Botulism (Clostridium botulinum)

Etiology

Botulism is the acute, flaccid paralysis caused by the neurotoxin produced by Clostridium botulinum or, infrequently, an equivalent neurotoxin produced by rare strains of Clostridium butyricum and Clostridium baratii. C. botulinum is a gram-positive, spore-forming, obligate anaerobe whose natural habitat worldwide is soil, dust, and marine sediments. The organism is found in a wide variety of fresh and cooked agricultural products. Spores of some C. botulinum strains endure boiling for several hours, enabling the organism to survive efforts at food preservation. In contrast, botulinum toxin is heat labile and easily destroyed by heating at ≥85°C (185°F) for 5 min. Neurotoxigenic C. butyricum has been isolated from soils near Lake Weishan in China, the site of foodborne botulism outbreaks associated with this organism, as well as from vegetables, soured milk, and cheeses. Although first recognized in China, cases of infant botulism due to C. butyricum have now been identified in Japan, Europe, and the United States. Little is known about the ecology of neurotoxigenic C. baratii.

Botulinum toxin is synthesized as a 150-kDa precursor protein that enters the circulation and is transported to the neuromuscular junction. The toxin is only released by actively replicating (vegetative) bacteria and not the spore form. At the neuromuscular junction, toxin binds to the neuronal membrane on the presynaptic side of the neural synapse. It undergoes autoproteolysis to a 100-kDa heavy chain and a 50-kDa light chain. These chains are joined via disulfide bond formation. The heavy chain contains the neuronal attachment sites that mediate binding to presynaptic nerve terminals. It also mediates translocation of the light chain into the cell cytoplasm after binding. The light chain, a key component of the toxin, is a member of the zinc metalloprotease family and mediates cleavage of the fusogenic SNARE protein family member, SNAP-25. Cleavage of this protein precludes release of acetylcholine from axon at the presynaptic terminal, abrogating nerve signaling and producing paralysis. Botulinum toxin is among the most potent poisons known to humankind; indeed, the parenteral human lethal dose is estimated to be on the order of 10 ⁻⁶ mg/kg. The toxin blocks neuromuscular transmission and causes death through airway and respiratory muscle paralysis. At least 7 antigenic toxin types, designated by letters A-G, are distinguished serologically, by demonstration of the inability of neutralizing antibody against one toxin type to protect against a different type. Toxin types are further differentiated into subtypes by differences in the nucleotide sequences of their toxin genes. As with the gene for tetanus toxin, the gene for botulinum toxin for some toxin types and subtypes resides on a plasmid.

The toxin types serve as convenient clinical and epidemiologic markers. Toxin types A, B, E, and F are well-established causes of human botulism, whereas types C and D cause illness in other animals. Toxin types A and B cause the majority of cases of infant botulism in the United States. Neurotoxigenic C. butyricum strains produce a type E toxin, whereas neurotoxigenic C. baratii strains produce a type F toxin. Type G toxin has not been established as a cause of either human or animal disease.

Epidemiology

Infant botulism has been reported from all inhabited continents except Africa. Notably, the infant is the only family member who is ill. The most striking epidemiologic feature of infant botulism is its age distribution, with 95% of cases involving infants 3 wk to 6 mo old, with a broad peak from 2-4 mo old. Cases have been recognized in infants as young as 1.5 days or as old as 382 days at onset. The male/female ratio of hospitalized cases is approximately 1 : 1, and cases occur in all racial and ethnic groups. Identified risk factors for the illness include breastfeeding, the ingestion of honey, a slow intestinal transit time (<1 stool/day), and ingestion of untreated well water. Although breastfeeding appears to provide protection against fulminant sudden death from infant botulism, cases can occur in breastfed infants at the time of introduction of nonhuman milk for feeding.

Although infant botulism is an uncommon and often unrecognized illness, it is the most common form of human botulism in the United States, with approximately 80-140 hospitalized cases diagnosed annually. The Council of State and Territorial Epidemiologists (CSTE) maintains a National Botulism Surveillance System for intensive surveillance for cases of botulism in the United States ( https://www.cdc.gov/botulism/surveillance.html ). In 2015, 141 confirmed cases of infant botulism were reported to the Centers for Disease Control and Prevention (CDC). There were no deaths. Approximately 56% of infant botulism cases were caused by type B, 43% by type A, and the remainder by other types. Cases were identified in 33 states and the District of Columbia, with California reporting the highest number of cases. Consistent with the known asymmetric soil distribution of C. botulinum toxin types, most cases west of the Mississippi River have been caused by type A strains, whereas most cases east of the Mississippi River have been caused by type B strains.

Foodborne botulism results from the ingestion of a food in which C. botulinum has multiplied and produced toxin. Although the traditional view of foodborne botulism has been thought of as resulting chiefly from ingestion of home-canned foods, in fact, outbreaks in North America have recently been more often associated with restaurant-prepared foods, including potatoes, sautéed onions, and chopped garlic. Other outbreaks in the United States have occurred from commercial foods sealed in plastic pouches that relied solely on refrigeration to prevent outgrowth of C. botulinum spores. Uncanned foods responsible for foodborne botulism cases include peyote tea, hazelnut flavoring added to yogurt, sweet cream cheese, sautéed onions in patty melt sandwiches, potato salad, and fresh and dried fish.

Many types of preserved foods have been implicated in foodborne botulism, but common foods implicated with exposure include low-acid (pH ≥6.0) home-canned foods such as jalapeño peppers, carrots, potatoes, asparagus, olives, and beans. The potential for foodborne botulism exists throughout the world, but outbreaks typically occur in the temperate zones rather than the tropics, where preservation of fruits, vegetables, and other foods is less commonly undertaken.

Approximately 5-10 outbreaks and 15-25 cases of foodborne botulism occur annually in the United States. There were 39 cases of confirmed foodborne botulism reported in the United States in 2015, including a large outbreak of 27 cases associated with a potluck meal in Ohio. Most of the continental U.S. outbreaks resulted from proteolytic type A or type B strains, which produce a strongly putrefactive odor in the food that some people find necessary to verify by tasting, exposing themselves to toxin in the process. In contrast, in Alaska and Canada, most foodborne outbreaks have resulted from nonproteolytic type E strains in Native American foods, such as fermented salmon eggs and seal flippers, which do not exhibit signs of spoilage. A further hazard of type E strains is their ability to grow at the temperatures maintained by household refrigerators (5°C [41°F]).

Wound botulism is an exceptionally rare disease, with <400 cases reported worldwide, but it is important to pediatrics because adolescents and children may be affected. Although many cases have occurred in young, physically active males who are at the greatest risk for traumatic injury, wound botulism also occurs with crush injuries in which no break in the skin is evident. In the past 15 yr, wound botulism from injection has become increasingly common in adult heroin abusers in the western United States and in Europe, not always with evident abscess formation or cellulitis.

A single outbreak of inhalational botulism was reported in 1962 in which 3 laboratory workers in Germany were exposed unintentionally to aerosolized botulinum toxin. Some patients in the United States have been hospitalized by accidental overdose of therapeutic or cosmetic botulinum toxin.

Pathogenesis

All forms of botulism produce disease through a final common pathway. Botulinum toxin is carried by the bloodstream to peripheral cholinergic synapses, where it binds irreversibly, blocking acetylcholine release and causing impaired neuromuscular and autonomic transmission. Infant botulism is an infectious disease that results from ingesting the spores of botulinum toxin–producing strains, with subsequent spore germination, multiplication, and production of botulinum toxin in the large intestine. This sequence is distinct from foodborne botulism , which is an intoxication that results when preformed botulinum toxin contained in an improperly preserved or inadequately cooked food is swallowed. Wound botulism results from spore germination and colonization of traumatized tissue by C. botulinum; the pathogenesis of this form of botulism is similar in this respect to that of tetanus. Inhalational botulism occurs when aerosolized botulinum toxin is inhaled. A bioterrorist attack could result in large or small outbreaks of inhalational or foodborne botulism (see Chapter 741 ).

Since botulinum toxin is not a cytotoxin, it does not cause overt macroscopic or microscopic pathology. Pathologic changes (pneumonia, petechiae on intrathoracic organs) may be found at autopsy, but these are secondary changes and not primarily attributable to botulinum toxin. No diagnostic technique is available to identify botulinum toxin binding at the neuromuscular junction. Nerve conduction velocity studies are typically normal. Electromyography (EMG) findings are often nonspecific and nondiagnostic (see later). The healing process in botulism consists of sprouting of new terminal unmyelinated motor neurons. Movement resumes when these new nerve terminals locate noncontracting muscle fibers and reinnervate them by inducing formation of a new motor end plate. In experimental animals, this process takes about 4 wk.