Severe Clostridium difficile Infection

Today’s hypothetical case centred around a middle-aged man recently diagnosed with diffuse large B-cell lymphoma.  He had been treated with R-CHOP, experienced an episode of neutropenic fever with no obvious source, and was admitted to hospital.  He received broad-spectrum antibiotics, and his counts improved.  Two days after discharge, he began to have non-bloody diarrhea.  This progressed for 7 days until he presented back to the ED with profuse, non-bloody diarrhea and crampy abdominal pain.  He was afebrile, but had tachycardia as well as orthostatic symptoms.  His physical examination was remarkable for volume depletion, but not peritonitis.  Laboratory investigations showed a leukocytosis, lactic acidosis, and acute renal injury.  Imaging did not demonstrate toxic megacolon.

The working diagnosis was acute C. difficile colitis with sepsis.  There were multiple learning points:

-Clostridium difficile is an interesting clinical entity.  Much of its pathogenesis depends on the absence of normal colonic flora, which is why it is so commonly associated with the use of broad spectrum antibiotics.  There is some variability in which antibiotics are more likely to precipitate a CDI (Clostridium difficile Infection) but not to the extent that some are certain to do so and others definitely won’t.

-The test for CDI is a stool PCR.  The test characteristics are very favourable to the point that repeat tests within 7 days for negative results are essentially forbidden by some electronic medical records.  In rare cases, the medical microbiologist will allow a second sample, but we’re talking about a very good test here.  Unfortunately, the nucleic acids can remain for quite a long time following resolution of infection, which makes diagnosis of a relapse challenging.

-Treatment of CDI depends on its severity, and whether it is an initial episode, or a recurrence.  The markers of severity are essentially the renal function (whether creatinine is greater than 1.5-fold increased) and the WBC count (> 15,000).  Very severe infections are characterized by peritonitis, toxic megacolon, and septic shock.  The IDSA guidelines and recent NEJM review summarize these.

-Although the Surviving Sepsis Campaign has dismantled some of our definitions, words like “SIRS” and “Severe Sepsis” are thrown around so frequently that it is helpful to know their definitions. SIRS (Systemic Inflammatory Response Syndrome) is characterized by two out of the following four criteria being present: HR > 90/min, Temperature < 36C or >38.5C, WBC count < 4, > 12, or 10% bands, and respiratory rate > 20 or PCO2 < 32mmHg.  SIRS indicates just what it says – an inflammatory systemic response – it is not specific to infection and can occur with other illnesses (classically pancreatitis among others).  SIRS + a documented or suspected source of infection is considered sepsis.  Sepsis with end-organ dysfunction (decreased or altered level of consciousnes, renal impairment, skin mottling, liver dysfunction, coagulopathy/DIC, etc.) is considered severe sepsis.  If the BP remains under 90mmHg systolic (despite the arbitrary nature of this number) even after a fluid challenge of 20-30cc/Kg, the patient is said to have septic shock.

-The Rivers trial in 2001 (before everyone used acronyms to name their trials) looked at Early Goal-Directed Therapy for sepsis.  Their protocol is a little unfathomable to us, because they had a dedicated area of the ED for patients essentially deemed to be “code sepsis.”  Early broad-spectrum antibiotics were administered, and ED physicians inserted central venous catheters in all patients.  The patients received intravenous fluids until their central venous pressures were 8-12mmHg.  If at that point, their mean arterial pressures were under 65mmHg, they received pressures (typically norepinephrine/Levophed®) to achieve that MAP.  Then the central venous saturation was measured and, if under 70%, they were either transfused (if low hematocrit) or given dobutamine (an inotrope) for presumed septic cardiomyopathy to improve oxygen delivery.  More recent trials including ProCESS (acronyms are in now) demonstrated that protocolized care like this is no more effective than usual care (probably because usual care incorporates the features of the Rivers protocol).  Critiques of Rivers include that certain portions of the protocol make a lot of sense, but others make a little less sense: most people do not transfuse for a low urine output or central venous saturation.  Furthermore, no one uses the special central cathether used by Rivers, which had a live measurement of the central venous oxygen saturation.  Finally, there may have been issues with conflicts of interest centred around patents for the aforementioned central venous catheters.

Image Credits: C. difficile image from www.bionews-tx.com, Surviving Sepsis Campaign image from survivingsepsis.org

Further Reading:

Leffler, D. A., & Lamont, J. T. (2015). Clostridium difficile Infection. New England Journal of Medicine, 372(16), 1539-1548.

Cohen, S. H., Gerding, D. N., Johnson, S., Kelly, C. P., Loo, V. G., McDonald, L. C., ... & Wilcox, M. H. (2010). Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infection Control, 31(05), 431-455.

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., ... & Tomlanovich, M. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368-1377.

Yealy, D. M., Kellum, J. A., Huang, D. T., Barnato, A. E., Weissfeld, L. A., Pike, F., ... & Angus, D. C. (2014). A randomized trial of protocol-based care for early septic shock. The New England journal of medicine, 370(18), 1683-1693.