C difficile Continues to Confound Clinicians
C difficile Continues to Confound Clinicians
Abstract & Commentary
Synopsis: Toxin A-negative strains may be missed by some diagnostic tests.
Source: Johnson S, et al. Fatal pseudomembranous colitis associated with a variant Clostridium difficile strain not detected by toxin A immunoassay. Ann Intern Med. 2001; 135:434-438.
It has been known since the early 1990s that there are pathogenic strains of Clostridium difficile which lack the A toxin, so called toxin-A negative strains. The extent and clinical importance of these strains are not known, so papers describing well-proven disease due to toxin-A-negative strains need to be publicized.
The work of Johnson and colleagues brings us a single but most interesting and distressing case report. An elderly man developed a hospital diarrhea 2 months before his final, fatal admission. Luckily, the C difficile isolate from the earlier admission was preserved from a culture, even though it was toxin A negative by immunoassay. After the earlier admission, the patient continued to have abdominal cramps and recurrent diarrhea. Additional stool specimens were negative for toxin, so even though colonoscopy and abdominal CT scans were suspicious for colitis, he was not treated.
On his final admission, he was febrile, had abdominal tenderness, and leukocytosis. He was treated for inflammatory bowel disease with steroids. The diarrhea improved but the abdominal pain persisted. He died shortly thereafter of a cardiopulmonary arrest.
Autopsy showed diffuse pseudomembranous colitis. A fourth C difficile isolate was recovered, again toxin A negative. All 4 clinical isolated were saved for testing and all were shown to be cytotoxic using a cell-culture assay.
Molecular analysis revealed identity among the 4 C difficile isolates from the patient. The endonuclease restriction pattern generated by HindIII restriction resembled that of a collection of C difficile isolates, designated CF, that are known to be toxin A negative. This isolate—and the isolate from the patient in question— are known to have a 108 base-pair deletion in the toxin A gene as described last year.1
To determine how many hospital laboratories might be prone to missing toxin A-negative isolates, Johnson et al conducted a phone survey of Chicago regional hospitals. Thirty-one of the 67 surveyed (47%) used only a single test for diagnosis of C difficile infection, most often the immunoassay for toxin A. Those labs could easily miss pathogenic strains of C difficile.
Comment by Joseph F. John, MD
An investigative team, focusing on C difficile disease, was first assembled by Dr. Dale Gerding at the Minneapolis Department of Veterans Medical Center in the 1980s. Efforts moved to Northwestern University School of Medicine and the Lakeside VAMC in the 1990s. Many basic and clinical investigators contributed to the font of knowledge generated by those collaborations over the years. Indeed, medicine is indebted to the body of work that Dr. Gerding and his able colleagues have produced for us since a time we called this disease antibiotic-associated colitis.
Now the plot thickens in regard to C difficile colitis. Stuart Johnson working in the Gerding team has raised a red flag for a disease so very dependent on laboratory confirmation, that flag being the presence of disease not requiring both the A and B toxin of C difficile to be elaborated. It is likely that in toxin A-negative strains, mutations in the toxin B gene allow for modification of the B toxin necessary and sufficient to produce colitis.2
Laboratories testing only for toxin A production for diagnosis of C difficile colitis will obviously misidentify pathogenic strains as nonpathogenic. Johnson et al went further in their work by asking the question—probably bugging the reader—of prevalence of toxin A-negative strains. By testing a large number of isolates from 3 Midwestern hospitals, they identified 58 of 3445 (1.7%) isolates that had the CF restriction pattern. The plethora of isolates resulted from the clinical microbiology laboratories using culture as well as cytotoxin assays to reach a diagnosis of C difficile infection.
Well, perhaps 1.7% does not alarm most clinicians and hospital epidemiologists, however, we have no data on the global distribution of toxin A-negative strains, nor if such strains may actually be more virulent. Furthermore, it is known that some strains prevail in certain hospitals and there is the possibility that toxin A-negative strains could become epidemic in given institutions and not be recognized.
How should this article influence the infection control of nosocomial diarrheal diseases? Many hospitals—including this observer’s—do not isolate patients with infection due to C difficile. The expanding observations implicating toxin A-negative C difficile as a true pathogen further challenge that approach. Without more data, it is premature to say that all patients with nosocomial diarrheal illness should be isolated, but a case for that position can be justified. At the least this highlights the potential for false-negative laboratory tests for pathogenic strains of C difficile. Physicians cognizant of the pathogenic potential of toxin A-negative strains of C difficile should not hesitate to initiate therapy based on their clinical suspicion, avoiding the catastrophe that awaited the unfortunate patient in this report.
Clinicians owe a true debt of gratitude to Dr. Dale Gerding and his colleagues for their pursuit over the years of a clearer understanding of the epidemiology and pathogenesis of infection due to C difficile.
References
1. Sambol SP, et al. Infect Immun. 2000;68:5480-5487.
2. Dr. Dale Gerding. Personal communication. Nov. 1, 2001.
Dr. John, Professor of Medicine and Microbiology, University of Medicine & Dentistry—New Jersey, Robert Wood-Johnson Medical School, is Co-Editor of Infectious Disease Alert.
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