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Sepsis, a deadly overreaction of the immune system to infection, has befuddled clinicians and researchers for decades. Covid-19 made things worse.

The early signs and symptoms of sepsis mimic those of both Covid-19 and influenza: fever, chills, dry cough, shortness of breath, fatigue, muscle or body aches, sore throat, nasal congestion, runny nose, and more. This overlap delays accurate diagnosis which, in the case of sepsis, can mean the difference between life and death.


Sepsis kills approximately 350,000 Americans a year, and as many as 11 million people globally. The U.S. spends an estimated $62 billion annually on sepsis treatment, making it the most expensive in-hospital therapeutic cost, and represents the most costly in-patient condition covered by Medicare. Early diagnosis is key to reducing the substantial burden of this condition.

By the time sepsis has been definitively diagnosed using traditional standard techniques, which can take between 24 to 72 hours, multisystem organ failure may have begun. Survivors of mild sepsis are at increased risk of developing future infections, while as many as 40% of those with severe sepsis and septic shock die. Every one-hour delay in administering targeted antibiotics, antifungals, or antivirals after emergency department triage or the onset of organ dysfunction or shock increases the odds of a poor outcome by 3% to 7%. Identifying the source of the infection that is putting the immune system into overdrive is a key step in treatment.

An article we recently published with several colleagues in the journal Open Forum Infectious Diseases explores the clinical challenge of identifying sepsis in people with severe Covid-19. The symptoms and organ dysfunction might be due to infection with SARS-CoV-2, the virus that causes Covid-19, or to sepsis from a concurrent viral, bacterial, or fungal infection, or both. It is critical to identify whether a second pathogen is present, as well as its sensitivity, for treatment to be effective.


Whenever the immune system is highjacked by a microbe, the body’s defenses can become self-destructive. The pathogens shut down one part of the immune cascade (the classical pathway) while shifting another part (the lectin pathway) into a hyperactive state. This hyperactivity drives the release of cytokines which, in their normal state, control the growth and activity of blood and immune system cells.

Hyperactivation of the lectin pathway generates what is known as a cytokine storm. System-wide inflammation ensues, most notably in the lining of blood vessels. The ensuing damage causes the formation of small blood clots, known as micro-clots. These can travel to every organ and incrementally cut off its blood supply.  With compromised circulation, the affected organ will begin to fail. Whether the immune system is disrupted by SARS-CoV-2, another virus, a bacterium, or a fungus, the damage is the same.

Despite the lack of rapid accurate diagnosis, many hospitals begin treating patients with suspected sepsis empirically with broad-spectrum therapies. Such treatment may not only be inappropriate and expensive, but may also harm patients. Another dangerous sequela of unnecessary treatment is the development of antimicrobial resistant organisms, which is a huge global problem.

Addressing this challenge requires investments in better diagnostics and therapeutics.

The development, adoption, and deployment of rapid point-of-service and bedside diagnostics that can accurately identify pathogens and any drug resistance is essential to correctly treat them. Apart from a few major academic medical centers, most patients and clinicians lack access to the latest diagnostic technologies. The lack of access results not only in delayed diagnosis and treatment, but also allows disease progression that makes patients sicker, more likely to need hospitalization, and more difficult to cure. Simple, rapid, accurate, and portable diagnostics have the potential to revolutionize health care. There may be pushback to such innovation from those vested in the traditional diagnostic laboratory infrastructure but the benefits to patients and clinicians will justify the effort.

Restoration of normal immune function is key to treating patients with sepsis. Agents that restart the classical pathway and rein in the runaway lectin pathway reduce damaging inflammation, endothelial blood cell damage, and clot formation, thus maintaining organ function. Researchers in Europe have found one such agent to be of great effectiveness in restoring immune system function in severe Covid-19 patients. Only with incentives, support, and funding, will such breakthroughs be accessible to US patients.

We see three obstacles to implementing our recommendations: clinical hubris, inertia, and reluctance to invest in biotechnology.

Hubris is an obstacle at all levels because, in science, there are few absolutes. Any individual, group, or society claiming to be all-knowing in matters scientific are deceiving themselves. Humility ensures consideration of advancements regardless of the country or strata of origination.

In medical practice, inertia is akin to complacency. Justifying one’s medical decision-making based on one’s education, training, and experience comes with a caveat. What was once standard practice may need to be refined as new information accrues. Continuing to treat because “I have always done it that way” is not sound practice. Most find change uncomfortable but, when it comes to medical care, it is essential.

The third obstacle is the need for more and better cooperation between the public and private sectors through incentives and funding of innovative research.

We live in a world of microbes. They are not going away. Covid-19 and Covid-related sepsis have a lot to teach us if only we listen and learn.

Richard A. Marfuggi is a surgeon, medical director of the WBB Research Institute, a commissioner of the American Medical Association Foundation, and a member of the New Jersey State Biomedical Ethics Committee. Aparna Ahuja is the Divisional Vice President, Medical, Clinical and Scientific Affairs at Abbott ID Rapid Diagnostics. Rick A. Bright is an immunologist, vaccine researcher, and public health official who served as director of the Biomedical Advanced Research and Development Authority from 2016 to 2020.

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