Botulism

INTRODUCTION — Botulism is a rare but potentially life threatening neuroparalytic syndrome resulting from the action of a neurotoxin elaborated by the bacterium Clostridium botulinum. This disease has a lengthy history; the first investigation of botulism occurred in the 1820s with a case series about hundreds of patients with "sausage poisoning" in a southern German town [1]. Several decades later in Belgium, the association was demonstrated between a neuromuscular paralysis and ham infected by a spore-forming bacillus that was isolated from the ham. The organism was named Bacillus botulinus after the Latin word for sausage, botulus.

The microbiology, pathogenesis, epidemiology, clinical manifestations, diagnosis, and treatment of botulism will be discussed here.

Infant botulism is discussed briefly here and in greater detail elsewhere. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

MICROBIOLOGY — C. botulinum is a gram-positive, rod-shaped, spore-forming, obligate anaerobic bacteria. It is ubiquitous and easily isolated from the surfaces of vegetables, fruits, and seafood, and exist in soil and marine sediment worldwide [2]. C. botulinum is divided into four distinct phenotypic groups (I to IV); it is more commonly classified into seven serotypes (A to G) based on the antigenicity of toxin production. A single strain almost always produces only one toxin, but some strains may produce multiple toxins [3].

C. botulinum spores are heat resistant and can survive 100°C at one atmosphere for five or more hours. However, spores can be destroyed by heating to 120°C for five minutes [4]. When appropriate environmental conditions are present, the spores will germinate and grow into toxin-producing bacilli. These environmental parameters include:

●Restricted oxygen exposure (either an anaerobic or semi-anaerobic environment).

●pH: Growth is facilitated in fluids or soil when the pH is near 7.0 or greater and inhibited when the pH is <4.6. However, once present, a low pH will not degrade existing toxin.

●A temperature of 25 to 37°C for ideal growth; however, some strains may grow in temperatures as low as 4°C.

Contamination of food cannot reliably be suspected on the basis of appearance, odor, or taste. Although some strains (A and B) produce proteolytic enzymes that denature and "spoil" food, producing an unpleasant appearance, taste, or smell; other strains do not have this effect.  

PATHOGENESIS — Eight distinct C. botulinum toxin types have been described: A through H. Of these eight, types A, B, E, and rarely F, G, and H, cause human disease, whereas C and D cause disease in animals such as cattle, ducks, and chickens. C. botulinum toxin type H was first reported in 2014 and is the first new botulinum toxin type to be recognized in over four decades [5,6]. Clostridium butyricum and Clostridium barati are two other distinct Clostridia species that are known to have produced botulinum type E and F toxins [7]. In contrast with the spores, the toxin is a heat-labile polypeptide readily denatured by heating above 80°C. The polypeptide toxin is composed of a light and heavy chain with a combined molecular weight of 150 to 165 kDa.

Botulinum toxin is released as a single precursor polypeptide chain that is then cleaved by bacterial proteases into a fully active neurotoxin composed of a 50-kDa light chain and a 100-kDa heavy chain [8]. Although the precise molecular mechanism of botulinum neurotoxin action is not fully understood, a growing body of evidence supports a multistep process including binding of the neurotoxin to specific receptors at the presynaptic nerve terminal, toxin internalization into the nerve cell with translocation across the endosomal membrane, and intracellular endopeptidase activity against proteins necessary for neurotransmitter release.

Botulinum neurotoxin can target multiple tissues including motor and sensory neurons and can block the cholinergic neuromuscular innervation of striated and smooth muscles as well as the cholinergic innervation of the tear, salivary, and sweat glands [8]. Botulinum toxin can affect both excitatory and inhibitory synapses but is more active in excitatory neurons. It has been demonstrated to inhibit the release of multiple compounds, including dopamine, serotonin, somatostatin, noradrenaline, and gamma aminobutyric acid. Because of its large size, it would be difficult for the neurotoxin to pass through the blood-brain barrier; however, evidence is mounting that it could reach the central nervous system through either systemic spread or axonal retrograde or anterograde transport.

Botulinum toxin is the most potent bacterial toxin and perhaps the most potent known poison. The minimum lethal dose in experimental mice (MLD) of botulinum toxin is 0.0003 mcg/kg. By comparison, the MLDs for curare and sodium cyanide are 500 and 10,000 mcg/kg, respectively [9]. It is estimated that one gram of aerosolized botulism toxin could kill at least 1.5 million people [10].

The toxin itself has no smell or taste. If ingested, the toxin is primarily absorbed by the stomach and small intestine, although the large intestine is capable of absorbing the toxin as well. The toxin is resistant to degradation by gastric acidity and human alimentary enzymes alike. However, botulinum toxin is inactivated in chlorinated water after only 20 minutes of exposure and in fresh water after three to six days [11].

EPIDEMIOLOGY

Types of botulism and their sources — The modern syndrome of botulism occurs in several forms, differentiated by the mode of acquisition.

Infant botulism — Infant botulism occurs when C. botulinum spores are ingested, colonize the host's gastrointestinal (GI) tract, and release toxin produced in vivo. In the United States, most cases are thought to result from ingestion of environmental dust and soil containing C. botulinum spores. The incidence of reported cases is highest in Utah, Pennsylvania, and California, states in which soil botulinum spore counts are high. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

Infant botulism has classically been associated with the ingestion of raw honey. However, this is most likely a minor environmental reservoir, since widespread education of the public has done little to affect the incidence of infant botulism in the United States.

Foodborne botulism — Foodborne botulism is caused by ingestion of food contaminated by preformed botulinum toxin. Toxin types A, B, and E have been associated with foodborne botulism.

Most cases of botulism are recognized when small outbreaks involving home-canned foods such as fruits, vegetables, and fish occur [12-15].

●In the United States, the highest rates of foodborne botulism are reported among Alaska Natives as a result of ingestion of aged fish and marine mammals (eg, seal or whale blubber, dried herring) [16,17]. Surveillance data from the US Centers for Disease Control and Prevention (CDC) between 1947 and 2007 found a mean annual incidence of 6.9 cases per 100,000 Alaska Natives compared with an overall national rate of 0.0068 cases per 100,000 persons. Toxin type E is the most commonly implicated type in foodborne botulism in Alaska [12].

Prison brew (also known as pruno, hooch, moonshine, or bootleg), an illicit beverage typically made by fermenting fruit and sugar in water along with bread or potato, has been identified as a major source of outbreaks within prison populations [18-20].

●In China, home-fermented tofu and other fermented bean products cause more than half of the cases of foodborne botulism [21].

Commercial products and restaurants are occasionally sources; specific commercial sources have included carrot juice and sausage that were improperly refrigerated [13,22-28]. Foods that have been recalled for potential C. botulinum contamination can be searched in catalogs maintained by food regulatory agencies in the United States, Canada, and the European Union.

In a systematic review of cases of foodborne botulism between 1920 and 2014, 197 reported outbreaks were identified, 55 percent of which occurred in the United States [29]. Outbreak sizes ranged from 2 to 97 (median 3) affected individuals. Commercial sources were associated with an outbreak size ≥12 cases. Outbreaks in the United States between 1973 and 2015 that have involved >10 cases are summarized in the following table (table 1). Toxin type A caused the majority of the outbreaks in the United States, Europe, and Asia, whereas type E caused the majority in Canada [29].

Wound botulism — C botulinum can infect wounds and subsequently produce neurotoxin in vivo. In theory, wound botulism should only be associated with puncture wounds, subcutaneous abscesses, and deep space infections, which provide the anaerobic environment required for spores to germinate and the organism to thrive. Accordingly, wound botulism is associated with injection drug use, particularly with "black tar" heroin and subcutaneous or intramuscular injection [30,31]. Recurrent wound botulism has occurred in some injection drug users [32].

However, cases have also been described involving abrasions, lacerations, open fractures, surgical incisions, and even a closed hematoma without appreciable skin defect [33]. A case has been reported of pelvic abscess, paralysis, and toxemia due to C. botulinum following a laparoscopic appendectomy [34].

Wound botulism has also been reported in patients who inhale cocaine [35]. In that case series, patients presented with sinusitis; C. botulinum was isolated from a sinus aspirate in one patient.

Iatrogenic botulism — Iatrogenic cases of botulism have been reported rarely in patients who have received botulinum toxin for cosmetic indications [36,37].

As an example, four cases of botulism were described in patients who had received botulinum toxin injections using an unlicensed, highly concentrated preparation of botulinum toxin A [36]. The patients may have received doses as high as 2857 times the estimated human lethal dose by injection and had serum toxin levels 21 to 43 times the estimated lethal human dose by injection. After administration of equine serum antitoxin, all patients survived but required prolonged mechanical ventilation and physical rehabilitation.

The safety record of botulism toxin for cosmetic use is discussed in detail separately. (See "Overview of botulinum toxin for cosmetic indications", section on 'Clinical safety record'.)

Adult intestinal colonization — Adult intestinal colonization is also known as adult intestinal toxemia or enteric infectious botulism. Similar to infant botulism, it occurs when food contaminated with C. botulinum spores (but not preformed toxin) is ingested, and the bacteria colonizes the GI tract and produces toxin in vivo. (See 'Infant botulism' above.)

This a rare form of botulism. Between 1980 and 2018, only 33 cases were reported in the literature [38]. After infancy, the GI tract is typically resistant to colonization by C. botulinum. The alterations in intestinal flora or gut mucosa that predispose adults to intestinal colonization are unknown. Botulism attributed to intestinal colonization has been reported in patients with inflammatory bowel disease, recent gastrointestinal surgery, and achlorhydria, as well as in an allogeneic hematopoietic cell transplant recipient [38,39].

Bioterrorism-associated botulism — Because C. botulinum toxin is extremely potent, it has been identified as a potential agent of bioterrorism [40,41]. The 1972 Biological and Toxin Weapons Convention prohibited both research on and production of bioweapons [40], although it is believed that Iran, Iraq, North Korea, and Syria have botulinum toxin supplies intended for state-sponsored terrorism [42]. Despite the potency of C. botulinum toxin, technical complexities in concentrating and stabilizing the toxin for aerosolization have remained major barriers to its deployment as a bioterrorism agent [40,41]. Aerosolized botulinum toxin was deployed unsuccessfully in Tokyo by the religious sect Aum Shinrikyo in 1995 prior to their use of sarin [43].

Bioterrorism-associated botulism toxin would presumably be aerosolized for transmission through inhalation [40,44]. Aerosolized botulinum toxin, if successfully deployed, would likely produce an acute symmetric descending flaccid paralysis with prominent bulbar palsies (diplopia, dysarthria, dysphonia, and dysphagia) within 12 to 72 hours of exposure [40].

Transmission through the GI route is another possible mode of attack.

Incidence — Botulism occurs globally. In the United States, an average of 110 cases of botulism are reported each year, according to the CDC [45]. Approximately 70 to 75 percent of cases are infant botulism, 20 to 25 percent are foodborne, and 5 to 10 percent are wound-related. Botulism due to intestinal colonization botulism is extremely rare.

The incidence of infant and foodborne botulism has remained stable over the past several decades. In contrast, the incidence of wound botulism has increased over time. As an example, the number of cases reported per year in California rose from an average of 0.49 cases between 1951 and 1987 to an average of 2.25 cases between 1988 and 1991 to 11 cases in 1994 and 23 cases in 1995 [46]. In the United States, the ongoing opioid epidemic has the potential to fuel further increases in wound-botulism incidence.

CLINICAL MANIFESTATIONS

Spectrum of findings — The classic presentation of botulism is acute onset of bilateral cranial neuropathies associated with symmetric descending weakness [4]. The United States Centers for Disease Control and Prevention (CDC) has also suggested that the following be considered as key features of the botulism syndrome:

●Absence of fever

●Symmetric neurologic deficits

●Normal sensorium and mental status

●Normal or slow heart rate and normal blood pressure

●Absence of sensory deficits, with the exception of blurred vision

In a report of 322 laboratory- or epidemiologically confirmed cases of botulism in the United States from 2002 to 2015, 99 percent were afebrile, 98 percent had at least one symptom related to cranial nerve dysfunction, 93 percent had descending paralysis, and 91 percent remained alert and oriented [47].

The onset of symptomatic illness is characterized by cranial nerve dysfunction, which includes blurred vision (secondary to fixed pupillary dilation and palsies of cranial nerves III, IV, and VI), diplopia, nystagmus, ptosis, dysphagia, dysarthria, and facial weakness. In a systematic review of 400 adults with botulism, 93 percent had cranial nerve findings at the time of presentation [48]. One-third of these patients had one to two cranial nerves affected, one-third had three or four cranial nerves affected, and the remaining one-third had five or more cranial nerves affected. The most commonly reported findings among non-infant children with botulism are dysphagia, dysarthria, and generalized weakness [49].

Neurologic deficits are usually bilateral; unilateral facial paralysis, extraocular palsy, and ptosis each occur in fewer than 15 percent of cases [47].

Descending muscle weakness usually progresses from the trunk and upper extremities to the lower extremities. Urinary retention and constipation resulting from smooth muscle paralysis are common. Occasionally, paresthesias and asymmetric limb weakness occur [50]. Respiratory difficulties (eg, dyspnea) can be caused by diaphragmatic paralysis, upper airway compromise, or both and are common, often requiring intubation and mechanical ventilation. In the systematic review of 400 adults with botulism, approximately 40 percent presented with respiratory involvement (shortness of breath, dyspnea, respiratory distress or failure) at the time of hospitalization; however, only 42 percent of these patients had concurrent evidence of extremity weakness [48].

Nonspecific gastrointestinal (GI) symptoms may also occur [51-53] and are rarely the predominant presenting complaint [52].

Cerebrospinal fluid (CSF) analysis and neuroimaging are usually normal [47]. Elevated CSF protein is occasionally seen [47].

Type-specific clinical features

Infant botulism — Infant botulism affects infants between 1 week and 12 months of age. Most cases occur between two and eight months of age, and the median age of onset is three to four months. Disease presentation and severity are variable, most likely due to variations in the size of the bacterial inoculum and in host susceptibility. Initial presenting symptoms and signs include constipation, shortly followed by weakness, feeding difficulties, descending or global hypotonia, drooling, anorexia, irritability, and weak cry (eg, floppy baby syndrome). A detailed discussion of infant botulism is presented separately. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

Clinicians in the United States should contact the California Department of Health Services' Infant Botulism Treatment and Prevention Program whenever infant botulism is suspected (www.infantbotulism.org or 510-231-7600).

Foodborne botulism — The onset and evolution of symptoms in foodborne botulism are highly variable. Symptoms usually begin within 12 to 36 hours after ingestion of the preformed toxin, but the incubation period may range from several hours to two weeks [48,49]. Prodromal symptoms often include nausea, vomiting, abdominal pain, diarrhea, and dry mouth with sore throat prior to the development of cranial neuropathies and descending weakness, but these symptoms can occur at any time throughout the course of the illness [54]. (See 'Spectrum of findings' above.)

Some presentations of foodborne botulism can be quite mild, with neurologic involvement that is minimal or confined to the ocular cranial nerves. As an example, in a small outbreak associated with home-salted fish contaminated with botulinum toxin type E, all five patients presented with GI symptoms, and only two had cranial nerve palsies, which were minimally symptomatic [52].

Wound botulism — Wound botulism differs only slightly from foodborne botulism in its presentation and clinical course, with three exceptions. First, prodromal GI symptoms common to foodborne botulism are typically absent; second, its incubation period (approximately 10 days) is longer; and third, fever and leukocytosis occur in nearly half of patients with wound botulism [33]. Fever and leukocytosis probably result from concurrent bacterial infection of the wound by non-clostridial species. The typical neurologic findings of botulism are discussed elsewhere. (See 'Spectrum of findings' above.)

Electromyographic findings — Abnormal electromyographic (EMG) and nerve conduction findings in patients with botulism include reduction in compound muscle action potential and M-wave amplitudes, excessive action potentials, and frequency-varying response to repetitive nerve stimulation. These are discussed in detail elsewhere. (See "Neuromuscular junction disorders in newborns and infants", section on 'Diagnosis' and "Overview of neuromuscular junction toxins", section on 'Neurophysiology'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of botulism includes myasthenia gravis and Lambert-Eaton myasthenic syndrome (LEMS), which also affect the neuromuscular junction. These can usually be distinguished from botulism by electromyography (EMG) and are discussed in detail elsewhere. (See "Overview of neuromuscular junction toxins" and "Differential diagnosis of myasthenia gravis".)

Other conditions that can present with acute onset of weakness include Guillain-Barré syndrome, poliomyelitis, stroke, and heavy metal intoxication. Clinical features may help distinguish these from botulism. Guillain-Barré syndrome usually involves ascending paralysis, sensory findings, and elevated cerebrospinal fluid (CSF) protein [33]. Poliomyelitis is typically asymmetric. These are discussed in detail elsewhere. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Differential diagnosis' and "Poliomyelitis and post-polio syndrome", section on 'Differential diagnosis' and "Evaluation of the adult with acute weakness in the emergency department".)

Less likely diagnoses include tetrodotoxin and shellfish poisoning, tick paralysis, and antimicrobial-associated paralysis [51]. (See "Overview of shellfish, pufferfish, and other marine toxin poisoning" and "Overview of neuromuscular junction toxins", section on 'Tick paralysis' and "Overview of neuromuscular junction toxins", section on 'Drugs'.)

Causes and evaluation of infants with acute weakness are discussed separately. (See "Etiology and evaluation of the child with weakness".)

DIAGNOSIS

Clinical suspicion and presumptive diagnosis

●Initial clinical suspicion — The most important issue in the diagnosis of any of the forms of botulism is the initial consideration of the disease. A careful history and physical examination are essential. Botulism should be suspected in a patient with acute onset of signs and symptoms of a cranial neuropathy and symmetric descending weakness, particularly in the absence of fever. In infants, botulism should be suspected when there is acute onset of weak suck, ptosis, inactivity, and constipation (eg, floppy baby syndrome), particularly if there is a history of honey consumption. The presumptive diagnosis can be made on clinical findings alone. Among causes of flaccid paralysis, botulism is distinctive because of the early involvement of cranial nerves, the symmetric descending paralysis, and the lack of sensory neuropathy. Similar symptoms in individuals who have similar exposures (eg, have eaten the same foods) should also heighten suspicion for botulism. (See 'Spectrum of findings' above and "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

In a study that included 241 cases of botulism recorded in the National Botulism Surveillance Database in the United States, three clinical criteria (lack of fever, at least one specific symptom of cranial neuropathy, and at least one specific sign of cranial neuropathy (table 2)) were met in 89 percent of patients [55]. In a medical record review of 99 other botulism cases from the database, these clinical criteria would have been able to identify 78 percent within 48 hours of hospitalization. This tool could be helpful for clinicians to prompt consideration of botulism earlier in the course of disease. However, the specificity of these three criteria is unknown, and the absence of one of these criteria does not rule out the possibility of botulism. As an example, fever may be present because of a reason other than botulism, as with concurrent bacterial infection in wound botulism.

●Contact public health officials — In the United States, clinicians caring for patients with suspected botulism should contact the state health department immediately for assistance with the clinical and laboratory evaluation. State public health officials can reach the CDC clinical emergency botulism service at 770-488-7100. For suspected infant botulism occurring in any state, the California Department of Health Services, Infant Botulism Treatment and Prevention Program should be contacted (www.infantbotulism.org or 510-231-7600).

●Initial evaluation — In addition to elucidating signs and symptoms suspicious for botulism, it is important to perform a thorough history to identify possible exposures. This includes a history of home canning, exposure to other possible food sources (including honey in infants <12 months of age), injection drug use, trauma, and cosmetic use of botulinum toxin. The possibility of bioterrorism should also be considered in patients presenting with suspected botulism, particularly if multiple cases occur in clusters.

Physical examination should include a tick check, as patients with tick paralysis can present similarly. In contrast to some polyneuropathies that botulism could be mistaken for (eg, Guillain-Barré syndrome), reflexes are typically normal in patients with botulism unless the affected muscle group is completely paralyzed [56].

Patients with botulism are typically fully alert and afebrile. Meningismus and headache are usually absent; lumbar puncture is not indicated.

Electromyography (EMG) is not necessary for the diagnosis but can be supportive in uncertain cases, as certain findings are suggestive of botulism. (See 'Electromyographic findings' above and "Neuromuscular junction disorders in newborns and infants", section on 'Diagnosis' and "Overview of neuromuscular junction toxins", section on 'Neurophysiology'.)

Tensilon (edrophonium) tests to rule out myasthenia gravis, if available, should not be conducted, as they are often falsely positive in patients with botulism [57].

Confirming the diagnosis — The diagnosis of botulism is confirmed by identification of toxin in serum, stool, vomitus, or food sources or by isolation of C. botulinum from stool, wound specimens, or food sources. However, initial detection of toxin requires one to four days and anaerobic cultures often take up to six days for growth and identification of the organism. Because these confirmatory tests do not yield timely results, the decision to administer antitoxin should be based on the presumptive clinical diagnosis of botulism and not be delayed while awaiting results of confirmatory diagnostic studies. (See 'Clinical suspicion and presumptive diagnosis' above and 'Antitoxin' below.)

Toxin detection is performed by special laboratories. In the United States, the locations of these laboratories can be obtained by contacting state epidemiologists or regional offices of the United States Centers for Disease Control and Prevention (CDC). State public health officials can reach the CDC clinical emergency botulism service at 770-488-7100.

The expected patterns of toxin or C. botulinum identification in different specimens vary for the different botulism syndromes.

●Infant botulism or adult intestinal colonization botulism – The diagnosis is supported by the isolation of C. botulinum spores from the stool and is confirmed by the identification of botulinum toxin in stool samples. Serum assays for botulinum toxin are often negative in cases of infant botulism. C. botulinum may be cultured from food sources, but these are generally negative for toxin.

The diagnosis of infant botulism is discussed in greater detail elsewhere. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

●Foodborne botulism – Botulinum toxin can be detected in the serum up to 12 days following ingestion [23,58] and is diagnostic. Toxin may also be identified in stool, vomitus, and/or suspected food sources.

●Wound botulism – Isolation of C. botulinum from the wound site is diagnostic. Specimens should be properly collected and transported using anaerobic transport media. When collecting a specimen for anaerobic culture, clinicians should generally consult with their microbiology laboratory to ensure that they are using proper technique. Pus or tissue specimens yield the best results. A wound swab can be sent, although its sensitivity for detecting C. botulinum is lower.

Stool and vomitus assays should not be attempted; they are not expected to be positive in wound botulism. Serum assays for toxin are frequently negative. As an example, among a cohort of 73 individuals with injection drug use-associated wound botulism, only 50 (68 percent) had toxin detected from the serum [59].

●Bioterrorism-associated botulism – In the event of an attack with aerosolized botulinum toxin, the level of toxin in serum or other specimens may not be high enough to be detected [56]. Thus, negative toxin tests should not rule out the possibility if large numbers of patients present with features clinically consistent with botulism.

Toxin is traditionally detected with the mouse bioassay, in which mice are followed for symptoms of botulism after injection with the specimen with or without concurrent administration of antitoxin [56,60]. Other techniques for toxin identification include enzyme-linked immunosorbent assays (ELISA) and mass spectroscopy, both of which can identify the toxin protein, and polymerase chain reaction (PCR), which identifies bacterial genetic material.

Laboratory confirmation is not necessary in an individual with suggestive clinical findings who shared the same food with a laboratory-confirmed case.

Public health evaluation — In the United States, each case of botulinum foodborne illness requires investigation by public health authorities under the guidance of the CDC. Suspected food sources should be retained for later investigation and testing when appropriate.

TREATMENT — Any patient with clinical signs, symptoms, or history suspicious for botulism should be hospitalized immediately and meticulously monitored for signs of respiratory failure. The treatment approach to all patients with botulism includes prompt intubation for respiratory failure, administration of antitoxin, and intensive care for those with paralysis.

A detailed discussion of infant botulism is presented separately. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

Monitoring — Monitoring should include pulse oximetry, spirometry, arterial blood gas measurement, and clinical evaluation of ventilation, perfusion, and upper airway integrity. Respiratory failure is the primary cause of death in these patients. Prompt intubation with mechanical ventilation will dramatically decrease the risk of mortality.

Intubation should be considered for those patients with inadequate or worsening upper airway competency and those with a vital capacity less than 30 percent of predicted. Infants and severe adult cases may require prolonged mechanical ventilation. Supportive care in these cases should also include small volume continuous nasogastric feedings (to minimize aspiration risk) [61]. When severe ileus is present, parenteral hyperalimentation may be required.

Antitoxin — Antitoxin is the main therapeutic option for botulism and should be administered as soon as possible after the diagnosis of botulism is made. If the clinical suspicion for botulism is high (eg, the patient is alert and afebrile but has the acute onset of bilateral cranial neuropathies associated with symmetric descending weakness) and symptoms are progressing, antitoxin should be administered as soon as possible and should not be delayed while awaiting results of diagnostic studies. In the United States, clinicians caring for patients with suspected botulism should contact the state health department immediately for assistance with the decision to administer botulism antitoxin and to obtain a supply of antitoxin. Botulinum antitoxin binds to circulating neurotoxins and prevents their binding to the neuromuscular junction. Because botulinum antitoxin cannot reverse paralysis, prompt administration early in the course of disease is critical. Dosing and administration depends on the formulation of botulinum toxin available. (See 'Formulations' below.)

Data informing the efficacy of botulinum antitoxin are limited and uncontrolled but demonstrate a benefit. In a meta-analysis of 61 studies and case series of patients with botulism, antitoxin was associated with a reduction in mortality (odds ratio [OR] 0.22, 95% CI 0.17-0.29), although there was substantial heterogeneity across studies [62]. Among the 27 studies that reported on toxin type involved and antitoxin type used, the results still demonstrated a mortality benefit (OR 0.16, 95% CI 0.09-0.30) without heterogeneity.

Some studies also suggest that earlier administration (eg, the first 48 to 96 hours of presentation) of botulinum antitoxin is associated with reduced mortality compared with later administration [62,63].

Formulations — Various forms of botulinum antitoxin therapies are available worldwide. In the United States, there are two botulism antitoxin therapies available. Equine serum heptavalent botulism antitoxin is used to treat children older than one year of age and adults; human-derived botulism immune globulin is used for infants less than one year of age. A pentavalent antitoxin is available within the Department of Defense but is not available for public use.

In other regions of the world, clinicians should contact their local health department for information on available botulinum antitoxins.

Heptavalent botulinum antitoxin (HBAT) — Equine serum heptavalent botulinum antitoxin contains antibodies to seven of the eight known botulism toxin types (A through G).

In the United States, it is available through state health departments or (if after regular business hours) the state health department representative on call, who can then obtain antitoxin through the US Centers for Disease Control and Prevention (CDC) [64]. Regional poison centers across the United States may also be of assistance in contacting on-call state health department representatives after hours (calling 1-800-222-1222 automatically forwards the caller to the regional poison center). If there is no response, the CDC’s clinical emergency botulism service should be contacted (770-488-7100) [51].

For adults, one vial should be administered intravenously (IV) [65]. For children aged 1 to 17 years, 20 to 100 percent of the adult dose should be given. For infants <1 year of age, 10 percent of the adult dose might be appropriate, depending on CDC consultation. There does not appear to be any benefit from additional doses.

Equine botulinum antitoxin can cause sensitization and anaphylaxis, with an estimated rate of anaphylaxis of 1 to 2 percent [66]. In those at risk of an acute hypersensitivity reaction (eg, those with allergies to horses, asthma, or seasonal allergies), skin testing can be performed prior to administration [65]. However, given the relatively low rate of anaphylaxis, treatment should not be delayed for skin testing if clinical suspicion is high or in the setting of a mass exposure event [66].

As with other antitoxin formulations, human data informing efficacy are limited. In a study of 104 patients with confirmed botulinum who were treated with heptavalent botulism antitoxin, the overall mortality rate was 7 percent [63]. Treatment within two days of symptom onset was associated with shorter hospital and intensive care unit stays and a non-statistically significant trend towards lower mortality.

Although heptavalent botulinum antitoxin does not contain antibodies to the H toxin, there is some evidence that it may be beneficial in botulism associated with H toxin. One study has suggested that the H toxin has a hybrid-like structure with regions of similarity to the A and F toxins [67]. In addition, the toxic effects of the H toxin were completely eliminated by existing serotype A antitoxins, including those contained in the heptavalent botulinum antitoxin formulation.

Most side effects associated with heptavalent botulinum antitoxin are nonserious. In a study of 249 patients who had received heptavalent botulism antitoxin, 9 percent had at least one adverse effect [63]. These included fever, chills, rash, itching, agitation, and nausea. Only one patient, a child, had a serious adverse event: hemodynamic instability. Because antitoxin is derived from horse serum, anaphylaxis and serum sickness may occur. Other reviews have reported incidences of 20 percent for serum sickness and 3 percent for anaphylaxis [66,68]. Guidelines for skin testing, desensitization, and dosing are included in the antitoxin prescribing information [65].

The heptavalent formulation replaces earlier formulations and was approved by the US Food and Drug Administration (FDA) in 2013 [69]. It is maintained in the Strategic National Stockpile and distributed through the CDC's drug service.

Botulinum immune globulin — Human-derived botulism immune globulin (called BIG-IV or BabyBIG) is available for intravenous use in infants less than one year of age who are diagnosed with infant botulism. BIG-IV should be administered as early as possible in the illness. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

Other management issues

Food-acquired botulism — In cases of foodborne botulism, laxatives, enemas, or other cathartics can be given, provided no significant ileus is present.

Antibiotics are not recommended for infant botulism [70] or for adults with suspected gastrointestinal botulism because lysis of intraluminal C. botulinum could increase the amount of toxin available for absorption [56,71]. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

Wound botulism — Patients presenting with wound botulism should undergo extensive debridement, even if the wound appears unimpressive. These patients should receive tetanus boosters as well if it has been five or more years since their last immunization. For wound botulism, antibiotics are used in addition to appropriate debridement. For complicated wounds, infectious disease consultation should be sought.

Antibiotic therapy is unproven by clinical trials but widely used and recommended for wound botulism after antitoxin has been administered [70]. Penicillin G (3 million units IV every four hours in adults) provides effective coverage of clostridial species and is frequently used. Metronidazole (500 mg IV every eight hours) is a possible alternative for penicillin-allergic patients.

For patients with wound botulism who have leukocytosis, fever, an abscess, or cellulitis, broader-spectrum antimicrobial therapy is warranted because of the risk of polymicrobial infection in such cases. The approach to antibiotic selection for skin and soft tissue infections is discussed elsewhere. (See "Acute cellulitis and erysipelas in adults: Treatment" and "Necrotizing soft tissue infections", section on 'Antibiotic therapy'.)

Although not commonly used for skin and soft tissue infections, aminoglycosides, tetracycline, and polymyxins should be avoided in patients with known or suspected botulism since they have been reported to induce neuromuscular blockade, potentiating the effects of the toxin [72]. (See "Neuromuscular junction disorders in newborns and infants", section on 'Aminoglycoside toxicity'.)

The duration of antimicrobial treatment will depend on the extent of the wound.

PREVENTION

Avoiding exposure — Since most cases of botulism are transmitted through food, the most critical aspect of botulism prevention is proper food handling and preparation [71,73]. Good home-canning techniques (eg, following pressure canner/cooker instructions regarding minimum cooking time, pressure, and temperature) will destroy spores. Food from damaged cans (cans with slits, holes, dents, or bulges) should not be consumed. Both home-canned items (especially foods with low acid content such as corn, green beans, asparagus, and beets) and commercial products (especially those associated with improper handling during manufacturing; examples including carrot juice, tomatoes, chopped garlic in oil, canned cheese sauce, baked potatoes wrapped in foil, and chili peppers) have been sources of botulism. Botulinum toxin is highly heat labile; therefore, boiling home-canned foods for at least 10 minutes before consumption will render the food safe.

The prevention of infant botulism is limited to the avoidance of honey in infants less than 12 months; older children can safely ingest honey.

The most important measure for the prevention of wound botulism is prompt medical evaluation and treatment of infected wounds. Injection of street drugs should be avoided.

Possible sources are discussed in greater detail above. (See 'Types of botulism and their sources' above.)

Investigational vaccine — An investigational pentavalent botulinum toxoid vaccine was available from 1965 until 2011 from the United States Centers for Disease Control and Prevention (CDC) for use in individuals at risk for occupational exposure to botulinum serotypes A, B, C, D, and E [74]. The CDC discontinued the availability of this vaccine in 2011 due to a decline in the immunogenicity of the vaccine (which was manufactured more than 30 years earlier) and an increase in local reactions to the vaccine following booster doses.

OUTCOME — Botulism of any type usually requires hospitalization for one to three months. With prompt attention to the impending respiratory failure and supportive care, mortality in botulism ranges from less than 5 percent to 8 percent (including infants) [54,75]; since 1980, the case-fatality rate has been ≤4 percent among patients with foodborne botulism in the United States [16]. The mortality rate for infant botulism, the most common form in the United States, is less than 1 percent [76]. Initial misdiagnosis and disease caused by toxin type A are both associated with fatal outcomes [16].

A retrospective review of 706 patients hospitalized for foodborne botulism in the Republic of Georgia, which has the highest reported rate of foodborne botulism in the world, suggested that the prognosis can be estimated based upon the manifestations of the disease [54]:

●Shortness of breath alone identified patients at increased mortality risk (18 versus 1 percent without this symptom). In addition, shortness of breath was present in 50 of the 54 patients who died.

●In comparison, there were no deaths among 209 patients without shortness of breath, facial muscle weakness, or vomiting.

Prospective validation of these observations is necessary.

Overall, most patients with prompt hospitalization and respiratory care can expect a complete or nearly complete recovery with return to previous level of functioning. Long-term morbidity is low in patients with mild disease, with complete resolution of symptoms generally occurring within the first three months. In comparison, patients with severe disease may experience protracted courses involving years of neurologic deficits, sequelae from extended mechanical ventilation, and nosocomial illness.

The largest reported experience on the long-term outcomes after acute paralytic botulism comes from a case-control study of 217 such patients in the Republic of Georgia and three randomly selected community controls for each patient [77]. During the initial infection, 15 had been hospitalized for at least one month, and 25 percent required mechanical ventilation.

The following findings were noted at a median of 4.3 years in the 211 patients who were still alive: 68 percent (compared with 17 percent of controls, matched odds ratio 17.6) reported their current health as being worse than six years before the interview; and 49 percent rated their health as fair or poor (compared with 25 percent of controls, matched odds ratio 5.0).

Compared with controls, the patients were also significantly more likely to report symptoms such as fatigue, weakness, dizziness, difficulty breathing with moderate exertion, and impaired psychosocial well-being. Requirement for mechanical ventilation during the acute illness and older age were independent predictors of worse long-term health.

SUMMARY AND RECOMMENDATIONS

●Botulism is a rare but potentially life-threatening neuroparalytic syndrome caused by a neurotoxin produced by Clostridium botulinum, a heterogeneous group of gram-positive, rod-shaped, spore-forming, obligate anaerobic bacteria. They are ubiquitous and are easily isolated from the surfaces of vegetables, fruits, and seafood, and exist in soil and marine sediment worldwide. (See 'Introduction' above and 'Microbiology' above.)

●Several forms of botulism exist. The most common are infant botulism, foodborne botulism, and wound botulism. (See 'Types of botulism and their sources' above.)

•Infant botulism occurs when C. botulinum spores are ingested, colonize the host's gastrointestinal (GI) tract, and release toxin produced in vivo; this can rarely occur in adults (adult intestinal colonization botulism). (See 'Infant botulism' above and "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

•Foodborne botulism is caused by ingestion of food contaminated with preformed botulinum toxin; it is typically associated with home-canned or fermented foods. (See 'Foodborne botulism' above.)

•Wound botulism occurs when C. botulinum infects wounds and elaborates toxin. It is associated with injection drug use, particularly with "black tar" heroin use and subcutaneous or intramuscular injection. (See 'Wound botulism' above.)

●Botulism is classically described as the acute onset of bilateral cranial neuropathies associated with symmetric descending weakness. Other key features include absence of fever, maintenance of alertness, and lack of sensory deficits other than blurred vision. Nonspecific GI symptoms may also be seen, particularly with foodborne botulism. (See 'Clinical manifestations' above.)

●A careful history and physical examination are essential to the diagnosis of botulism, which can be made based on the clinical findings alone. It is also important to identify possible exposures, including home-canned or other possible food sources (including honey in infants <12 months of age), injection drug use, trauma, and cosmetic use of botulinum toxin. The possibility of bioterrorism should also be considered in patients presenting with suspected botulism. (See 'Clinical suspicion and presumptive diagnosis' above.)

●The diagnosis of botulism is confirmed by identification of toxin in serum, stool, vomitus, or food sources or by isolation of C. botulinum from stool, wound specimens, or food sources. However, the decision to administer antitoxin should be based on the presumptive clinical diagnosis of botulism and not be delayed while awaiting results of confirmatory diagnostic studies. (See 'Confirming the diagnosis' above.)

●Any patient with clinical signs, symptoms, or history suspicious for botulism should be hospitalized immediately and meticulously monitored for signs of respiratory failure. The treatment approach to all patients with botulism includes prompt intubation for respiratory failure, administration of antitoxin, and intensive care for those with paralysis. (See 'Treatment' above.)

●Antitoxin is the main therapeutic option for botulism. For patients with confirmed or highly suspected botulism, we recommend prompt administration of botulinum antitoxin (Grade 1B). In the United States, the clinician should contact the state health department immediately for assistance with the decision of whether botulism antitoxin is indicated and to obtain a supply of antitoxin. (See 'Antitoxin' above.)

●Several formulations of botulinum antitoxin therapies are available. In the United States, equine serum heptavalent botulism antitoxin is used to treat children older than one year of age and adults; human-derived botulism immune globulin is used for infants less than one year of age. (See 'Heptavalent botulinum antitoxin (HBAT)' above and "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.)

●For patients with wound botulism, we suggest antibiotic therapy following antitoxin administration (Grade 2C). Penicillin G (3 million units intravenously [IV] every four hours in adults) provides effective coverage of clostridial species and is frequently used. Patients with wound botulism with fever, leukocytosis, cellulitis, or skin abscess warrant broader antibiotic coverage as indicated for skin and soft tissue infections because of the possibility of a polymicrobial infection. Antibiotics are not warranted for other forms of botulism; for infant botulism or adult intestinal colonization botulism, there is concern that lysis of intraluminal C. botulinum with antibiotic therapy could increase the amount of toxin available for absorption. (See 'Wound botulism' above and "Acute cellulitis and erysipelas in adults: Treatment".)

●Since most cases of botulism are acquired through food ingestion, the most critical aspect of botulism prevention is proper food handling and preparation. Good home-canning techniques will destroy spores. Infants <12 months of age should not ingest honey. The most important measure for the prevention of wound botulism is prompt medical evaluation and treatment of infected wounds. Injection of street drugs should be avoided. (See 'Prevention' above.)

ACKNOWLEDGMENT — We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges Dr. Bartlett's role as section editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases, and his dedicated and longstanding involvement with the UpToDate program.