Loop ileostomy for : Know thy enemyClostridium difficile: Know thy enemy infection: Know thy enemy

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To the Editor:
The EAST Multi-Institutional Trials Committee has produced a valuable study (J Trauma Acute Care Surg. 2017 Jul;83(1):36–40) investigating a possible role for constructing a diverting loop ileostomy (LI) as an alternative to a total colectomy in patients with Clostridium difficile infection (CDI) who are deemed to be deteriorating despite appropriate medical therapy. The number of CDI patients who require surgical intervention has, historically, been quite low (estimated to be <5% of all inpatients with CDI), making the multi-institutional retrospective methodology of this study more likely to accrue an adequate sample size compared with previous, unsuccessful attempts with prospective approaches. The authors of this study have provided a measured recommendation in favor of LI based, in part, on various adjusted mortality measures, including mortality attributed to second surgeries. I appreciate how reserved the authors' conclusions were, though I am concerned that the data presented in this study should be interpreted with even greater caution when previous research on the genetics and physiology of C. difficile is taken into account.
CDI is unique among the infections that surgeons treat in terms of the degree of inflammasome activation it induces, through both toxin-dependent and toxin-independent mechanisms.1 An example of this unique pathogen-host interaction is the frequent finding of white blood cell counts of 25 to 50 × 109/L or higher in CDI. A leukocytosis of this degree in virtually any other colorectal disease would be both uncommon as well as an indication for emergent surgical intervention. In CDI, there is evidence that although elevated white blood cell counts should not be ignored wholesale, they are unreliable in predicting mortality, the need for surgery, or even the severity of colitis.2 A further consideration is that although surgeons tend to discuss CDI as one disease, the contribution of bacterial strain to disease behavior is paramount to understanding CDI as well as for predicting whether a surgery such as LI would, from a microbiological perspective, even make sense as a treatment. Different strains of C. difficile have differential virulence patterns based in large part on phage-mediated horizontal gene transfer and the coevolution of bacterial docking sites for phage islands, which affect bacterial intoxication;3 more germane to the article being discussed, lysogeny can affect organism response to changes in the gut environment. Nonclinical studies have demonstrated increased toxin production in response to interruptions in glucose-based sources of nutrition4 and even in response to antibiotics, which happen to be similar ambient changes created by diverting a patient with CDI and irrigating their large intestine with intraluminal antibiotics. Thus far, surgeons investigating the role of LI in CDI have yet to incorporate these factors into their discussion of the disease; many surgeons may not even be aware of these considerations, since they are exclusively reported in nonclinical journals.
In the current study, the median white blood cell counts, blood pressures, and heart rates of study subjects were either normal or close to normal, raising concerns that perhaps the patients with renal failure and hemodynamic compromise requiring vasopressors may have been underresuscitated as opposed to having medically refractory CDI despite maximal supportive care. There is no mention of whether immunocompromised patients were included, and how such subjects were analyzed if present. This point is extremely important since although immunosuppression may be associated with an increased risk of developing CDI, it may also serve to decrease the severity of toxin-induced cytopathy, since the large Clostridial toxins require fully functional neutrophils5 to exert their full effect.
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