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The Sepsis Umbrella

November 15, 2022

When most people hear the diagnosis of sepsis, they think of one of two things: oh my god or…what the heck is that? However, when I see the diagnosis of sepsis, my mind turns to one thing which I call the sepsis umbrella. For the sepsis umbrella to make sense, let’s first define what sepsis is and why this particular disease is so baffling. 

 

Sepsis is often defined as an uncontrolled systemic immunological response to an infection through which progression can result in organ dysfunction and death. This is not the only definition of sepsis as, in 2016, sepsis was redefined as a “life threatening organ dysfunction caused by a dysregulated host response to infection”, aka Sepsis-3 (Singer, et al.). If this wasn’t already convoluted enough, it gets worse as there is an additional subsection of sepsis known as septic shock. Septic shock is a highly severe form of sepsis where “underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone” (Shankar-Hari, et al.). This is a lot to unravel and there’s no better place to start then with the actual symptoms and progression of sepsis.

 

At this point you probably won’t be surprised when I tell you that, like its definition, the symptoms of sepsis are very non-specific. A patient with a mild case can appear almost asymptomatic while other sepsis patients can be at death’s door. So how is sepsis even diagnosed? Generally, a patient diagnosed with sepsis will have a pre-existing infection such as skin or wound infections, infections to a surgical site, or even viral infections. The initial infection must also present with symptoms that fall under the systemic inflammatory response syndrome (SIRS) or the multiorgan dysfunction syndrome (MODS) criteria to be qualified as sepsis. 

 

The SIRS criteria consist of four key symptoms: fever, tachycardia (elevated heart rate), tachypnea (breathing fast), and leukocytosis (elevated white blood cell count). To have sepsis a patient must have an initial infection coupled with 2 of the SIRS symptoms. As the infection and uncontrolled immune response progresses past the SIRS criteria, the patient begins to experience a decline in peripheral vascular perfusion (decreased blood flow to peripheral tissues) and tissue hypoperfusion (decreased blood flow to the organs). At this point the patient is entering septic shock as their body continues its inflammatory response with decreased blood movement and increased organ dysfunction. If the patient is being treated at this time but continues to decline, then they have reached MODS criteria and are in critical state. Unfortunately, there is a 75% mortality rate after MODS is reached.

So why bring all of this up? While sepsis is a diagnosis on its own, it is not a disease that begins without an initiating infection. This is important because it can have massive effects on the way we study sepsis. Consider this: sepsis can stem from any form of infection including viral infections, fungal infections, and bacterial infections. Each of these infections have a different infectious process and they can result in sepsis at different rates, frequencies, and severities.

 

 Furthermore, when do we classify an infection as being septic rather than a natural progression of the disease? For example, there are many symptom similarities between severe COVID-19 (progressed infection leading to decreased oxygen levels, tachycardic, fever, etc.) as sepsis, which could classify many COVID-19 patients as having sepsis. And yet, these patients are not classified as having sepsis. Additionally, a patient with cancer may produce laboratory results that correlate with sepsis but not actually be septic. How do you narrow this down to form one conclusive definition and treatment? Simply put, you can’t. Sepsis is, by its epidemiology and definition, an umbrella term. 

 

This sepsis umbrella is detrimental for scientists studying sepsis. To counter this, I’d like to propose a new use of the sepsis umbrella. Instead of diagnosing sepsis at any progressed infection with uncontrolled immune response, we should shift to describing an infection as becoming septic rather than being sepsis. While this may seem like a simple change, it opens the door for researchers to specify what they are studying and to consider how individual pathogens are able to produce such drastic responses. Shifting our use of sepsis would also prevent infections, such as COVID -19, from being ruled out of this definition due to their prevalence or acute manifestations. Ultimately, getting rid of the sepsis umbrella isn’t the answer but we do need to learn how to close it. After all, opening an umbrella indoors is bad luck. 

 

 

References:

Center of disease control: What is sepsis – https://www.cdc.gov/sepsis/what-is-sepsis.html

Gyawali, B., Ramakrishna, K., & Dhamoon, A. S. (2019). Sepsis: The evolution in definition, pathophysiology, and management. SAGE open medicine, 7, 2050312119835043. https://doi.org/10.1177/2050312119835043

 

Huang, M., Cai, S., & Su, J. (2019). The Pathogenesis of Sepsis and Potential Therapeutic Targets. International journal of molecular sciences, 20(21), 5376. https://doi.org/10.3390/ijms20215376

 

Koçak Tufan, Z., Kayaaslan, B., & Mer, M. (2021). COVID-19 and Sepsis. Turkish journal of medical sciences, 51(SI-1), 3301–3311. https://doi.org/10.3906/sag-2108-239

 

Mahapatra S, Heffner AC. Septic Shock. [Updated 2022 Jun 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430939/

 

Markwart, R., Saito, H., Harder, T., Tomczyk, S., Cassini, A., Fleischmann-Struzek, C., Reichert, F., Eckmanns, T., & Allegranzi, B. (2020). Epidemiology and burden of sepsis acquired in hospitals and intensive care units: a systematic review and meta-analysis. Intensive care medicine, 46(8), 1536–1551. https://doi.org/10.1007/s00134-020-06106-2

 

 Shankar-Hari, M., Phillips, G. S., Levy, M. L., Seymour, C. W., Liu, V. X., Deutschman, C. S., Angus, D. C., Rubenfeld, G. D., Singer, M., & Sepsis Definitions Task Force (2016). Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315(8), 775–787. https://doi.org/10.1001/jama.2016.0289

 

Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G. R., Chiche, J. D., Coopersmith, C. M., Hotchkiss, R. S., Levy, M. M., Marshall, J. C., Martin, G. S., Opal, S. M., Rubenfeld, G. D., van der Poll, T., Vincent, J. L., & Angus, D. C. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315(8), 801–810. https://doi.org/10.1001/jama.2016.0287

 

World health organization: Sepsis – https://www.who.int/news-room/fact-sheets/detail/sepsis

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About Author

As a GT undergrade in biology and medical scribe, Jamesie has a passion for medicine and understanding the physiological and underlying mechanisms behind our favorite diseases.

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  Timothy Durham was convicted of rape when a test showed his DNA genotype matched the DNA recovered from the crime scene. Eye witnesses testified that Durham was in a different state at the time of the incident, but he wasn’t exonerated from his 3000 year sentence until follow up DNA analysis showed that the preliminary forensic analysis used in the trial was misinterpreted (Thomas et al.). DNA testing serves an invaluable part in our criminal justice system, but it comes with complications and bias that can lead to wrongful convictions and misinformed juries.  

Background:

Forensic genetics aims to identify the origin of a biological sample. It can be traced back to Karl Landsteiner who discovered human ABO blood groups. With blood groups, suspects could be eliminated based on their blood type. For example, if a suspect had type A blood and there was type B blood left at the scene by the perpetrator, the investigators could rule out the suspect. Unfortunately, the reverse didn’t work. If the suspect and perpetrator both had the same blood type, it can’t be concluded that the suspect was guilty. Blood identifiers evolved into 8 distinct categories which improved the ability to eliminate suspects, but could only conclude that (if the system matched) it might be the perpetrator or this person might be related to the perpetrator (Jobling and Gill). The field evolved in the 1980s with the discovery of Minisatellites, lines of repetitive DNA that don’t encode proteins. Minisatellite patterns in DNA create what we know today as the DNA fingerprint, and it has a much higher accuracy rate than previous methods (Augustyn et al.). Around the same time, a breakthrough for victims of sexual assault was discovered. In the case of assault, bodily fluids of both the victim and the assaulter can get mixed. A process called differential lysis was created which could selectively increase the concentration of sperm in a fluid sample thereby allowing for accurate DNA testing (Jobling and Gill). Forensics evolved to use single-locus probe testing after several years because of its ease of interpretation. It looked at specific minisatellites that had high variability between subjects. This was the first DNA-based method to be used in a criminal investigation. Two murder homicides from several years apart were connected using DNA evidence. The evidence was then used to exonerate an innocent man, and the guilty party was found when he tried to evade mandatory DNA testing for all men in the small town. His guilt was then reinforced when the DNA profiles matched, and he gave a confession (Jobling and Gill). Finding DNA at a crime scene doesn’t guarantee that you’ll find a murderer. There are issues with non-pure samples and limited samples that make DNA work difficult, and accreditation of facilities and new techniques and take time (Jobling and Gill).  

Subjectivity of DNA Interpretation:

In a 2009 publication, the National Academy of Science discusses the possibility for subjective influence in lab based forensics. The interpretation bias happens in complex cases where, for example, there could be a mixture of DNA. A study published in 2011 looked specifically at this issue. A gang rape happened in Georgia, and the mixture in DNA from the case was used to prosecute one suspect after another suspect took a plea bargain to testify against him. With DNA mixtures, there are three possible conclusions: suspect excluded, suspect cannot be excluded, and inconclusive. If the suspect is excluded, it means that there’s little to no possibility that his DNA is part of the sample. If the suspect cannot be excluded, it means that there’s a possibility that his DNA is part of the sample. In the trial, the DNA examiners who knew the context of the case concluded that the suspect being prosecuted could not be excluded. The 2011 study gave the DNA evidence from this case and the DNA profiles of the suspects to 17 forensic examiners. These examiners had no context of the case, and they all worked independently. Of the 17, only 1 came to the same conclusion (suspect cannot be excluded) as the examiners who knew the context of the case. Twelve of the 17 concluded that the suspect who was prosecuted and convicted had no relation to the DNA found in the sample. Not only does this show that subjectivity occurs due to the context of the case, but the 17 examiners came up with different findings based on their past experiences meaning that not all DNA analysis is objective. Some organizations like the Scientific Working Group on DNA Analysis Methods say that quantitative statistical evidence should be presented with every categorical conclusion, but the US doesn’t require this (Dror and Hampikian).

False Positives:

There are two categories that cause wrongful identification in a DNA report: coincidental matches and false positives. Coincidental matches are DNA matches between two unrelated people. The probability of these matches is about 1 to 500,000 for white individuals and about 1 to 350,000 for black individuals. This small probability of coincidental matches makes people feel confident in DNA evidence. False positives, on the other hand, are matches between DNA and test DNA that result from issues in the forensics lab. There have been multiple cases of forensics labs accidentally switching victim and suspected rapist DNA which lead to convictions that were later overturned when the lab realized the error. There are also cases of misreading or misunderstanding a sample. In a case from 1993, a man was convicted of rape because someone interpreted a mixed sample of victim and perpetrator DNA as an individual sample. The conviction was again overturned. To prevent false convictions, retesting DNA is allowed, but it’s not an efficient solution. Many people are pushing for statistical information on the probability of false positives, so that the jurors can make accurate judgements based on DNA evidence (Thomas et al.).  

Conclusion:

DNA analysis is a useful tool for the criminal justice system, but subjectivity can be an issue in forensic testing. To combat wrongful convictions, there are organizations like The Innocence Project who use DNA testing to free the innocent, but reformed forensic testing standards should be put in place to prevent subjectivity and to ensure juries are correctly informed during trials. https://www.innocenceproject.org/    

Citation:

Augustyn , Adam, et al. “DNA Finerprinting.” Encyclopedia Britannica , 26 Apr. 2018, www.britannica.com/science/DNA-fingerprinting#ref153186. Dror, Itiel E., and Greg Hampikian. “Subjectivity and Bias in Forensic DNA Mixture Interpretation.” Science & Justice, vol. 51, no. 4, 2011, pp. 204–208., doi:10.1016/j.scijus.2011.08.004. Jobling, Mark A., and Peter Gill. “Encoded Evidence: DNA in Forensic Analysis.” Nature Reviews: Genetics, vol. 5, no. 10, Oct. 2004, pp. 739–751., doi:10.1038/nrg1455. Thompson, William C, et al. “How the Probability of a False Positive Affects the Value of DNA Evidence.” Journal of Forensic Sciences, vol. 48, no. 1, Jan. 2003, pp. 1–8., doi:10.1520/jfs2001171.