Unmasking the Impact of SARS-CoV-2: Viral Sepsis and Its Hidden Toll on Global Health


Sepsis, a life-threatening condition characterized by a dysregulated host response to infection, has long been synonymous with bacterial infections in both clinical practice and medical research.

However, the landscape of sepsis is far more complex than this traditional association suggests. In recent years, there has been a growing realization that viral infections can also lead to sepsis, challenging our understanding of this critical medical condition.

The Changing Face of Sepsis

Sepsis is a global health crisis, responsible for a significant proportion of deaths, disabilities, and healthcare expenditure worldwide. Historically, the medical community primarily equated sepsis with bacterial infections, leading to a skewed perception of its epidemiology. Many epidemiological studies of sepsis have reported negligible proportions of viral sepsis, often due to underrecognition and undertesting rather than the actual absence of viral sepsis.

However, recent events, particularly the SARS-CoV-2 pandemic, have dramatically shifted this perspective. Alongside COVID-19, surges in respiratory syncytial virus (RSV) and influenza have highlighted the significant role that viral infections can play in the overall burden of sepsis. As our understanding of sepsis evolves, it has become clear that viral sepsis is a crucial aspect of this condition, deserving of rigorous study and analysis.

The Missing Data on Viral Sepsis

Despite the growing recognition of viral sepsis, comprehensive data regarding its incidence and mortality remain elusive. The limited availability of such data is largely attributed to factors like slow adoption and inconsistent use of the term “sepsis” to describe severe viral infections accompanied by organ dysfunction. Previous investigations into SARS-CoV-2-associated sepsis have been hampered by small sample sizes, single-center designs, heterogeneous definitions of organ dysfunction, and reliance on data from the early stages of the pandemic.

A New Approach to Surveillance

In response to these challenges, electronic health record (EHR)-based surveillance has emerged as the gold standard for widescale sepsis monitoring. This approach employs clinical markers of concurrent infection and organ dysfunction to provide objective and reproducible analyses across different healthcare facilities.

The US Centers for Disease Control and Prevention (CDC) has embraced this method to quantify the national burden of sepsis. EHR-based surveillance is particularly well-suited to adapt to changes in the perception of sepsis, improved diagnostic awareness, evolving definitions, changes in reimbursement mechanisms, and a deeper understanding of the potential for viruses to induce sepsis, as underscored by the COVID-19 pandemic.

EHR-Based Surveillance for Viral Sepsis

This study represents a significant step forward in the understanding of viral sepsis. Researchers developed and validated an EHR-based definition of SARS-CoV-2-associated sepsis, modeled after the CDC’s adult sepsis event (ASE) criteria.

The application of this definition to a large healthcare system allowed for robust estimates of the incidence, mortality, and trends associated with SARS-CoV-2-associated sepsis throughout different phases of the COVID-19 pandemic. These findings were then compared with traditional presumed bacterial sepsis, shedding light on the relative impact of viral and bacterial infections on sepsis.

Discussion: Unveiling the Impact of SARS-CoV-2 and Viral Sepsis

In this comprehensive study, we delved into the previously uncharted territory of SARS-CoV-2-associated sepsis, shedding light on its incidence, mortality, and impact in comparison to presumed bacterial sepsis. The data collected from over 400,000 hospital admissions across five Massachusetts hospitals during the first 33 months of the COVID-19 pandemic provided valuable insights into this evolving medical landscape.

Incidence and Trends in SARS-CoV-2-Associated Sepsis

Our findings unveiled a startling revelation: SARS-CoV-2-associated sepsis was present in a substantial 28.2% of patients admitted with SARS-CoV-2 infections. This discovery challenges the conventional understanding of sepsis as primarily bacterial in origin. Moreover, the incidence of SARS-CoV-2-associated sepsis fluctuated in concert with changes in local community incidence. It’s important to note that this incidence trended toward fewer cases over time, reflecting the dynamic nature of the COVID-19 pandemic.

In contrast, bacterial sepsis, though less common at 7.1% of hospitalizations, exhibited a relatively stable in-hospital mortality rate of 14.5% throughout the study. This comparison emphasizes the variability and complexity of sepsis, with viral sepsis contributing significantly to the burden of this condition during the study period.

A Groundbreaking Study

To our knowledge, this study stands as the first systematic comparison of the incidence and mortality rates between SARS-CoV-2-associated sepsis and presumed bacterial sepsis. Prior investigations during the early stages of the COVID-19 pandemic relied on pooled organ dysfunction and replacement as proxies for sepsis, limiting their ability to precisely calculate mortality rates. Our study addressed this limitation by employing objective EHR-based criteria adapted from the CDC’s ASE, ensuring accurate and consistent estimates of sepsis prevalence and mortality throughout the study period.

Our approach to surveillance was bolstered by the near-universal testing of all hospitalized patients during the initial years of the pandemic. This strategy allowed us to capture cases comprehensively, overcoming the historical challenge of undertesting for viral sepsis. Our surveillance definition demonstrated robust performance in identifying SARS-CoV-2-associated sepsis, with high sensitivity and specificity compared to sepsis-3 criteria applied through physician review. This alignment between our EHR-based approach and previous methods using medical record reviews underscores its validity.

Mortality Trends: Lessons Learned

The analysis of in-hospital mortality rates yielded intriguing results. Initially, the mortality rate for SARS-CoV-2-associated sepsis was alarmingly high at 33.4%. However, this rate steadily decreased to 14.9% by November 2022, mirroring trends in improving outcomes for patients with COVID-19. Several factors likely contributed to this decline, including increased immunity due to vaccines and prior infections, advancements in patient management, such as the use of antivirals and immunomodulators, and the reduced strain on hospital capacity. Notably, our analysis revealed nonlinear improvements and even increases in severe COVID-19-associated mortality during certain phases of the pandemic, potentially related to variant virulence and healthcare system strain.

Challenges in Distinguishing Viral from Bacterial Sepsis

Distinguishing pure viral sepsis from bacterial sepsis related to non-SARS-CoV-2 coinfections or superinfections remains a challenge in an EHR-based approach. Nevertheless, the majority of patients with SARS-CoV-2-associated sepsis exhibited negative blood or sputum cultures, indicating that SARS-CoV-2 itself was the primary driver of sepsis in most cases. This aligns with prior studies demonstrating that bacterial coinfections were exceptions rather than the norm in COVID-19 hospitalizations. However, these patients remained at high risk for nosocomial bacterial infections, as evidenced by a higher prevalence of positive cultures during their hospitalizations.

Implications and Future Directions

Our findings carry significant implications for clinical practice and research. Firstly, they underscore the underrecognized contribution of viral pathogens to sepsis and highlight the need for a nuanced approach to sepsis diagnosis and treatment. Current protocols often assume bacterial sepsis and recommend broad-spectrum antibiotics and intravenous fluids for all sepsis patients. Increasing awareness of nonbacterial sepsis underscores the necessity of tailoring diagnostic and therapeutic strategies to the specific syndrome and likely pathogen of each patient.

Research aimed at developing diagnostic tests and biomarkers for viral pathogens, as well as host-pathogen metagenomics, is actively underway. Future studies should focus on safe and effective strategies for rapidly distinguishing sepsis caused by different pathogens, enabling more targeted treatment and better antibiotic stewardship.

Lastly, while our analysis centered on SARS-CoV-2-associated sepsis, other respiratory viruses, such as influenza A, influenza B, and RSV, can also induce severe disease resembling viral sepsis. The approach outlined in this study can serve as a valuable template for defining the burden and outcomes of other causes of respiratory viral sepsis, particularly during seasonal surges. As we continue to unravel the complexities of sepsis, it is crucial to remain vigilant in our pursuit of knowledge and innovation to improve patient care and reduce the global burden of this life-threatening condition.


In conclusion, sepsis is a multifaceted medical condition that extends beyond the historical association with bacterial infections. Viral sepsis, as demonstrated by the SARS-CoV-2 pandemic and other viral outbreaks, represents a significant and underrecognized aspect of the sepsis landscape. This study’s innovative use of electronic health records and refined definitions offers valuable insights into the true incidence and mortality of SARS-CoV-2-associated sepsis. By acknowledging and studying viral sepsis alongside bacterial sepsis, we can enhance our ability to diagnose, treat, and prevent this deadly condition, ultimately saving more lives and reducing its global burden.

reference link:https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2809966


Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.