The premise of the question highlights two major issues with sepsis
- One, infections associated with sepsis.
- Two, how sepsis is diagnosed.
Infections associated with sepsis
- While infections are indeed often associated with sepsis, it doesn’t necessarily start with an infection.
- Sepsis results from a complex interaction between an acute triggering insult, its fallout and the body’s response.
- The triggering insult could start out local and become systemic, i.e., spread throughout the body, or start as a systemic insult.
- This is because the triggering insult in sepsis includes not just infection but also major trauma like vehicular accidents, burns, major surgery, severe tissue injury due to such as after a cardiac arrest, etc.
- Common feature is an inadequately controlled or out of control distress response that through the bloodstream becomes systemic, i.e., involving the entire body.
- Infections could thus be either triggers that start the process or opportunists that become involved as a result of the body’s depleted capacity to maintain its homeostasis, especially at the barriers.
- The body’s barriers function to maintain its integrity by limiting entry and damage by triggering insults, be they infections or trauma.
- The body’s barriers essentially consist of two types.
- The outside barriers are the portals of entry, namely, skin and mucosal surfaces, i.e., epithelia.
- Barrier within our body is blood circulation, i.e., the endothelia, which limits distribution within and between tissues and organs.
- Major problem in sepsis is that both epithelia and endothelia malfunction in their barrier function.
- Thus, after major trauma such as auto accidents, burns, major surgery, heart attacks, etc., even if an infection doesn’t start the sepsis process, it’s often, not always, part of the fallout of the initial trigger.
- Why does trauma sometimes and not always result in sepsis? Reason is still unclear.
- The following hypothesis (1) tries to explain how, rather than the infection per se, baseline circulating immune status of patients could explain whether they can quickly control post-trauma opportunist infection (bacteria/fungi/parasites/viruses) or not (see figure below from 1).
How sepsis is diagnosed
- Given this inherent complexity in how sepsis starts, there is a long-standing problem with its definition and diagnosis.
- Roger Bone first attempted a medical definition of sepsis or rather ‘sepsis syndrome‘ in 1987 (2).
- ~30 years later, there is still no consensus on its definition in medicine.
- This makes it a most acute problem for patients who aren’t accurately diagnosed with severe sepsis.
- This is because the current consensus requires Infection + Organ failure + SIRS.
- SIRS or Systemic Inflammatory Response Syndrome is a list of ambiguous clinical signs and symptoms considered indicative of sepsis (see figure below from 3).
- A recent, large retrospective study (4) highlights this flaw in current sepsis definition.
- They studied data from 172 intensive care units in Australia and New Zealand from 2000 until 2013.
- They examined the records of a total 1, 171, 797 patients.
- 109, 663 had Infection + Organ failure; 96, 385 of these were SIRS-positive and 13, 278 SIRS-negative.
- Both groups had similar mortality rates yet the latter group of 13, 278, i.e., 1 in 8, would be excluded from a severe sepsis diagnosis, and thus not treated for it. Neither did SIRS diagnosis improve prediction of mortality.
- Fact that the two groups still had similar mortality also highlights deficiencies in current sepsis treatments, much of it fueled by the ongoing ambiguity in sepsis definition and diagnosis.
- The most recent Surviving Sepsis Campaign guidelines define sepsis as ‘the presence (probable or documented) of infection together with systemic manifestations of infection‘ (5).
- Since this modified definition doesn’t emphasize SIRS, theoretically, patients with infection + organ dysfunction/failure could be diagnosed with sepsis, and treated accordingly (see figure below from 3).
- However, consensus on sepsis definition remains a work in progress.
‘If so, then how is the infection found?’.
- An extremely vexing question for a clinician since post-trauma opportunist infection could be bacteria/fungi/parasite/virus.
- Bacteria are relatively easy to diagnose through culture.
- Fungi and parasites are suspected based on clinical symptoms.
- Viruses could be detected using sensitive molecular assays.
- Given such a broad possibility of suspected infectious agent, the problem is two-fold,
- First, to diagnose sepsis as early in the process as possible. This is currently far from straight-forward as we see above. Sepsis research suggests high circulating levels of certain molecules such as procalcitonon or C-reactive protein are related to ongoing systemic infection. Problem is so far nearly 200 molecules have been identified as so-called sepsis markers and there is no consensus yet on which, if any, are definitive (6, 7). As a recent review notes, ‘Unfortunately, no satisfactory biomarkers exist that can be used to diagnose sepsis, unlike disorders such as hypertension or diabetes mellitus, which have clear cut, internationally accepted criteria‘ (8).
- Two, start measures to control the infection as early in the process as possible. This is easiest to do to control bacteria, i.e. broad-spectrum antibiotics. If patient’s condition improves with this, it’s proof that opportunist infection was likely bacteria. In other words, purely empirical.
Ultimately, empirical data generated over the past 3 decades in developed countries suggests that timely antibiotics, fluids and oxygen prevent sepsis mortality, but only in subsets of patients, not in all. We still lack essential understanding of host factors that predispose humans to sepsis.
- Chen, Peter, Mile Stanojcic, and Marc G. Jeschke. “Differences between murine and human sepsis.” Surgical Clinics of North America 94.6 (2014): 1135-1149.
- Bone, Roger C., et al. “A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock.” New England Journal of Medicine 317.11 (1987): 653-658.
- Drewry, Anne M., and Richard S. Hotchkiss. “Sepsis: Revising definitions of sepsis.” Nature Reviews Nephrology 11.6 (2015): 326-328.
- Kaukonen, Kirsi-Maija, et al. “Systemic inflammatory response syndrome criteria in defining severe sepsis.” New England Journal of Medicine 372.17 (2015): 1629-1638.
- Dellinger, R. Phillip, et al. “Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012.” Intensive care medicine 39.2 (2013): 165-228.
- Reinhart, Konrad, et al. “New approaches to sepsis: molecular diagnostics and biomarkers.” Clinical microbiology reviews 25.4 (2012): 609-634.
- Seymour, Christopher W., and Matthew R. Rosengart. “Septic Shock: Advances in Diagnosis and Treatment.” JAMA 314.7 (2015): 708-717.
- Cohen, Jonathan, et al. “Sepsis: a roadmap for future research.” The Lancet Infectious Diseases 15.5 (2015): 581-614.