exhaustion, and the development of organ patients develop the critical disease with respiratory failure and
dysfunctions. Currently, the optimal treatment for severe coronavirus organ dysfunctions (1). Pneumonia is the most frequent serious
disease 2019 is uncertain. Supportive treatment and immunomodu- manifestation of infection, while acute respiratory distress syn-
lators have a critical place in the treatment of severe patients until drome (ARDS) is the major complication in patients with severe
effective antivirals are developed. Interleukin-6 antagonists, one of illness. Other complications include as follows: coagulopathy,
the immunomodulating agents, appears to be effective in the treat- microvascular thrombosis (such as myocardial infarction and
ment of cytokine storm, but some patients continue to have severe stroke), arrhythmias, acute cardiac injury, liver injury, acute kid-
lymphopenia and immunosuppression. We believe it can be useful ney injury, and shock (1–5). In a series of 21 severely ill patients
as immunomodulator therapy in critical coronavirus disease 2019 admitted to the ICU in the United States, ARDS was observed
patients because of the benefits of immune checkpoint inhibitors in in most patients, and one-third developed cardiomyopathy (4).
cancer and sepsis patients. Human angiotensin-converting enzyme 2 (ACE2) is a func-
Key Words: acute respiratory distress syndrome; coronavirus disease tional receptor attacked by SARS-CoV-2 for cell entry, similar to
2019; lymphopenia; NKG2A; programmed cell death protein 1; sepsis SARS-CoV (6). ACE2 is broadly expressed in the nasal mucosa,
bronchus, lung, heart, esophagus, kidney, stomach, bladder, and
ileum, and these human organs are all vulnerable to SARS-CoV-2,
especially in severe cases with viremia (7). Presumably, viral rep-
lication of SARS-CoV-2 in target organs, as well as resulting cel-
SEVERE CORONAVIRUS DISEASE 2019 AND lular damage, causes a systemic inflammatory response, cytokine
VIRAL SEPSIS storm, mainly ARDS, and multiple organ damage. Some autopsy
Although the severe acute respiratory syndrome coronavirus studies support these findings. In an autopsy study of 21 severe
2 (SARS-CoV-2) continues to spread rapidly around the world, COVID-19 patients, the primary cause of death was respiratory
research is being actively conducted on the pathogenesis and failure with exudative diffuse alveolar damage with massive cap-
illary congestion accompanied by microthrombi (8). In another
1
Department of Infectious Diseases, School of Medicine, Marmara University, postmortem study conducted on 12 patients, a high concentra-
Istanbul, Turkey. tion of SARS-CoV-2 RNA was detected in the lung tissue of all the
2
Department of Anesthesiology and Intensive Care, School of Medicine, patients and around half of them had high titers of viral RNA in
Marmara University, Istanbul, Turkey.
the liver, kidney, or heart, in addition to viremia (9).
Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc.
on behalf of the Society of Critical Care Medicine. This is an open-access According to the Third International Consensus Definitions for
article distributed under the terms of the Creative Commons Attribution-Non Sepsis and Septic Shock (Sepsis-3), sepsis is defined as “life-threat-
Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permis- ening organ dysfunction caused by a dysregulated host response to
sible to download and share the work provided it is properly cited. The work
cannot be changed in any way or used commercially without permission from infection” (10). Considering the multisystemic clinical and autopsy
the journal. findings in “severe COVID-19 patients,” viral sepsis would be a
Crit Care Expl 2020; 2:e0141 more accurate term to describe the whole clinical picture (Fig. 1).
DOI: 10.1097/CCE.0000000000000141 To put it simply, if mild to moderate COVID-19 is considered

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Odabasi and Cinel

Figure 1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, sepsis, and multisystemic effects. Severe SARS-CoV-2 infection due to
high viral load causes immune dysregulation, suppression in CD8+ T cells and Natural Killer (NK) cells, and multisystemic effects due to viral sepsis. *ARDS =
acute respiratory distress syndrome, **MI = myocardial infarction, PD-1 = programmed cell death protein 1.

“bad infection,” then severe COVID-19 is “viral sepsis” or “bad cells, macrophages, and dendritic cells all express cytokines to
viral sepsis.” Viral sepsis can be caused by a variety of viruses such some extent during influenza infection via the activation of pattern
as herpes simplex virus, influenza, enteroviruses, human parecho- recognition receptors, including TLR3, TLR7, and TLR8, a retinoic
viruses, ebola, and dengue virus (11). Common features of viral acid-inducible gene I, and the nucleotide-binding oligomerization
sepsis are intense cytokine release, prolonged inflammation, and domain-like receptor family members (14). Cytokine storm, which
consequently, immunosuppression, T cell exhaustion, the devel- is a key factor in the rapid progression of COVID-19, induces not
opment of multiple organ damage, and increased susceptibility to only inflammation but also apoptosis-related immunosuppres-
secondary bacterial infections. A combination of these concepts sion (13, 15, 16). The primary features of the cytokine storm are
has led to a new approach to severe COVID-19 patients as “a sub- fever, progressive dyspnea, tachypnea, elevated interleukin (IL)-6,
set of sepsis,” in which particularly profound cellular, immuno- C-reactive protein, ferritin, and other inflammatory markers (17,
logic, and metabolic abnormalities are associated with a higher 18). The treatment of cytokine storm is of vital importance as it
risk of mortality than with infection alone. is associated with severe and mortal disease. Currently, there are
no specific therapeutic agents for SARS-CoV-2 and cytokine storm
THERAPEUTIC APPROACHES FOR SEVERE induced by COVID-19. However, IL-6 receptor antibodies, as an
COVID-19 AND CYTOKINE STORM immunotherapeutic agent, have been under compassionate use for
Currently, the optimal approach to the treatment for COVID-19 cytokine storm treatment in COVID-19 patients.
is uncertain. We can classify treatment approaches under three IL-6 is a multifunctional cytokine produced by different
main headings: potential anti-infectives, supportive treatments cells such as immune cells, mesenchymal cells, endothelial cells,
for specific target organ systems, and immunomodulators (Fig. 2). and fibroblasts in response to infections and tissue damage.
Understanding the mechanism of viral sepsis and associated immu- Betacoronavirus infection of monocytes, macrophages, and den-
nosuppression in COVID-19 is vitally important. In this way, it will dritic cells results in their activation and the secretion of IL-6 and
be possible to develop effective treatment approaches (12). other inflammatory cytokines that result in cytokine release syn-
The identification of the toll-like receptors (TLRs) and the asso- drome (CRS). IL-6 can signal through different pathways: classic
ciated concept of innate immunity based upon pathogen-associ- signaling, trans-signaling, and trans-presentation (18). In classi-
ated molecular pattern molecules allowed for significant advances cal signaling, IL-6 binds to the membrane-bound IL-6 receptor
in our understanding of the molecular biology and pathophysiol- (mIL-6R, found mainly on macrophages, neutrophils, T cells, etc.)
ogy of sepsis (13). Previous studies revealed that lung epithelial and shows pleiotropic effects on the acquired and innate immune

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 Commentary

Figure 2. Potential therapeutic approaches that can be used in severe coronavirus disease 2019 (COVID-19) patients. *Hydroxychloroquine and chloroquine
also have immunomodulatory effects. PD-1 = programmed cell death protein 1.

system. On the other hand, in the trans-signaling pathway, IL-6 in patients with COVID-19, a concomitant rise in inflammatory
forms a complex with soluble IL-6 receptor (sIL-6R) and can cytokine levels may lead to the depletion and exhaustion of T cell
activate virtually all cells of the body, especially the endothelial populations. As a result, the adaptive immune response cannot be
cells, and develop inflammatory effects (19). Both classic- and effectively initiated because of the substantial reduction and dys-
trans-signals contribute to the development of cytokine storm, function of lymphocytes. The uncontrolled virus infection leads to
pulmonary dysfunction, and ARDS. CRS may also be the con- more macrophage infiltration and a further worsening organ injury.
tributing factor to T cell exhaustion, apoptosis, and lymphopenia. The degree of lymphopenia has been shown to correlate with the
Tocilizumab is a humanized anti-IL-6R monoclonal antibody severity of COVID-19 and the mortality of septic shock (21, 23).
that binds both mIL-6R and sIL-6R and then inhibits classical A recent study conducted by Zheng et al (24) showed that the total
and trans-signals. A small clinical trial in China examined the number of NK cells and CD8+ T lymphocytes had decreased sig-
effectiveness of tocilizumab in patients who met the criteria for nificantly in severe COVID-19 patients. Furthermore, it showed
severe COVID-19. After a few days of tocilizumab treatment, that NKG2A expression had significantly increased in immune cells
symptoms such as fever, pulmonary infiltrates, and oxygenation whose functions were suppressed, a picture consistent with T cell
improved, and also the lymphocyte counts returned to normal exhaustion. Furthermore, the number of NK and CD8+ T cells had
(20). Unfortunately, despite the use of tocilizumab and antivirals, increased in recovering patients, while the expression of NKG2A
some severe COVID-19 patients still have lymphopenia, and the had decreased.
prognosis in these patients is poor. At this point, we need alter- Similarly, a previous study has shown that NKG2A receptors on
native therapeutic agents that will boost the immune system and cytotoxic T lymphocytes are over-upregulated during acute poly-
correct the lymphopenia in severe COVID-19 patients. omavirus infection. Consequently, there was a noticeable decrease
in the cytotoxic cellular immune response to prevent viral clear-
T CELL EXHAUSTION AND IMMUNE ance and viral oncogenesis (25). T cell exhaustion and similar
CHECKPOINT INHIBITORS AS A THERAPEUTIC findings were also seen in HIV, chronic hepatitis B, and hepatitis
OPTION C infections (26). It is well known that patients with sepsis have
CD8+ cytotoxic T cells and Natural Killer (NK) cells play a critical an increased checkpoint molecule expression—cytotoxic T lym-
role in the protection and control of viral infections. Lymphopenia is phocyte antigen-4 (CTLA-4) and programmed cell death protein
commonly seen in patients with severe COVID-19 disease and may 1 (PD-1)—and this condition causes lymphopenia (27–29). In
be a sign of poor prognosis (21). Immunopathologically, in severe another study, which involved patients with Candida bloodstream
COVID-19 patients, there is a marked increase in inflammatory infection, circulating immune effector cells displayed an immuno-
cytokines (IL-2, IL-6) combined with lymphopenia (22). There was phenotype consistent with immunosuppression, as evidenced by
also an unexpected increase in anti-inflammatory cytokines such T cell exhaustion and the number of PD-1 positive CD8+ T cells
as IL-10 and IL-4, which is an uncommon phenomenon for acute- that had significantly increased (30). Taken together, these obser-
phase viral infection (17). As the severity of the disease progresses vations point to a common cascade of events during viral and/

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Odabasi and Cinel

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