# 40 - 158 Botulism

### 158 Botulism

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Van Hao N et al: Human versus equine intramuscular antitoxin, with 
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Glob Health 10:e862, 2022.
Yen LM, Thwaites CL: Tetanus. Lancet 393:1657, 2019.
■
■WEBSITES
Centers for Disease Control and Prevention: Pink Book. Teta­
nus. 2021. www.cdc.gov/vaccines/pubs/pinkbook/downloads/tetanus

.pdf.
Centers for Disease Control and Prevention: Recommended 
catch-up immunization schedule for children and adolescents who 
start late or who are more than 1 month behind. https://www.cdc.gov/
vaccines/schedules/hcp/imz/catchup.html.
Health Protection Agency: Tetanus: Information for health 
professionals. 
2013. 
www.gov.uk/government/publications/
tetanus-advice-for-health-professionals.
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1980 to 2022, by year. www.statista.com/statistics/1122819/
tetanus-cases-us-by-year/.
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.int/news-room/fact-sheets/detail/immunization-coverage.
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nus (MNT) elimination. www.who.int/immunization/diseases/
MNTE_initiative/en/.
World Health Organization: Tetanus. www.who.int/news-room/
fact-sheets/detail/tetanus.
Carolina Lúquez, Jeremy Sobel

Botulism
Botulism is a rare, life-threatening disease characterized by cranial 
nerve palsies and symmetric descending flaccid paralysis. Four forms 
of naturally occurring botulism have been described: foodborne 
botulism, infant botulism, wound botulism, and adult intestinal 
colonization. Other forms of botulism include iatrogenic botulism and 
inhalational botulism. Effective treatment depends on early clinical 
diagnosis.
■
■ETIOLOGY AND PATHOGENESIS
Botulism is caused by botulinum neurotoxins (BoNTs), which are 
produced by Clostridium botulinum. Rare strains of Clostridium 
butyricum and Clostridium baratii can also produce BoNTs. Seven 
distinct serotypes of BoNT (A through G) are well characterized; sero­
types A, B, E, and F reportedly cause disease in humans. Novel serotypes—
BoNT/FA (or H or HA), BoNT/En, and BoNT/X—have been proposed, 
but the scientific community has not yet reached a consensus as to 
whether each represents a new serotype or a combination of known 
serotypes, as in the case of BoNT/FA (or H or HA), or whether they 
represent true toxins or botulinum-like proteins, as in the case of 
BoNT/En and BoNT/X. BoNTs are encoded by the bont gene, which is 
also diverse in its DNA sequence. At least 40 unique subtypes of BoNT 
have been identified within serotypes A, B, E, and F. By definition, a 
variant of BoNT represents a new subtype when its amino acid 
sequence differs by at least 2.6% from those of all known subtypes 
within that particular serotype. Although 2.6% is an arbitrary thresh­
old, this figure has provided the basis for genetic subtype designations 

for the past decade, aiding in the classification of BoNTs as new DNA 
or amino acid sequences become publicly available. In addition, bont 
genes typically reside within two types of gene clusters. One type 
includes ha genes encoding hemagglutinin proteins, which facilitate 
the absorption of toxins across the epithelial barrier. The other type of 
cluster includes orfX genes that encode proteins with unknown func­
tions. Both cluster types include an ntnh gene, which encodes for a 
nontoxic nonhemagglutinin protein. It has been proposed that these 
accessory proteins form a complex with BoNTs and protect them from 
external proteolytic activity.

Despite their structural variability, BoNTs all have a similar mecha­
nism of action: they target neurons and block neurotransmission by 
cleaving SNARE-family proteins in the host, with consequent inhibi­
tion of acetylcholine release. BoNTs are metalloproteases composed of 
a light chain and a heavy chain. The light chain has catalytic activity, 
and the heavy chain contains a translocation domain and a receptorbinding domain. The receptor-binding domain of the heavy chain 
mediates the neurospecific binding of BoNTs, which leads to its inter­
nalization within endocytic compartments. Interaction of the trans­
location domain of the heavy chain with the membrane of endocytic 
vesicles leads to the translocation of the light chain into the cytosol. 
Once in the cytosol, the light chain cleaves specific SNARE-family 
proteins. Serotypes A and E cleave SNAP-25; serotypes B, D, F, and G 
cleave VAMP; and serotype C cleaves SNAP-25 and syntaxin. Cleavage 
of any of these proteins disrupts the assembly of synaptic fusion com­
plexes, and this disruption inhibits the fusion of the membrane of the 
synaptic vesicle containing acetylcholine with the neuronal cell mem­
brane. Clinically, the result is flaccid paralysis of voluntary muscles. 
The irreversible binding of BoNTs to their targets has a clinical conse­
quence: once toxin binding has occurred, the resulting paralysis per­
sists for weeks or months, until nerve endings have been regenerated.
CHAPTER 158
BoNTs are produced by C. botulinum and a few strains of C. butyricum 
and C. baratii, which are all gram-positive, rod-shaped, spore-forming, 
anaerobic bacteria. Under most environmental conditions, C. botulinum 
exists as spores that are heat-resistant and ubiquitous in soil. In gen­
eral, C. botulinum spores require temperatures above boiling to ensure 
destruction; their thermal resistance increases with higher pH and 
lower salt content. Spores present in foods can survive most preserva­
tion methods and, if the conditions allow it, can germinate and pro­
duce BoNTs in significant amounts to cause disease. Commercial retort 
canning reliably destroys botulinal spores.
Botulism
BoNTs are among the most toxic substances known. Extremely 
small amounts of BoNT can cause severe disease and death. Sever­
ity of disease varies with dose, serotype, and route of exposure. The 
lethal dose of BoNT in humans is not known but can be estimated 
by extrapolation of toxicity data from animal studies. The estimated 
human lethal dose of BoNT acquired via the IV or IM route is 0.1–1 
ng/kg of body weight. The human lethal dose of BoNT acquired by 
inhalation of aerosolized toxin is estimated at 1–75 ng/kg. The degree 
of toxicity of BoNT acquired by the oral route is estimated to be much 
lower: 0.1–1 μg/kg.
As stated above, four naturally occurring and two non–naturally 
occurring forms of botulism are known. Foodborne botulism is caused 
by the ingestion of foods contaminated with BoNT. Wound botulism 
occurs when spores of BoNT-producing species of Clostridium con­
taminate a wound and then germinate, multiply, and produce toxin. 
Infant botulism is caused by BoNT-producing species of Clostridium 
colonizing the intestinal tract of infants ≤1 year of age. Adult intestinal 
colonization is similar to infant botulism but affects persons >1 year 
of age. Iatrogenic botulism occurs when a patient given injections 
of BoNT experiences signs of systemic botulism. BoNTs can also be 
aerosolized and used as a bioweapon, entering the human body by 
inhalation.
Foodborne Botulism 
Foodborne botulism is the most common 
form reported in many countries. Every case of foodborne botulism 
represents a public health emergency because of the potential for caus­
ing outbreaks. Foodborne botulism is an intoxication in which food 
containing preformed toxin is ingested. Spores of BoNT-producing

species of Clostridium are ubiquitous in soil and can be found on veg­
etables and other foodstuffs. C. botulinum type E is commonly found 
in aquatic environments and in aquatic animals. Because the spores 
are found in many foods, improper preparation or storage may pro­
duce the confluence of conditions that allow germination and growth 
of BoNT-producing species of Clostridium, which in turn result in 
production of BoNT. Both historically and at the present time, canned 
foods are of concern because they create anaerobic environments. To 
render these foods safe, proper processing procedures in conditions of 
enough heat and pressure to inactivate Clostridium spores, along with 
sufficient acidity, salinity, or other preservative methods to limit the 
organism’s growth and its production of BoNT, are required. Low-acidity 
foods, such as corn, peppers, potatoes, and beets, represent a higher 
risk. A series of botulism outbreaks from commercially canned foods 
in the early twentieth century resulted in standardization of retort can­
ning methods and promulgation and enforcement of production safety 
codes. Consumption of fish or other foods of marine origin can cause 
botulism if prepared or conserved improperly. Most foodborne botu­
lism cases in the United States are caused by home-canned vegetables 
such as green beans; however, commercially prepared foods, including 
chicken broth, carrot juice, hot dog chili sauce, and nacho cheese, also 
have been implicated in recent outbreaks. Marine mammal and fish 
products traditionally prepared by Alaskan Natives and First Peoples 
are the main source of botulism in Alaska and Canada.

Wound Botulism 
Wound botulism is caused by germination and 
growth of C. botulinum spores in a wound or necrotic tissue where they 
produce BoNT, which then enters circulation and produces systemic 
disease. Few cases of wound botulism were described in the United 
States until 1981, when the first case associated with injection drug 
use was reported. Since then, botulism cases due to injection drug use, 
especially in association with subcutaneous or tissue injection (skin 
popping) of black tar heroin, have substantially increased in the 
United States. Black tar heroin was introduced into the United States in 
the 1970s and, since the late 1980s, has become the predominant form 
of heroin west of the Mississippi River. Black tar heroin is contaminated 
with by-products of the manufacturing process, adulterants, and 
diluents and therefore is considered the most probable source of 
C. botulinum spores. In recent decades, the few cases of wound botu­
lism not associated with injection drug use have been associated with 
vehicle crashes, gunshot wounds, open-fracture wounds, and penetrat­
ing wounds caused by contaminated objects.
PART 5
Infectious Diseases
Infant Botulism 
Infant botulism is the most common form of 
botulism in the United States. It affects infants ≤1 year old, with a 
mean age at onset of 14 weeks. It has been suggested that the intestinal 
microbiota in infants may induce susceptibility to botulism; animal 
models seem to support this claim. Spores of BoNT-producing species 
of Clostridium can enter the body by ingestion. The highly resistant 
spores survive passage through the stomach and colonize the intes­
tine, where they germinate, grow, and produce BoNT in situ. Infants 
can continue excreting C. botulinum for weeks after clinical recovery. 
Spores of BoNT-producing species of Clostridium have been found in 
honey. Consumption of honey has been epidemiologically implicated 
in infant botulism; therefore, honey should not be fed to babies ≤1 year 
of age. Honey exposure, however, explains only a small proportion 
of cases. As spores are found in dust and soil, most infant botulism 
patients probably acquire BoNT-producing species of Clostridium by 
swallowing dust particles. Why only a few dozen infants are affected 
each year when presumably most infants regularly ingest clostridial 
spores remains unknown.
Adult Intestinal Botulism 
Similar to infant botulism, adult 
intestinal colonization is caused by spores of BoNT-producing species 
of Clostridium colonizing the large intestine, growing, and producing 
BoNT in situ. Although spores are routinely ingested and excreted by 
humans, the adult intestinal tract does not support spore germination 
and toxin production under normal circumstances. Adult intestinal 
colonization is usually associated with inborn anatomic abnormalities, 
gastrointestinal surgery, or prolonged use of antibiotics, which may 

alter the normal intestinal microbiota and facilitate colonization by 
BoNT-producing species of Clostridium. Although these associated 
conditions are relatively common, fewer than 30 cases of adult intesti­
nal colonization have been reported worldwide.
Iatrogenic Botulism 
Iatrogenic botulism occurs in patients 
injected with large doses of BoNT for treatment of muscle complica­
tions related to such conditions as cerebral palsy and spastic dystonia. 
The small doses of botulinum toxin used for wrinkle elimination in 
dermatologic practice are usually insufficient to cause systemic dis­
ease. In 2004, an outbreak of four cases caused by the injection of an 
unlicensed, highly concentrated BoNT product for cosmetic purposes 
occurred in the United States. Similarly, in 2017, an outbreak of nine 
cases occurred in Egypt in association with an unlicensed, highly con­
centrated BoNT preparation.
Weaponized Inhalational Botulism 
BoNTs were weaponized by 
the biological weapons programs of several countries in the twentieth 
century. Aerosolized BoNTs can be used as a bioweapon, exerting 
their effect by entering the body through inhalation. In the United States, 
BoNTs are designated as Tier 1 select agents—i.e., agents that present 
the greatest risk of deliberate misuse with significant potential for mass 
casualties or devastating effects on the economy, critical infrastructure, 
or public confidence. Tier 1 agents pose a severe threat to public health 
and safety. Terrorists have attempted to use BoNT as a bioweapon: 
Aum Shinrikyo, a Japanese cult, tried unsuccessfully to aerosolize 
BoNT in terrorism attacks at multiple sites in Japan between 1990 
and 1995.
■
■EPIDEMIOLOGY
Foodborne Botulism 
In the United States, foodborne botulism 
is the third most common form of botulism. From 2001 to 2019, 362 
foodborne botulism cases were reported, with a mean of 19 cases per 
year. Most cases (64%) were caused by serotype A BoNT, which was 
followed in frequency by serotype E (26%). Serotypes B and F caused 
7% and 2% of foodborne botulism cases, respectively. Outbreaks caused 
by serotype E usually had a shorter incubation period, those caused 
by type A had higher numbers of patients who required mechanical 
ventilation, and those caused by type B had lower numbers of deaths.
Foodborne botulism cases are usually sporadic (i.e., cases occur 
singly), but small and large outbreaks also can occur. From 2001 to 
2019, 5 foodborne botulism outbreaks affecting 10 or more people 
were reported in the United States (Table 158-1). Every case of food­
borne botulism is considered a public health emergency because it may 
be the first in an outbreak involving additional patients.
Most foodborne botulism cases in the United States are due to a 
wide variety of home-canned vegetables and pickled vegetables (e.g., 
beets, green beans, carrots, mushrooms, asparagus, peppers, beans, 
mustard greens, corn, tomato sauce, olives, pumpkin butter), vegeta­
bles baked in aluminum foil (e.g., potatoes, beets), home-canned meatbased foods (e.g., tuna, pickled pigs’ feet, stew, pasta in meat sauce), 
TABLE 158-1  Total Foodborne Botulism Outbreaks of 10 or More 
Cases Reported in the United States Between 2001 and 2019
NO. OF CONFIRMED 
CASES
YEAR
STATE
FOOD SOURCE

Texas
Chili

Multistate
Commercially canned hot dog 
chili sauce

Ohio
Home-canned potatoes used to 
prepare a potato salad, served at 
a church potluck

Mississippi
Pruno, illegal alcoholic beverage 
consumed by persons who were 
incarcerated at a federal facility

California
Commercially produced nacho 
cheese, sold at a convenience 
store

oil-based foods (e.g., pasta and jarred pesto, homemade garlic-infused 
oil), herbal deer antler tea, home-prepared fermented tofu, commercial 
clam chowder, or commercial grain and vegetable products. In Alaska, 
traditional Alaskan Native foods linked to foodborne botulism cases 
have included seal oil, seal blubber, dried herring in seal oil, fermented 
seal flipper, stinkheads and other fermented fish heads, stinkfish, 
salmon eggs, beaver tail, whitefish, fish eggs, fermented beluga, and 
whale blubber.
Commercial food manufacturing processes include retort canning, 
in which high temperature and pressure destroy the highly resistant 
clostridial spores, and manipulations that inhibit bacterial growth, 
such as acidification or addition of growth inhibitors that prevent 
germination and growth of BoNT-producing species of Clostridium 
and the production of BoNT. However, commercial foods occasionally 
still cause botulism if safe manufacturing processes are not followed 
or fail or if foods are stored or used inappropriately by the retailer or 
consumer. For instance, an outbreak of 10 cases associated with com­
mercially canned hot dog chili sauce occurred in 2007 as a result of 
deficiencies in the canning process. Other commercial food–associated 
outbreaks that occurred in the United States between 2001 and 2019 
include a 2001 outbreak of 16 cases linked to chili that was stored at 
inappropriate temperatures and later served at a church event in Texas 
and a 2006 outbreak linked to commercial carrot juice, which included 
four cases in the United States and two cases in Canada. The investiga­
tion of the latter outbreak led to an international product recall. The 
juice, which had no added sugar, salt, or preservatives, was stored at 
inappropriate temperatures.
Pruno, an illicit prison-brewed alcoholic beverage, first caused a 
botulism outbreak in a California prison in 2004, affecting 4 prisoners. 
In 2011, a second outbreak due to pruno was reported and involved 
8 patients at a prison in Utah. In 2012, 2 outbreaks associated with 
pruno occurred in a single prison in Arizona, with 4 and 8 cases, 
respectively. The largest outbreak from pruno occurred in 2016 in a 
Mississippi prison; 31 cases were identified, including 19 confirmed 
and 12 suspected.
Wound Botulism 
Wound botulism was once rare in the United 
States, but its frequency has been increasing for decades, and it is now 
the second most common form of botulism. Between 2001 and 2019, 
452 cases of wound botulism were reported, with an average of 24 cases 
per year. Most cases (92%) were caused by BoNT serotype A and by 
serotype B (5%). Most cases (96%) were among persons who injected 
drugs (mainly black tar heroin), and the remaining 4% of cases were 
due to traumatic injuries.
Infant Botulism 
Infant botulism is the most common form of 
botulism in the United States. Between 2001 and 2019, 2172 infant 
botulism cases were reported. BoNT serotypes A and B caused most 
cases (40% and 58%, respectively). Only 2 cases were due to serotype 
E. Of these 2 cases, 1 was due to C. botulinum type E and the other to 
C. butyricum type E; both cases represented the first report anywhere 
in this country of infant botulism due to those respective organisms. 
A small fraction (<1%) of cases were caused by serotype F. Of note, 
22 infant botulism cases were due to strains of C. botulinum that can 
produce two BoNT serotypes (A and B or B and F).
Botulism of Other Etiologies 
Between 2001 and 2019, 51 cases 
were reported as being of “unknown or other etiology.” This category 
includes laboratory-confirmed botulism cases that do not meet the 
definition of foodborne, infant, or wound botulism. Most of these cases 
were caused by serotype A (63%) and serotype F (27%). Many were 
thought to be cases of adult intestinal colonization, although confirma­
tion of this form of botulism is not always possible.
■
■CLINICAL MANIFESTATIONS
Botulism produces a syndrome characterized by bilateral cranial nerve 
palsies that may be followed by symmetric, descending flaccid paralysis 
that may cause respiratory arrest. There are no sensory deficits; patients 
are fully conscious, with normal intellectual function, although cranial 
nerve palsies may give a mistaken impression of altered consciousness. 

The typical incubation period (based on data for foodborne botulism 
cases, where exposure can be identified) is 1 or 2 days, but a range of 
6 h to >7 days has been reported. Several recent systematic reviews 
substantiate long-known observations that the syndrome is essentially 
identical for all types of botulism in patients of all ages, although elici­
tation of the typical signs and symptoms may be challenging in infants 
and young children. A recent systematic review of 16 cases of botulism 
in pregnant women reported the same clinical syndrome as in non­
pregnant individuals. In all botulism syndromes, the first neurologic 
manifestation usually is ptosis, which can be striking. Ocular findings 
of fuzzy vision or frank diplopia are caused by extraocular muscle 
paralysis due to palsies of cranial nerves III, IV, and VI. Flat, youthfully 
unlined, expressionless facies are produced by cranial nerve VII (facial 
nerve) palsy. Dysarthria is also a prominent manifestation. Oral and 
nasal regurgitation of foods or beverages is caused by cranial nerve 
IX (glossopharyngeal nerve) palsy. The autonomic system may be 
affected, producing anhidrosis manifesting as severe pharyngeal pain 
and erythema that has been mistaken for pharyngitis; paradoxically, 
other patients experience an inability to manage copious oral secre­
tions. Autonomic dysfunction may produce hemodynamic instability 
requiring monitoring. Cranial nerve palsy may produce pharyngeal 
muscle flaccidity, causing airway collapse and respiratory arrest early 
in the course of illness, while reduction in diaphragmatic and accessory 
muscle function may cause respiratory compromise hours or days later. 
Cranial nerve palsies may be followed by descending symmetric flaccid 
paralysis of the muscles of the neck, shoulders, upper limbs, and lower 
limbs; proximal muscle groups of each limb are affected before distal 
muscle groups.

CHAPTER 158
A recent analysis of 332 U.S. botulism cases found the following 
frequencies for patient-reported symptoms: difficulty swallowing, 86%; 
fatigue, 85%; blurred vision, 80%; slurred speech, 78%; double vision, 
76%; shortness of breath, 65%; and dry mouth, 62%. The analysis also 
reported the following frequencies of observed signs: afebrile body 
temperature, 99%; descending paralysis, 93%; alert and oriented status, 
93%; ptosis, 81%; limb weakness, 78%; decreased palatal reflex, 54%; 
facial palsy, 47%; and dilated pupils, 20%. Sixty-six percent of patients 
were intubated and received mechanical ventilation. These findings are 
similar to those reported in many smaller series. Rarely, asymmetry of 
cranial nerve palsies or distal muscle paralysis is reported and, at least 
in some cases (especially those described in reports based on chart 
abstractions), may reflect an incomplete or incompletely recorded 
neurologic examination. Despite intact sensorium, symptoms such as 
ptosis, dysarthria, and gait instability may be mistaken for diminished 
consciousness and lack of coordination and may be erroneously attrib­
uted to intoxication from alcohol or other substances. Paresthesias have 
been reported in some patients; these sensations are not explained by 
the known activity of botulinum toxin. Paralysis of the diaphragm and 
accessory muscles of respiration may occur, producing respiratory 
compromise. Distal tendon reflexes diminish symmetrically. Constipa­
tion due to intestinal paralysis develops in almost all patients. Nausea 
and vomiting may occur in foodborne botulism, preceding neurologic 
symptoms. Whether these manifestations are due to BoNT, other prod­
ucts of BoNT-producing species of Clostridium, or other contaminants 
of spoiled food is unknown. These gastrointestinal symptoms have not 
been reported in wound botulism.
Botulism
Death in untreated patients during the first hours to days of illness 
is caused by airway obstruction resulting from pharyngeal muscle 
paralysis and inadequate tidal volume resulting from paralysis of dia­
phragmatic and accessory respiratory muscles. The combination of 
expressionless facies from cranial nerve paralysis and immobility from 
voluntary muscle paralysis may give patients with botulism a placid 
appearance that masks the agitation expected with respiratory distress. 
Respiratory compromise occurs early in the course of disease in a sub­
stantial proportion of patients: the largest systematic literature review 
to date of foodborne and wound botulism cases (402 patients) reported 
that the average time from symptom onset to hospitalization was 2 days 
and that, at hospital admission, 42% of patients had respiratory symp­
toms; of these patients, 42% presented with no extremity weakness. In 
the same review, 87% of patients who required mechanical ventilation

were intubated during the first 2 days of hospitalization. The severity 
of disease varies greatly between patients and is probably governed by 
the dose of toxin to which they have been exposed. Without treatment, 
some patients do not progress beyond ptosis and mild palsy in one or 
two cranial nerves; others experience fulminant cranial nerve palsies 
and rapidly progressive descending flaccid paralysis eventually affect­
ing most or all voluntary muscles as well as respiratory failure requiring 
intubation and mechanical ventilation within hours.

The different BoNT serotypes are associated with variations in the 
botulism syndrome. BoNT type A is associated with more rapid disease 
progression, more frequent respiratory compromise and mechanical 
ventilation, and longer duration of paralysis. Type B is associated with 
a milder syndrome, with less severe and shorter-duration paralysis. 
Intoxication with the rarely occurring type F produces a syndrome of 
rapidly progressing paralysis that often leads to respiratory failure, with 
more rapid recovery than occurs with other toxin types. However, all 
toxin types causing human illness can cause severe disease; the clinical 
approach is the same for all.
The paralysis of botulism can last for weeks or months—the time 
required for regeneration of affected nerve endings and recovery of 
voluntary muscle function. For severely affected patients with exten­
sive paralysis, management consists of protracted intensive care, with 
detection and treatment of attendant risks not specific to botulism, 
such as ventilator-associated pneumonia, decubitus ulcers, and psy­
chological trauma. More than 95% of noninfant botulism patients 
in the United States recover; hospital discharge is often followed by 
protracted rehabilitative care. The survival rate for infant botulism is 
near 100%.
PART 5
Infectious Diseases
■
■CLINICAL DIAGNOSIS AND LABORATORY 
CONFIRMATION
Rapid clinical diagnosis is essential. A diagnostic aid for botulism, 
“Clinical Criteria to Trigger Suspicion of Botulism,” has been published 
by botulism consultants at the Centers for Disease Control and Pre­
vention (CDC; accessible at academic.oup.com/cid/article/66/suppl_1/
S38/4780423). The paralysis of botulism lasts for weeks or months, 
and administration of equine-source botulinum antitoxin (BAT)—the 
specific therapy to arrest the progression of paralysis—depends on the 
correct diagnosis. At this time, laboratory confirmation of botulism, 
which may require ≥24 h, must take place at a specialized public health 
laboratory. Therefore, effective, timely treatment relies on rapid clini­
cal diagnosis of botulism in a patient with clinically compatible find­
ings, without awaiting laboratory confirmation. A clinician suspecting 
noninfant botulism in a patient should immediately contact the state 
health department’s emergency 24-h line. The state will connect the 
clinician with a botulism clinical consultant at the CDC (or, in Alaska, 
California, and Colorado, at the state health department), who will 
review the case with the clinician, assist in the shipping of appropri­
ate specimens to a public health laboratory for definitive diagnosis, 
and, when indicated, arrange for immediate shipping of BAT from the 
federal stockpile at no charge. A clinician suspecting infant botulism 
in a patient should immediately contact the Infant Botulism Treat­
ment and Prevention Program’s on-call physician at (510)231-7600, 
who will provide consultation, assist with specimen collection, and, 
when indicated, assist with the provision of human-derived botulinum 
antitoxin (BabyBIG), a specific treatment licensed for treatment of 
infant botulism.
The neurologic examination is the key to clinical diagnosis of botu­
lism, as it readily uncovers the cranial nerve deficits that are invariably 
present in botulism and focuses the differential diagnosis. In principle, 
the distinct syndrome of bilateral cranial palsies and descending flac­
cid paralysis in a fully conscious patient should render the diagnosis 
and prompt treatment of botulism straightforward. The presentation 
of two or more patients with this syndrome is almost pathognomonic, 
since other illnesses considered during the differential diagnosis of 
botulism do not produce outbreaks. In practice, however, sporadic 
(lone) cases of botulism are misdiagnosed, and sometimes the diagno­
sis is missed even in the setting of an outbreak. In part, these failures 
may be due to the rarity of botulism and the clinician’s unfamiliarity 

with its presentation. A possible cause of misdiagnosis is failure to 
perform a complete neurologic examination; indeed, review of some 
botulism patients’ charts reveals documentation of the first neurologic 
examination, which suggested the correct diagnosis, days after hospital 
admission. As stated earlier, the combination of ptosis, dysarthria, and 
perceived gait instability from muscle paralysis in some cases may be 
misinterpreted as intoxication from alcohol or other substances. In 
other cases, rapidly progressing botulism may result in pharyngeal col­
lapse and respiratory distress relatively early in the course, leading the 
clinical team to focus on airway management and primary respiratory 
diagnoses and thus delaying the neurologic evaluation.
Standard clinical studies, including bloodwork and radiology, are 
not useful in diagnosing botulism. In contrast to the findings in 
Guillain-Barré syndrome (GBS; see below), lumbar-puncture cere­
brospinal fluid (CSF) values—and specifically the protein level—are 
usually normal in botulism. The CSF protein level may be very slightly 
elevated in a minority of botulism cases. The fact that botulism pro­
duces no abnormal findings on brain imaging may help rule out rare 
basilar strokes that produce nonlateralizing symptoms. Serological 
antibody tests and rapid nerve stimulation tests can rule out myas­
thenia gravis. Electromyography, when performed by an experienced 
practitioner, can provide support for the diagnosis. Botulism is indi­
cated by findings consistent with neuromuscular junction blockage, 
normal axonal conduction, and potentiation with rapid repetitive 
stimulation in affected muscles.
Once a neurologic examination reveals the cranial nerve palsies of 
botulism and any additional bilateral flaccid paralysis, the differential 
diagnosis may include GBS, myasthenia gravis, Lambert-Eaton syn­
drome, and tick paralysis. Less likely conditions include tetrodotoxin 
or shellfish poisoning, antimicrobial-associated paralysis, and rarer 
poisonings. A careful history and physical examination can further 
narrow the range of diagnoses. GBS is a rare (~1 case per 100,000 
population per year in the United States) autoimmune demyelinating 
polyneuropathy that follows acute infection by Campylobacter jejuni, 
certain viruses, and other bacteria. In 95% of cases, GBS presents as 
an ascending paralysis. Recent reports from Peru indicate massive 
outbreaks of GBS of unknown cause, challenging the previously held 
notion that conditions causing flaccid paralysis other than botulism 
occur only as sporadic cases. The 5% of GBS cases presenting as the 
Miller Fisher variant are characterized by the triad of ophthalmoplegia, 
ataxia, and areflexia, which may resemble early descending paralysis. 
The CSF protein level is elevated in GBS, but the increase may take 
place days after symptom onset; thus, normal CSF levels should be 
taken into account along with the duration of symptoms, and lumbar 
puncture may need to be repeated. Electromyography performed by 
an experienced operator may yield findings indicative of GBS and not 
botulism. Serological antibody tests or rapid nerve stimulation tests 
can confirm myasthenia gravis; borderline positive Tensilon tests have 
been reported in botulism patients. In most stroke patients, the physi­
cal examination should reveal asymmetric paralysis and upper motor 
neuron signs; brain imaging can help reveal rare basilar strokes that can 
produce symmetric bulbar palsies. The history and physical examina­
tion should rule out Lambert-Eaton syndrome, which is characterized 
by proximal limb weakness in patients with advanced cancer.
Laboratory testing confirms clinically diagnosed botulism cases and 
determines the BoNT serotype causing the disease. In addition, labo­
ratory testing can confirm epidemiologic data by demonstrating pres­
ence of BoNT in the suspected food. Botulism cases are confirmed by 
the laboratory when BoNT is identified in serum or stool specimens or 
when a BoNT-producing species of Clostridium is isolated from stool 
specimens or wound cultures. Identification of preformed BoNT in 
food consumed by patients also confirms foodborne botulism.
The gold standard for identification and serotyping of BoNT in 
clinical or food specimens is the mouse bioassay. The drawback is that 
this highly sensitive and specific method requires the use of animals. 
Specimens are injected IP into the mice with and without antitoxin; 
the mice are then observed for up to 96 h for signs of botulism. If the 
specimen contains BoNT at levels sufficient to affect the mice quickly, 
results may be available within 24 h of injection. Low levels of toxin

may produce signs later, so mice should be monitored for 4 days after 
injection. Many in vitro methods have been developed for detection of 
BoNT and BoNT-producing species of Clostridium in clinical and food 
specimens. For instance, public health laboratories in the United States 
can use a real-time polymerase chain reaction test that detects bont 
genes encoding serotypes A through G. This test is a useful screening 
method to determine whether BoNT-producing species of Clostridium 
are present in cultures of clinical specimens, but positive results must 
be confirmed. Another in vitro method, the Endopep mass spectrom­
etry (Endopep-MS) assay, is highly sensitive and specific and can detect 
BoNT in clinical specimens and foods. The advantage of Endopep-MS 
is that it detects active BoNT and therefore represents an ideal alterna­
tive to the mouse bioassay. Immune-based assays can provide rapid 
and sensitive results; their main limitation is that they detect antigens, 
which may not necessarily represent active BoNT. Cell-based in vitro 
assays are also a possible alternative to the mouse bioassay as they 
detect biologic activity of BoNT.
TREATMENT
Botulism
Treatment for botulism consists of two components: meticulous 
monitoring and supportive care, including admittance to the inten­
sive care unit when indicated, and administration of botulinum 
antitoxin, the only specific therapy for botulism, as quickly as 
possible. Paralysis from botulism can be rapidly progressive. Vital 
capacity, and often hemodynamic parameters, should be frequently 
monitored and mechanical ventilation instituted immediately if 
needed. Paralysis induced by BoNT lasts weeks or months, and 
patients with extensive paralysis require painstaking care to avoid 
complications associated with protracted immobilization, including 
respirator-dependent pneumonia, decubitus ulcers, and psycho­
logical trauma. Patients who have recovered from severe botulism 
report that their appearance and immobility often led caregivers 
to assume they were unconscious; as a consequence, patients were 
sometimes subjected to painful procedures without warning and 
to insensitive comments. Signage should remind all caregivers that 
botulism patients are conscious but “locked in.” Psychological sup­
port should be instituted for intubated botulism patients from the 
outset. With proper supportive care, >95% of botulism patients in 
the United States recover, even without antitoxin therapy; however, 
antitoxin, if promptly administered, can substantially reduce the 
extent and duration of illness (see below).
Botulinum antitoxin is the only specific treatment for botulism. 
The antitoxin prevents the progression of paralysis but does not 
reverse existing paralysis. If given early enough in the course of 
disease, it may avert respiratory compromise, obviate mechanical 
intubation, and forestall protracted paralysis and hospitalization 
along with associated complications. Accordingly, it is essential 
to administer antitoxin as soon as possible. A recent systematic 
literature review and meta-analysis covering nearly a century of 
the published literature in noninfant botulism patients confirmed 
long-known findings from smaller studies by showing significantly 
reduced mortality rates among patients treated with equine anti­
toxin, especially when treatment was administered within 48 h 
of symptom onset. Another large systematic literature review of 
pediatric noninfant botulism recently showed significantly reduced 
mortality risk among children treated with equine antitoxin. Pub­
lished studies have demonstrated a substantial reduction in the 
duration and severity of illness among patients with infant botulism 
who are treated with human-derived botulinum antitoxin.
The equine botulinum antitoxin used to treat noninfant botulism 
consists of antibodies produced in horses immunized with botu­
linum toxoids (inactivated toxins) and toxins. The antibodies are 
type-specific (anti-A neutralizes BoNT type A and so forth). The 
currently licensed antitoxin product in the United States, heptava­
lent botulinum antitoxin (BAT), contains antibodies to BoNT types 
A, B, C, D, E, F, and G. These equine antibodies have undergone 

despeciation to reduce antigenicity and the risk of anaphylaxis to 
foreign protein. A recent systematic literature review, along with 
studies of BAT use, indicated that <2% of recipients experience 
serious adverse reactions. Administration of one vial of BAT elicits 
circulating antitoxin concentrations sufficient to neutralize toxin 
levels one to two orders of magnitude higher than those found in 
the serum of most botulism patients. As noted earlier, clinicians 
suspecting botulism in a patient should immediately call their state 
health department’s emergency contact to be put in touch with a 
botulism clinical consultant who will review the case and assist in 
its management, including shipment of BAT from the federal stock­
pile at no charge. The botulinum antitoxin used to treat infants, 
BabyBIG, consists of human antibodies obtained from hyperim­
munized volunteers. The product is licensed for treatment of infant 
botulism due to BoNT types A and B and, as noted earlier, can be 
obtained through the Infant Botulism Treatment and Prevention 
Program.

There is no prophylactic treatment for botulism. Persons who 
may have been exposed to botulinum toxin should be evaluated by 
a physician and carefully observed for the development of symp­
toms of botulism. If symptoms appear, the patient should be treated 
immediately with botulinum antitoxin.
■
■PREVENTION
No vaccine is licensed for the prevention of botulism. In the United 
States, a botulinum toxoid vaccine was available through the CDC until 
2011, but it was discontinued because of a decline in immunogenicity 
of some serotypes and an increase in occurrence of moderate local 
reactions. Several vaccine candidates are currently in clinical trials.
CHAPTER 158
Because most foodborne botulism cases are caused by home-canned 
or home-preserved foods, the prevention of foodborne botulism 
depends mainly on proper preparation and preservation that ensures 
the destruction of spores of BoNT-producing species of Clostridium 
that may be present in the food or on the creation of an environment 
that will not allow the germination and growth of these spores, such as 
low pH or low water activity. Water activity is a measure of how much 
water is free, unbound, and thus available to microorganisms to use 
for growth. If foods have low water activity, it means they do not have 
much free water, and growth of C. botulinum will be limited or inhib­
ited. Using pressure canners and properly cleaning items employed in 
the canning process can reduce the risk of foodborne botulism. Among 
other resources, the USDA Complete Guide to Home Canning provides 
a detailed description of safe home-canning practices. Other ways of 
preventing foodborne botulism include refrigerating homemade oils 
infused with garlic or herbs and discarding any of these oils that have 
not been used after 4 days; maintaining baked potatoes or similar foods 
wrapped in aluminum foil at temperatures above 140°F until served 
and then refrigerating leftovers; refrigerating canned or pickled foods 
after opening; and boiling home-canned foods before eating, especially 
those foods that are low in acid.
Botulism
Wound botulism largely affects people who inject drugs, especially 
black tar heroin. Using safe injection practices may help prevent wound 
botulism and many other infections, such as HIV and hepatitis C virus 
infections. Thus, educating injection drug users on the prevention of 
wound botulism and other infections is vital in protecting their health. 
As wound botulism can also follow traumatic injuries, keeping wounds 
clean is key.
The risk factors for infant botulism are not fully understood, but pos­
sible sources of spores of BoNT-producing species of Clostridium include 
foods and dust. In most cases of infant botulism, no source of spores is 
identified. Honey is the only food that has been identified as an epide­
miologically associated reservoir of spores of BoNT-producing species of 
Clostridium. Honey should not be fed to infants ≤1 year of age.
■
■GLOBAL CONSIDERATIONS
Botulism has been reported from all parts of the world. The European 
Centre for Disease Prevention and Control has reported an average of 
110 botulism cases each year from 2007 to 2018. During that period,