1212 PART 5 Infectious Diseases

abortion, or drug injection) are associated with more severe disease

and worse outcomes. In neonates, infection of the umbilical stump

can result from inadequate umbilical-cord care; in some cultures, for

example, the cord is cut with grass or animal dung is applied to the

stump. Circumcision or ear-piercing also can result in neonatal tetanus.

■ EPIDEMIOLOGY

Tetanus is a rare disease in the developed world. Two cases of neonatal tetanus have occurred in the United States since 2009. In 2018, 23

cases of tetanus were reported to the U.S. national surveillance system,

almost all of which were in adults. Most cases occur in incompletely

vaccinated or unvaccinated individuals. Vaccination status is known

in 25% of cases reported in the United States between 2009 and 2015;

among these cases, only 20% of patients had received three or more

doses of tetanus toxoid–containing vaccine.

Persons >60 years of age are at greater risk of tetanus because antibody

levels decrease over time. Approximately one-quarter of recent cases in

the United States were in persons >65 years old. Diabetes is associated

with increased tetanus risk, representing 13% of all cases and 25% of

deaths in 2009–2015. People who inject drugs—particularly those

injecting heroin subcutaneously (“skin-popping”)—also are recognized

as a high-risk group. Approximately 6% of all tetanus cases between

2009 and 2015 were in injection-drug users. The reasons for these

outbreaks remain unclear but are thought to involve a combination

of heroin contamination, skin-popping, and incomplete vaccination.

The global incidence of neonatal tetanus has reduced significantly

following a concerted elimination program by WHO partnering with

the United Nations Children’s Fund (UNICEF) and the United Nations

Population Fund (UNFPA). The incidence of tetanus among older children and adults is unknown, as few countries have good surveillance

systems, although in 2015 there were estimated to be between 30,000

and 62,000 deaths from tetanus in this age group.

■ PATHOGENESIS

Genome sequencing of C. tetani has allowed identification of several

exotoxins and virulence factors. Only those bacteria producing tetanus

toxin (tetanospasmin) can cause tetanus. Although closely related to

the botulinum toxins in structure and mode of action, tetanus toxin

undergoes retrograde transport into the central nervous system (CNS)

and thus produces clinical effects different from those caused by the

botulinum toxins, which remain at the neuromuscular junction.

Tetanus toxin is intra-axonally transported to motor nuclei of the

cranial nerves or ventral horns of the spinal cord. This toxin is produced as a single 150-kDa protein that is cleaved to produce heavy

(100-kDa) and light (50-kDa) chains linked by a disulfide bond and

noncovalent forces. The carboxy terminal of the heavy chain binds

to specific membrane components in presynaptic α-motor nerve terminals; evidence suggests binding to both polysialogangliosides and

membrane proteins. This binding results in toxin internalization and

uptake into the nerves. Once inside the neuron, the toxin enters a

retrograde transport pathway, whereby it is carried proximally to the

motor neuron body. It is known that tetanus toxin exhibits several different pH-dependent conformations and therefore can interact with a

variety of different receptors. During its passage from the periphery to

the central nervous system, tetanus toxin can access neuronal trafficking systems and evade degradation.

Following retrograde transport in the motor neuron, the tetanus

toxin undergoes translocation across the synapse to the GABA-ergic

presynaptic inhibitory interneuron terminals. Here the light chain,

which is a zinc-dependent endopeptidase, cleaves vesicle-associated

membrane protein 2 (VAMP2, also known as synaptobrevin). This molecule is necessary for presynaptic binding and release of neurotransmitter; thus tetanus toxin prevents transmitter release and effectively

blocks inhibitory interneuron discharge. The result is unregulated

activity in the motor nervous system. Similar activity in the autonomic

system accounts for the characteristic features of skeletal muscle spasm

and autonomic system disturbance. The increased circulating catecholamine levels in severe tetanus are associated with cardiovascular

complications.

Relatively little is known about the processes of recovery from

tetanus. Recovery can take several weeks. Peripheral nerve sprouting

is involved in recovery from botulism, and similar CNS sprouting

may occur in tetanus. Other evidence suggests toxin degradation as a

mechanism of recovery.

APPROACH TO THE PATIENT

Tetanus

The clinical manifestations of tetanus occur only after tetanus

toxin has reached presynaptic inhibitory nerves. Once these effects

become apparent, there may be little that can be done to affect

disease progression. Treatment should not be delayed while the

results of laboratory tests are awaited. Management strategies aim

to neutralize remaining unbound toxin and support vital functions until the effects of the toxin have worn off. Recent interest

has focused on intrathecal methods of antitoxin administration to

neutralize toxin within the CNS and limit disease progression (see

“Treatment,” below).

■ CLINICAL MANIFESTATIONS

Tetanus produces a wide spectrum of clinical features that are broadly

divided into generalized (including neonatal) and local. In the usually

mild form of local tetanus, only isolated areas of the body are affected

and only small areas of local muscle spasm may be apparent. If the cranial nerves are involved in localized cephalic tetanus, the pharyngeal

or laryngeal muscles may spasm, with consequent aspiration or airway

obstruction, and the prognosis may be poor. In the typical progression

of generalized tetanus (Fig. 152-1), muscles of the face and jaw often

are affected first, presumably because of the shorter distances toxin

must travel up motor nerves to reach presynaptic terminals. Neonates

typically present with an inability to suck.

In assessing prognosis, the speed at which tetanus develops is

important. The incubation period (time from wound to first symptom)

and the period of onset (time from first symptom to first generalized

spasm) are of particular significance; shorter times are associated with

worse outcome. In neonatal tetanus, the younger the infant is when

symptoms occur, the worse the prognosis.

The most common initial symptoms are trismus (lockjaw), muscle

pain and stiffness, back pain, and difficulty swallowing. In neonates,

difficulty in feeding is the usual presentation. As the disease progresses, muscle spasm develops. Generalized muscle spasm can be

very painful. Commonly, the laryngeal muscles are involved early or

even in isolation. This is a life-threatening event as complete airway

obstruction may ensue. Spasm of the respiratory muscles results in

respiratory failure. Without ventilatory support, respiratory failure is

the most common cause of death in tetanus. Spasms strong enough to

produce tendon avulsions and crush fractures have been reported, but

this outcome is extremely rare.

Autonomic disturbance is maximal during the second week of

severe tetanus, and death due to cardiovascular events becomes the

major risk. Blood pressure is usually labile, with rapid fluctuations

from high to low accompanied by tachycardia. Episodes of bradycardia

and heart block also can occur. Autonomic involvement is evidenced

by gastrointestinal stasis, sweating, increased tracheal secretions, and

acute (often high-output) renal failure.

■ DIAGNOSIS

The diagnosis of tetanus is based on clinical findings. As stated above,

treatment should not be delayed while laboratory tests are conducted.

Culture of C. tetani from a wound provides supportive evidence. Serum

anti-tetanus immunoglobulin G also may be measured in a sample

taken before the administration of antitoxin or immunoglobulin; levels

>0.1 IU/mL (measured by standard enzyme-linked immunosorbent

assay) are deemed protective and do not support the diagnosis of

tetanus. If levels are below this threshold, a bioassay for serum tetanus

toxin may be helpful, but a negative result does not exclude the diagnosis, and these levels are not generally performed. Polymerase chain

1213CHAPTER 152 Tetanus

reaction also has been used for detection of tetanus toxin, but its sensitivity is unknown, and, similarly, a negative result does not exclude

the diagnosis.

The few conditions that mimic generalized tetanus include strychnine poisoning and dystonic reactions to antidopaminergic drugs.

Abdominal muscle rigidity is characteristically continuous in tetanus

but is episodic in the latter two conditions. Cephalic tetanus can be

confused with trismus of other etiologies, such as oropharyngeal

infection. Hypocalcemia and meningoencephalitis are included in the

differential diagnosis of neonatal tetanus.

TREATMENT

Tetanus

If possible, the entry wound should be identified, cleaned, and

debrided of necrotic material in order to remove anaerobic foci

of infection and prevent further toxin production. Metronidazole

(400 mg rectally or 500 mg IV every 6 h for 7 days) is preferred for

antibiotic therapy. An alternative is penicillin (100,000–200,000 IU/

kg per day), although this drug theoretically may exacerbate spasms

and in one study was associated with increased mortality. Failure

to remove pockets of ongoing infection may result in recurrent or

prolonged tetanus.

Antitoxin should be given early in an attempt to deactivate any

circulating tetanus toxin and prevent its uptake into the nervous

system. Two preparations are available: human tetanus immune

globulin (TIG) and equine antitoxin. TIG is the preparation of

choice, as it is less likely to be associated with anaphylactoid reactions. A single IM dose (500–5000 IU) is given, with a portion

injected around the wound. Equine-derived antitoxin is available

widely and is used in low-income countries; after hypersensitivity

testing, 10,000–20,000 U is administered IM as a single dose or as

divided doses. Some evidence indicates that intrathecal administration of TIG inhibits disease progression and leads to a better

outcome. The results of relevant studies have been supported by a

meta-analysis of trials involving both adults and neonates, with TIG

doses of 50–1500 IU administered intrathecally. However, most

preparations are not licensed for intrathecal use.

Spasms are controlled by heavy sedation with benzodiazepines.

Chlorpromazine and phenobarbital are commonly used worldwide,

and IV magnesium sulfate has been used as a muscle relaxant. A

significant problem with all these treatments is that the doses necessary to control spasms also cause respiratory depression; thus, in

resource-limited settings without mechanical ventilators, controlling spasms while maintaining adequate ventilation is problematic,

and respiratory failure is a common cause of death. In locations

with ventilation equipment, severe spasms are best controlled with a

combination of sedatives or magnesium and relatively short-acting,

cardiovascularly inert, nondepolarizing neuromuscular blocking

agents that allow titration against spasm intensity. Infusions of

propofol also have been used successfully to control spasms and

provide sedation.

It is important to establish a secure airway early in severe tetanus. Ideally, patients should be nursed in calm, quiet environments

because light and noise can trigger spasms. Tracheal secretions are

increased in tetanus, and dysphagia due to pharyngeal involvement

combined with hyperactivity of laryngeal muscles makes endotracheal intubation difficult. Patients may need ventilator support for

several weeks. Thus tracheostomy is the usual method of securing

the airway in severe tetanus.

Cardiovascular instability in severe tetanus is notoriously difficult to treat. Rapid fluctuations in blood pressure and heart rate can

occur. Cardiovascular stability is improved by increasing sedation

with IV magnesium sulfate (plasma concentration, 2–4 mmol/L

or titrated against disappearance of the patella reflex), morphine,

fentanyl, or other sedatives. In addition, drugs acting specifically

on the cardiovascular system (e.g., esmolol, calcium antagonists,

and inotropes) may be required. Short-acting drugs that allow

rapid titration are preferred; particular care should be taken when

longer-acting β antagonists are administered, as their use has been

associated with hypotensive cardiac arrest.

Complications arising from treatment are common and include

thrombophlebitis associated with diazepam injection, ventilatorassociated pneumonia, central-line infections, and septicemia.

In some centers, prophylaxis against deep-vein thrombosis and

thromboembolism is routine.

Recovery from tetanus may take 4–6 weeks. Patients must be

given a full primary course of immunization as tetanus toxin is

poorly immunogenic and the immune response following natural

infection is inadequate.

Cardiovascular

instability: labile BP,

tachy- or bradycardia

Pyrexia, increased

respiratory and GI

secretions

Initial symptoms:

muscle aches,

trismus, myalgia

Muscle spasm: local

and generalized

Cardiovascular and

autonomic control

Cessation of spasms,

restoration of normal

muscle tone

Tetanus toxin

uptake into nervous

system and VAMP

cleavage in GABA

inhibitory neurons

Wound infection,

multiplication of

Clostridium tetani

Toxin degradation

Further toxin effects causing

widespread disinhibition of

motor and autonomic

nervous system

No symptoms

7–10

days

24–72

hours

4–6

weeks

FIGURE 152-1 Clinical and pathologic progression of tetanus. BP, blood pressure; GABA, γ-aminobutyric acid; GI, gastrointestinal; VAMP, vesicle-associated membrane

protein (synaptobrevin).

1214 PART 5 Infectious Diseases

TABLE 152-1 Factors Associated with a Poor Prognosis in Tetanus

ADULT TETANUS NEONATAL TETANUS

Age >70 years Younger age, premature birth

Incubation period <7 days Incubation period <6 days

Short time from first symptom to

admission

Puerperal, IV, postsurgery, burn

entry site

Period of onseta

 <48 h

Delay in hospital admission

Grass used to cut cord

Low birth weight

Fever on admission

Heart rate >140 beats/minb

Systolic blood pressure >140 mmHgb

Severe disease or spasmsb

Temperature >38.5°Cb

a

Time from first symptom to first generalized spasm. b

At hospital admission.

■ PROGNOSIS

Rapid development of tetanus is associated with more severe disease

and poorer outcome; it is important to note time of onset and length

of incubation period. More sophisticated modeling has revealed other

important predictors of prognosis (Table 152-1). In many adults,

particularly in the elderly, surviving tetanus is associated with reduced

long-term functional outcome measures. Studies of children and

neonates have suggested a higher incidence of neurologic sequelae.

Neonates may be at increased risk of learning disabilities, behavioral

problems, cerebral palsy, and deafness.

■ PREVENTION

Tetanus is prevented by good wound care and immunization (Chap.

123). In neonates, use of safe, clean delivery and cord-care practices

as well as maternal vaccination are essential. The WHO guidelines

for tetanus vaccination consist of a primary course of three doses in

infancy, boosters at 4–7 and 12–15 years of age, and one booster in

adulthood. In the United States, the CDC suggests an additional dose

at 15–18 months with booster at 11–12 years of age and every 10 years

thereafter. For those with incomplete primary vaccination series in

infancy, specific “catch-up” schedules are published. For those age

7 years or older, the recommendation is a three-dose primary course

with 4 weeks between the first two doses, followed by a booster

6–12 months later. Catch-up schedules for those under 7 years involve

a primary series of four doses of tetanus toxoid–containing vaccine if

the child is under 12 months when the first dose is given, or three doses

for those over 12 months at first dose.

Standard WHO recommendations for prevention of maternal and

neonatal tetanus call for administration of two doses of tetanus toxoid

at least 4 weeks apart to previously unimmunized pregnant women. A

third dose should be given at least 6 months later, followed by one dose

in subsequent pregnancies (or intervals of at least 1 year), to a total

of five doses to provide long-term immunity. However, in high-risk

areas, a more intensive approach has been successful, with all women

of childbearing age receiving a primary course along with education on

safe delivery and postnatal practices.

Individuals sustaining tetanus-prone wounds should be immunized

if their vaccination status is incomplete or unknown or if their last

booster was given >10 years earlier. Patients with an inadequate vaccine

status who sustain wounds not classified as clean or minor should also

undergo passive immunization with TIG. It is recommended that tetanus toxoid be given in conjunction with diphtheria toxoid in a preparation with or without acellular pertussis: DTaP for children <7 years old,

Td for 7- to 9-year-olds, and Tdap for children >9 years old and adults.

In the early 1980s, tetanus caused more than 1 million deaths a year,

accounting for an estimated 5% of maternal deaths and 14% of all neonatal deaths. In 1989, the World Health Assembly adopted a resolution

to eliminate neonatal tetanus by the year 2000; elimination was defined

as <1 case/1000 live births in every district in every country. By 1999,

elimination was still to be achieved in 57 countries and the deadline was

extended until 2005, with the additional target of eliminating maternal

tetanus (tetanus occurring during pregnancy or within 6 weeks of its

end). Ratification of the Millennium Development Goals, in particular

goal 4 (achieving a two-thirds reduction in the mortality rate among

children under 5), has further focused attention on reducing deaths

from vaccine-preventable disease, particularly in the first 4 weeks of life.

The target was to achieve maternal and neonatal tetanus elimination by

2020, but as of December 2020, 12 countries have yet to achieve this goal.

Because vaccination reduces the incidence of neonatal tetanus by an

estimated 94%, immunization of pregnant women with two doses of

tetanus toxoid at least 4 weeks apart has been the primary method of

maternal and neonatal tetanus elimination. In some areas, all women

of childbearing age have been targeted as a means of increasing vaccination coverage. In addition, educational programs have focused on

improving hygiene during the birth process, an intervention that in

itself is estimated to reduce neonatal tetanus deaths by up to 40%.

The latest available data show that significant progress has been

made: in recent years, 47 countries have achieved maternal and

neonatal tetanus elimination, including China, India, and Indonesia.

Worldwide, deaths from neonatal tetanus fell by 96% between 1990 and

2015; in the latter year, with 72% of mothers receiving at least 2 doses

of tetanus toxoid–containing vaccine and an estimated 34,000 neonatal

tetanus deaths, mainly in Africa and Southeast Asia. Despite this relative success, immunization programs need to be ongoing as there is

no herd immunity effect for tetanus and C. tetani contamination of soil

and feces is widespread.

The rate of primary vaccination coverage in infancy (three doses of

DTP) is 86%, but rates for the subsequent boosters necessary for longterm protection are unknown. Dedicated public health initiatives are

lacking, and the continuing reports of sizable case series in the medical

literature suggest that tetanus continues to pose a significant global

health burden.

■ FURTHER READING

Borrow R et al: The immunological basis for immunization series.

Module 3: Tetanus update 2018. Edited by Vaccines and Biologicals

Immunization. World Health Organization, 2018.

Kyu HH et al: Mortality from tetanus between 1990 and 2015: Findings

from the global burden of disease study 2015. BMC Public Health

17:179, 2017.

Rodrigo C et al: Pharmacological management of tetanus: An

evidence-based review. Crit Care 18:217, 2014.

Yen LM, Thwaites CL: Tetanus. Lancet 393:1657, 2019.

■ WEBSITES

Centers for Disease Control and Prevention: Pink Book. Tetanus. 1997. www.cdc.gov/vaccines/pubs/pinkbook/downloads/tetanus

.pdf.

Health Protection Agency: Tetanus: Information for health

professionals. 2013. www.gov.uk/government/publications/

tetanus-advice-for-health-professionals.

World Health Organization: Maternal and neonatal tetanus (MNT) elimination. www.who.int/immunization/diseases/

MNTE_initiative/en/.

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.

153 Botulism

Carolina Lúquez, Jeremy Sobel

1215CHAPTER 153 Botulism

by the ingestion of foods contaminated with BoNT. Wound botulism

occurs when spores of BoNT-producing species of Clostridium contaminate 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 causing 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 vegetables 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 produce 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. Lowacidity 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 canning 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 botulism 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, have also 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 botulism

not associated with injection drug use have been associated with vehicle crashes, gunshot wounds, open-fracture wounds, and penetrating

wounds caused by contaminated objects.

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 intestine, 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

■ 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; serotypes 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 threshold, 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 functions. 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 mechanism of action: they target neurons and block neurotransmission

by cleaving SNARE-family proteins in the host, with consequent

inhibition 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

receptor-binding domain. The receptor-binding domain of the heavy

chain mediates the neurospecific binding of BoNTs, which leads to

its internalization within endocytic compartments. Interaction of the

translocation 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 complexes, and this disruption inhibits the fusion of the membrane of the

synaptic vesicle containing acetylcholine with the neuronal cell membrane. Clinically, the result is flaccid paralysis of voluntary muscles.

The irreversible binding of BoNTs to their targets has a clinical consequence: once toxin binding has occurred, the resulting paralysis persists for weeks or months, until nerve endings have been regenerated.

BoNTs are produced by C. botulinum and some strains of C.

butyricum and C. baratii, which are gram-positive, rod-shaped, sporeforming, anaerobic bacteria. Under most environmental conditions,

C. botulinum exists as spores that are heat-resistant and ubiquitous in

soil. In general, 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

preservation methods and, if the conditions allow it, can germinate and

produce BoNTs in significant amounts to cause disease.

BoNTs are among the most toxic substances known. Extremely small

amounts of BoNT can cause severe disease and death. Severity 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

1216 PART 5 Infectious Diseases

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 intestinal colonization have been reported worldwide.

Iatrogenic Botulism Iatrogenic botulism occurs in patients

injected with large doses of BoNT for treatment of muscle complications 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 disease. 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 concentrated 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 2017, 326

foodborne botulism cases were reported, with a mean of 19 cases per

year. Most cases (65%) were caused by serotype A BoNT, which was

followed in frequency by serotype E (25%). Serotypes B and F caused

7% and 1% 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 can also occur. From 2001 to 2017,

five foodborne botulism outbreaks affecting 10 or more people were

reported in the United States (Table 153-1). Every case of foodborne

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, and pumpkin butter), vegetables

baked in aluminum foil (e.g., potatoes and beets), home-canned meatbased foods (e.g., tuna, pickled pigs’ feet, stew, and pasta in meat sauce),

oil-based foods (e.g., pasta and jarred pesto or 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 commercially 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 2017

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 investigation 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 four

prisoners. In 2011, a second outbreak due to pruno was reported and

involved eight patients at a prison in Utah. In 2012, two outbreaks

associated with pruno occurred in a single prison in Arizona, with four

and eight 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 2017,

372 cases of wound botulism were reported, with an average of 22 cases

per year. Most cases (92%) were caused by BoNT serotype A and 5% by

serotype B (5%). Most cases (95%) were among persons who injected

drugs (mainly black tar heroin), and the remaining 5% 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 2017, 1858 infant botulism cases were reported. BoNT serotypes A and B caused most cases

(40% and 58%, respectively). Only two cases were due to serotype E.

One of these two cases 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,

13 infant botulism cases were due to strains of C. botulinum that can

produce two BoNT serotypes (A and B or B and F).

TABLE 153-1 Total Foodborne Botulism Outbreaks of 10 or More

Cases Reported in the United States Between 2001 and 2017

YEAR STATE FOOD SOURCE

NO. OF CONFIRMED

CASES

2001 Texas Chili 16

2007 Multistate Commercially canned hot dog

chili sauce

10

2015 Ohio Home-canned potatoes used

to prepare a potato salad,

served at a church potluck

27

2016 Mississippi Pruno, illegal alcoholic

beverage consumed by

inmates at a federal facility

19

2017 California Commercially produced nacho

cheese, sold at a convenience

store

10

1217CHAPTER 153 Botulism

Botulism of Other Etiologies Between 2001 and 2017, 49 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 (65%) and serotype F (25%). Many were

thought to be cases of adult intestinal colonization, although confirmation 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 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 elicitation

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 nonpregnant 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 secretions. 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.

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. 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 attributed 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. Constipation 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 products of BoNT-producing species of Clostridium, or other contaminants

of spoiled food is unknown. These gastrointestinal symptoms have not

been reported in wound 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 diaphragmatic 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 substantial 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 symptoms; 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 affecting 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 extensive

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 psychological

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%.

■ 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 Prevention (CDC; accessible at https://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 clinical diagnosis of botulism in a patient with clinically compatible findings. 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 and California, at the state health

department), who will review the case with the clinician, assist in

the shipping of appropriate 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 Treatment 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 humanderived botulinum antitoxin (BabyBIG), a specific treatment licensed

for treatment of infant botulism.