Rapid death of infant rhesus monkeys injected with Clostridium difficile toxins A and B: Physiologic and pathologic basis2

https://doi.org/10.1016/S0022-3476(84)80585-5Get rights and content

Clostridium botulinum can colonize and produce botulinal toxin in the human infant intestine, which the toxin then permeates to cause generalized flaccid paralysis, and occasionally, sudden death. This study was undertaken to test the hypothesis that toxins produced by other intestinal clostridia, e.g., C. difficile, might also cause systemic illness and sometimes death in infants (J Pediatr 100:568, 1982). Because this hypothesis could not be evaluated clinically until the systemic manifestations of C. difficile toxins in primates were known, infant rhesus monkeys were given 6 to 11 μg/kg of the recently purified C. difficile toxins A or B, either intravenously or intraperitoneally. The animals showed no abnormalities for several hours, but then developed lethargy, hypotonia, hypothermia, and, shortly before death, sudden elevation of serum concentrations of potassium, magnesium, and phosphorus and of enzymes that derived mainly from skeletal muscle, heart, and brain. Five of six animals died quietly 3.5 to 8.0 hours after onset of symptoms. Death appeared to result from cessation of breathing, after which the sinus tachycardia then deteriorated to a flat ECG. Necropsy findings were insufficient to explain the cause of death. It appears that in infant monkeys microgram amounts of C. difficile toxins A and B can produce a rapid quiet death, the cause of which is undetectable at necropsy, a situation pathologically reminiscent of crib death in human infants, although the possible clinical identity of these two conditions has yet to be established.

References (39)

  • TaylorNS et al.

    Comparison of two toxins produced by Clostridium difficile

    Infect Immun

    (1981)
  • SullivanNM et al.

    Purification and characterization of toxins A and B of Clostridium difficile

    Infect Immun

    (1982)
  • BannoY et al.

    Two toxins (D-1 and D-2) of Clostridium difficile causing antibiotic-associated colitis: Purification and some characterization

    Biochem Int

    (1981)
  • BartlettJG et al.

    Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia

    N Engl J Med

    (1978)
  • GeorgeRH et al.

    Identification of Clostridium difficile as a cause of pseudomembranous colitis

    Br Med J

    (1978)
  • GeorgeWL et al.

    Clostridium difficile and its cytotoxin in feces of patients with antimicrobial agent-associated diarrhea and miscellaneous conditions

    J Clin Microbiol

    (1982)
  • AronssonB et al.

    Occurrence of toxin-producing Clostridium difficile in antibiotic-associated diarrhea in Sweden

    Med Microbiol Immunol

    (1981)
  • BrettleRP et al.

    Clostridium difficile in association with sporadic diarrhea

    Br Med J

    (1982)
  • NashJQ et al.

    Clostridium difficile and cytotoxin in routine faecal specimens

    J Clin Pathol

    (1982)
  • Cited by (40)

    • Are Clostridium difficile toxins nephrotoxic?

      2019, Medical Hypotheses
      Citation Excerpt :

      Post-mortem tissue has been available from both experimental animal models and human deaths. Infant monkeys were exposed to C. difficile toxin either through the intravenous or intraperitoneal routes, and they suffered demise [60]. Both toxin A and B exposures were associated with increases in serum creatinine up until the time of animal death, but the peak levels were relatively low even though a 100–200% change in values was determinable.

    • Severe Nervous System Complications After Botulinum Type A Therapy: Three Case Reports With Reviews of FDA-Reported Nervous System Adverse Effects

      2012, PM and R
      Citation Excerpt :

      Cowdry and Nickolson concluded that, in humans, secondary causes such as pneumonia or the consequences of hypoxia were likely and were mistakenly reported as a primary etiology of death [35]. Death attributable to other toxins in the clostridium family showed similar pathology results [38], suggesting that unless SNAP-25 enzyme activity is specifically investigated in patients who died after receiving BoNT/A, a causal relationship to the toxin may not be established. This scenario is not surprising because botulinum causes neuronal and cell-to-cell communication failure, impairing the function of the organism as a whole rather than killing singular cells [36,39].

    • The role of infectious agents in sudden infant death syndrome

      1994, FEMS Immunology and Medical Microbiology
    View all citing articles on Scopus
    2

    Presented in part at the 82nd Annual Meeting of the American Society for Microbiology, Atlanta, March 11, 1982.

    1

    From the California Department of Health Services: the California Primate Research Center, University of California, Davis; and the Virginia Polytechnic Institute and State University.

    Supported by a grant from the Henry J. Kaiser Family Foundation, the National Institutes of Health (grants HD-14548, HD-12530, AI-16354, AI-15749, and RR-00169), the California Department of Health Services, and the Commonwealth of Virginia.

    View full text