COMMENTARY

Does COVID-19 Cause Sepsis?

Christina S. Boncyk, MD; Matthew F. Mart, MD; E. Wesley Ely, MD, MPH

Disclosures

October 16, 2020

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Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that can be bacterial, fungal, protozoal, or viral in origin, including the virus that causes COVID-19 infection — severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). When a person experiences a dysregulated immunologic (ie, inflammation) or coagulopathic (ie, micro- or macroclotting and bleeding) host response initiated by SARS-CoV-2 infection, it is a form of viral sepsis. Current literature supports that severe COVID-19 often leads to a cascade of dysregulated host responses in the days that follow direct viral invasion.

When the Third International Consensus Definitions for Sepsis and Septic Shock Task Force met in 2015, they presented updated definitions of sepsis and septic shock (SEPSIS-3) that aimed to be inclusive of the heterogeneous causes of sepsis while emphasizing the importance of urgent recognition and diagnosis of this deadly condition. As we continue to learn about COVID-19 and its effects within the human body, this definition is important in our communication and recognition of illness severity.

Similar and Unique Attributes of COVID-19 Sepsis

SARS-CoV-2 infection frequently leads to organ dysfunction that is similar to that seen in forms of sepsis from other pathogenic organisms, including acute kidney injury, acute respiratory distress syndrome (ARDS), and coagulopathy. These organ dysfunctions are, in large part, driven by an aberrant iteration of host immunologic responses consistent with sepsis definitions. Thus, it makes sense that our most effective therapies to date are aimed at mitigating the dysregulated host response (ie, use of corticosteroids or remdesivir) or its impact (with anticoagulation and supportive treatment).

There is much speculation about the pathobiology of COVID-19, including whether the disease is associated with unique manifestations of common critical illness syndromes such as ARDS. Thus far, we have no strong evidence that COVID-19 ARDS differs substantially from other forms of ARDS to the point of changing evidence-based practice. The best evidence to date regarding sepsis from SARS-CoV-2 infection is that while viral sepsis in general may differ in some of its manifestations from classic bacterial sepsis, it's still sepsis.

There are clinically relevant differences between manifestations of COVID-19 sepsis and typical bacterial sepsis, but they are quantitative rather than qualitative differences. That is, all clinicians have seen them before in other sepsis patients, even before this virus infected its first human. They are just more commonly part of the fabric of daily care for patients with COVID-19 than we have been used to.

For example, one difference is the near total loss of the mucociliary escalator of the tracheobronchial tree, which is related to destruction of the ciliated respiratory epithelium. Similar to influenza pneumonia and sepsis, this predisposes patients to subsequent superinfection from bacteria. In influenza, these superinfections have been caused predominantly, but not exclusively, by Gram-positive organisms such as staphylococci and streptococci.

In the COVID-19 intensive care unit (ICU), we are always on alert to begin antibiotics to cover such a complication of what initially was a pure viral infection. Identifying when the virus stops and the superimposed bacterial problem starts is the conundrum. With influenza, bacterial problems usually follow the virus, whereas with COVID-19, to add insult to injury, the prolonged duration of the viral infection usually means we are actively dealing with organ damage directly and indirectly from virus and bacteria simultaneously.

This highlights another clinically relevant difference in SARS-CoV-2 sepsis: the extremely long duration of the illness (weeks rather than days) and the fact that late complications are so frequent even when patients appear to be improving. The most notorious late complication is clotting, related to a resurgence of coagulopathy even after the ARDS is better to the point of extubation. This exquisitely prominent endothelial dysfunction and coagulopathy, characterized more by clotting than by bleeding (though both occur), is a focus of intense ongoing basic science and clinical research. But it has already prompted heavy use of prophylactic and therapeutic anticoagulation and intense monitoring of heparin anti–factor Xa activity levels.

Sepsis Identification and Diagnosis Improve Care

Sepsis recognition and diagnosis are associated with improved patient outcomes. At the bedside, the diagnosis initiates a series of downstream actions, including investigation into source control and treatment; guidance on hemodynamic and respiratory monitoring; and awareness among care teams, patients, and families of this life-threatening condition and possible need for escalation of care. The SEPSIS-3 consensus definition establishes the clinical framework for clinicians to understand and recognize a dysregulated host response to infection in their patients and implement early evidence-based practices to decrease morbidity and improve patient survival.

On a larger scale, a diagnosis of sepsis carries vital communication, research, and population health benefits. Physicians in France can interpret a study of septic COVID-19 patients in Australia and feel confident that the study applies to COVID-19 patients fulfilling the same sepsis criteria within their own institution.

In addition, appropriate recognition and diagnosis give public health officials and epidemiologists more accurate measurements of the scale and burden of COVID-19 sepsis within a population, while allowing for monitoring of trends over time. This proves vital to our understanding of patients' responses to treatments and interventions across hospital systems and countries.

In critical care medicine, recognition and appropriate diagnosis is particularly important because of the numerous heterogeneous diseases and syndromes that lead to the common clinical manifestations of critical illness. In like manner, the importance of how clinicians describe and communicate COVID-19 illness and its clinical manifestations is influential across all levels of patient care and public health.

Current Definitions of COVID-19 Illness Severity Are Not Uniform

Throughout the literature, attempts to categorize COVID-19 illness severity have been broken down into "mild," "moderate," "severe," or "critical" categories, defined slightly differently depending on the source. The Centers for Disease Control and Prevention  has defined COVID-19 illness severity as "mild to moderate," "severe," and "critical." Under these definitions, severe COVID-19 includes dyspnea, hypoxia, and more than 50% lung involvement on imaging studies, and "critical" includes patients with evidence of multiorgan dysfunction and a dysregulated inflammatory response. Other sources define COVID-19 illness severity by respiratory criteria or ICU admission.

Although there is frequent overlap, we caution that these labels add to confusion in communication that can be detrimental to scientific and community understanding. Under these definitions, one region or individual clinician may characterize a patient as "severe" while another may characterize that same patient as "critical." This not only impairs communication, but it can also lead to skepticism and distrust. Applying consensus definitions mitigates this and utilizes structured communication systems already in place.

The World Health Organization defines COVID-19 severity of symptoms as they pertain to the severity of the resulting disease manifestation. In this guidance, established and agreed-upon definitions of pneumonia, ARDS, and sepsis are used as they apply to patients with COVID-19. If a patient meets diagnostic criteria for pneumonia caused by SARS-CoV-2 infection, they would have "COVID-19 pneumonia," which is categorized as moderate disease. If they fulfill ARDS or sepsis criteria, they are then classified as having "critical" disease. The definitions of pneumonia, ARDS, and sepsis do not change and are vital to characterizing disease severity while communicating an underlying pathophysiologic framework.

While ICU teams may still be gaining experience in understanding "severe COVID-19," they are experts in managing sepsis and ARDS. Using these established definitions can contribute to early recognition and diagnosis of sepsis and trigger important downstream actions focused on evidence-based treatment approaches to improve patient care. From a public health perspective, applying these appropriate diagnoses aids in providing a more accurate account of the epidemiology of the disease, implications for disease burden, and effectiveness of treatments or health interventions while guiding clinicians at the bedside.

Viral Sepsis Is Often Overlooked

The prevalence of viral sepsis globally is not unique to COVID-19 sepsis and is poorly understood in part because of underdiagnosis. This may be caused by an inability or failure to perform virus-specific diagnostic tests, undercounting due to "culture-negative" sepsis (which accounts for up to 42% of all cases), or attributing sepsis to common secondary bacterial infections. Underdiagnosis is problematic because appropriate recognition is important to understanding the interactions among the patient, the virus, and the immune response.

Furthermore, a diagnosis of viral sepsis carries important treatment and prognostic information gained from dedicated, extensive research. We have seen this in the use of tenofovir and interferon for hepatitis B infection and yearly updated vaccines and oseltamivir treatment for the influenza virus. With COVID-19 infection, therapies include corticosteroids, remdesivir, and anticoagulation, which have all been shown to decrease morbidity and improve patient outcomes in select populations. As we learn more, these therapies may expand to include convalescent plasma therapy, targeted antiviral drugs, vaccines, or other interventions aimed at reducing or preventing the manifestations of dysregulated responses to infection.

So why are we so hesitant to diagnose viral sepsis? For one, there are systems implications from hospitals reporting to the Centers for Medicare & Medicaid Services  wherein the Sepsis Management Bundle adherence is recorded. Under these bundles, hospitals could be penalized for failing to give the required 30-mL/kg volume expansion with an intravenous crystalloid or start broad-spectrum antibiotics in patients diagnosed as septic. Such actions, as a part of protocolized care, are potentially harmful for patients with viral sepsis, wherein large-volume resuscitation may worsen hypoxia and antibiotics may cause more harm than benefit.

It is more likely, however, that a diagnosis of viral sepsis is not made because of the misconception that sepsis is synonymous with a bacterial infection that has been identified (culture-positive sepsis) or not (culture-negative sepsis). This tunnel vision has potentially inhibited our awareness of the multitude of other causative sources of viral sepsis such as systemic herpes simplex virus, norovirus, viral meningitis, or HIV. Despite this common misperception, COVID-19 in its most severe manifestations can clearly be understood as a cause of sepsis that includes the subsequent organ dysfunctions commonly seen with this syndrome.

In Summary

The COVID-19 pandemic has presented monumental challenges to clinicians, scientists, epidemiologists, and public health officials. As we continue to treat this disease in the midst of rapidly accumulating knowledge, we must remember the importance of clarifying our language regarding the disease within our scientific and public health communities to fully capture its clinical impact. Appropriate diagnosis is crucial to how clinicians communicate with one another, patients and families, and policymakers.

We must navigate through many new phenomena in this global pandemic, but our diagnostic criteria have not changed for sepsis or other syndromes of critical illness. It is vital to patient care, both local and global, that we communicate effectively on behalf of our patients to define COVID-19 severity using established definitions, including clarifying COVID-19 as a potential cause of sepsis.

Christina S. Boncyk, MD, is an assistant professor in the Department of Anesthesiology, Division of Critical Care Medicine, at Vanderbilt University Medical Center in Nashville, Tennessee.

Matthew F. Mart, MD, is a clinical fellow in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University Medical Center.

E. Wesley Ely, MD, MPH, a subspecialist in pulmonary and critical care medicine, conducts patient-oriented health services research as a professor of medicine in the Division of Allergy, Pulmonary, and Critical Care Medicine at Vanderbilt University Medical Center. He is also a practicing intensivist with a focus on geriatric ICU care as the associate director for research for the VA Tennessee Valley Geriatric Research and Education Clinical Center.

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