Did They Just Prove That a Diagnosis of “Septic Shock” Is Meaningless?

Annane and colleagues’ oft-cited 2005 review of septic shock in The Lancet features a lovely set of graphics (1). In their Figure 1, there is a small oval at the top labeled “Bacteria.” This generic infection triggers at least eight separately identified effector pathways, which ramify out to show the multiple systems that lead “from bacteria to disease.” In their Figure 2, dozens of intracellular interactions are laid out, but the only vestige of the bacteria is an extracellular lipopolysaccharide. By 2013, Figure 1 of Angus and van der Poll’s NEJM review is entirely about the “Host Response in Severe Sepsis”—the pathogens are nearly invisible (2). In this understanding of severe sepsis, the story is about the host response, particularly the dysregulated inflammatory and coagulopathic cascades. Pathogens enter only to the extent that they create physiologically interesting molecular patterns that trigger this host response. In this issue of the Journal (pp. 1204–1213), the Co-operative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group, led by Dr. Leligdowicz, seeks to inject a note of discord into this perspective (3). This is a group well known to intensive care unit practitioners and researchers alike—the group whence our best evidence for the critical importance of time to antibiotics in septic shock came (4). In an expanded database, the authors now ask, are all infections really the same once they produce septic shock? Leligdowicz and colleagues suggest there are important differences within septic shock. The group examined a cohort of nearly 8,000 patients diagnosed with septic shock. They found that there was clinically meaningful and statistically significant variation in hospital mortality as a function of the source of infection. Adjusted mortality varied among sites from about one-third (diverticulitis and obstruction-related urinary tract infection) to nearly three-fourths (several abdominal infections). This variation persisted after adjusting for a multitude of predisposing and downstream factors, including year of admission, demographics, 12 comorbidities, and even Acute Physiology and Chronic Health Evaluation II (APACHE II) score. The authors suggest that we should take into account sources of infection so that patients are appropriately risk stratified and all potential factors impacting mortality are evaluated for interventions. The authors have shown that there are crucial differences in short-term outcomes by source of infection in patients with septic shock. Have they thereby proven the “host response” consensus to be wrong? More generally, have they shown that our current understanding of “sepsis” as a meaningful diagnosis is too severe an oversimplification? These questions hinge on what exactly we want from a diagnosis. The conflict over the Berlin definition of acute respiratory distress syndrome may be interpreted in a similar light (5, 6). It may be, we would like to suggest, that we want too many things from a single diagnosis—even a disease diagnosis, let alone an admittedly “syndromic” diagnosis (see Table 1). Table 1: The Uses of Diagnosis For some situations, particularly those of research, a diagnosis should be straightforward: it is a clinical representation of a unique pathological disturbance. What we want from a diagnosis is to define a sufficiently homogenous clinical entity for which we can work to identify the specific mechanism that produces said diagnosis. Such an understanding of diagnosis is particularly useful for driving forward animal-based research and ensuring close correlations between animal and human models of a condition. In contrast, at other times, the point of making a diagnosis is that it allows one to bring treatment to bear. Distinctions in diagnosis that do not lead to differences in treatment may be intellectually intriguing, but are thought to be of no clinical consequence. The art of diagnosis is then the art of matching efficacious treatments to the patients who will benefit from those interventions. In still other situations, we want a diagnosis to imply a coherent natural history and predictable course. A diagnosis that implies too wide an array of outcomes can lead to little informed patient decision making. In the long term, such a diagnosis implies the need to simply wait and see. In the short term, such variability precludes the ability to detect when things are going off track, or even when a second look is necessary to reconsider an alternative diagnosis. From this prognostic standpoint, consistency of future course is the key requirement for a workable diagnosis. Finally, sometimes the point of a diagnosis is communication—with ourselves and with other clinicians. A diagnosis is a cognitive shorthand that lets us reduce the complexity of an individual’s story into an archetype so we can remember what is going on with that patient and share that understanding with others to coordinate care. In an ideal world, these different desires would all point in one direction. In the real world, there is at best a loose coupling between any of these. Dr. Leligdowicz and colleagues’ work certainly suggests that septic shock, as currently implemented, fails to meet the coherent natural history standard. This is true at least for short-term mortality, and we can only speculate about longer-term patient-centered outcomes. Such heterogeneity implies concerns about a host of dependent issues, including unmeasured heterogeneity in clinical trials and insufficient risk adjustment in current severity of illness scores that lump everything together as “septic shock.” These findings also imply that there is important work to be done in understanding the variation in host response between sources of infection, and in finding practical ways to get all abdominal infections to behave more likely diverticulitis. This article may suggest that insufficient attention is being devoted to source-specific treatment investigations. In the meantime, septic shock remains a pragmatically useful organizing concept—although perhaps more like “cancer” than “HER2/neu–overexpressing stage IIA breast cancer.” Our resuscitations are still usefully guided by a notion of septic shock while we complete our efforts at source control (7, 8). Long-term outcome studies have not yet shown meaningful differences in outcomes across sites of infection, although existing efforts were underpowered to rule out such a possibility (9). The urgent challenge remains to integrate epidemiologic insights such as those from the current article into clinically relevant animal models and treatment trials. Dr. Leligdowicz and colleagues suggest there may be great benefits from bringing the source of the infection back into the forefront of septic shock research.