Botulism

Etiology

Botulism is a neuroparalytic syndrome that results from the systemic effects of a neurotoxin produced by the Gram-positive, rod-shaped, spore-forming, obligate anaerobic bacterium Clostridium botulinum and 6 other clostridial genospecies. The clostridial genospecies that produce 7 serologically distinct BoNTs, classified as BoNT/A-G, several of which have multiple serotypes, are as follows: C parabotulinum, C sporogenes, C botulinum, C novyi sensu lato, C baratii, C butyricum, and C argentinense.[1] The BoNTS produced by C botulinum has seven different serotypes with varying prevalence: A, B C, D, E, F, and G. Most foodborne botulism cases worldwide are caused by BoNT types A, B, E, and F.[9]

BoNT-producing clostridial genospecies are heterogeneous ubiquitous bacteria, usually divided into 4 groups, groups I, II, III, and IV, based on physiologic characteristics.[9] C baratii and C butyricum are ungrouped genospecies that produce BoNT/F7 and BoNT/E4, E5 toxin subtypes, respectively.[9] C botulinum is easily isolated from soil, marine sediment, seafood, fruits, and vegetables. This species forms heat-resistant spores that germinate in anaerobic, substrate-rich conditions to grow into toxin-producing bacilli.[10][11]

BoNT is considered the deadliest known toxin due to its extreme potency, with a lethal dose (LD50, the amount required to kill 50% of a test sample) of 1 to 3 ng/kg of body mass. The flaccid paralysis of botulism results from the irreversible inhibition of acetylcholine release at the presynaptic nerve terminal of the body's neuromuscular junctions.[9] Botulism may be acquired through exposure to the preformed toxin via improperly stored food, iatrogenic injection, or bioterrorism. The condition may also result from the systemic release of the toxin in vivo, as in cases of infantile and wound botulism. Please see StatPearls' companion reference, "Infantile Botulism" for a more comprehensive discussion of this disease variant.

When appropriate hygienic and sterilization conditions are implemented during the manufacturing of commercially processed products, botulism rarely ensues. Botulism can occur when there are deficiencies in the manufacturing of such products, which allows the food to be contaminated with already produced BoNT and/or C botulinum endospores, which can produce BoNT.[12] Metabolically dormant endospores of clostridial genospecies cause disease.[13] The endospores are ubiquitous and resistant to high temperatures, enzyme digestion, and pressure changes.[14] Thus, the presence of the endospore in foods, with conditions of poor sterilization and processing, leads to anaerobic environments that allow the endospore to germinate and form BoNT.[13] Such conditions can occur during home canning, which leads to toxin-producing vegetative cells that intoxicate the food.

Epidemiology

A systematic review published in 2015 identified 197 outbreaks of foodborne botulism from 1920 to 2014.[15] These serotypes are classified according to their neutralization with specific polyclonal antisera.[16] Of these, A, B, and E are the most commonly implicated types found in human botulism. Most foodborne botulism cases worldwide are caused by BoNT types A, B, E, and F.[9] The most commonly implicated cause of botulism were toxin types A, B, E, and F in 34%, 16%, 17%, and 1% of outbreaks, respectively.[15] Outbreaks were reported from 27 countries, and most of the outbreaks, 55%, occurred in the United States, followed by Canada at 15%, Europe at 13%, Asia at 13%, Africa at 3%, and Australia at 2%.[15] 

Most cases of botulism during this time frame in the United States were due to home-canning of foods; in Europe, they were primarily due to commercial foods. Toxin A was the cause of 58% of the outbreaks in the United States, 45% in Europe, and 50% in Asia, whereas toxin type E was responsible for 50% of Canadian outbreaks.[17] The incubation period was shorter in toxin type E botulism than in cases caused by toxin A; case-patients involving type A toxin had the highest mean percentage of mechanical ventilation, and mortality was lower for outbreaks in which all cases with toxin A and E botulism had received matching antitoxin (7.8% vs 53.9%; P < .001).[15] These findings are consistent with other reports.[18]

Since 1973, the United States Centers for Disease Control and Prevention has maintained the National Botulism Surveillance System to monitor cases of botulism in the United States. An average of 162 botulism cases annually was reported from 2011 through 2015. The respective proportions of each botulism type ranged from 71% to 88% for infant botulism, 1% to 20% for foodborne botulism, 5% to 10% for wound botulism, and 1% to 4% for botulism of other or unknown origin. [CDC. National Botulism Surveillance]

With the exception of rare, large outbreaks (an outbreak of foodborne botulism in Ohio in April 2015 accounted for 27 cases alone), the total number of botulism cases and relative proportions of each subtype has remained relatively stable over the past 10 years. Botulism due to bioterrorism has not been reported in the United States. Only 1 case of iatrogenic botulism, which resulted from the use of an unlicensed, highly concentrated form of BoNT, has been documented.[19][20]

Mortality from botulism is low. Before the 1950s, mortality rates for foodborne botulism ranged from 60% to 70%. The overall mortality between 1975 and 2009 was 3.0%, with 109 botulism-related deaths among 3618 botulism cases. Eighteen deaths (less than 1%) occurred from 2352 cases of infant botulism, 61 deaths (7.1%) resulted from 854 cases of foodborne botulism, 18 deaths (5.0%) were linked to 359 cases of wound botulism, and 12 deaths (22.6%) stemmed from 53 cases of botulism of other or unknown origin.[21] Much of this decline in mortality is attributed to the availability of supportive measures and improved healthcare over time, including the availability of botulinum antitoxin in well-resourced facilities.

A 2023 report from Canada has documented 55 cases of foodborne botulism from 2006 until 2021.[17] The mean annual incidence was 0.01 cases per 100,000 individuals. Botulinum toxin E was identified as the cause in 52% of cases, type A was responsible in 24%, type B in 16%, type F in 3%, and type AB in 1%. Seventy percent of cases required mechanical ventilation, and 7 deaths were reported. Type A toxin was responsible for longer hospital stays.

Results from an epidemiological study from Taiwan reported 50 cases of botulism between 2003 and 2020, with an incidence ranging from 0 to 0.48 per 100,000 from 2003 to 2020 and an overall decreasing trend.[12] Most patients were women (56%) aged 50 or older and living in Taipei and northern Taiwan (44%). From 2010 to 2020, however, botulism in individuals younger than 20 showed an increasing trend, and most of those affected were boys (66.7%). Infections mainly occurred during the spring and summer months (66.7%).[12] Data from 2015 and 2022 from the European Centre for Disease Prevention and Control report a stable number of cases of botulism in Europe at less than 0.1 cases per 100,000 individuals. Infant botulism, defined as children younger than 1, was the group with the highest rate of botulism.[22]

Pathophysiology

BoNT is a zinc-dependent 150-kDa metalloproteinase that comprises a 100-kDa heavy chain and a 50-kDa light chain linked by a single disulfide bridge. BoNT/A and BoNT/B cause most of the botulism cases reported in the United States. While most clostridial genospecies produce only 1 toxin serotype, dual toxin-producing strains have been identified. BoNT/A is the most potent, followed by BoNT/B; BoNT/A causes the most severe botulism.[3] A potential eighth BoNT was previously described and labeled BoNT/H; this subtype has been deemed a mosaic.[23]

The toxin's mode of entry into the bloodstream depends on the type of exposure. In infant botulism, the lack of a robust immune system allows the proliferation of toxin-elaborating clostridial colonies in the digestive tract or bronchioles following ingestion or inhaling spores. Once released, BoNT crosses the mucosal barrier—intestinal or pulmonary—into the circulation through transcytosis. In foodborne botulism, the preformed toxin from improperly stored food is similarly absorbed in the intestinal tract. Wound botulism is the result of spore germination in devitalized tissue, most commonly as a result of subcutaneous injection of spore-contaminated illicit drugs, with the release of BoNT into the local circulation.

Once in the bloodstream, BoNT travels to and binds presynaptic nerve terminals of the voluntary motor and autonomic neuromuscular junctions (NMJ). The toxin's heavy chain moiety promotes endocytosis, after which the light chain is cleaved and released into the cytosol. The light chain targets and cleaves serotype-specific targets of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors, SNARE (ie, synaptosomal-associated protein-25 [SNAP-25], vesicle-associated membrane protein, or syntaxin) polypeptide complex, proteins required for fusion of acetylcholine (ACh)-containing vesicles with the presynaptic membrane.[24] Fusion allows exocytosis of ACh into the NMJ and depolarization of the postsynaptic membrane. By cleaving these fusion complexes, BoNT blocks presynaptic ACh release and inhibits muscle contraction, causing flaccid paralysis. Despite differences in target sites, all BoNT serotypes share the downstream syndrome of flaccid paralysis secondary to failure of ACh release at the NMJ.

The BoNT is absorbed into the bloodstream from either a foodborne, wound, intestinal,  or inhalational exposure and moves to the peripheral cholinergic nerve terminals, which include the NMJs, postganglionic parasympathetic nerve endings, and peripheral ganglia.[3] The BoNT binds to the neuron, is internalized by endocytosis, and moves to the cytosol. Then, it cleaves the proteins that release Ach at the nerve junctions, and by inhibiting the release of Ach, it blocks the transmission of the neurotransmitter across the junction, resulting in flaccid paralysis. BoNT does not cross the blood-brain barrier; the BoNT binds irreversibly to the nerve terminal, and recovery only occurs when new nerve terminals have sprouted. This process may take weeks to months.[3]

Toxicokinetics

After BoNT exposure, the time to symptom onset depends upon the toxin dose and the relevant absorption kinetics. For foodborne botulism, symptoms typically appear within 12 to 72 hours of ingesting contaminated food, although onset times from as little as 2 hours to as long as 8 days have been recorded.[15][25] For infectious (ie, wound and infant) botulism, the onset depends on the duration of spore exposure, the time required for germination, and the rate at which the resulting colonies produce enough BoNT to induce symptoms, which varies significantly based on bacterial species, toxin serotype, and the patient’s age and immunological status.[26]

In one study, the results showed the incubation time for wound botulism was 4 to 14 days from the time of spore introduction.[27] An extensive systematic review by Chatham-Stephens et al identified 233 studies and 171 patients with botulism with available data on foodborne and wound botulism clinical features from 1935 to 2015.[28] The median incubation period was 1 day, and the shortest reported was 2 hours. Inhalational botulism is rare and is likely to be associated with accidental exposure from the environment (such as oral ingestion or laboratory inhalation) or intentional malintent.[29] Exposed individuals may receive a lethal dose following 2 nanograms of BoNT per kilogram weight. Exposure can also occur via direct inoculation in iatrogenic botulism. 

Following symptom onset, the duration of symptoms becomes a function of toxin dose, toxin elimination, and regeneration of cleaved polypeptide components of the SNARE complex. The LD50 of BoNT is 1 to 3 ng/kg of body mass.[30] Smaller doses affect fewer SNARE components and are cleared more quickly than larger doses. Conversely, the longer the exposure to BoNT intoxication, the greater the toxin retention at nerve termini.[31] The elimination half-life (t1/2) of each toxin serotype is unknown. However, a murine model of BoNT/A administered parenterally demonstrated a serum t1/2 of approximately 230 minutes.[32]

Elimination of BoNT from the blood is enhanced by administering serotype-specific neutralizing antibodies (antitoxins) to limit the total number of SNARE complexes affected by the toxin.[33] BoNT is sequestered in the liver and spleen once bound by antitoxin. Time to antitoxin administration significantly affects the clinical course. In a study of infant botulism, results showed untreated infants had a significantly longer duration of mechanical ventilation (2.4 weeks versus 0.7 weeks), hospital admission (5.7 weeks versus 2.6 weeks), and tube feeding (10 weeks versus 3.6 weeks) compared to treated infants. Similarly, earlier antitoxin administration (less than 12 hours) has been shown to reduce intensive care unit length of stay in both foodborne and wound botulism.[32]

Regeneration of SNARE polypeptides is required for the resumption of normal ACh release and muscle function and is related in part to the specific polypeptide targets of BoNT serotypes. Results from a recent study comparing the activity of BoNT/A to BoNT/B revealed a significantly longer time to regeneration of the BoNT/A target protein SNAP-25.[34] Case reports of infant botulism by different Clostridium species that elaborate the BoNT/E and BoNT/F serotypes describe a much faster onset and resolution of symptoms compared to cases caused by the typical BoNT/A, which further supports the importance of SNARE component regeneration for the duration of the syndrome.[30]

History and Physical

Botulism is a potentially life-threatening paralytic illness, and clinicians must have a high index of suspicion when evaluating patients. Early clinical diagnosis of botulism is essential because the paralysis can quickly result in respiratory failure, and the antitoxin should be given as soon as possible.[35] A complete travel, exposure, and risk factor history is essential to evaluate the possibility of ingestion or contamination of clostridial spores or toxins. Such exposures include ingestion of improperly canned, preserved, or fermented foods, use of injectable drugs (particularly black-tar heroin), recent surgical procedures or injections, occurrence of contaminated wounds, ingestion of honey, any environmental exposure to soil containing clostridial endospores, and having received a large dose of BoNT for therapeutic or cosmetic purposes.[25]

Botulism classically begins with cranial nerve palsies (“bulbar symptoms”) that progress to a symmetrical descending weakness of the trunk, extremities, and smooth muscles, with eventual flaccid paralysis. However, these symptoms usually begin following early symptoms that include marked lassitude, diplopia, ptosis, ophthalmoparesis, dysphagia, dysphonia, and dysarthria, reflecting the high susceptibility of cranial nerve efferent presynaptic terminals to BoNT activity.[36] Fixed and dilated pupils, resulting in blurred vision, can result from the inhibition of Ach release from the short ciliary nerves that innervate the sphincter muscles of the iris.[37] Patients usually have no sensory deficits except for blurred vision, although paresthesias are occasionally seen. Neurological sequelae are usually symmetrical without altered cognition or hemodynamic instability.[3] Diaphragm involvement precipitates respiratory failure, often requiring intubation and mechanical ventilation. Autonomic smooth muscle palsies cause constipation and urinary retention. Clinical criteria have been proposed by Rao et al to "trigger suspicion for botulism" so that rapid diagnosis and treatment can be performed.[3][38]

Botulism is primarily categorized into 3 primary types based on the source of toxin exposure: foodborne, wound-related, and infant botulism. Foodborne botulism often presents with a prodrome of abdominal pain, nausea, and vomiting beginning 12 to 72 hours after ingestion of the preformed toxin. Constipation is a nearly universal eventual symptom.[39][28]

The presentation and severity of infant botulism are variable due to different inoculum sizes, host susceptibilities, and time to presentation. Early symptoms frequently involve constipation, weakness, feeding difficulties, a weak cry, and drooling. A "floppy baby" exhibiting global hypotonia implies the need for immediate intubation and mechanical ventilation.

Wound botulism is the only variant presenting with fever and signs of infection, but otherwise behaves similarly to foodborne botulism but with fewer gastrointestinal symptoms.[28] Iatrogenic botulism, through direct inoculation into the skin, presents similarly to wound and foodborne botulism.[40] Inhalational botulism, while rare, may cause affected individuals to experience an irritant upper airway prodrome before the onset of neurological complications. Otherwise, symptoms are expected to be similar to that of foodborne botulism, except the lethal dose from inhalational botulism is 3 times greater than that of foodborne botulism.[41]

Evaluation

Many presentations of botulism are subtle and easily missed. However, the clinical course of a patient with botulism can evolve rapidly. Treatment typically proceeds based on clinical suspicion alone because laboratory confirmation of botulism takes several days, and therapy should be administered as early as possible. Obtaining a comprehensive medical history and performing a thorough physical examination are, therefore, essential. Botulism should be considered in any patient in whom Guillain-Barré or myasthenia gravis is suspected, and serial neurological examinations should be performed.[3]

Electrophysiologic studies such as electromyography or nerve conduction can support a presumptive diagnosis of botulism based on history and physical examination while laboratory results are pending.[42] Classical findings may present with small evoked action potentials in the affected muscles following supramaximal nerve stimulation.[26] Classical findings may present with small evoked action potentials in the affected muscles following supramaximal nerve stimulation.[26] Post-tetanic facilitation of amplitudes from evoked motor action potentials (MAP) may also be similar but less than Lambert-Eaton syndrome. The post-tetanic facilitation may last several minutes, and post-tetanic depression might not occur or may not be prominent. Repetitive single nerve stimulation may show low compound MAP amplitude, decremental responses to low stimulation rates, insignificant incremental responses to high rates of stimulation, decremental responses towards Lactate Ringer solution, increased jitter, and blocking.[37][43] However, such studies may be negative or normal early in the disease course.[3]

Laboratory confirmation of botulism may be obtained with serum and stool assays for BoNT, (with an aim of 25 g obtained from stool), gastric aspirates or rectal swabs, stool microscopy for spores, stool cultures, and wound cultures for wound botulism. Laboratory testing for BoNT detection has traditionally relied on the mouse lethality bioassay, wherein a live mouse is injected with a sample of stool or serum from a subject and observed for signs of botulism and death compared to control mice with and without botulism. Efforts to develop immunologic assays for BoNT detection, such as enzyme-linked immunosorbent assay and electrochemiluminescence, face challenges due to low-quality antibodies and interference from factors in complex matrices like stool and serum, resulting in low sensitivity.[3] Endopeptidase assays have shown high sensitivity and specificity and are still under development. Healthcare professionals should be mindful of potential cases of intentional botulism inoculation, especially when multiple individuals present with similar symptoms within a short period. In the event of a suspected or probable case of bioterrorism with mass exposure, local and public health authorities should be contacted to notify of concerns.

Treatment / Management

Treatment of botulism consists of antitoxin administration, hospital admission, close monitoring, respiratory support as required, and debridement with antibiotic coverage in the case of wound botulism. Any patient with a clinical presentation concerning botulism should be hospitalized immediately for close observation. Antitoxin therapy available to healthcare professionals currently exists in 2 forms: heptavalent equine serum antitoxin, indicated for patients older than 1 year, and human-derived immunoglobulin, indicated for infants younger than 1 year. Heptavalent equine serum antitoxin contains antibodies to serotypes BoNT/A through BoNT/G and is available through State Health Departments and the Centers for Disease Control, CDC.[44][45] The administration of antitoxin will not reverse neurological paralysis, given that BoNT binds irreversibly, but it will help stop disease progression.

When botulism is suspected in the United States, the clinician should seek immediate assistance from their regional Poison Control Center, the State's Health Department, or the CDC Director’s Emergency Operations Center. Similar authorities should be reached in other countries to guide antitoxin management. Immediate antitoxin acquisition and administration are indicated if suspicion is high and symptoms are progressing. The dose for adults is 1 vial. The dose for infants, children, and adolescents should be established in conjunction with Poison Control. Foodborne botulism dosing in pregnant and non-pregnant cases remains the same.[3] Adverse events from equine-derived heptavalent antitoxin may include changes in heart rate, hypersensitivity, fevers, and, in rare cases, anaphylactic reactions (<1.5%).[46] These should be monitored for during antitoxin administration, with doses administered in a supervised clinical setting. Please see StatPearls' companion reference, "Botulism Antitoxin," for a comprehensive discussion of the uses, dosage, and administration of this antitoxin. Close monitoring should include frequent clinical evaluation of ventilation, perfusion, upper airway integrity, continuous pulse oximetry, spirometry, and arterial blood gas measurement. Intubation should be considered for patients with upper airway compromise or vital capacity of less than 30% of the predicted value.(A1)

For wound botulism, debridement and antibiotic therapy are indicated following antitoxin administration.[47] An appropriate regimen may consist of 3 million units of penicillin G intravenously every 4 hours or metronidazole 500 mg every 8 hours for patients who are penicillin-allergic. Aminoglycosides are relatively contraindicated, as they have been shown to potentiate botulism-induced neuromuscular blockade. Debridement and tetanus vaccination may also be required in wound botulism. Antibiotics should not be used in infant botulism because of possible BoNT release following cell lysis. Additional therapies include total parenteral nutrition in cases of severe ileus and whole bowel irrigation in cases of foodborne botulism without severe ileus.

The following measures are also recommended:

• Aggressive supportive care in an intensive care unit setting
• Monitoring the airway, as respiratory failure is common
• Monitoring the vital signs, oxygenation, and arterial blood gases
• Intubation if even the slightest signs of respiratory distress are present
• Tracheostomy to manage secretions in some patients
• Avoidance of magnesium salts, which can potentiate the neuromuscular block
• Inserting a Foley catheter and providing stress ulcer prophylaxis

Differential Diagnosis

The differential diagnosis of botulism includes:

• Basilar artery stroke
• Diphtheria
• Encephalitis
• Familial Mediterranean fever
• Hypermagnesemia
• Hyperthyroidism and thyrotoxicosis
• Neurasthenia
• Poliomyelitis
• Guillan-Barré syndrome
• Lambert Eaton Syndrome
• Myasthenia gravis
• Acute intermittent porphyria
• Tick paralysis
• Cerebrovascular disease of the brainstem

Prognosis

Mortality from botulism has significantly declined in the last 3 decades. Today, the risk of death for an infant is less than 1%. However, the recovery is often prolonged, and symptoms may take months or even years to resolve fully. Lifelong neurological deficits can occur in patients who develop hypoxic brain injury.[48][49][50]

A survival analysis from an outbreak of botulism in Thailand reported that from the 91 patients who were hospitalized with botulism, all of whom had received antitoxin, 42 required mechanical ventilation, the median time on the ventilator was 14 days, mechanical ventilation was associated with a shorter incubation and pupillary abnormalities, and there were no deaths.[51] Early administration of antitoxin is key to survival. In one meta-analysis of multiple studies, prompt antitoxin administration was associated with decreased mortality.[52]

Almost all patients can survive, even without the antitoxin, as long as they receive supportive care, including mechanical ventilation.[3] Mortality from botulism has markedly decreased from 60% to 70% at the beginning of the century to the current rate of 3% to 5%. This decrease is most likely due to many factors, including increased awareness and faster diagnosis, more evolved intensive care methods, including mechanical ventilation, and the administration of antitoxin.

Complications

The complications of botulism include but are not limited to:

• Secondary nosocomial infections, including pneumonia
• Urinary tract infection due to urinary retention
• Thrombophlebitis and deep vein thrombosis following BoNT injection [53]
• Pressure injuries due to paralysis and immobility
• Respiratory failure with a need for mechanical ventilation
• Failure-to-thrive in infant botulism
• Neuromuscular changes with muscular atrophy [54]
• Chronic fatigue and weakness [55]
• Long-term decrease in quality-of-life