Search

From 1976 to 2016, neurotoxigenic Clostridium baratii type F caused 18 (

ically defined cases of wound botulism. Wheeler and colleagues surely know wound botulism when they see it, because they consult on most wound botulism cases, and to the mind of most experts familiar with the diagnostic challenges of botulism, they are fully justified in using clinical diagnosis as the gold standard against which to measure the mouse bioassay’s limited sensitivity. The sensitivity calculated in the article is not the intrinsic sensitivity of a test under ideal laboratory conditions, but rather that of the clinical setting, calculation of which depends on a complicated set of real-world factors. This calculation must take into account the quality of the gold standard clinical diagnosis, which depends on the initial astuteness of the admitting physician and the diagnostic skill of the California Department of Public Health consultant, and variations in toxin levels in clinical samples, which depend on the timeliness of sample collection, the size of the Clostridium botulinum colony in the infected wound, kinetics of toxin absorption from the abscess, its migrations to the extracirculatory compartment, and possibly other factors. One must also keep in mind that the sensitivity of mouse bioassay results may be different for the other principal forms of botulism—foodborne botulism and infant botulism. Most foodborne botulism cases are diagnosed by other expert con

Clostridium botulinum is not a well-defined species of bacterium. Instead, it is a conglomerate of four culturally distinct groups of organisms that, among them, produce seven serologically distinct toxins, all with similar pharmacological action. The principal habitat of C. botulinum is the soil, although its distribution in the soil is sometimes highly regional. Infant botulism is caused by two types of C. botulinum: type A and the proteolytic strains of type B. Type A strains, to whose toxin humans seem most susceptible, are found most frequently in the soil of the western United States; type B strains are somewhat more universally distributed, with a higher frequency of isolation from the soil of some Appalachian areas. The frequency of occurrence of type A and type B food-borne botulism parallels the distribution of these types in the soil.

Between January 1, 1975, and July 31, 1978, 81 cases (47 type A, 34 type B) of infant botulism were reported to the Center for Disease Control (CDC), Atlanta, Georgia. Most cases occurred in the western states, with the majority in California and Utah, where active surveillance is in progress. Most of the cases reported have occurred in the fall months, but this pattern may be attributable to a reporting artifact. The median age at onset of illness was 10 weeks, with a range of three to 35 weeks. The case-fatality ratio was 3.7% (3 of 81). CDC has developed a reporting form for case investigation and has encouraged private physicians and state and territorial epidemiologists and laboratory directors to keep active surveillance of cases of infant botulism. State health departments and CDC are available for consultation regarding suspected cases of the illness.

Intestinal infection with Clostridium botulinum was produced by intragastric administration of C. botulinum spores in conventionally reared mice seven to 13 days old but not in younger or older mice. The 50% infective dose of one of the culture strains administered was 170 spores per nine-day-old mouse. Overt botulism did not develop in these animals, but infection with C. botulinum was evidenced by the presence of botulinal toxin in the colon for up to seven days after challenge. Infant mice were at least as sensitive to the lethal action of botulinal toxin as were adult mice, and evidence suggests that infant rats may have a similar age-related susceptibility to enteric botulinal infection. Germfree adult mice were very susceptible to infection with C. botulinum, acquiring intestinally infective doses of airborne spores. Within a few days after exposure to normal mice, the axenic mice became resistant to challenge with 10(5) C. botulinum spores.

tioning of the "mucosal immune system" in humans. The hypothesis that some crib deaths might also result from other intestinally produced bacterial toxins was investigated by injecting infant rhesus monkeys with microgram amounts of purified Clostridium difficile toxins A and B; quiet death pathologically consistent with human crib death occurred within 4 hr to 10 hr. This and other evidence suggest that infant botulism may be the prototype of a putative class of heretofore unrecognized diseases, the "toxigenic intestinal infections of infancy." Collectively, these illnesses may account for a modest proportion of crib death, against which human milk may provide relative protection. This paper attempts to indicate how the investigation of a single infectious disease, infant botulism, has led to a hypothesis about the cause of some cases of sudden infant death syndrome (SIDS or crib death) that may unify and explain existing epidemiologic, physiologic, and pathologic information. The hypothesis, if correct, suggests the present availability of a few practical preventive measures.

The recent development and evaluation of procedures for examination of fecal specimens for botulinal toxin and Clostridium botulinum have provided the means by which infant botulism can be recognized. The toxicity for mice of fecal extracts containing botulinal toxin can be neutralized with specific botulinal antitoxin. The presence of C. botulinum in the feces is detected by demonstrating the presence of botulinal toxin in enrichment culture supernatant by means of toxicity tests in mice. C. botulinum is isolated by streaking enrichment cultures on egg yolk agar and picking typical lipase-positive colonies. The experience of both the Center for Disease Control (CDC) Botulism Laboratory and other laboratories has been that botulinal toxin and C. botulinum are rarely, if ever, found in the feces of humans (infants or older people) not afflicted with botulism. Results of the examination in the CDC laboratory of specimens from 24 babies with infant botulism are given.

The intestinal flora of experimental animals interferes with infection by species of Salmonella and Shigella. Protection against infection with these organisms appears to be related to high concentrations of volatile acids, low pH, and low oxidation-reduction potential of the intestinal contents of animals with an intact flora. There are no data to show that the flora influences colonization of the intestine with clostridial species, but indirect evidence suggests that the intestinal flora may be involved in this process. The impact of the intestinal flora on the ecology of the large intestine may be the most important determinant of resistance to infant botulism.

Fecal and serum specimens taken from 30 cases of sudden infant death and from eight cases of nonsudden infant death that were diagnosed at a single facility in King County, Wash., were examined for the presence of Clostridium botulinum organisms and toxin. Organisms, but not toxin, were recovered from a fecal specimen in one case of sudden infant death, results that parallel those from studies previously reported by investigators in California. Studies made in our laboratory of a nonfatal case of infant botulism revealed that an estimated 366,000 mouse minimal lethal doses of toxin were excreted in feces collected by purging the infant. Organisms and toxin were excreted for at least 15 days after the infant was hospitalized. Observations made in our laboratory of atypical responses in mice to both fecal and serum extracts, coupled with recently described experiments in which mice were used as an animal model for infant botulism in humans, provide a biologically plausible foundation for the hypothesis that C. botulinum may be implicated etiologically in some sudden infant deaths. Additional microbiologic, physiologic, and toxicologic data are needed to adequately test this hypothesis.

Clinical investigations of infants hospitalized with botulism demonstrate a remarkable uniformity of complaints and physical findings. Constipation precedes a course of progressive weakness and cranial nerve dysfunction. Examination reveals hypotonia, hyporeflexia, and a variable pattern of involvement of the motor cranial nerves. Initial laboratory investigations should include electrodiagnostic tests, because findings of an incremental response to rapid, repetitive nerve stimulation and of brief, small-amplitude motor units on electromyography are virtually pathognomonic of botulism in the infant. Differential diagnosis includes disorders that may produce generalized depression of the central nervous system, such as septicemia, meningitis, metabolic disturbances, and intoxications. Specific involvement of the neuromuscular system includes acute polyneuropathies, diseases of the anterior horn cell, congenital myopathies or muscular dystrophy, and neonatal myasthenia gravis. Recent studies have expanded the clinical spectrum of infant botulism to include some cases of sudden infant death syndrome and otherwise nonspecific constipation.

Oral toxicity of botulinal toxin is manifested when the toxin is absorbed from one or more anatomic regions of the intestinal tract and reaches target neurons. Toxin is absorbed primarily in the small intestine, although in infants the large intestine may be a site of absorption. Nanogram amounts of toxin that escape proteolytic digestion in the intestine may be sufficient to produce neurologic symptoms. It is estimated that approximately 10(11) molecules of toxin reaching peripheral nerve endings is sufficient to cause clinical botulism in adults, although the amount required to cause infant botulism is probably less. Absorption of toxin from the intestine is achieved by means of an endocytic mechanism, as is the absorption of nutritional proteins. Specific toxin receptors may be involved in the movement of toxin from the gastro-intestinal epithelium to target neurons across cellular barriers.