B: FOOD, DIET, AND NUTRITION

HISTORY AND EPIDEMIOLOGY

Botulism, a potentially fatal neuroparalytic illness, results from exposure to botulinum neurotoxin (BoNT), which is produced by the bacterium Clostridium botulinum and other Clostridium species. The earliest cases of botulism were described in Europe in 1735 and were attributed to improperly preserved German sausage; the name of the disease alludes to this association because botulus is the Latin word for sausage. Emile van Ermengem identified the causative organism in 1897 and named it Bacillus botulinum; it was later renamed Clostridium botulinum.²⁵ These gram-positive, spore-forming bacteria produce eight serotypes of BoNT, denoted A through H.^88,134

In adults, most cases result from ingestion of toxin in contaminated food, but in infants, most cases result from consumption of bacterial spores that proliferate and produce toxin in the gastrointestinal (GI) tract. Less common forms of botulism include wound botulism, in which spores are inoculated into a wound and locally produce toxin, and inhalational botulism caused by aerosolized BoNT, which potentially can be used as a weapon of bioterrorism.

Botulism outbreaks occur throughout the world¹⁴⁹ and have been reported from such diverse areas as Uganda,¹⁷⁹ Iran,¹³⁷ Japan,¹²⁸ Thailand,⁹⁶ Pakistan,⁹³ Australia,¹¹³ France,¹ Portugal,¹⁰³ Poland,⁵⁸ Greenland,⁸² Chile,¹² and Canada.¹²³ In 2016, a total of 150 laboratory-confirmed cases and 10 probable cases of botulism were reported to the US Centers for Disease Control and Prevention (CDC).³⁹ Foodborne botulism constituted 14% of cases, infant botulism 73% of cases, and wound botulism 12%. In this analysis, toxin type A accounted for 83% of cases of foodborne botulism, with the remainder split between type A and type B (27% each). Toxin type A was responsible in at least 88% of cases of wound botulism, and infant botulism was caused by toxin type A in 36% and to toxin type B in 59% of cases. Two deaths from foodborne botulism were reported in 2016.³⁹ The case fatality rate has improved for all botulism toxin types, probably caused by increasing awareness of the condition and consequent earlier diagnosis, appropriate and early use of antitoxin, and better and more accessible life support techniques.

In the past 50 years, home-processed food has accounted for 65% of outbreaks, with commercial food processing constituting only 7% of reported cases; in the remaining outbreaks, the origin is unknown.⁴⁵ Common home-canning errors responsible for botulism include failure to use a pressure cooker and allowing food to putrefy at room temperature. Minimally processed foods such as soft cheeses lack sufficient quantities of intrinsic barriers to BoNT production, such as salt and acidifying agents.¹⁴³ These foods become high-risk sources of botulism when refrigeration standards are violated. The US Food and Drug Administration (FDA) continuously reviews recommendations for appropriate measures to process such foods.^168,169

Awareness of evolving trends and unusual presentations or locations of botulism permits the establishment of preventive education programs. Outbreaks of botulism have been associated with specialty foods consumed by different ethnic groups, such as chopped garlic in soy oil by Chinese in Vancouver, British Columbia;^123,163 uneviscerated salted fish—called kapchunka—eaten by Russian immigrants in New York City;^36,167 and the same fish—called faseikh—eaten in Egypt.¹⁸² The incidence of botulism is high in Alaska where traditional foods include fermented fish and fish eggs, seal, beaver, and whale; between 2001 and 2014, one-third of cases of foodborne botulism in the United States occurred in Alaska. Approximately 90% of toxin type E outbreaks have occurred in Alaska because of home-processed fish or meat from marine animals,^52,107,181 and one incident occurred in New Jersey.³⁷ In the 1990s, three cases of botulism involved members of a Native American church after they ingested a ceremonial tea made from the buttons of dried, alkaline-ground peyote cactus that were stored for 2 months in a water-filled refrigerated jar. The resultant alkaline and anaerobic milieu presumably fostered the growth of toxin from naturally occurring spores.⁸³ In 1996, eight cases of foodborne botulism in Italy were linked to mascarpone cream cheese eaten either alone or in tiramisu contaminated with BoNT type A.¹⁴ Other outbreaks have been linked to mushrooms bottled in a restaurant,³⁸ home-canned bamboo shoots,^44,47 home-pickled eggs,⁴⁸ commercial carrot juice,⁴⁰ commercially processed chili sauce,⁴¹ home-prepared tofu,^42,49 improperly stored potato soup,⁵¹ and improperly jarred pesto.³¹

Larger outbreaks are especially concerning. In April 2015, 29 patients in Ohio developed botulism (25 laboratory-confirmed cases and 4 probable cases) after consuming home-canned potatoes at a church potluck meal; one died of respiratory failure.¹¹⁴ In June 2016, 31 male inmates in a medium-security federal correctional institution in Mississippi developed botulism after drinking “pruno,” an illicit alcohol made by the prisoners;¹¹⁵ similar preparations were responsible for four prior outbreaks in prisons in California, Utah, and Arizona.^43,180,186 Twenty-four patients were hospitalized and nine required mechanical ventilation, but none died. This botulism outbreak was the largest in the United States since 1978, when 32 people were affected after eating at a New Mexico country club.³⁵

Among cases attributed to commercial food processing, vegetables (peppers, beans, mushrooms, tomatoes, and beets, with or without meat) were thought to be the causative agents in approximately 70%, meat in 17%, and fish in 13% of cases.⁴⁵ Although only 4% of foodborne botulism is associated with food purchased in restaurants, restaurant-related outbreaks usually affect large numbers of individuals.¹⁰⁷

Of 29 laboratory-confirmed cases of foodborne botulism in 2016, there were three multi-case outbreaks, each involving two or three patients.³⁹ Among hundreds of reports of botulism from 1975 to 1988 involving more than 400 persons, approximately 70% involved only one person, 20% involved two persons, and only 10% involved more than two persons, yielding a mean of 2.7 cases per outbreak.¹⁸⁵ Single affected patients were more severely ill, with 85% requiring intubation compared with only 42% requiring intubation in multi-person outbreaks, presumably because diagnosis in the index case leads to more rapid therapeutic intervention for associated cases.

Infant botulism is more common in certain geographic areas than in others presumably because of higher concentrations of botulinum spores in soil. Raw honey is a potential source of spores.¹²⁴ Most affected infants are younger than 6 months of age. Of 128 confirmed cases reported in 2014, most were from California (38%), New Jersey (8%), Maryland (7%), Pennsylvania (6%), or Texas (5%). The median age was 17 weeks (range, 2–54 weeks), and 46% were female. No US deaths from infant botulism were reported in 2014.³⁹ With appropriate support and treatment, a favorable outcome is achieved in the majority of cases.

In 2016, 24 cases of wound botulism were confirmed in the United States; 15 of these cases occurred in California. Age ranged from 25 to 68 years, with a median of 45 years, and 29% were women. Patients continue to be almost exclusively injection drug users.³⁹

In ways unimaginable when the first edition of this book was published, medical and public health realities associated with terrorism in the 21st century unfortunately have resulted in increased relevance of botulism to medical practitioners (Chaps. 126 and 127). The advent of therapeutic BoNT injections has raised other concerns regarding potential adverse consequences.¹⁰

BACTERIOLOGY

The genus Clostridium comprises a group of four spore-forming anaerobic gram-positive bacillary species that produce eight different neurotoxic proteins. C. botulinum produces all BoNT serotypes A through H, C. baratii produces toxin type F, C. butyricum produces toxin type E, and C. argentinense (sometimes considered a subgroup of C. botulinum) produces toxin type G.⁸⁸ Some strains produce two different toxin types. Most cases of botulism result from BoNT types A, B, E, or F.^39,65,170 Reports of cases caused by BoNT type F have increased in recent years in parallel with improved ability of laboratories to detect C. baratii and other clostridial species producing toxin type F. The seven types A to G were recognized for over 40 years until in 2014 when a new toxin was identified in an infant with botulism and was designated type H.²¹

Clostridial species are ubiquitous, and the bacteria and spores are present in soil, seawater, and air.¹⁶⁰ Genomic sequence analysis shows that multiple toxin subtypes exist within each of the eight main types A through H; for example, there are eight subtypes of type A, designated A1 through A8.⁸⁸ In the United States, toxin type A is found in soil west of the Mississippi;¹⁰⁶ type B is found east of the Mississippi, particularly in the Allegheny range; and type E is found in the Pacific northwest and the Great Lakes states.^46,160 Toxin types A and B typically are found in poorly processed meats and vegetables. Toxin type E is commonly found in raw or fermented marine fish and mammals. Toxin types C and D cause disease in birds and mammals. Toxin type G has not been associated with naturally occurring disease. Although the different botulinum toxins differ in the cellular molecules they target, their ultimate pathophysiology and clinical syndromes are identical.

All botulinum spores are dormant and highly resistant to damage. They withstand boiling at 212°F (100°C) for hours, although they usually are destroyed by 30 minutes of moist heat at 248°F (120°C). Factors that promote germination of spores in food are pH greater than 4.5, sodium chloride content less than 3.5%, and low nitrite concentration. Most viable organisms produce toxin in an anaerobic milieu with temperatures greater than 80.6°F (27°C), although some strains produce toxins even when conditions are not optimal. Clostridia produce toxin type E at temperatures as low as 41°F (5°C). To prevent spore germination, acidifying agents such as phosphoric or citric acid are added to canned or bottled foods that have a low acid content, such as green beans, corn, beets, asparagus, chili peppers, mushrooms, spinach, figs, olives, and certain nonacidic tomatoes. Unlike the spores, the toxin itself is heat labile and is destroyed by heating to 176°F (80°C) for 30 minutes or to 212°F (100°C) for 10 minutes. At high altitudes, where the boiling point of water may be as low as 202.5°F (94.7°C), boiling for a full 30 minutes is prudent to ensure that the toxin is destroyed. Under high-altitude conditions, pressure cooking at 13 to 14 lb of pressure often is necessary to achieve appropriate temperatures to destroy the toxin in a timely fashion.

Foods contaminated with C. botulinum toxin types A and B often look or smell putrefied because of the action of proteolytic enzymes.⁸¹ In contrast, because toxin type E organisms are saccharolytic and not proteolytic, foods contaminated with toxin type E typically look and taste normal.¹⁷

PHARMACOKINETICS AND TOXICOKINETICS

BoNT is the most potent toxin known. The LD₅₀ for mice is 3 million molecules injected intraperitoneally. The human oral lethal dose is 1 mcg.¹⁴⁷

Foodborne botulism results from ingestion of preformed BoNT from food contaminated with Clostridium spores. The toxin is complexed to associated proteins (hemagglutinins and a nontoxic nonhemagglutin)⁸⁸ that protect it from the acidic and proteolytic environment in the stomach. In the intestine, the alkaline pH dissociates the toxin from the associated proteins, allowing for subsequent absorption into the bloodstream.¹²¹ Because the toxin is often demonstrated only in the stool, determining the percentage of the toxin actually absorbed is difficult.^64,67 The median incubation period for all patients is 1 day, but it ranges from 0 to 7 days for toxin type A, 0 to 5 days for toxin type B, and 0 to 2 days for toxin type E.¹⁸⁵

Infant botulism does not result from ingestion of preformed BoNT but rather from ingestion of C. botulinum spores, which germinate in the GI tract and produce toxin. The immaturity of the bacterial flora in the infant GI tract facilitates colonization by the organisms. Adults with altered GI tracts (eg, those who have undergone gastric bypass or are taking proton pump inhibitors or H₂ antagonists) also rarely develop botulism in the same way, with the onset of symptoms typically following ingestion by 1 or 2 months. Cases of foodborne infant botulism associated with home-canned food have been reportedly extremely rarely.^6,105

In wound botulism, spores proliferate in a wound or abscess and locally elaborate toxin. The incubation period is typically less than 2 weeks, but delays as long as 51 days are reported.⁸⁶

The duration of action of the BoNT types varies depending on the components of the neurotransmitter release apparatus that are disrupted (see Pathophysiology). It is unclear whether the persistence of clinical effect results from the individual cleavage target, the intraneuronal biological half-life of the toxin, or both. Current evidence indicating intraneuronal toxin metabolism or elimination is inadequate.

PATHOPHYSIOLOGY

Botulinum neurotoxin is produced as a protein consisting of a single polypeptide chain with a molecular weight of 900 kDa, which includes a 750-kDa nontoxic protein and a 150-kDa neurotoxic component. To become fully active, the single-chain polypeptide 150-kDa neurotoxin must undergo proteolytic cleavage to generate a dichain structure consisting of a 100-kDa heavy chain linked by a disulfide bond to a 50-kDa light chain. The dichain form of the molecule is responsible for all clinical manifestations.^29,84 Both the single polypeptide chain toxin and the dichain form are resistant to GI degradation.¹⁰⁸

The ingested toxin binds to serotype-specific receptors on the mucosal surfaces of gastric and small intestinal epithelial cells, where endocytosis is followed by transcytosis, permitting release of the toxin on the serosal (basolateral) cell surface.^100,142 The dichain form travels intravascularly to peripheral cholinergic nerve terminals, where it binds rapidly and irreversibly to the cell membrane and is taken up by endocytosis. The heavy chain is responsible for cell-specific membrane binding to acetylcholine-containing neurons (Fig. 38–1). Botulinum neurotoxin use dual host receptors to achieve their high affinity; whereas BoNT A binds a ganglioside and synaptic vesicle glycoprotein 2, BoNT B uses synaptotagmin. This mechanism allows rapid toxin entry via synaptic vesicles. The subsequent acidification of the synaptic vesicle lumen triggers the heavy chain N-terminal domain to form a channel to facilitate translocation of the light chain into the cytosol.⁹⁷

When inside the cell, the light chain acts as a zinc-dependent endopeptidase to cleave presynaptic membrane polypeptides that are essential components of the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) apparatus that subserves acetylcholine exocytosis, thereby inhibiting release.¹⁴⁷ Botulinum neurotoxin types specifically cleave different proteins belonging to the SNARE family, and these differences are one possible reason for their variable toxicity.¹⁵⁵ SNARE proteins targeted by proteolysis include vesicle-associated membrane protein (VAMP) called synaptobrevin which is localized on synaptic vesicles, syntaxin found on the presynaptic membrane, and synaptosomal-associated protein (SNAP)-25, which is attached to syntaxin and to the presynaptic membrane. Toxin types A and E cleave SNAP-25; types B, D, F, and G act on VAMP/synaptobrevin; and type C cleaves both syntaxin and SNAP-25 (Fig. 38–1).¹⁰⁰ All BoNT types impair transmission at acetylcholine-dependent synapses in the peripheral nervous system, but cholinergic synapses in the central nervous system are not thought to be affected. Very high concentrations of BoNT also impair release of other neurotransmitters, including norepinephrine and serotonin.⁸⁰ Botulinum neurotoxin also exerts effects via mechanisms other than cleavage of SNARE proteins, possibly including apoptosis or gene expression.¹¹²

CLINICAL MANIFESTATIONS

Foodborne Botulism

Although botulism is the most dreaded of all food poisonings, the initial phase of the disease often is so subtle that it goes unnoticed. Botulism frequently is misdiagnosed on the first visit to a health care provider.³² When GI effects are striking and food poisoning is suspected, the differential diagnosis should include other acute poisonings, such as metals; plants; mushrooms; and the common bacterial, viral, and parasitic agents discussed in Chap. 39.

The onset of symptoms typically occurs the day after ingestion. Early GI signs and symptoms of botulism include nausea, vomiting, abdominal distension, and pain. A time lag (from 12 hours to several days but usually not more than 24 hours) typically occurs before neurologic signs and symptoms appear. Common findings include diplopia (often horizontal); blurred vision with impaired accommodation; and bilaterally symmetric flaccid paralysis, which typically begins in cranial muscles and descends to the limbs. Constipation caused by smooth muscle involvement is frequent, and urinary retention and ileus also occur. Anticholinergiclike effects such as dry mouth, dysphagia, and dysarthria or dysphonia (manifested by a nasal quality to the voice) occur, and many patients exhibit fixed mydriatic pupils with ptosis. Deep tendon reflexes are usually reduced or absent. Hypotension and bradycardia sometimes develop, but temperature regulation is normal.

Severe weakness of respiratory muscles necessitates intubation and mechanical ventilation. Approximately 67% of botulism patients with toxin type A require intubation compared with 52% of patients with toxin type B and 39% with toxin type E.¹⁸⁵

Importantly, mental status and sensation remain normal. These findings, along with the absence of tachycardia, distinguish botulism from the anticholinergic syndrome, which shares many initial features with botulism.

The differential diagnosis of botulism includes a variety of toxicologic and nontoxicologic conditions (Table 38–1). All of these disorders have weakness as a prominent feature, but many are readily differentiated from botulism based on their time course or a history of exposure. The most difficult and frequently encountered diagnostic challenge is differentiating between botulism and the Miller Fisher variant of Guillain-Barré syndrome (Table 38–2). Because physicians so rarely encounter botulism (especially compared with other much more common disorders in the differential diagnosis), initiation of appropriate management often is significantly delayed. The index case of an epidemic or an isolated case often is misdiagnosed at a stage when the risk of morbidity and mortality still could be substantially diminished. This is particularly true of toxin type E botulism, which typically initially causes much more prominent GI signs than neurologic signs.¹⁷

Infant Botulism

First described in California in 1976, several thousand cases of infant botulism have now been confirmed across the world,^9,85,90 from all inhabited continents except Africa.⁷⁰ Interestingly, 95% of reported cases occur in the United States.^56,130 In 2016, 47 of 150 laboratory-confirmed cases occurred in California.³⁹ Aggressive surveillance and educational efforts have been practiced in that state since 1976, which may help to explain the disproportionate distribution of reported cases.⁸

Infant botulism is the most common form of botulism in the United States, and virtually all cases are caused by BoNT type A or B. Affected children are younger than 1 year (median, 15 weeks) and characteristically have normal gestation and birth. The first signs of infant botulism are constipation; difficulty with feeding, sucking, and swallowing; a feeble cry; and diffusely decreased muscle tone (“floppy baby”).⁵⁰ The hypotonia is particularly apparent in the limbs and neck. Ophthalmoplegia, loss of facial grimacing, dysphagia, diminished gag reflex, poor anal sphincter tone, and respiratory failure are often present, but fever does not occur. Mydriasis typically is present. The differential diagnosis of infant botulism initially includes salt and water depletion, failure to thrive, sepsis, and a viral syndrome. Because the toxin in infant botulism is absorbed gradually as it is produced, the onset of clinical manifestations commonly is less abrupt than in severe cases of foodborne botulism, which are caused by large amounts of preformed toxin absorbed over a brief period of time.

Infant botulism results from ingestion of C. botulinum organisms in food or following the inhalation or ingestion of organism-laden aerosolized dust. Many cases occur near construction sites or soil disruption for other reasons, or in children of parents who work in construction, farming, plant nursery, or plumbing.⁶³ A number of factors determine a child’s susceptibility to development of botulism. Although bile acids and gastric acid in the GI tract inhibit clostridial growth in older children and adults, gastric acidity is reduced in the infant during the first few months of life.¹⁰⁹ Also, some infants are deficient in immunologic mechanisms for spore control, resulting in a permissive environment for spore germination and toxin development within their GI tracts with subsequent absorption. Approximately 70% of infant botulism cases occur in breastfed infants, even though only 45% to 50% of all infants are breastfed. Formula-fed infants are rapidly colonized by Coliforme spp, Enterococcus spp, and Bacteroides spp, which inhibit C. botulinum proliferation; conversely, the absence of these typical organisms in breastfed infants facilitates C. botulinum multiplication.⁸⁵

Epidemiologic studies in Europe found that ingestion of honey was associated with 59% of cases of infant botulism.¹⁵ When C. botulinum spores were isolated from honey implicated in cases of infant botulism, the same toxin type was isolated from the infant and, as expected, no preformed toxin was isolated from the honey.⁹ It is possible that pollen and nectar carried by worker bees results in contamination of honey with spores of Clostridia found in soil.¹²⁴ In addition, the oxidative metabolism of Bacillus alvei, another common contaminant of honey, may promote spore germination by creating a anaerobic microenvironment.¹²¹ Honey is the only food generally considered likely to be a risk factor for infant botulism,⁹ although a 2001 report from the United Kingdom implicated an infant formula.²⁸

Previous studies suggested a correlation between the presence of both C. botulinum organisms and toxin and sudden infant death syndrome (SIDS).^8,161 However, in a prospective study of 248 infants with SIDS, C. botulinum was not found in the stool cultures of any of the children.³³

Patients with infant botulism must be managed in the hospital, preferably in a pediatric intensive care unit, at least for the first week, when the risk of respiratory arrest is greatest. In one study, approximately 80% of children with botulism required intubation for reduced vital capacity on pulmonary function testing, and 25% of these children had frank respiratory compromise.¹⁴⁸ In a group of 57 affected infants aged 18 days to 7 months managed during the decade ending in the mid-1980s, 77% were intubated, and 68% required mechanical ventilation. In the subsequent decade, investigators from the same institution found that 37 of 60 (62%) infants required endotracheal intubation (for a mean duration of 21 days).⁴ The apparent decrease in intubations and complications was ascribed to better understanding of disease progression and closer observation of patients. However, a similar study at another institution revealed that 13 of 24 (54%) infants admitted between 1985 and 1994 required ventilatory support, compared to 15 of 20 (75%) infants admitted in the subsequent decade.¹⁷¹ All but one patient in this study required nasogastric feeding. In one series, younger patients were more likely to require mechanical ventilation.¹²⁷ Airway complications of intubation such as stridor, granuloma formation, and subglottic stenosis are common, yet tracheotomy is infrequently required.⁴ The survival rate in infant botulism is approximately 98% and most patients are discharged home from the hospital.^127,148

Wound Botulism

The first recorded case of wound botulism occurred in 1943 and was reported in 1951.⁵⁹ The classic presentation of wound botulism involves a motor vehicle crash resulting in a deep muscle laceration, crush injury, or compound fracture treated with open reduction. The wound typically is dirty and associated with inadequate débridement, subsequent purulent drainage, and local tenderness, although in some cases, the wound appears clean and uninfected. Four to 18 days later, cranial nerve palsies and other neurologic findings typical of botulism appear.¹¹⁹ Other manifestations characteristic of food-related botulism, such as GI symptoms, usually are absent.

In wound botulism, an abscess, sinusitis, or other tissue infection harbors the Clostridial organisms. Recognition of botulism as a potential complication of wound infections is essential for appropriate early and aggressive therapy. In one analysis, fever was present in only 7% of patients with wound botulism.⁷⁷

The CDC identified 24 cases of wound botulism in the United States in 2014.³⁹ Botulinum neurotoxin type A accounted for 88% of the cases.³⁹ Use of heroin, particularly subcutaneous injection (“skin popping”) of black tar heroin, is associated with an increased risk of wound botulism.^53,132,183 This association appears to be related, at least in part, to the physical characteristics of black tar heroin such as its viscosity, its potential to facilitate anaerobic growth and spore germination, and its ability to devitalize tissue or inhibit wound resolution.²⁰ Wound botulism also is reported in association with subcutaneous,¹³⁸ intraveneous,¹⁶⁴ and intranasal^98,139 cocaine use. The first case of wound botulism with BoNT type E was reported in 2007, affecting a drug user in Sweden.¹³

Adult Intestinal Colonization Botulism

Although GI colonization is the typical pathogenic mechanism responsible for infant botulism, it is rare in adults. Prior to 1997, only 15 cases were reported.^79,117 Patients invariably have anatomic or functional GI abnormalities. Risk factors favoring organism persistence and C. botulinum colonization include achlorhydria (surgically or pharmacologically induced), previous intestinal surgery, and probably recent antibiotic therapy. These factors compromise the gastric and bile acid barrier, gut flora, and motility, thus allowing spore germination, altered bacterial growth, and toxin development.

Cases of adult infectious botulism are reported in patients with Crohn disease after ileal bypass surgery,⁷⁹ jejunoileal bypass for obesity,^73,116 gastroduodenostomy,¹¹⁶ vagotomy and pyloroplasty,¹¹⁶ and necrotic ­volvulus.¹⁰⁷ In such hosts, botulism results from the ingestion of food ­contaminated with C. botulinum organisms and no preformed toxin, with intraluminal elaboration of toxin occurring in vivo.⁵⁶

In one case of adult intestinal colonization botulism, a high concentration of endogenously produced antibody to toxin type A was identified.⁷⁹ This finding highlights a distinct characteristic of this form of botulism, because endogenous antitoxin immunity does not develop in patients with foodborne botulism.¹⁴⁷

Iatrogenic Botulism

Botulinum toxins are used therapeutically in the treatment of a variety of disorders. Three preparations of BoNT type A are available in the United States: onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin). Botulinum neurotoxin type B is available as rimabotulinumtoxinB (Myobloc). All are approved by the FDA for treatment of cervical dystonia and upper limb spasticity; onabotulinumtoxinA is also approved for lower limb spasticity. OnabotulinumtoxinA and incobotulinumtoxinA are also indicated for treatment of blepharospasm. Additionally, onabotulinumtoxinA is approved for strabismus, chronic migraine, severe axillary hyperhidrosis inadequately managed by topical therapies, and detrusor overactivity associated with a neurologic condition. All three formulations of BoNT type A are approved for cosmetic purposes. Botulinum neurotoxin is also used off-label for a variety of neurologic and non-neurologic conditions. In Japan and the United Kingdom, a preparation of BoNT type F is available.¹⁵⁴ Some studies suggest that animals receiving BoNT type F have more transient and reversible weakness than that associated with types A and B.²⁶

A 2016 practice guideline update by the American Academy of Neurology assessed the level of evidence of the four BoNT products for various neurologic indications. Based on the evidence, the authors issued Level A recommendations (denoting an intervention that should be offered) for treatment of cervical dystonia with abobotulinumtoxinA or rimabotulinumtoxinB; treatment of upper limb spasticity with abobotulinumtoxinA, incobotulinumtoxinA, or onabotulinumtoxinA; treatment of lower limb spasticity with abobotulinumtoxinA or onabotulinumtoxinA; and treatment of chronic migraine with onabotulinumtoxinA.¹⁵⁹

Botulinum neurotoxin is thought to exert its therapeutic effect in most cases by temporarily weakening muscles whose overactivity results in the clinical condition. Doses range widely depending on the size of the muscles to be treated, the severity of the muscular contraction, and the commercial preparation of the toxin. The injected toxin blocks the local neuromuscular junction by inhibiting release of acetylcholine. The “chemodenervated” muscles recover within 2 to 4 months as nerve transmission is restored through sprouting of new nerve endings and formation of functional connections at motor endplates,^2,147 necessitating repeated injections of BoNT for sustained clinical efficacy.

Doses of BoNT are measured in functional units corresponding to the median intraperitoneal lethal dose (LD₅₀) in female Swiss-Webster mice weighing 18 to 20 g.¹³¹ The units of each marketed pharmaceutical are distinctly different, which has led to inadvertent overdosing.¹⁷⁵ The potential for confusion is substantial when switching between products because their relative potencies are quite different.^125,144,151 Attempts to establish precise lethal doses of BoNT are complicated by the lack of human data, use of varying formulations of toxin by different investigators, changes in manufacturing processes, and factual errors in the published literature.²⁹ One group of investigators estimated that “lethal amounts of crystalline type A toxin for a 70-kg human would be approximately 0.09 to 0.15 mcg intravenously or intramuscularly, 0.70 to 0.90 mcg inhalationally, and 70 mcg orally,”¹⁰ but it is unclear whether these values can be applied reliably to any currently available commercial product.

In a series of 139 patients with cervical dystonia randomized to treatment with BoNT type A or BoNT type B, no difference in efficacy was found between serotypes; the groups were also equivalent in frequency of adverse effects such as neck pain and neck weakness, but dry mouth and dysphagia were more common in the group treated with BoNT type B.⁵⁷

After repeated injections of therapeutic doses of BoNT, patients develop neutralizing antibodies that would limit the subsequent efficacy of the toxins; this prompts switching to a different toxin type. In 1998, the formulation of Botox was changed to reduce the amount of potentially antigenic protein from 25 ng of neurotoxin complex protein per 100 units to 5 ng of complex protein per 100 units, and studies in patients with cervical dystonia demonstrate a sixfold lower rate of development of anti-BoNT antibodies with the newer formulation.⁸⁹ For Xeomin, the protein content is 0.6 ng per 100 units; Dysport contains 4.35 ng of protein per 500-unit vial (ie, 0.87 ng per 100 units).

Although one early marketing assumption was that the neurotoxin does not diffuse from the injection site, BoNT can diffuse into adjacent tissues and produce local adverse effects.¹⁴¹ Systemic manifestations are of concern when an inadvertent, excessive, or misdirected dose of toxin is administered or in the setting of a neuromuscular disorder that may be previously undiagnosed, as in one case in which injection of BoNT type A unmasked Lambert-Eaton myasthenic syndrome (LEMS).⁶⁶ In addition, a number of studies demonstrate that even appropriately injected doses result in neuromuscular junction abnormalities throughout the body, occasionally producing autonomic dysfunction without muscle weakness.^75,101,126 Several cases of iatrogenic botulismlike symptoms, including diplopia and severe generalized muscle weakness with widespread electromyographic (EMG) abnormalities, resulted from therapeutic or cosmetic use of intramuscular BoNT injections.^{18,24,69,172,187} A 2008 report raised the possibility that BoNT type A undergoes retrograde axonal transport and transcytosis to afferent neurons,⁵ suggesting a potential mechanism for such generalized effects. However, the reproducibility and clinical significance of these findings have yet to be established.

In a much publicized case from late 2004, four patients in Florida developed paralysis after being injected with BoNT type A. An FDA investigation revealed that these patients were injected by an unlicensed physician who obtained raw toxin (not approved for medical purposes) and administered it at a dose 2,000 to 100,000 times greater than that used in clinical practice.³ These events were not believed to be relevant to the use of approved pharmaceutical BoNT. In February 2008, the FDA issued an Early Communication stating that it was reviewing safety data on BoNT after receiving reports of hospitalization or death in patients injected with these therapies, mostly in children treated for spasticity associated with cerebral palsy.¹⁷³ In 2009, the FDA mandated changes to the prescribing information for the BoNT products, requiring a Boxed Warning highlighting the possibility of potentially life-threatening effects distant from the injection site; a Risk Evaluation and Mitigation Strategy, including a medication guide to help patients understand the risks and benefits of the botulinum neurotoxin; and changes of the drug names to underscore differences between the potencies of the individual products and the lack of interchangeability among them.¹⁷⁵

Inhalational Botulism

Inhaled BoNT is estimated to be 100 times more potent than ingested BoNT; a single gram of toxin, if disseminated evenly, could kill more than 1 million people.¹⁰ A 1962 report from West Germany described three veterinary workers who inhaled BoNT type A from the fur of animals they were handling; on the third day after exposure, they developed mucus in the throat, dysphagia, and dizziness, and on the next day, they developed ophthalmoparesis, mydriasis, dysarthria, gait dysfunction, and weakness.¹⁰ Use of aerosolized BoNT as a bioweapon has been attempted by terrorists in Japan, and both the Soviet Union and Iraq developed BoNT as part of biological warfare ­programs (Chap. 127).^10,61,188

DIAGNOSTIC TESTING

The CDC case definition for foodborne botulism is established in a patient with a neurologic disorder manifested by diplopia, blurred vision, bulbar weakness, or symmetric paralysis in whom:

• Botulinum neurotoxin is detected in serum, stool, or implicated food samples or

• C. botulinum is isolated from stool or

• A clinically compatible case is epidemiologically linked to a laboratory-confirmed case of botulism⁴⁶

Routine laboratory studies, including cerebrospinal fluid analysis, are normal in patients with botulism but are usually performed to exclude other etiologies. Specific tests can be helpful in diagnosing botulism.

Edrophonium Testing

Edrophonium is a rapidly acting cholinesterase inhibitor of short duration that is useful in the diagnosis of myasthenia gravis. It is occasionally used to differentiate myasthenia gravis from botulism. This drug inhibits the metabolism of acetylcholine located in synapses, permitting continued binding with the reduced number of postsynaptic acetylcholine receptors in myasthenia gravis.

A syringe containing 10 mg of edrophonium is prepared, and then a test dose of 1 to 2 mg is administered intravenously. A positive result (ie, supportive of myasthenia gravis) consists of dramatic improvement in the strength of weak muscles within 30 to 60 seconds and lasting 3 to 5 minutes. If there is no effect, the remainder of the edrophonium is given and the same effect sought. Ideally, a second syringe is filled with saline and the test performed under double-blind conditions to ensure accurate assessment and remove the potential of a placebo effect.

Because release of acetylcholine is impaired in botulism, preventing its catabolism with an anticholinesterase medication typically has little clinical benefit, but a weaker effect is occasionally observed if some neurons maintain the ability to release acetylcholine. Thus, in rare cases, early in the course of botulism, injection of edrophonium results in limited improvement in strength, but this is far less dramatic than the improvement that occurs in patients with myasthenia gravis.¹³⁶

Electrophysiologic Testing

In all forms of botulism, sensory nerve action potentials are normal. Motor potentials in severely affected muscles typically are reduced in amplitude, but conduction velocity is not affected. Repetitive nerve stimulation at high frequencies would be expected to result in an increment of the amplitude of the motor potential, given the presynaptic localization of the defect, but this finding is neither sensitive nor specific; it also is more common in disease caused by BoNT type B than with type A.^55,110 A marked incremental response with high-frequency repetitive stimulation is more likely to suggest LEMS than botulism. Likewise, a decremental response to low-frequency repetitive nerve stimulation is characteristic of LEMS but is not consistently present in botulism.¹¹⁰

The needle EMG examination in botulism is characterized by low-amplitude, short-duration motor unit action potentials (MUAPs) caused by blockade of neuromuscular transmission in many muscle fibers (Fig. 38–2). Polyphasic MUAPs are also common. Recruitment is usually normal but is reduced in severely affected muscles if all muscle fibers of a motor unit are blocked. Spontaneous activity, including positive sharp waves and fibrillation potentials, is often seen. Single-fiber EMG is useful in demonstrating abnormal neuromuscular transmission; for patients who cannot control voluntary muscle activation (eg, as infants), stimulated jitter analysis is proposed but is not universally available.^129,177

Although these electrodiagnostic abnormalities support the diagnosis of botulism, there are no pathognomonic electrophysiologic findings. Nerve conduction studies and EMG are most useful for excluding alternative diagnoses, including Guillain-Barré syndrome and other neuropathies (both demyelinating and axonal), poliomyelitis, myasthenia gravis, and myopathies. Occasionally, muscle biopsy is necessary to exclude a myopathic process.¹¹⁰

Laboratory Testing

If foodborne botulism is suspected, samples of serum, stool, vomitus, gastric contents, and suspected foods should be subjected to anaerobic culture (for C. botulinum) and mouse bioassay (for BoNT) (Table 38–3). A list of the patient’s medications should accompany each sample to exclude other xenobiotics that might interfere with the assay (eg, pyridostigmine) or be toxic to the mice. The serum samples must be collected before initiation of antitoxin therapy. When wound botulism is considered, serum, stool, exudate, débrided tissue, and swab samples should be collected. For infant botulism, feces and serum samples also should be obtained. In infants who are constipated, an enema with nonbacteriostatic sterile water will facilitate collection. All enema fluid and stool should be sent for analysis. The specimens should be refrigerated (not frozen) and examined as soon as possible after collection. Detailed information on specimen collection and examination is available online from the CDC (https://www.cdc.gov/botulism/pdf/bot-manual.pdf).⁴⁵

In the mouse lethality assay, which remains the gold standard for diagnosis, the sample (serum, stool, or food) is injected intraperitoneally into mice, which are then observed for development of signs of botulism. Control mice are injected with the sample as well as antitoxin. This test is very sensitive, with a detection limit of 0.01 ng/mL of sample eluate. However, it is laborious and expensive, and a positive result is often delayed for several days, reducing its usefulness in early diagnosis of botulism.¹⁰⁴ Alternative methods for detecting BoNT, including immunologic methods (eg, enzyme-linked immunosorbent assay, endopeptidase assays, and analysis of synaptic activity in neuronal cell cultures) have been used successfully.^{23,135,140,158}

Clostridium botulinum can be cultured under strict anaerobic conditions. Stool specimens are incubated anaerobically and then subcultured on egg yolk agar to assess for lipase production, although this test is not specific as other clostridia also produce lipase. Various protocols using polymerase chain reaction and probe hybridization to detect and identify C. botulinum are described but are not widely applied in clinical practice.^94,104

MANAGEMENT

Supportive Care

Respiratory compromise is the usual cause of death from botulism. To prevent or treat this complication, hospital admission of the patient and of all individuals with suspected exposure is mandatory. Careful continuous monitoring of respiratory status using parameters such as vital capacity, peak expiratory flow rate, negative inspiratory force (NIF), pulse oximetry, end-tidal CO₂, and the presence or absence of a gag reflex is essential to determine the need for intubation if a patient begins to manifest signs of bulbar paralysis.¹⁴⁸ The NIF is the most reliable, readily obtainable test for determining the need for intubation. When suspicion of botulism is high and the vital capacity is less than 20 mL/kg or the NIF is poorer than −30 cm H₂O, intubation is generally indicated.^102,118

Reverse Trendelenburg positioning at 20 to 25 degrees with cervical support has been suggested to be beneficial by enhancing diaphragmatic function. In theory, this approach would reduce the risk of aspiration while decreasing the pressure of abdominal viscera on the diaphragm, with resultant improvement in ventilatory effort. However, its clinical application to seriously ill patients has not been validated.¹⁰

In addition to attention to respiratory issues, patients require nutrition (enteral or parenteral), prompt recognition and treatment of secondary infections, and prophylaxis against deep vein thromboses.

Gastrointestinal Decontamination

Removal of the spores and toxin from the gut should be attempted. Although most patients present after a substantial time delay, the bacteria or BoNT (or both) can still be present hours or even days later. Activated charcoal is recommended as a routine part of supportive care because in vitro it adsorbs BoNT type A and probably also the other BoNT types.⁷⁶ Gastric lavage or emesis should be initiated only for an asymptomatic person who has very recently ingested a known contaminated food. If a cathartic is chosen, sorbitol is preferable because other cathartics such as magnesium salts potentially exacerbate neuromuscular blockade. Theoretically, whole-bowel irrigation has a role in decontamination, particularly if there is concern about initiating emesis, but interventions other than activated charcoal have not been evaluated under these circumstances.

Wound Care

Thorough wound débridement is the most critical aspect in the management of wound botulism and should be performed promptly.^86,107 Antibiotic therapy alone is inadequate, as evidenced by several case reports of disease despite antibiotic therapy. Penicillin G is one of many drugs with excellent in vitro antimicrobial efficacy against C. botulinum and is useful for wound management.¹⁶⁵ However, penicillin has no role in the management of botulism caused by preformed toxin nor does it prevent gut spores from germinating. For these reasons, penicillin is not considered useful in infant and adult infectious botulism, and it is not by itself adequate for wound botulism. We recommend against using medications that interfere with neuromuscular transmission, such as aminoglycoside¹⁴⁶ and fluoroquinolone antibiotics⁹¹ and clindamycin.¹⁵⁰

Guanidine, Dalfampridine, and 3,4-Diaminopyridine

Guanidine is no longer recommended for treatment of botulism because its merits were not substantiated.^68,92 (See previous editions of this text for a more extensive discussion.) Several studies¹⁴⁵ and case reports⁶² have proposed that dalfampridine (4-aminopyridine) and 3,4-diaminopyridine are effective in improving neuromuscular transmission by enhancing acetylcholine release from the motor nerve terminal. In a rat BoNT type A model of botulism, 3,4-diaminopyridine restored neuromuscular function and enhanced animal survival.¹⁵⁶ Results in humans have been mostly disheartening,^60,157 but given the promising animal data and the apparent response in some patients,⁷⁴ along with the effectiveness in patients with LEMS, further investigative efforts may prove fruitful. Dalfampridine (Ampyra) is FDA approved to improve walking in patients with multiple sclerosis, but its potential to induce seizures at therapeutic doses limits its clinical usefulness. The fact that 3,4-diaminopyridine does not substantially cross the blood–brain barrier, resulting in limited central nervous system manifestations, makes this xenobiotic appropriate for further investigation, but cannot be recommended for routine use at the current time.

Botulinum Antitoxin

Since the 1960s, passive immunization with antitoxin has been used to neutralize unbound BoNT. In the United States, botulinum antitoxin (BAT) is available for adults and children older than 1 year through the CDC, the Alaska Division of Public Health, and the California Department of Public Health. State public health officials can obtain the antitoxin through the CDC by calling 770-488-7100. In 2013, the FDA approved a heptavalent BAT containing equine-derived antibody to botulinum toxin types A through G. It currently is the only BAT available in the United States for the treatment of botulism in adults and for cases of infant botulism caused by nerve toxins other than types A and B.¹⁷⁴

Because of the rarity and severity of botulism, randomized controlled studies of antitoxin in humans are neither feasible nor ethical. The current heptavalent BAT was shown to increase survival in guinea pig and rhesus macaque animal models.²² In a CDC analysis of an open-label observational study involving 109 patients with suspected or confirmed botulism, treatment with BAT within 2 days of symptom onset was associated with a shorter length of hospitalization (13.7 days less), shorter duration in intensive care unit (6.6 days less), and shorter duration of mechanical ventilation (11.8 days less) compared with patients treated later.²² Because of the benefit of earlier treatment, physicians should contact their state health department at the time the diagnosis of botulism is first suspected to expedite obtaining antitoxin from the CDC.

In a review of 132 cases of type A foodborne botulism from 1984 (when only trivalent antitoxin was available), a lower fatality rate and a shorter course of illness were demonstrated for patients who received the antitoxin, even after controlling for age and incubation period.¹⁶⁶ The earlier a patient received antitoxin, the shorter was the clinical course. In addition, no respiratory arrests occurred more than 5 hours after antitoxin was administered. Two studies on the use of antitoxin in the presence of wound botulism demonstrated that the longer the delay to antitoxin administration, the more prolonged the requirement for ventilatory support and the poorer the outcome.⁵⁴

Serum, stool, and gastric aspirate samples should be collected before administration of antitoxin. In adults (17 years and older), the entire vial of botulinal antitoxin should be given intravenously as a 1:10 vol/vol dilution in 0.9% sodium chloride at rate of 0.5 mL/min for 30 minutes, optionally increasing to 1 mL/min for 30 minutes and then 2 mL/min if tolerated. In children 1 to 17 years of age, the dose and infusion rate are modified based on body weight; in infants (younger than 1 year), the dose is 10% of the adult dose and infusion rate is based on body weight.²² Premedication with corticosteroids and antihistamines is reasonable in children and in patients with a suspected history of reaction to equine-derived products. Epinephrine and diphenhydramine should be readily available to treat anaphylaxis or hypersensitivity reactions.²² The overall rate of adverse reactions, including hypersensitivity and serum sickness,²⁷ to equine-derived BATs is reported as 9% to 17%, with an incidence of anaphylaxis as high as 1.9%.^17,120 However, because BAT is despeciated, the risk of such reactions likely is lower.

The antitoxin neutralizes only unbound toxin; consequently, it can prevent paralysis but does not affect already paralyzed muscles.⁷² Because of the potential lethality of foodborne botulism, the antitoxin should be given to patients in whom the diagnosis is suspected; treatment should not be delayed while awaiting laboratory confirmation of the diagnosis. In the event of a potential outbreak of foodborne botulism, asymptomatic individuals should be closely monitored for early signs of illness so that antitoxin can be administered promptly¹⁵³ (Antidotes in Depth: A6).

Treatment of Infant Botulism

Similar to adults, infants with botulism require intensive care, with meticulous monitoring for respiratory compromise and autonomic dysfunction.¹³³ Constipation can be severe.

In October 2003, the FDA licensed human-derived botulism antitoxin antibodies as botulism immune globulin (BabyBIG) for treatment of infant botulism types A and B.⁷ A randomized trial of 122 cases of infant botulism showed that treatment with intravenous botulism immune globulin significantly reduced the length of hospital stay and intensive care, duration of mechanical ventilation and tube or intravenous feeding, and cost of hospitalization relative to placebo without causing serious adverse effects.^11,71 Similar results were seen in a 2007 retrospective chart review.¹⁷⁶ BabyBIG is available from the California Department of Health Services Infant Botulism Treatment and Prevention Program (510-231-7600; http://www.infantbotulism.org).³⁴

Prevention

Measures used to prevent infant botulism include limiting exposure to spores by thoroughly washing foods and objects that might be placed in a child’s mouth. In addition, honey should not be given to infants younger than 6 months of age.

Vaccination strategies are under investigation, including several recombinant vaccines that have shown promise in protecting against botulism in animal and human trials.^19,160 Future approaches may include treatments that inhibit BoNT trafficking or promote toxin clearance or acetylcholine potentiation, among other mechanisms.^16,95

PROGNOSIS

The prolonged and variable period of recovery that occurs after exposure to BoNT is directly related to the extent of neuromuscular blockade and neurogenic atrophy as well as the regeneration rates of nerve endings and presynaptic membranes.¹¹¹ If the patient has excellent respiratory support during the acute phase and receives adequate parenteral nutrition, residual neurologic disability may not occur. Although the initial course sometimes is protracted, near-total functional recovery can follow within several months to 1 year. Common long-term sequelae include dysgeusia, dry mouth, constipation, dyspepsia, arthralgia, exertional dyspnea, tachycardia, and easy fatigability.

The status of 13 patients who survived a toxin type B botulinum outbreak was characterized 2 years later by persistent dyspnea and fatigue, although surprisingly, pulmonary function test results had returned to normal in all patients.¹⁸⁴ Inspiratory muscle weakness persisted in 4 of 13 patients. Maximal oxygen consumption and maximal workload during exercise were diminished in all patients, and all had more rapid shallow breathing and a higher dyspnea score than controls. The reasons for premature exercise termination may be multifactorial. Although persistent respiratory muscle weakness may be an explanation, most dyspnea and fatigue appeared to be related to reduced cardiovascular fitness, leg fatigue, and diminished nutrition.¹⁸⁴

A 2007 case-control series reported long-term outcomes in 217 adults with foodborne botulism in the Republic of Georgia. Six patients died; the remaining 211 were interviewed a median of 4.3 years after onset of disease. They were significantly more likely than control participants to report ongoing fatigue, dizziness, weakness, dry mouth, difficulty lifting things, and difficulty breathing with moderate exertion.⁷⁸

PREGNANCY

At least eight cases of botulism occurring during pregnancy are reported.³⁰ None of the neonates had neurologic evidence of botulism, though two (one with a heroin-abusing mother) had complications apparently unrelated to the botulism.^122,162 The large molecular weight of the neurotoxin (150 kDa) makes passive diffusion through the placenta unlikely, and experimental results in rabbits attest that this does not take place.⁸⁷ Appropriate care of the affected mother and preparation for maternal complications of delivery appear to ensure the best potential outcome for the infant.

All commercially available BoNT products are FDA Pregnancy Category C. Published case reports regarding therapeutic use of BoNT during pregnancy mostly describe uncomplicated births, although two miscarriages have been reported. In a review of 137 prospective pregnancies in the Allergan safety database of women treated with onabotulinumtoxinA during pregnancy or within 3 months before pregnancy, 79% resulted in live births, of which 2.7% were associated with fetal defects. These prevalence rates are said to be similar to those in the general population.³⁰

It is unknown whether BoNT is excreted in breast milk.

EPIDEMIOLOGIC AND THERAPEUTIC ASSISTANCE

Whenever botulism is suspected or proven, the local health department should be contacted. The health department should report to the CDC Emergency Operations Center at 770-488-7100. The CDC can provide or facilitate diagnostic, consultative, and laboratory testing services, access to BAT, and assistance in epidemiologic investigations. All foods that are potentially responsible for the illness should be refrigerated and preserved for epidemiologic investigation. The merits of this surveillance and antitoxin release system were demonstrated in Argentina,¹⁷⁸ where the CDC assisted in establishing nation-specific principles, including local stocking of antitoxin and establishing mechanisms for distribution, emergency identification, response, and laboratory confirmation of suspected cases. Expansion of this system to other nations will enhance worldwide botulism surveillance for foodborne botulism and for potential terrorist dissemination of BoNT.¹⁵²

SUMMARY

• Most cases of botulism in the United States affect infants younger than 6 months of age. Because of an epidemiologic association, honey should not be given to babies younger than 1 year of age.

• Most cases of foodborne botulism relate to food processed at home under improper conditions.

• Treatment of botulism should not be delayed while awaiting laboratory confirmation in patients presenting with diplopia, blurred vision, bulbar weakness, or symmetric paralysis.

• BabyBIG, a botulism immune globulin, is available for treatment of infant botulism types A and B, and there is a heptavalent BAT against serotypes A through G for infants with botulism caused by other BoNT types and for noninfants. Treatment should not be delayed while laboratory diagnosis is pending.

Acknowledgment

Neal E. Flomenbaum, MD, contributed to this chapter in previous editions.

REFERENCES

INTRODUCTION

Antidotal therapies for adult and infant Clostridium botulinum infection are available as equine- and human-derived immunoglobulin antitoxins. Antitoxins are beneficial for most clinical forms of botulism, although their utility is restricted to limiting disease progression rather than to reversing clinical manifestations.

HISTORY

Beginning in the 1930s, a formalin-inactivated toxoid against botulinum neurotoxin was first tested in humans, and in 1946, a bivalent (against types A and B) formaldehyde-inactivated toxoid was deployed by the Department of Defense as prophylaxis for at-risk individuals during the US Offensive Biological Warfare Program.^56,65 Before 1999, an equine trivalent antitoxin (BAT-ABE) was used to treat botulism.¹³ From 1999 to 2010, equine-derived, licensed bivalent botulinum antitoxin AB (BAT-AB) and investigational monovalent serotype E botulinum antitoxin (BAT-E) were available in the United States as immunoglobulin preparations. Patients with presumed wound botulism received BAT-AB. BAT-AB and BAT-E antitoxins were coadministered to patients with foodborne botulism. On March 13, 2010, equine heptavalent botulinum antitoxin (H-BAT, NP-018), an investigational new drug sponsored by the Centers for Disease Control and Prevention (CDC), replaced licensed bivalent BAT-AB and investigational BAT-E.¹⁶ Effective November 30, 2011, the CDC also stopped providing the investigational pentavalent (ABCDE) botulinum toxoid (PBT) for vaccination of workers at risk for occupational exposure.¹⁷ Botulism Immune Globulin Intravenous (Human) (BIG-IV), or BabyBIG was created by the California Department of Health Services (CDHS) in 1991 to treat infants affected by type A or type B botulism; it received Food and Drug Administration (FDA) approval in 2003.^2,27 On March 22, 2013, the FDA approved H-BAT, equine Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G), which is currently available.

PHARMACOLOGY

Chemistry and Preparation

A toxoid is an inactivated form of a bacterial toxin. An antitoxin is an antibody or antibody fragment capable of neutralizing a toxin. Multiple injections of formalin-inactivated toxoid are required over months to effectively immunize horses against botulinum toxin and to produce equine-derived antitoxins.³⁷ The resultant antibotulinum immunoglobulin requires several purification and preparation steps.³⁰ Heptavalent botulism antitoxin is produced by pooling plasma from horses immunized with seven specific botulinum toxoid types (A–G) followed by pepsin digestion and blending of the seven unique serotype antitoxins into a heptavalent product.¹¹ The antitoxin potencies for botulism serotypes A to G in H-BAT are provided in Table A6–1. By convention, 1 IU of BAT neutralizes 10,000 mouse intraperitoneal median lethal doses (MIPLD₅₀) of toxin types A, B, C, D, and F and 1,000 MIPLD₅₀ of toxin type E (the IU for type G remains undefined).¹⁵ As the equine H-BAT is “despeciated” by pepsin enzymatic cleavage to remove the Fc fragment portion, the resultant product is composed of 90% or greater Fab and F(ab′)₂ immunoglobulin fragments and less than 2% intact immunoglobulin G (IgG).¹⁶ This decreases the risk of immediate hypersensitivity reactions and serum sickness.

Human whole IgG BIG-IV was formerly produced from pooled adult plasma collected from human donors immunized multiple times with PBT (A-E).^45,61 The current purified immunoglobulin is derived from cold ethanol precipitation of pooled adult plasma from persons who were immunized with a recombinant botulinum vaccine for serotypes A and B (rBV A/B) followed by a number of purification steps to inactivate and/or remove infectious agents.³⁴ The reconstituted product (2 mL containing 50 ± 10 mg immunoglobulin in each milliliter) is primarily IgG, with trace amounts of IgA and IgM, and contains greater than or equal to 15 IU/mL anti-type A toxin ­activity and greater than or equal to 4 IU/mL anti-type B toxin activity; antibody titers against botulinum neurotoxins C, D, and E are undetermined.^27,34

Mechanism of Action

Current antitoxins (whether equine or human derived) bind to and neutralize free botulinum toxin.¹³ Thus, antitoxins are ineffective against toxin bound to presynaptic acetylcholine release sites, toxin endocytosed by peripheral neuronal cells, and intracellular botulinum toxin light chain endopeptidase activity.⁹ Affected presynaptic endplates must regenerate to regain function.

Pharmacokinetics and Pharmacodynamics

Antidotal antibody fragments {eg, (F(ab′)₂, F(ab′), and single-chain variable fragments (scFvs)} demonstrate shortened half-lives in vivo compared with whole immunoglobulins.³⁹ Improved renal clearance and uptake by vascular endothelium and surrounding tissues contributes to this effect.⁵⁰ Although linking fragments to polyethylene glycol (PEG) can extend the half-life,¹⁹ this methodology remains investigational. Half-lives for antitoxin types A, B, and E were 6.5, 7.6, and 5.3 days, respectively, in a patient provided whole intact IgG trivalent antitoxin.²⁹ Because H-BAT contains primarily Fab and F(ab′)₂ immunoglobulin fragments and minimal intact whole IgG, administration of H-BAT antitoxin yields shorter half-lives which are on the order of hours (Table A6–1). These half-lives generally increase in a nonlinear fashion when two vials were administered (Table A6–1). The total volume of distribution ranges from 1,465 mL (anti-D) to 14,172 mL (anti-E) and tends to increase with multiple vials.¹² The more rapid clearance of Fab and F(ab′)₂ fragments compared with whole IgG, infrequently necessitates repeat H-BAT dosing in patients with wound or intestinal colonization or other cases in which in situ botulinum toxin production continues after antitoxin clearance.¹⁶ Indeed, recurrence of paralysis was reported after H-BAT therapy in a patient with persistent type F intestinal colonization.²⁴ Given the neutralization parameters provided by each IU of BAT as indicated previously, the antitoxin in H-BAT would offset a total amount of toxin ranging from 5.1 × 10⁶ MIPLD₅₀ of botulinum E toxin to 4.5 × 10⁷ MIPLD₅₀ of botulinum A toxin (Table A6–1).⁵⁴ These values would be anticipated to provide significant neutralization, because patient serum botulinum toxin concentrations in foodborne botulism are usually less than 10 MIPLD₅₀/mL and rarely exceed 32 MIPLD₅₀/mL using a plasma volume of 3,000 mL reported previously.^3,29,53 However, in isolated outbreaks, botulinum toxin concentrations in adult serum samples collected less than 18 hours after exposure are reported to be as high as 160 MIPLD₅₀/mL.⁵ Other extremely rare cases have yielded human serum botulinum toxin concentrations of type A of 1,800 MIPLD₅₀/mL.⁵⁴ Nevertheless, even with these elevated exposures, the reported H-BAT maximum concentration values¹² after single-vial administration are anticipated to sufficiently neutralize 26,900 MIPLD₅₀/mL of botulinum A toxin, 19,000 MIPLD₅₀/mL of botulinum B toxin, 22,600 MIPLD₅₀/mL of botulinum C toxin, 8,100 MIPLD₅₀/mL of botulinum D toxin, 940 MIPLD₅₀/mL of botulinum E toxin, and 23,700 MIPLD₅₀/mL of botulinum F toxin (Table A6–1). A second vial would provide even greater protection (Table A6–1). This might be warranted in particularly severe exposures because circulating neutralizing antibody concentrations and botulinum toxin interactions are nonlinear and lead to a more efficacious, disproportional increase in botulinum toxin neutralization when antibody concentrations are increased.^38,53 Although anticipating or interpreting absolute neutralization efficacy is inexact because of numerous factors, one study that measured four patients’ serum antitoxin concentrations after trivalent antitoxin (BAT-ABE) administration determined that the patients’ measured antitoxin titers would retain the capability to neutralize 1,500, 1,000, and 12 times the anticipated toxin concentrations of types A, B, and E, respectively.²⁹

A new botulinum neurotoxin “type H” recovered from a naturally occurring infant botulism case raised concern because it was unable to be neutralized by available monovalent botulinum neurotoxin types (A–G) or a heptavalent antitoxin product.^6,21 Botulinum neurotoxin “type H” shares sequence homology with the botulinum neurotoxin type A1 heavy chain binding domain and the botulinum neurotoxin F5 light chain enzymatic domain. Subsequent mouse bioassay and neuronal cell-based assays demonstrated that commercial H-BAT provides complete neutralization of botulinum neurotoxin “type H” at exposures of 100 MIPLD₅₀/mL and complete neutralization with a single exception at 2,000 MIPLD₅₀/mL.³⁸ Given that serum botulinum toxin concentrations in foodborne botulism rarely exceed 32 MIPLD₅₀/mL, one H-BAT vial is anticipated to be sufficient to treat most botulism type H cases and bivalent strain cases (a strain that produces dual, distinct botulinum neurotoxins).^29,38

The half-life of BIG-IV is approximately 28 days.³⁴ BabyBIG Lot 2 anti-A titers were 0.5371 ± 0.2134 IU/mL on day 1 after administration, declining to 0.0193 ± 0.0141 IU/mL by week 20.³⁴ Because 1 IU neutralizes 10,000 mouse intraperitoneal median lethal doses (MIPLD₅₀) of botulinum toxin A, this yields approximate neutralization titers of 5,370 MIPLD₅₀/mL on day 1 and 193 MIPLD₅₀/mL by week 20.^15,34 Thus, a single infusion is anticipated to neutralize all botulinum toxin that might be absorbed from an infant’s colon for several months.⁴

Related Agents

To properly interpret earlier botulism studies, it is important to recall that the previously available, equine BAT-AB antitoxin contained 7,500 IU of anti-A antitoxin and 5,500 IU of anti-B antitoxin.⁴⁹ Monovalent serotype E botulinum antitoxin contained 5,000 IU of antitoxin. Trivalent antitoxin (BAT-ABE), contained 7,500 IU anti-A, 5,500 IU anti-B, and 8,500 IU anti-E antitoxins.³² Investigational, whole and fragment-derived monoclonal antibodies that are raised in murine and equine species against type A and B are also being explored.^37,39 Investigational PBT vaccine, combining individual monovalent toxoids, was initially manufactured by Parke Davis more than 50 years ago and was subsequently produced by the Michigan Department of Public Health under contract from the US Army.^26,55

The US Department of Defense Medical Countermeasure Systems-Joint Vaccine Acquisition Program (MCS-JVAP) manages the development pipeline for the lead replacement vaccine—recombinant botulinum vaccine (rBV A/B)—which is intended to protect adults 18 to 55 years old against botulism type A (subtype A1) and type B (subtype B1).^28,52 Other monoclonal antibodies, small peptides and peptide mimetics, receptor mimics and antagonists, endosome modulators, and endopeptidase inhibitors are being explored for botulism treatment.¹

ANTITOXIN ROLE IN ADULT BOTULISM

Rigorous adult morbidity and mortality studies are difficult to perform because the rarity of botulism, varied exposure and presentation, delayed recognition when bound toxin is no longer scavengable by antitoxin, and inconsistent clinical care. Given the delay involved in confirmatory testing by the CDC or public health laboratories, which could decrease the window of opportunity for antitoxin reversal potential, the decision to administer H-BAT is often made on the basis of empirical clinical and epidemiologic grounds. Earlier disease recognition and an organized public health approach consisting of surveillance, emergency notification, stocking, a release and distribution system, and laboratory confirmation appear to be responsible for decreasing morbidity and increasing survival after typical foodborne botulism.^51,64 Simian experiments demonstrate reduced mortality with antitoxin administration.⁴³ Early antitoxin administration appears to be a critical factor affecting clinical course and outcome. In a 1963 type E outbreak, all three patients who died failed to receive antitoxin, but three of five who received BAT survived.³⁵ Trivalent equine antitoxin decreased the fatality rate of botulinum A poisoning in a case series of 132 patients from 1973 to 1980.⁵⁹ The mortality rate was 10% in patients receiving antitoxin within 24 hours after onset, 15% in those who received antitoxin more than 24 hours after onset, and 46% in those without antitoxin administration. Age over 60 years and being an index patient conferred a greater mortality risk; a shorter incubation period of less than 36 hours (a likely measure of toxin dose) increased duration of hospitalization, mechanical ventilation, and time to sustained improvement.⁵⁹ The case-fatality rate was 3.5% in patients with type E botulism who were provided antitoxin and 28.9% for untreated control participants from previous years, although the utilization of supportive measures was uncontrolled.³³ In a retrospective review of 29 patients admitted between 1991 and 2005 with type A and a single case of type B wound botulism, a delay in antitoxin administration correlated with increased length of intensive care unit (ICU) stay.⁴⁴ In 20 patients with type A wound botulism treated from 1991 to 1998, those who received antitoxin within 12 hours of presentation required mechanical ventilation 57% of the time for a median duration of 11 days compared with those who failed to received antitoxin within 12 hours in whom 85% required mechanical ventilation for a median duration of 54 days.⁴⁸ Again, a shorter time to presentation heralded more severe disease (respiratory failure). A third wound botulism series (types A and B) with seven patients confirmed the importance of early therapy. Those receiving antitoxin more than 8 days from symptom onset or not at all (1 case) had worse outcomes compared with those receiving it within 4 days of symptom onset, including need for persistent mechanical ventilation (40%), bedridden (100%), inability to discharge to home setting (100%), andprolonged hospital course.¹⁸ In an uncontrolled, retrospective review of 205 cases of foodborne botulinum (predominantly type E) in Canada from 1985 to 2005, patients receiving antitoxin experienced a median hospital length of stay of 5 days, which was significantly shorter than the group that did not receive antitoxin (median length of stay, 11 days).³⁶

An earlier despeciated heptavalent botulism immune globulin (dBIG), which was prepared by the University of Minnesota under US Army contract, was deployed in the 1991 Egyptian type E botulism outbreak.³⁰ In a 2006 Thailand type A outbreak, a heptavalent antitoxin was administered to 20 patients 5 days after toxin ingestion when respiratory failure was already present. Mechanical ventilation and hospital duration were shorter compared with a historical study, and there were no deaths in those receiving antitoxin.⁶⁸ In a 2011 Utah prison botulism outbreak caused by potato-based pruno (prison-brewed alcohol), H-BAT was administered to eight patients a median of 12 hours after emergency department (ED) arrival and 73.3 hours after exposure.⁶⁷ Three patients required intubation; all survived.⁶⁷ Heptavalent botulism antitoxin was used in a separate prison botulism outbreak in Arizona in 2012 in eight inmates who also had consumed potato-based pruno.⁷⁰ Incubation periods ranged from 10 to 67 hours. All patients received antitoxin within 24 hours of hospital admission, seven required intubation and percutaneous endoscopic gastrostomies, and none died.⁷⁰ In the largest US botulism outbreak in nearly 40 years, which resulted from home-canned potato salad at a church potluck meal, 25 of 29 confirmed or probable cases received heptavalent botulinum antitoxin (H-BAT); 11 required intubation and mechanical intubation; and 1 patient died of respiratory failure shortly after arriving at the ED.⁴⁰

The absolute time frame for efficacy remains undetermined. In 109 patients treated under the CDC open-label protocol, H-BAT administration within 2 days after symptom onset (compared with longer than 2 days) was associated with clinically significant, shorter mean durations of hospitalization (12.4 versus 26.1 days), ICU utilization (9.2 versus 15.8 days), and mechanical ventilation (11.6 versus 23.4 days).¹² However, circulating toxin can persist for long periods in patients with foodborne botulism. One study reported toxin detection in almost 20% of serum specimens taken greater than or equal to 10 days after toxin ingestion.⁶⁹ Furthermore, persistent, viable organisms or spores were present in stools 40% of the time at 10 days or more after toxin ingestion. A review of laboratory-confirmed botulism cases in Alaska from 1959 to 2007 demonstrated that toxin could be recovered in patients’ sera up to 11 days after ingestion, but no serum specimens collected after antitoxin administration tested positive.²³ In one case, toxin was detected in serum 12 days after the onset of descending paralysis.²² Another patient in a multinational foodborne outbreak had toxin detected at 25 days after symptom onset.⁵⁴ Other isolated cases detail detectible circulating toxin as late as 3.5 weeks after contaminated food consumption.²⁰ Botulinum toxin–associated ileus can result in conditions conducive for continued absorption and prolonged toxin exposure. In other scenarios, contaminated wounds and orthopedic hardware can harbor Clostridia species despite antibiotic therapy.⁶⁰ Collectively, these factors suggest that H-BAT could still provide clinical benefit in patients with delayed presentations or disease recognition, in whom gastrointestinal or circulating toxin presents a persistent risk. Indeed, one report documented improvement when H-BAT was administered 48 hours after admission and many days after consumption of type-unspecified, botulism-contaminated canned corn.³¹ Clinically significant improvement (weaning from mechanical ventilation and resumption of feeding) was documented in a case of BIG-IV administered 13 days after onset of infant botulism.¹⁰ Botulinal antitoxins are also provided in cases of iatrogenic botulism.⁵⁷ In two patients with cosmetic iatrogenic botulism type A, administration of monovalent type A antitoxin as late as 7 and 9 days after the onset of weakness and bulbar symptoms improved symptoms.²⁵ Based on these limited data, it would be reasonable to provide BAT in delayed scenarios.

Botulism poisoning does not appear to induce protective immunity or decrease morbidity or mortality associated with subsequent exposure in food or wound botulism.^7,13,71 Thus, retreatment with antitoxin is required upon reexposure or in recurrent cases.

ANTITOXIN ROLE IN INFANT BOTULISM

BabyBIG is approved for treatment of patients younger than 1 year of age with infant botulism caused by toxin type A or B. BabyBIG is no longer derived from human donors vaccinated with PBT (A–E), only those immunized with recombinant botulinum vaccine for serotypes A and B. Thus, H-BAT is required to treat infants with non–type A or B botulism. In a double-blind and subsequent open-label trial, treatment with BabyBIG-IV significantly reduced the overall length of hospital and intensive care stay, the duration of mechanical ventilation, tube and intravenous (IV) feeding, and the cost of hospitalization.^2,4 A retrospective review of 67 ICU patients with type A or B botulinum toxin from 1976 to 2005 found clinically significant decreases in length of hospital stay, ICU stay, and mechanical ventilation in patients who received BabyBIG-IV and those who did not.⁶² Another retrospective review of patients with type A or B botulinum toxin from 1985 to 2005 reported a significant decrease in length of stay a reduced need for nasogastric feeding and duration of tracheal intubation in infants treated with botulism immune globulin.⁷¹

Bivalent BAT-AB and other equine derived products were rarely used in infants because of concern for anaphylaxis, lifelong hypersensitivity, and unclear efficacy.¹⁵ However, in situations when BabyBIG-IV was unavailable because of lack of access or cost, BAT-AB treatment within 5 days of symptom onset significantly reduced overall hospital and ICU stays, duration of mechanical ventilation, tube feedings, and incidence of sepsis.⁶³

ADVERSE EFFECTS AND SAFETY ISSUES

Despite purification, inactivation, and filtration measures, potential transmission of bloodborne infectious agents from animal or human donors (pooled equine or human plasma) may still occur. Treatment with whole equine-derived antitoxins risks hypersensitivity reactions and serum sickness.⁴⁹ Early rates of adverse reactions during the first decade during which BAT was available (1967–1977) ranged from 9% to 21%.^8,42 The reported rates of anaphylaxis and serum sickness were 1.9% and 3.7%, respectively.⁸ However, the doses of antitoxin were larger than those subsequently used. Heptavalent botulism antitoxin despeciation further decreases, but does not eliminate this risk. Heptavalent botulism immune globulin (dBIG) produced adverse reactions in 10 of 45 patients when used in one botulism type E outbreak.³⁰ These included nine “mild” reactions (local skin reactions, 6; pruritus, 1; urticaria, 1; shivering, 1) and one episode of “suggested serum sickness” without additional detail. The incidence of adverse effects of dBIG was similar to other internationally available antitoxins.³⁰ Healthy participants administered H-BAT in clinical trials (56 total, of whom 20 received two vials) reported headache, pruritus, nausea, and urticaria at rates of 9%, 5%, 5%, and 5%, respectively.¹² Two moderate allergic reactions required treatment. Eleven subjects produced anti-BAT antibodies. The open-label CDC observation study revealed adverse reactions in 10% of 228 assessable patients: pyrexia (4%), rash (2%), chills (1%), nausea (1%), and edema (1%).¹² There were no immediate hypersensitivity reactions, one cardiac arrest, and one episode of serum sickness. Heptavalent botulism antitoxin contains maltose, which can interfere with certain non–glucose-specific blood glucose monitoring systems and falsely elevated glucose readings.¹²

Hypersensitivity reactions might also occur to human BIG-IV, although this was not reported in clinical trials.³⁴ Human BIG is contraindicated in patients with a prior history of severe reactions to other human immunoglobulin preparations.³⁴ Patients with selective immunoglobulin A deficiency have the potential to develop antibodies to immunoglobulin A and could have anaphylactic reactions to subsequent administration of blood products that contain immunoglobulin A. The most commonly reported adverse reaction was a mild, transient erythematous rash on the face or trunk. Kidney function should be assessed and monitored; if compromised, BabyBIG-IV is administered at minimum concentration and rate of infusion. The prescribing information warns of adverse events from immune globulin therapy, including aseptic meningitis, hemolytic anemia, thrombosis, transfusion-related acute lung injury, and hyperviscosity, although these are unreported with the Human BIG-IV immune globulin product.³⁴ Administration of live-virus vaccines (ie, measles, mumps, rubella, and varicella) utilization should be delayed for 3 or more months after BabyBIG-IV treatment because of concerns of loss of immunization efficacy.

PREGNANCY AND LACTATION

Although there is limited information regarding H-BAT use in pregnancy, whole equine bivalent and trivalent antitoxins have been previously administered without apparent harm to the mother or the fetus.^{14,41,46,47,58} Pregnancy is not a contraindication to H-BAT. Given the morbidity and mortality of botulism, maternal treatment benefits would presumably exceed risks of harm, although all decisions are ultimately made on a case-by-case basis. The breast milk distribution of heptavalent botulism antitoxin is unknown.

DOSING AND ADMINISTRATION

Close monitoring; medications, including epinephrine, diphenhydramine, and corticosteroids; therapeutic modalities; and practitioners who are capable of diagnosing and treating anaphylactic or anaphylactoid reactions (including intubation competence) should be immediately available before and during antitoxin administration.

Botulism Antitoxin Heptavalent (A, B, C, D, E, F, and G)

Unlike prior equine-derived products, H-BAT does not require routine sensitivity testing before administration. In patients at risk for hypersensitivity reactions—those with previous therapy with an equine-derived antivenom or antitoxin or a history of hypersensitivity to horses, asthma, or hay fever—H-BAT administration is begun at the lowest rate achievable (<0.01 mL/min) and monitored.¹² Three separate dosing strategies are recommended for adults, pediatric patients (1–17 years of age), and infants younger than 1 year of age. The adult dose is one vial. The vial is diluted 1:10 in 0.9% sodium chloride and administered intravenously via an optional 15-micron in-line filter. Barring any infusion-related safety concerns, the initial rate is 0.5 mL/min for the first 30 minutes, which is increased to 1 mL/min for the next 30 minutes and then to 2 mL/min until completion of the infusion. For pediatric patients, the dose is a percentage of the adult (one vial) dose calculated according to the dosing rule summarized in the package insert. For pediatric patients with a body weight of 30 kg or less, the percentage of the adult dose to administer is equal to twice the body weight (in kilograms); for patients with a body weight greater than 30 kg, the percentage of the adult dose to administer equals the weight (in kilograms) + 30.¹² This rule yields the recommended percentages of the adult dose to administer for pediatric weight intervals from 10 to greater than 55 kg reproduced in the package insert.¹² Without ever exceeding the adult rates, the infusion is initiated at a rate of 0.01 mL/kg/min for the first 30 minutes, which is increased 0.01 mL/kg/min every 30 minutes, to a maximum infusion rate of 0.03 mL/kg/min until completion. Infants (younger than 1 year of age) receive 10% of the adult dose regardless of body weight. The infusion is initiated at a rate of 0.01 mL/kg/min for the first 30 minutes, which is increased 0.01 mL/kg/min every 30 minutes, to a maximum infusion rate of 0.03 mL/kg/min until completion.

Botulism Immune Globulin Intravenous (Human)

The lyophilized product is reconstituted with 2 mL of Sterile Water for Injection USP, to obtain a 50 mg/mL human BIG-IV solution. The vial should not be shaken because this causes foaming. Infusion should begin within 2 hours of reconstitution. A dedicated IV line using low volume tubing and a constant infusion pump are used to provide 75 mg/kg (1.5 mL/kg of reconstituted 50-mg/mL BIG-IV solution). The BIG-IV solution can be “piggybacked” into a preexisting line if it contains Sodium Chloride Injection USP, 2.5% dextrose in water, 5% dextrose in water, 10% dextrose in water, or 20% dextrose in water (with or without added sodium chloride). If a preexisting line must be used, BIG-IV should not be diluted more than 1:2 with any of these solutions.³⁴ Human BIG-IV is administered at an initial rate of 25 mg/kg/h (0.5 mL/kg/h of reconstituted 50-mg/mL BIG-IV solution) for the first 15 minutes, which is then increased to 50 mg/kg/hr (1 mL/kg/hr of reconstituted 50 mg/mL BIG-IV solution), for a total infusion time of 97.5 minutes at the recommended dose.

Other Immunoglobulins

In regions where whole, equine-derived antitoxins are still available, it is important to note that these products required sensitivity testing and potential desensitization, and the package inserts should be consulted for specific procedural details for dosing and administration, particularly because titers and volumes may differ by brand.⁴⁹ For prophylaxis, the recommended dose of BAT-AB for an individual ate food suspected of being infected with C. botulinum depends on the amount of food eaten and is 1,500 to 7,500 IU of anti-type A and 1,100 to 5,500 IU of anti-type B intramuscularly (20%–100% of one vial). This initial therapy was followed in 12 to 24 hours by the injection of a second vial if any signs or symptoms of botulism developed.⁴⁹ In addition, 1,000 IU to 5,000 IU (20% to 100% of one vial) of investigational anti-type E, based on the estimated ingested quantity of botulinum toxin, was used for type E outbreaks.⁶⁶ The BAT-AB and BAT-E treatment doses were one vial of antitoxin diluted 1:10 (vol/vol) in 0.9% sodium chloride solution and administered slowly intravenously over 30 to 60 minutes.^32,49 Subsequent doses could be provided intravenously every 2 to 4 hours if progression of clinical findings occurs. The BAT-AB and BAT-E are administered separately.

FORMULATION AND ACQUISITION

Heptavalent botulism antitoxin is supplied in either 20-mL or 50-mL single-dose vials. Despite variable vial filling of 10 to 22 mL/vial, the amount of A to G antitoxin contained per vial is fixed: more than 4,500 IU of anti-A, more than 3,300 IU of anti-B, more than 3,000 IU of anti-C, more than 600 IU of anti-D, more than 5,100 IU of anti-E, more than 3,000 IU of anti-F, and morethan 600 IU of anti-G.¹² The bulk material contains approximately 30 to 70 mg/mL of protein. Heptavalent botulism antitoxin contains 10% maltose and 0.03% polysorbate 80. Heptavalent botulism antitoxin is stored frozen at or below 5°F (–15°C) until used. Thawed H-BAT must be maintained at 36° to 46°F (2°–8°C) and used within 36 months or until 48 months from the manufacture date, whichever occurs earliest. Heptavalent botulism antitoxin should not be refrozen. Frozen H-BAT can be thawed in a refrigerator at 36° to 46°F (2°–8°C) over approximately 14 hours. Rapid thawing can be achieved by placing at room temperature for 1 hour followed by a water bath at 98.6°F (37°C) until thawed. Reconstituted H-BAT may be stored refrigerated for use within 8 to 10 hours.

BabyBIG is formulated as a single-use, solvent-detergent-treated, sterile vial containing 100 ± 20 mg of lyophilized immunoglobin (primarily IgG with trace amounts of IgA and IgM), stabilized with 5% sucrose and 1% albumin (human), without preservative and supplied with 2 mL of Sterile Water for Injection USP for reconstitution.^27,34

Bivalent BAT-AB, which may be available outside of the United States, must be maintained at 2° to 8°C (35°–46°F) and not frozen. It contains phenol 0.4% as a preservative.

Clinicians who suspect botulism should immediately call their local or state health department’s emergency 24-hour telephone service to request release of BAT and comply with legal reporting requirements; a single case is considered a public health emergency. When local and state public health authorities are unavailable, the CDC Emergency Operations Center telephone contact is 770-488-7100. The CDC controls H-BAT distribution from stocks located throughout a national network of decentralized Quarantine Stations. The California Infant Botulism Treatment and Prevention Program (510-231-7600) maintains the supply of BabyBIG for infant botulism treatment. The Biomedical Advanced Research and Development Authority (BARDA) within the US Department of Health and Human Services has obtained approximately 120,000 H-BAT doses for the Strategic National Stockpile (SNS), with anticipated completion of delivery of 80,000 additional doses by 2018.⁶⁵ The CDC released 50 doses of H-BAT from the SNS to Ohio during a large outbreak from home-canned potato salad.⁴⁰

SUMMARY

• In conjunction with frequent clinical assessments and aggressive supportive care of respiratory, gastric, and urinary function, BAT decreases morbidity and mortality after typical foodborne or wound botulism.

• Preliminary data suggest that early administration of licensed H-BAT decreases duration of hospitalization, ICU utilization, and mechanical ventilation.

• Licensed BabyBIG-IV provides effective treatment for infant botulism.

• Early consultation with local and state health departments, the CDC Emergency Operations Center (770-488-7100), or a regional poison control center (or other comparable agencies in other parts of the world) should occur to rapidly access effective therapeutic modalities and diagnostic tests for botulism.

REFERENCES

INTRODUCTION

Each year in the United States known foodborne pathogens are responsible for approximately 30.7 million illnesses, 228,144 hospitalizations, and 2,612 deaths.⁴⁷ It is estimated that foodborne illness costs an annual burden to the American society of 36 billion dollars, which is estimated to be an average cost burden per illness of $3,630.¹⁴³ Worldwide food distribution, large-scale national food preparation and distribution networks, limited food regulatory practices, and corporate greed place everyone at risk. Food poisoning causes morbidity and mortality by one or more of the following mechanisms: (bacteria, viruses and parasites) that can be transmitted in food; toxins that are produced by organisms, can be consumed in food; and xenobiotics can be inadvertently or purposefully used to contaminate food and ultimately be ingested.

This chapter is organized into four major types of food poisoning: foodborne poisoning with neurologic effects, food poisoning with gastrointestinal (GI) symptoms, foodborne poisoning with anaphylaxislike effects, and food poisoning used for bioterrorism.

HISTORY AND EPIDEMIOLOGY

In the United States, viruses are the most responsible cause of foodborne outbreaks (82%) followed by bacteria (12%), and parasites (6%). Norovirus was the most common cause of single, confirmed etiology outbreaks (54%). The bacteria that caused the largest number of food poisonings were Salmonella spp, Clostridium perfringens, Staphylococcus aureus enterotoxin, and Shigella spp. The estimated annual number of episodes of foodborne pathogen related illness, hospitalization and death in the United States is shown in Table 39–1.⁴⁸

Globally, researchers estimated foodborne pathogens were found to cause 582 million cases of illnesses annually. The leading cause of foodborne illness was norovirus (125 million cases) followed by campylobacter (96 million). Most important, around 43% of the disease burden from contaminated food occurred in children younger than 5 years of age, who make up 9% of the population.¹¹⁰

In the past decade, large numbers of people have also had food poisoning because of purposeful placement of chemicals in food.⁵¹

Many foodborne illnesses result in long-term sequelae to the GI, immune, nervous, respiratory, renal, cardiovascular, endocrine, and hepatic systems.¹⁴

FOODBORNE POISONING WITH NEUROLOGIC SYMPTOMS

The differential diagnosis of patients with foodborne poisoning presenting with neurologic symptoms is vast (Tables 39–2 and 39–3). The sources of many of these cases are ichthyosarcotoxic, involving toxins from the muscles, viscera, skin, gonads, and mucous surfaces of the fish; rarely, toxicity follows consumption of the fish blood or skeleton. Most episodes of poisoning are not species specific, although particular forms of toxicity from Tetraodontiformes (puffer fish), Gymnothoraces (moray eel), and newts (Taricha and other species) are recognized.

In cases of ciguatera poisoning, the major symptoms usually are neurotoxic, and the GI symptoms are minor. Knowing where the fish was caught often helps establish a diagnosis, but refrigerated transport of foods and rapid worldwide travel can complicate the assessment. Travelers to Caribbean, Pacific, and Canary islands, as well as those traveling within the United States, have experienced ciguatera poisoning.^119,155 In geographically disparate regions of Canada,¹⁶¹ individuals have experienced domoic acid poisoning caused by ingestion of cultivated mussels from Prince Edward Island.

In the differential diagnosis of foodborne poisons presenting with neurologic findings, activities other than eating must always be considered. In particular, sport divers often perform their activities in high-risk areas such as Florida, California, and Hawaii and often during the high-risk periods from May through August. In the process, they may sustain a sting from a stingray tail, or laceration (from a deltoid or pectoral fin spine of a lionfish or stonefish) that can cause consequential marine toxicity (Chap. 116). Scientists have found that the chance of encountering numerous bacterial pathogens harmful to both human and marine life was cut in half near seagrass meadows. Swimmers and divers can limit disease by choosing waters rich in seagrass meadows.¹⁶⁵

Ciguatera Poisoning

Ciguatera poisoning is one of the most commonly reported forms of vertebrate fishborne poisonings in the United States, accounting for almost half of the reported cases.⁸⁵ Ciguatoxins are lipid soluble, polyether compounds consisting of 13 to 14 rings fused by ether linkages into a rigid ladder-like structure (Fig. 39–1). Ciguatera poisoning is endemic to warm water, bottom-dwelling reef fish living around the globe between 35° North and 35° South latitude, which includes tropical areas such as the Indian Ocean, the South Pacific, and the Caribbean. Hawaii and Florida report 90% of all cases occurring in the United States, most commonly from May through August.¹²⁵ The incidence and geographical distribution of ciguatera are increasing because of increased fish trade and consumption, international tourism, and climate changes.

More than 500 fish species have caused human cases of ciguatera poisoning, with the barracuda, sea bass, parrot fish, red snapper, grouper, amber jack, kingfish, and sturgeon the most common sources. The common factor is the comparably large size of the fish involved.

Large fish (1.5–3.0 kg or more) become vectors of ciguatera poisoning in accordance with complex feeding patterns inherent in aquatic life. This traditional teaching is challenged by a recent study. The lack of relationship between toxicity and size observed for most of the species and families from the six islands in French Polynesia suggests that fish size cannot be used as an efficient predictor of fish toxicity.⁷⁵ Ciguatoxin is found in blue-green algae, protozoa, and the free algae dinoflagellates. These plankton members of the phylum Protozoa are single-celled, motile, flagellated, pigmented organisms thriving through photosynthesis. Photosynthetic dinoflagellates such as Gambierdiscus toxicus and bacteria within the dinoflagellates are the origins of ciguatoxin.^66,97,130 Dinoflagellates are the main nutritional source for small herbivorous fish, which, in turn, are the major food source for larger carnivorous fish, thereby increasing the ciguatoxin concentrations in the flesh, adipose tissue, and viscera of larger and larger fish.¹²

Ciguatoxin is heat stable, lipid soluble, acid stable, odorless, and tasteless. When purified, the toxin is a large (molecular weight, 1,100 Da) complex ester that does not harm the fish but is stored in its tissues.^125,131 The molecule binds to voltage-sensitive sodium channels in diverse tissues and increases the sodium permeability of the channel.¹⁹¹ The ciguatoxins cause hyperpolarization and a shift in the voltage dependence of channel activation, which opens the sodium channels. Ciguatoxins bind selectively to a particular binding site on the neuron’s voltage-sensitive sodium channel protein.¹²⁹

Multiple ciguatoxins are identified in the same fish, perhaps explaining the variability of symptoms and differing severity.¹³⁰ People can be affected after eating fresh or frozen fish that was prepared by all common methods: boiling, baking, frying, stewing, or broiling. The appearance, taste, and smell of the ciguatoxic fish are usually unremarkable. The majority of symptomatic episodes begin 2 to 6 hours after ingestion, 75% within 12 hours, and 96% within 24 hours.¹² Symptoms include acute onset of diaphoresis; headaches, abdominal pain with cramps, nausea, or vomiting; profuse watery diarrhea; and a constellation of dramatic neurologic symptoms.²⁰⁹ A sensation of loose or painful teeth is reported. Typically, peripheral dysesthesias and paresthesias predominate. Watery eyes, tingling, and numbness of the tongue, lips, throat, and perioral area occur. A strange metallic taste is frequently reported as is a reversal of temperature discrimination, the pathophysiology of which remains to be elucidated.³⁴ Myalgias, most often in the lower extremities; arthralgias; ataxia; and weakness are commonly experienced.¹²

Dysuria⁸¹ and symptoms of dyspareunia and vaginal and pelvic discomfort are reported to occur in some women after sexual intercourse with men who are ciguatoxic and whose semen contains the toxin.¹¹⁸ Vertigo, seizures, and visual disturbances (eg, blurred vision, scotomata, and transient blindness) are reported.

Bradycardia and orthostatic hypotension are described.⁷⁷ The GI symptoms usually subside within 24 to 48 hours; however, cardiovascular and neurologic symptoms typically persist for several days to weeks, depending on the amount of toxin ingested. Delayed effects include protracted itching and hiccoughs. Ciguatoxin is transmitted in breast milk²³ and can cross the placenta.¹⁵⁹

Although deaths are reported, internationally, none have been documented in the United States.⁸⁵ When it occurs, death is a result of respiratory paralysis and seizures not managed with adequate life support. One study showed that the main contributory factors associated with death were the consumption of ciguatoxin-rich fish parts (viscera and head) in larger amounts, ingestion of the ciguatoxic fish species (eg, barracuda, sea bass, red snapper, grouper), ingestion of reef fish collected after storms, and ultimately individual susceptibility.⁵²

The Food and Drug Administration’ (FDA’s) and Ciguatoxin (CTX) fish testing procedure is performed in an analytical laboratory setting and uses a two-tiered protocol involving: (1) in vitro mouse neuroblastoma (N2a) cell assay as a semiquantitative screen for toxicity consistent with CTX mode of action and (2) liquid chromatography tandem–mass spectrometry (LC-MS/MS) for molecular confirmation of CTX. To date, there is no commercially available, rapid, cost-effective, fish-testing product that has been demonstrated by independent investigations to provide CTX detection in seafood with adequate reliability or accuracy.

Laboratory testing is not readily available, and it often takes days to weeks to receive the result. A useful approach to diagnosis and management includes laboratory testing to exclude other possible etiologies and determine the need for, or extent of, specific therapeutic interventions.

Initial treatment for victims of ciguatoxin poisoning includes standard supportive care for a toxic ingestion.²⁰⁹ In most patients, elimination of the toxin is accelerated if vomiting (40%) and diarrhea (70%) have occurred. Administration of activated charcoal has benefit for patients who are not vomiting. In patients with significant GI fluid loss through vomiting, diarrhea, or both, intravenous (IV) fluid and electrolyte repletion are essential. The orthostatic hypotension responds to IV fluids and α-adrenergic agonists. Symptomatic bradycardia is treated with atropine.⁷³

Intravenous mannitol is reported to alleviate neurologic and muscular dysfunctional symptoms associated with ciguatera; however, GI symptoms are not ameliorated.^158,160 An in vivo study showed that there was no change in neuronal swelling when ciguatera-poisoned cells were treated with mannitol but did show some prevention of the membrane depolarization and repetitive firing of action potentials induced by ciguatera.¹⁹ Despite these findings, one prospective randomized control trial, mannitol failed to produce any greater improvement in symptoms than did IV normal saline solution. This study is a randomized double-blinded control trial to answer this question. Most of the previous data on the use of mannitol in ciguatera poisoning was either obtained in an uncontrolled or randomized but nonblinded fashion or is the result of case reports.¹⁷⁹ Mannitol should be used with caution because it causes hypotension. Vascular reexpansion and cardiovascular stability should be initial treatment priorities. Mannitol works by inhibiting the ciguatoxin-induced opening of sodium channels on the neuron membranes or reducing the neural edema via an osmotic gradient and is recommended in the hemodynamically stable patient. The search for a treatment for ciguatera poisoning that has minimal side effects and is easily accessible is ongoing. Two cases were reported of symptomatic patients exposed to ciguatera who were successfully treated with pregabalin.³⁰

There is limited evidence for the efficacy of pregabalin.³⁰

Admission to the hospital for cautious supportive care is essential when the diagnosis is uncertain or when volume depletion or any consequential manifestations are present (Tables 39–2 and 39–3). The etiology of the symptoms must be rapidly identified to provide specific therapy, if available. Diaphoresis is a common clinical finding and an important factor in the differential diagnosis. Late in the course of ciguatera poisoning, amitriptyline 25 mg orally twice daily helps alleviate symptoms,²⁷ which have been reported to persist up to 1 year. Patients recovering from ciguatera should avoid alcohol and nuts for 3 to 6 months if their consumption exacerbates symptoms.

Ciguateralike Poisoning

Moray, conger, and anguillid eels carry a ciguatoxinlike neurotoxin in their viscera, muscles, and gonads that does not affect the eel itself. The toxin is a complex ester that is structurally very similar to ciguatoxin and is heat stable.¹⁵⁴ Individuals who eat these eels can infrequently manifest neurotoxic symptoms similar to ciguatoxin or show signs of cholinergic toxicity, such as hypersalivation, nausea, vomiting, and diarrhea. Shortness of breath, mucosal erythema, and cutaneous eruptions also occur. These findings are present in addition to the neurotoxic symptoms.⁹⁰ Management is supportive. Death is related to the complications of neurotoxicity, such as seizures and respiratory paralysis.

Shellfish Poisoning

Healthy mollusks living between 30° North and 30° South latitude ingest and filter large quantities of dinoflagellates. These dinoflagellates are the major source of available ocean food during the “non-R” months (May through August) in the northern hemisphere. During this time, these dinoflagellates are responsible for the “red tides” that occur from California to Alaska, from New England to the St. Lawrence, and across the west coast of Europe.¹³⁷ The number of toxic dinoflagellates in these “red tides” is often so overwhelming that birds and fish die, and humans who walk along the beach experience respiratory symptoms caused by aerosolized toxin.¹⁴⁰

Ingestion of shellfish, including oysters, clams, mussels, and scallops, contaminated by dinoflagellates or algae causes neurotoxic, paralytic, and amnestic syndromes. The dinoflagellates most frequently implicated are Karenia brevis (originally named Gymnodinium breve in 1948, renamed Ptychodiscus brevis in 1979, and reclassified again to the current nomenclature in 2000). The diatoms causing neurotoxic shellfish poisoning (NSP) include Protogonyaulax catanella and Protogonyaulax tamarensis, which cause paralytic shellfish poisoning, and Nitzschia pungens, the diatom implicated in amnestic shellfish poisoning. Proliferation of these diatoms cause a red tide, but shellfish poisoning occurs even in the absence of this extreme proliferation.

Paralytic shellfish poisoning is caused by saxitoxin. Saxitoxin blocks the voltage-sensitive sodium channel in a manner identical to tetrodotoxin (TTX; see later). The shellfish implicated usually are clams, oysters, mussels, and scallops, but poisoning has occurred through consumption of crustaceans, gastropods, and fish. In the summer of 2013, a saxitoxin outbreak was identified among 31 individuals in the who consumed green mussels in the Philippines. The symptoms in these individuals ranged from circumoral and extremity numbness to dizziness and lightheadedness. One adult and one child died secondary to cardiorespiratory arrest.⁵⁶

The higher the number of affected shellfish consumed, the more severe the symptoms. Symptoms usually occur within 30 minutes of ingestion. Neurologic effects predominate and include paresthesias and numbness of the mouth and extremities, a sensation of floating, headache, ataxia, vertigo, muscle weakness, paralysis, and cranial nerve dysfunction manifested by dysphagia, dysarthria, dysphonia, and transient blindness. Gastrointestinal symptoms are less common and include nausea, vomiting, abdominal pain, and diarrhea. Fatalities occur as a result of respiratory failure, usually within the first 12 hours after symptom onset. Muscle weakness often persists for weeks.

Treatment is supportive. Early intervention for respiratory failure is indicated. Orogastric lavage and cathartics were used to remove unabsorbed toxin from the GI tract and were not efficacious and thus are not recommended.^{31,127,145,183} Activated charcoal is reasonable if vomiting has not occurred. Antibodies against saxitoxin have reversed cardiorespiratory failure in animals,¹⁶ but this therapy is not yet available for humans. Assays for saxitoxin include a mouse bioassay, enzyme-linked immunosorbent assay (ELISA), and high-performance liquid chromatography (HPLC). High-performance liquid chromatography is demonstrated to result in good interlaboratory accuracy,²⁰³ but the differences in saxitoxin derivatives make standardization of an analytic test difficult.^11,121

Neurotoxic shellfish poisoning is caused by brevetoxin. Brevetoxin, which is produced by K. brevis (previously Gymnodium brevis, and subsequently P. brevis), is a lipid-soluble, heat-stable polyether toxin similar to ciguatoxin. It acts by stimulating sodium flux through the sodium channels of both nerve and muscle.^8,35 Similar to paralytic shellfish poisoning, the shellfish implicated usually are clams, oysters, mussels, and other filter feeders. Neurotoxic shellfish poisoning is characterized by gastroenteric manifestations with associated neurologic symptoms. Gastrointestinal symptoms include abdominal pain, nausea, vomiting, diarrhea, and rectal burning. Neurologic features include paresthesias, reversal of hot and cold temperature sensation, myalgias, vertigo, and ataxia. Other effects include headache, malaise, tremor, dysphagia, bradycardia, decreased reflexes, and mydriasis. Paralysis does not occur. Bradycardia and mydriasis are not commonly present in an individual patent. The incubation period is 3 hours (range, 15 minutes–18 hours). Gastrointestinal and neurologic symptoms appear simultaneously. Other manifestations of brevetoxin poisoning include mucosal irritation, cough, and bronchospasm, which occur when P. brevis is aerosolized by wave action during red tides. The duration of effects averages 17 hours (range, 1–72 hours).¹⁴⁵

Brevetoxins are identified by mouse bioassay; ELISA; and, more recently, antibody radioimmunoassay and reconstituted sodium channels. (Reconstitution is when a purified membrane protein is incorporated into a membrane bilayer and the reconstituted channel is then used as a tool for the measurement of specific toxin binding.^163,200) Treatment is supportive, and severe respiratory depression is very uncommon. Therapy includes removal of the patient from the environment and the administration of bronchodilators. An antagonist to brevetoxin named brevenal has been discovered and is in the early research phase as a potential therapy.⁸² Neurotoxic shellfish poisoning is not fatal.

Amnestic shellfish poisoning is caused by domoic acid, which is produced by the diatom a N. pungens. Domoic acid is structurally similar to glutamic acid, kainic acid, and aspartic acid (Fig. 39–2). Because of this structural similarity, domoic acid interacts with the glutamate receptors on nerve cell terminals. Glutamate is the principal neuroexcitatory transmitter in the brain and is necessary for synaptic transmission (Chap. 13). However, excessive glutamate is associated with neurodegeneration, seizures, and apoptosis.¹²⁴

The most extensively documented human outbreak occurred in Canada in 1987, when 107 individuals who had consumed mussels harvested from cultivated river estuaries on Prince Edward Island were affected.¹⁶¹ Other human outbreaks have occurred due to a similar diatom—Pseudonitzschia australis—which has been isolated in shellfish from other areas.⁷⁴ Pelican deaths caused by domoic acid–laden anchovies were reported in 1991 and Canada instituted monitoring for domoic acid after this outbreak.¹⁹⁷ The death of 400 sea lions in California in 1998 was linked to domoic acid from the same diatom.¹⁸⁰

Amnestic shellfish poisoning is characterized by GI symptoms of nausea, vomiting, abdominal cramps, diarrhea, and neurologic symptoms of memory loss and, less frequently, coma, seizures, hemiparesis, ophthalmoplegia, purposeless chewing, and grimacing. Other signs and symptoms include hemodynamic instability and cardiac dysrhythmias. Symptoms typically begin 5 hours (range, 15 minutes–38 hours) after ingestion of mussels. The mortality rate is 2%, with death most frequently occurring in older patients, who experience more severe neurologic symptoms. Ten percent of victims have long-term antegrade memory deficits, as well as motor and sensory neuropathy. Postmortem examinations revealed neuronal damage in the hippocampus and amygdala.¹⁹⁵ Animal studies show that domoic acid can cross the placenta.¹³⁸

Tetrodotoxin Poisoning

This type of fish poisoning involves only the order Tetraodontiformes. Although this order of fish is not restricted geographically, it is eaten most frequently in Japan, California, Africa, South America, and Australia.⁹⁰ Cases also occurred in Florida and New Jersey, as well as Europe, the Mediterranean, and Bangladesh. Approximately 100 freshwater and saltwater species exist in this order, including a number of pufferlike fish such as the globe fish, balloon fish, blowfish, and toad fish.¹⁴⁷ Tetrodotoxin (TTX) found in these fish is also isolated from the blue-ringed octopus⁷¹ and the gastropod mollusk²¹¹ and are responsible for fatalities from ingestion of horseshoe crab eggs.¹⁰² Certain TTX-containing newts (Taricha, notophthalmus, triturus, and cynops), particularly Taricha granulosa, found in Oregon, California, and southern Alaska, are reportedly fatal when ingested. Most newts and salamanders with bright colors and rough skins contain toxins.²⁸ In Japan, fugu (a local variety of puffer fish) is considered a delicacy, but special licensing is required to prepare this exceedingly toxic fish. In 1989, the US FDA legalized the importation of puffer fish. However, before exportation from Japan, the fish must be laboratory tested and certified by two Japanese organizations to be free of TTX.⁴⁹

Tetrodotoxin is a heat-stable, water-soluble nonprotein found mainly in the fish skin, liver, ovary, intestine, and possibly muscle.^90,175 The ovary has a high concentration of the toxin and is most poisonous if eaten during the spawning season. Tetrodotoxin is detected by mouse bioassay. It is unstable when heated to 212°F (100°C) in acid, distinguishing it from saxitoxin. Tetrodotoxin from fish is detected using fluorescent spectrometry¹¹ or from the urine of poisoned patients using a combination of immunoaffinity chromatography and fluorometric HPLC.¹⁰⁵

Similar to saxitoxin, TTX is produced by marine bacteria and likely accumulate in animals higher on the food chain that consume these bacteria.¹⁵¹ Accumulation of toxins, primarily in the skin, of two species of Asian puffer fish is documented. Whether this accumulation of toxin is simply an evolutionary adaptation, to remove a toxic substance, or one that has evolutionary advantages of protection is unclear.¹⁵⁰

Neurotoxicity is produced by inhibition of sodium channels and blockade of neuromuscular transmission. The sodium channel is blocked from the external surface of the neuron by the TTX molecule, which contains a guanidinium group that fits into the external orifice of the sodium channel. This causes external “plugging” of the sodium channel, although the gating mechanism remains functional.^148,149

Effects of TTX poisoning typically occur within minutes of ingestion. Headache, diaphoresis, dysesthesias, and paresthesias of the lips, tongue, mouth, face, fingers, and toes evolve rapidly. Buccal bullae and salivation develop. Dysphagia, dysarthria, nausea, vomiting, and abdominal pain ensue. Generalized malaise, loss of coordination, weakness, fasciculations, and an ascending paralysis (with risk of respiratory paralysis) occur in 4 to 24 hours. Other cranial nerves are involved. In more severe toxicity, hypotension is present. In some studies, the mortality rate approaches 50%.¹⁸⁶

Therapy is supportive. Removal of the toxin and prevention of absorption are the essential measures. Supportive respiratory care emphasizing airway protection, including intubation, if necessary, is extremely important. Neostigmine, a cholinesterase inhibitor, is proposed as a therapy for tetrodotoxicity. The theory is that increasing acetylcholine at the neuromuscular junction combats TTX effects at the motor end plate and motor axon. Although this sounds promising, a recent literature review found the data insufficient to make an evidence-based recommendation.¹³²

Clostridium botulinum

In 2015, the CDC reported 39 cases of laboratory-confirmed foodborne botulism and 141 cases of infant botulism.⁵⁰ Home-canned fruits and vegetables, as well as commercial fish products, are among the common foods causing botulism. The incubation period usually is 12 to 36 hours; typical signs and symptoms include some initial GI symptoms followed by malaise, fatigue, diplopia, dysphagia, and rapid development of small muscle incoordination.¹²² In botulism, the toxin is irreversibly bound to the structures within the nerve terminal, where it impairs the presynaptic release of acetylcholine.¹¹⁵ A patient’s survival depends on rapidly diagnosing botulism and immediate initiation of aggressive respiratory therapy. Establishing the diagnosis early makes it possible to treat the “sentinel” or index patient and also others who consumed the contaminated food with antitoxin before their developing signs and symptoms (Chap. 38 and Antidotes in Depth: A6). The differential diagnosis of botulism includes myasthenia gravis, atypical Guillain-Barré syndrome, tick-induced paralysis, and certain chemical ingestions (Tables 39–1 and 39–2).

PREVENTION OF MARINE FOODBORNE DISEASE

Careful evaluation of the symptoms and meticulous reporting to local and state health departments, as well as to the US Centers for Disease Control and Prevention (CDC), will allow for more precise analysis of epidemics of poisoning from contaminated or poisonous food or fish. Many states and countries have developed rigorous health codes with regard to harvesting certain species of fish in certain areas at certain times.

Some examples of actions taken by state, federal, and foreign health agencies in controlling epidemics of seafood-borne food poisoning are the following: The health code of Miami, Florida, prohibits the sale of barracuda and warns against eating fillets from large and potentially toxic fish containing ciguatoxin. A 3,230-km stretch of the Massachusetts coastline was noted to be unsafe for shellfish harvesting because of a red tide bloom. The National Oceanic and Atmospheric Administration’s Fisheries Service along with the FDA declared a health emergency and confiscated shellfish harvested in this area and prohibited the marketing, export, and serving of shellfish.³³ The Japanese closely regulate preparation and selling of the puffer fish (fugu), requiring that preparers receive special training and licensing. The sale of fugu is now also permitted under strict control in the United States as well. The Canadian government identifies and registers the location and time of harvesting of mussels, and mussels are tested for the presence of domoic acid.^74,161

Less Common Poisonings

Echinoderms

The sea urchin usually causes toxicity by contact with its spinous processes, but this Caribbean delicacy is also toxic upon ingestion. When the sea urchin is prepared as food, the venom-containing gonads should be removed because they contain an acetylcholine-like substance that causes the cholinergic syndrome of profuse salivation, abdominal pain, nausea, vomiting, and diarrhea.

Haff Disease

The consumption of cooked seafood can potentially lead to a syndrome of myalgias and rhabdomyolysis. This syndrome is termed Haff disease, after an outbreak occurred in the 1920s in approximately 1,000 persons living along the Koenigsberg Haff, an inlet of the Baltic Sea. The actual etiology of Haff disease is unknown, but it is suspected that the causative agent is similar to a palytoxin (potent vasoconstrictor). Treatment is hydration with intravenous fluids.⁶³

FOOD POISONING ASSOCIATED WITH DIARRHEA

The initial differential diagnosis for acute diarrhea involves several etiologies: infectious (bacterial, viral, parasitic, and fungal), structural (including surgical), metabolic, functional, inflammatory, toxin induced, and food induced. The differential diagnosis is described in greater detail in Chap. 18.

An elevated temperature is caused by invasive organisms, including Salmonella spp, Shigella spp, Campylobacter spp, invasive E. coli, Vibrio parahaemolyticus, and Yersinia spp, as well as some viruses. Episodes of acute gastroenteritis not typically associated with fever are caused by organisms producing toxins, including S. aureus, Bacillus cereus, Clostridium perfringens, enterotoxigenic E. coli, and viruses.⁴

Fecal leukocytes typically are found in patients with invasive shigellosis, salmonellosis, Campylobacter enteritis, typhoid fever, invasive E. coli colitis, V. parahaemolyticus, Yersinia enterocolitica, and inflammatory bowel disease. In all of these conditions, except typhoid fever, the leukocytes are primarily polymorphonuclear; in typhoid fever, they are mononuclear. No stool leukocytes are noted in cholera, viral diarrheas, noninvasive E. coli diarrhea, or nonspecific diarrhea.⁹⁵

The timing of diarrheal onset after exposure or the incubation period is useful in differentiating the cause. Extremely short incubation periods of less than 6 hours are typical for Staphylococcus spp, B. cereus (type I), enterotoxigenic E. coli,^4,134,194 and preformed enterotoxins, as well as roundworm larval ingestions. Intermediate incubation periods of 8 to 24 hours are found with C. perfringens, B. cereus (type II enterotoxin), enteroinvasive E. coli,^64,142 and Salmonella. Longer incubation periods occur in other bacterial causes of acute gastroenteritis (Table 39–4).

The three most likely etiologies of diarrhea are infectious, xenobiotics (chemicals found in an organism, not normally present, frequently a pollutant or contaminant), and foodborne. These three etiologies are not mutually exclusive. The differential diagnosis must be established among these groups. When the time from exposure to onset of symptoms is brief, all of the nonbacterial infectious etiologies (viral, parasitic, fungal, and algal), except for upper GI invasion by roundworm larvae, can be eliminated and the possibility of a bacterial etiology with enterotoxin production becomes more likely (Table 39–4).^4,24

Epidemiology

Epidemiologic analysis is of immediate importance, particularly when GI diseases strike more than one person in a group. The questions raised in Table 39–5 should be answered.¹⁷⁴ If available, an infectious disease consultant or infection control officer should be called for assistance. Alternatively, assistance from state and local health departments should be sought. Often, only the CDC or state health department has the resources to investigate and confirm a presumptive diagnosis in an outbreak. Sophisticated techniques such as toxin detection, matching the organism in the food by phage type with a food handler, matching an organism by phage type with other persons, isolating 10 or more organisms per gram of implicated food,^64,68 or polymerase chain reaction (PCR) identification of bacterial or plasmid DNA are potentially useful, although generally not possible using the laboratory and personnel available in most hospitals.^32,39,83 Structural, metabolic, and functional causes often can be eliminated. As in these diseases, neither a significant grouping of cases nor a limited clinical history is characteristic. Foodborne parasites such as Trichinella spiralis (trichinosis), Toxoplasma gondii (toxoplasmosis), and G. lamblia (giardiasis) must be considered, although acute GI symptoms are not usually prominent.

Salmonella Species

Salmonella enterica infections are of great concern in the United States. Two particular outbreaks define very special problems. In the 1980s, recurrent outbreaks associated with grade A eggs or food containing such eggs occurred. In the past, such outbreaks of Salmonella enteritis were attributed to infection of the egg with Salmonella (from the GI tract of the chicken) through cracks in the shell. More recently, outbreaks involved noncracked, nonsoiled eggs.¹⁴⁴ In these cases, presumably, the Salmonella has infected the eggs before the shell was formed. In either case, people who consume raw or undercooked eggs are at most risk for Salmonella enteritis. Raw eggs are standard ingredients of chocolate mousse, hollandaise sauce, eggnog, Caesar salads, and homemade ice cream. Whole, partially cooked eggs are problematic when eaten sunny side up or poached.⁴⁵ The second group of outbreaks was associated with raw milk,¹⁶⁴ which has become very popular in certain communities. Inadequate microwave cooking also causes small outbreaks.⁶⁸ These outbreaks are of great concern because they frequently involve multiple drug-resistant Salmonella infections.⁵⁸ Drinking pasteurized milk is not absolutely protective. An outbreak of salmonellosis resulting in more than 16,000 culture-proven cases was traced to one Illinois dairy. The probable cause of the outbreak was a transfer line connecting raw and pasteurized milk containment tanks.¹⁷¹

The contamination of food that is widely distributed places thousands at risk. An outbreak of Salmonella food poisoning from peanut butter caused 529 confirmed illnesses in 48 states and Canada, 116 hospitalizations, and possibly 8 deaths.⁴⁴ The CDC estimates that the proportion of Salmonella infections that are confirmed by laboratory testing is 3% of the total, so that the estimated magnitude of infected people affected by this type of contamination incident is more than 15,000 individuals annually. News reports state that the peanut butter contamination with Salmonella was suspected; however, the peanut butter was then nationally distributed before confirmatory testing resulted.^93,94 The ethical and public health implications of maintaining meticulous standards are highlighted by this epidemic.

Additional concern developed over the widespread use of antibiotics in animal feed, responsible for meats, poultry, and manure-fertilized vegetables now frequently containing resistant bacterial strains to which virtually the entire population is exposed.^58,171

The diagnosis of Salmonella infection is made through culture of the stool. The treatment of Salmonella is fluid and, electrolyte resuscitation, and antibiotics (ciprofloxacin or alternatively azithromycin).¹¹²

FOODBORNE POISONING ASSOCIATED WITH MULTIORGAN SYSTEM DYSFUNCTION

The hemolytic uremic syndrome (HUS) is frequently caused by a bacterial gastroenteritis. The most commonly responsible organism is E. coli O157:H7.⁸⁷ Other bacteria and xenobiotics cause the same findings. Typical laboratory findings in HUS include microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI).

Hemolytic uremic syndrome begins with a prodrome of diarrhea 90% of the time. The diarrhea lasts for 3 to 4 days and frequently becomes bloody. Abdominal pain caused by colitis is common, and vomiting, altered mental status (irritability or lethargy), pallor, and low-grade fever frequently occur. At presentation, many patients have oliguria or anuria, and 10% of children have a generalized seizure at HUS onset.¹⁸²

Hemolytic uremic syndrome is frequently associated with enterohemorrhagic E. coli (EHEC) or E. coli O157:H7 with postdiarrheal HUS.^{29,136,156,157,169,206} Food products from cattle (ground beef, milk, yogurt, cheese) and water contaminated with fecal material are EHEC sources.^62,139 Contaminated water used in gardens and unpasteurized apple cider have caused bloody diarrhea and HUS as a result of EHEC.^18,57

Enterohemorrhagic E. coli, including E. coli O157:H7, produces a toxin similar to that produced by Shigella dysenteriae type I, referred to as Shigalike toxin (SLT) or verotoxin.²⁴ The proposed mechanism for SLT damage is intestinal absorption, bloodstream access to renal glomerular endothelium, intracellular adsorption via glycolipid receptors, ribosomal inactivation, and cell death.¹⁹³ In animal models, organ damage is more severe if endothelial cells have high concentrations of globotriaosylceramide receptors, which have a high binding affinity for Shiga toxin. Other organs with these receptors include the kidney, GI, and central nervous systems, which explain the pattern of organ damage in children with HUS. Endothelial cell damage and other pathologic processes, including platelet and leukocyte activation, triggering of the coagulation cascade, and the production of cytokines, occur.^104,202 Types of SLT exist as SLT-1, SLT-2, and additional variants of SLT-2 structure are identified.²⁰

Detection of E. coli O157:H7 through stool culture early in the course of disease is useful. The recovery of organisms decreases after the first week of illness.¹⁹³ Escherichia coli O157:H7 almost always produces SLT; therefore, if stool cultures are negative, enzyme immunoassay (EIA) and PCR tests can be used to detect SLT in the stool when E. coli can no longer be identified by culture.³²

Treatment of HUS should focus on meticulous supportive care, with fluid and electrolyte balance the priority. Dialysis should be instituted early for azotemia, hyperkalemia, acidemia, and fluid overload. Red blood cells and platelet transfusions are required. It is reasonable to treat hypertension with short-acting calcium channel blockers (nifedipine 0.25–0.5 mg/kg/dose orally) and seizures with benzodiazepines. Plasmapheresis was in nondiarrheal HUS and in recurrent HUS after renal transplantation. Anti–SLT-2 antibodies protected mice from SLT-2 toxicity, but IV immunoglobulin with SLT-2 activity did not improve outcome in children with HUS. A double-blind, placebo-controlled study on the use of synthetic SLT receptors attached to an oral carrier found that mortality or serious morbidity of HUS syndrome did not change as a result.¹⁹⁹

The mortality rate from HUS with good supportive care is approximately 5%; another 5% of victims have end-stage kidney disease or cerebral ischemic events and chronic neurologic impairment. Prolonged anuria (longer than 1 week), oliguria (longer than 2 weeks), or severe extrarenal disease serve as markers for higher mortality and morbidity.¹⁶²

There is some evidence that early treatment with antibiotics increases the risk of development HUS in children with E. coli O157:H7 infections.¹⁸⁷ An earlier meta-analysis and randomized trial did not find this association.^166,172 Because of this concern, it is not typically recommended to treat patients with clinical or epidemiologic presentations consistent with E. coli O157:H7 infections (crampy abdominal pain, bloody diarrhea, regional outbreak) until a definitive pathogen can be identified.¹⁹⁶

Approximately 10% of the cases of HUS are not caused by SLT-producing bacteria or streptococci and are classified as atypical. Atypical HUS has a poor prognosis, with death rates as high as 25% and progression to end-stage kidney disease in half of the patients.¹⁵³

Strategies to prevent the spread of E. coli O157:H7 and subsequent HUS include public education on the importance of thorough cooking of beef to a “well-done” temperature of 170°F (77°C), pasteurization of milk and apple cider, and thorough cleaning of vegetables. Public health measures include education of clinicians to consider E. coli O157:H7 in patients with bloody diarrhea and ensuring the routine capability of microbiology laboratories to culture E. coli O157:H7 and provide for EIA or PCR determination of SLT. Public health departments should provide active surveillance systems to identify early outbreaks of E. coli O157:H7 infection.

Staphylococcus Species

In cases of suspected food poisoning with a short incubation period, the physician should first assess the risk for staphylococcal causes. The usual foods associated with staphylococcal toxin production include milk products and other proteinaceous foods, cream-filled baked goods, potato and chicken salads, sausages, ham, tongue, and gravy. Pie crust can act as an insulator, maintaining the temperature of the cream filling and occasionally permitting toxin production even during refrigeration.⁶ A routine assessment must be made for the presence of lesions on the hands or nose of any food handlers involved. Unfortunately, carriers of enterotoxigenic staphylococci are difficult to recognize because they usually lack lesions and appear healthy.⁹⁶ A fixed association between a particular food and an illness would be most helpful epidemiologically but rarely occurs clinically. Factors such as environment, host resistance, nature of the agent, and dose make the results surprisingly variable.

Although patients with staphylococcal food poisoning rarely have significant temperature elevations, 16% of 2,992 documented cases in a published review had a subjective sense of fever.⁹⁶ Abdominal pain, nausea followed by vomiting, and diarrhea dominate the clinical findings. Diarrhea does not occur in the absence of nausea and vomiting. The mean incubation period is 4.4 hours with a mean duration of illness of 20 hours. Two staphylococcal enterotoxin food poisoning incidents involving large numbers of people are reported. At a public event in Brazil in 1998, half of the 8,000 people who attended had nausea, emesis, diarrhea, abdominal pain, and dizziness within hours of consuming food. Of the ill patients, 2,000 overwhelmed the capacity of local emergency departments; 396 (20%) were admitted, including 81 to intensive care units; and 16 young children and older adults died.¹⁸⁵ In another report, 328 individuals became ill with symptoms of diarrhea, vomiting, dizziness, chills, and headache after eating cheese or milk.¹⁸² In both reports, staphylococcus enterotoxin was found in the food consumed.

Most enterotoxins are produced by S. aureus coagulase–positive species. The enterotoxins initiate an inflammatory response in GI mucosal cells and lead to cell destruction. The enterotoxins also result in sudden effects on the emesis center in the brain and diverse other organ systems. Discrimination of unique S. aureus isolates from those found in foodborne outbreaks is established using restriction fragment length polymorphism analysis by pulsed-field gel electrophoresis and PCR techniques.²⁰⁷ The illness usually lasts for 24 to 48 hours. The treatment is supportive care with hydration and electrolyte repletion.¹⁸⁸

Bacillus cereus

Another foodborne toxin that produces GI effects is associated with eating reheated fried rice. Bacillus cereus type I is the causative organism, and bacterial overgrowth and toxin production causes consequential early onset nausea and vomiting.² Infrequently, this toxin causes liver failure.¹³⁵ Bacillus cereus type II has a delayed onset of similar GI effects including diarrhea.⁷⁶ The diagnosis of B. cereus infection is made through culture of the stool. The treatment of B. cereus is fluid and electrolyte resuscitation, and antibiotics (including ciprofloxacin or vancomycin).²⁵

Campylobacter jejuni

Campylobacter jejuni is a major cause of bacterial enteritis. The organism is most commonly isolated in children younger than 5 years and in adults 20 to 40 years of age. Campylobacter enteritis outbreaks are more common in the summer months in temperate climates. Although most cases of Campylobacter enteritis are sporadic, outbreaks are associated with contaminated food and water. The most frequent sources of Campylobacter spp in food are raw or undercooked poultry products⁷⁰ and unpasteurized milk.¹⁸⁹ Birds are a common reservoir, and small outbreaks are associated with contamination of milk by birds pecking on milk-container tops.¹⁸⁹ Contaminated water supplies are also frequent sources of Campylobacter enteritis involving large numbers of individuals.²² Campylobacter jejuni is heat labile; cooking of food, pasteurization of milk, and chlorination of water prevent human transmission.

The incubation period for Campylobacter enteritis varies from 1 to 7 days (mean, 3 days). Typical symptoms include diarrhea, abdominal cramps, and fever. Other symptoms include headache, vomiting, excessive gas, and malaise. The diarrhea contains gross blood, and leukocytes are frequently present on microscopic examination.⁹⁵ Illness usually lasts 5 to 6 days (range, 1–8 days). Rarely, symptoms last for several weeks. Severely affected individuals present with lower GI hemorrhage, abdominal pain mimicking appendicitis, a typhoidlike syndrome, reactive polyarthritis (Reiter syndrome), or meningitis. Guillain-Barré is associated with the disease with an incidence of less than 1 in 1,000 cases.³ The organism is detected using PCR identification techniques.⁷⁹ Treatment is supportive and consists of volume resuscitation and antibiotics for the more severe cases.⁴

Group A Streptococcus

Bacterial infections not usually associated with food or food handling are nevertheless occasionally transmitted by food or food handling. Transmission of streptococci in food prepared by an individual with streptococcal pharyngitis is demonstrated.⁶⁰ A Swedish food handler caused 153 people to become ill with streptococcal pharyngitis when his infected finger wound contaminated a layer cake served at a birthday party.⁹

Yersinia enterocolitica

Yersinia enterocolitica causes enteritis most frequently in children and young adults. Typical clinical features include fever, abdominal pain, and diarrhea, which usually contains mucus and blood.^10,192,204 Other associated findings include nausea, vomiting, anorexia, and weight loss. The incubation period is 1 to 7 days or more. Less common features include prolonged enteritis, reactive polyarthritis, pharyngeal and hepatic involvement, and rash. Yersinia is a common pathogen in many animals, including dogs and pigs. Sources of human infection include milk products, raw pork products, infected household pets, and person-to-person transmission.^26,89,123 The diagnosis is based on cultures of food, stool, blood, and, less frequently, skin abscesses, pharyngeal cultures, or cultures from other organ tissues (mesenteric lymph nodes, liver). Yersinia is identified by PCR.¹⁰³ Patients receiving the chelator deferoxamine (Antidotes in Depth: A7) frequently acquire Yersinia infections because the deferoxamine–iron complex acts as a siderophore for organism growth. Therapy is usually supportive, but patients with invasive disease (eg, bacteremia, bacterial arthritis) should be treated with IV antibiotics. Fluoroquinolones and third-generation cephalosporins are highly bacteriocidal against Yersinia spp.

Listeria monocytogenes

Listeriosis transmitted by food usually occurs in pregnant women and their fetuses, older adults, and immunocompromised individuals using corticosteroids or with malignancies, diabetes mellitus, kidney disease, or HIV infection.^17,41,43,178 Typical food sources include undercooked chicken and unpasteurized milk as well as soft cheeses such as feta, queso fresco, queso blanco, queso panela, blue cheese, and brie. Individuals at risk should avoid the usual sources and should be evaluated for listeriosis if typical symptoms of fever, severe headache, muscle aches, and pharyngitis develop. Treatment with IV ampicillin and aminoglycoside, or trimethoprim–sulfamethoxazole is indicated for systemic Listeria infections.

Xenobiotic-Induced Diseases

In addition to the aforementioned saxitoxin, tetrodotoxin, domoic acid, and ciguatoxin, many other xenobiotics contaminate our food sources. Careful assessment for possible foodborne pesticide poisoning is essential. For example, aldicarb contamination has occurred in hydroponically grown vegetables and watermelons contaminated with pesticides.⁸⁶ Eating malathion-contaminated chapatti and wheat flour resulted in 60 poisonings, including a death in one outbreak⁵⁴ (Chap. 110). Insecticides, rodenticides, arsenic, lead, or fluoride preparations can be mistaken for a food ingredient. These poisonings usually have a rapid onset of signs and symptoms after exposure.

The possibility of unintentional acute metal salt ingestion must also be evaluated. This type of poisoning most typically occurs when very acidic fruit punch is served in metal-lined containers. Antimony, zinc, copper, tin, or cadmium in a container are dissolved in an acidic food or juice medium.

Mushroom-Induced Disease

Some species produce major GI effects. Amanita phalloides, the most poisonous mushroom, usually causes GI symptoms as well as hepatotoxic effects with a delay to clinical manifestations. The rapid onset of symptoms suggests some of the gastroenterotoxic mushrooms, but this is not always true as in the case of Amanita smithiana, which has an early GI phase followed later by acute kidney injury (Chap. 117).

Intestinal Parasitic Infections

The popularity of eating raw fish, or sushi, led to an increase in reported intestinal parasitic infections. Etiologic agents are roundworms (Eustrongyloides anisakis) and fish tapeworms (Diphyllobothrium spp). Symptoms of anisakiasis are either upper intestinal (occur 1–12 hours after eating) or lower intestinal (delayed for days or weeks). Typical symptoms include nausea, vomiting, and severe crampy abdominal pain; with intestinal perforation, severe pain, rebound, and guarding occur. A dietary history of eating raw fish is needed to establish diagnosis and therapy. Visual inspection of the larvae (on endoscopy, laparotomy, or pathologic examination) is useful. Treatment of intestinal infection involves surgical or laparoscopic removal. Anisakis simplex and Pseudoterranova decipiens are Anisakidae that are found in several types of consumed raw fish, including mackerel, cod, herring, rockfish, salmon, yellow fin tuna, and squid. Reliable methods of preventing ingestion of live anisakid larvae are freezing at –4°F (–20°C) for 60 hours or cooking at 140°F (60°C) for 5 minutes.^{38,111,133,170,176,210}

Diphyllobothriasis (fish tapeworm disease) is caused by eating uncooked fish such as herring, salmon, pike, and whitefish that harbor the parasite. The symptoms are less acute than with intestinal roundworm ingestions and usually begin 1 to 2 weeks after ingestion.³⁷ Signs and symptoms include nausea, vomiting, abdominal cramping, flatulence, abdominal distension, diarrhea, and megaloblastic anemia due to vitamin B₁₂ deficiency. The diagnosis is based on a history of ingesting raw fish and on identification of the tapeworm proglottids in stool. Treatment with niclosamide, praziquantel, or paromomycin usually is effective.⁴²

Monosodium Glutamate

This clinical presentation is misnamed “Chinese restaurant syndrome” because it results from the ingestion of monosodium glutamate (MSG), which has multicultural use in the preparation of many foods. Monosodium glutamate (regarded as “safe” by the FDA) can cause other acute and bizarre neurologic symptoms. Affected individuals present with a burning sensation of the upper torso, facial pressure, headache, flushing, chest pain, nausea and vomiting, and, infrequently, life-threatening bronchospasm⁴ and angioedema.¹⁹⁰ The intensity and duration of symptoms are generally dose related but with significant variation in individual responses to the amount ingested.^177,212 Monosodium glutamate causes “shudder attacks” or a seizurelike syndrome in young children. Absorption is more rapid after fasting, and the typical burning symptoms rapidly spread over the back, neck, shoulders, abdomen, and occasionally the thighs. Gastrointestinal symptoms are rarely prominent and symptoms can usually be prevented by prior ingestion of food. When symptoms do occur, they tend to last approximately 1 hour. Monosodium glutamate is also marketed as an effective flavor enhancer.¹⁵ Many sausages and canned soups contain large doses of MSG.

There is evidence that humans have a unique taste receptor for glutamate.¹¹⁴ This explains its ability to act as a flavor enhancer for foods. Glutamate is also an excitatory neurotransmitter that can stimulate central nervous system neurons through activation of glutamate receptors and be the explanation for some of the neurologic symptoms described with ingestion.²¹³

Animal studies in which MSG was administered perorally in doses similar to average human intake or intake of extreme users showed that MSG led to disturbances in metabolism affecting insulin, fatty acids, and triglycerides in serum. Monosodium glutamate also affected several genes implicated in adipocytes differentiation. It elevated aminotransferase concentrations and bile synthesis and led to oxidative stress in the liver and to pathological changes in ovaries and fallopian tubes. These more recent findings will lead to further understanding of MSG and its safety in long-term use.¹⁰⁰

Anaphylaxis and Anaphylactoid Presentations

Some foods and foodborne toxins cause allergic or anaphylacticlike manifestations,¹⁰⁶ also sometimes referred to as “restaurant syndromes”¹⁸¹ (Table 39–6). The similarity of these syndromes complicates a patient’s future approach to safe eating. Isolating the precipitant is essential so that the risk can be effectively assessed. Manufacturers of processed foods should provide an unambiguous listing of ingredients on package labels. Sensitive individuals (or in the cases of children, their parents) must be rigorously attentive.^173,215 Those who experience severe reactions should make sure that epinephrine and antihistamines are always available immediately. Attempts to prevent allergic reactions to dairy products by avoiding dairy-containing foods may fail. Nondairy foods are still periodically processed in equipment used for dairy products or contain flavor enhancers of a dairy origin (eg, partially hydrolyzed sodium caseinate), both of which cause morbidity and mortality in allergic individuals.⁷⁸ Individuals with known food allergies do not always carry prescribed autoinjectable epinephrine syringes, in some cases from a belief that the allergen is easily identifiable and avoidable.¹⁰⁶ Food additives that cause anaphylactic or anaphylactoid reactions include antibiotics, aspartame, butylated hydroxyanisole, butylated hydroxytoluene, nitrates or nitrites, sulfites, and paraben esters.¹²⁸ Regulation of these preservatives is limited, and xenobiotics such as sulfites are so ubiquitous that predicting which guacamole, cider, vinegar, fresh or dried fruits, wines, or beers contain these sensitizing xenobiotics may be impossible.

Scombroid Poisoning

Scombroid poisoning originally was described with the Scombridae fish (including the large dark-meat marine tuna, albacore, bonito, mackerel, and skipjack). However, the most commonly ingested vectors identified by the CDC are nonscombroid fish, such as mahi mahi and amber jack. All of the implicated fish species live in temperate or tropical waters. Ingestion of bluefish and tilapia is associated with scombroid poisoning.^67,152 The incidence of this disease is probably far greater than was originally perceived. This type of poisoning differs from other fishborne causes of illness in that it is entirely preventable if the fish is properly stored after removal from the water.

Scombroid poisoning can result from eating cooked, smoked, canned, or raw fish. The implicated fish all have a high concentration of histidine in their dark meat. Morganella morganii, E. coli, and Klebsiella pneumoniae, commonly found on the surface of the fish, contain a histidine decarboxylase enzyme that acts on a warm (not refrigerated), freshly killed fish, converting histidine to histamine, saurine, and other heat-stable substances. Although saurine was suggested as the causative toxin, chromatographic analysis demonstrates that histamine is found as histamine phosphate and saurine is merely histamine hydrochloride.^72,146 The term saurine originated from saury, a Japanese dried fish delicacy often associated with scombroid poisoning. The extent of spoilage usually correlates with histamine concentrations. Histamine concentrations in healthy fish are less than 0.1 mg/100 g fish meat. In fish left at room temperature, the concentration rapidly increases, reaching toxic concentrations of 100 mg/100 g fish within 12 hours.

The appearance, taste, and smell of the fish are usually unremarkable.⁷ Rarely, the skin has an abnormal “honeycombing” character or a pungent, peppery taste that is a clue to its toxicity. Within minutes to hours after eating the fish, the individual experiences numbness, tingling, or a burning sensation of the mouth; dysphagia; headache; and, of particular significance for scombroid poisoning, a unique flush characterized by an intense diffuse erythema of the face, neck, and upper torso.¹⁰⁷ Rarely, pruritus, urticaria, angioedema, or bronchospasm ensues. Nausea, vomiting, dizziness, palpitations, abdominal pain, diarrhea, and prostration may develop.^{55,61,80,107,141}

The prognosis is good with appropriate supportive care and parenteral antihistamines such as diphenhydramine. Histamine (H₂)-receptor antagonists such as cimetidine or ranitidine are also reasonable to administer because they can also be useful in alleviating GI symptoms.²¹ Toxic substance removal using orogastric suctioning or adsorption from the gut by activated charcoal are reportedly used, but no randomized trials demonstrate benefit over treatment with antihistamines. Inhaled β₂-adrenergic agonists and epinephrine are necessary if bronchospasm is prominent. Although rare, another concern with scombroid toxicity is coronary vasospasm.^5,59 Patients usually show significant improvement within a few hours.

Elevated serum or urine histamine concentrations can confirm the diagnosis but are clinically unnecessary. If any uncooked fish remains, isolation of causative bacteria from the flesh is suggestive but not diagnostic. A capillary electrophoretic assay makes rapid histamine detection possible.⁹⁶ Histamine concentrations greater than 50 mg/100 g fish meat are considered hazardous by the FDA; in Europe, the concentrations are 100 to 200 mg/100 g.⁹⁹ Research demonstrates that human subjects can tolerate up to 180 mg of pure histamine orally without noticeable effects.⁵ Isoniazidincreases the severity of the reaction to scombroid fish by inhibiting enzymes that metabolize histamine.^99,201

Patients should be reassured that they are not allergic to fish if other individuals experience a similar reaction while eating the same fish at the same time or if any remaining fish can be preserved and tested for elevated histamine concentrations. If this information is not available, then an anaphylactic reaction to the fish cannot be excluded. Table 39–6 represents the differential diagnosis of flushing, bronchospasm, and headache. Because many people often consume alcohol with fish, alcohol is an independent variable.

The differential diagnosis of the scombrotoxic flush apart from a disulfiramlike reaction includes ingestion of niacin or nicotinic acid, pheochromocytoma and carcinoid syndrome. The history and clinical evolution usually establish the diagnosis quickly.

Global Food Distribution: Illegal Food Additives

The United States imports food from all over the world, year round. Approximately 19% of the food consumed in the United States is imported. An analysis of outbreak data from 1996 to 2014 shows 195 outbreak investigations implicated an imported food, resulting in about 11,000 illnesses, about 1,000 hospitalizations, and 19 deaths. The number of outbreaks associated with an imported food has increased from an average of 3 per year (1996–2000) to an average of 18 per year (2009–2014).⁸⁴ Xenobiotics are given to animals to increase their health and growth. Clenbuterol, a β₂ agonist, was administered to cattle raised for human consumption. Clenbuterol causes toxicity in humans who eat contaminated animal meat. Tachycardia, tremors, nausea, epigastric pain, headache, muscle pain, and diarrhea were present in 50 poisoned patients. Other findings included hypertension, hypokalemia, and leukocytosis.¹⁶⁸ No deaths are reported. The use of antibiotics, β₂ agonists, and other growth enhancers continues, despite safety concerns and laws against their use, because these practices increase yield and profit.

The globalization of food supplies and international agricultural trade has created a new global threat—the apparent purposeful contamination of food for profit. In 2008, almost 300,000 children in China were affected by melamine contamination of milk. Of these, 50,000 were hospitalized, and 6 reported deaths occurred.

The melamine-contaminated milk was sold in China as powdered infant formula, with more than 22 brands containing melamine. The contamination was not limited to China because melamine has been found in candy, chocolate, cookies, and biscuits sold in the United States, likely because of the adulteration of milk used in preparation of these products.

Melamine is a non-nutritious, nitrogen-containing compound, usually used in glues, plastics, and fertilizers. To increase profits, milk sold in China was previously diluted, causing protein malnutrition in children. Because the nitrogen content of milk (a surrogate measure for protein content) is now carefully monitored to detect dilution and to prevent another episode of malnutrition, melamine was added to increase the measured nitrogen content and hide the dilution. This purposeful addition of melamine is suspected to be the cause of the melamine contamination of powdered milk in China.

Melamine and its metabolite cyanuric acid are excreted in the kidneys. Kidney stones containing melamine and uric acid were found in 13 children with acute kidney injury who had consumed melamine containing milk formula.^88,205 Both melamine and cyanuric acid appear necessary to cause kidney stones in animals. The combination alone caused renal crystals in cats.¹⁶⁴ Melamine found in wheat gluten was added to pet food in 2007 resulted in thousands of complaints and dozens of suspected animal deaths in the United States.

The melamine milk contamination is one of the largest reported deliberate food adulteration incidents. It affected about 300,000 Chinese infants and young children and caused 6 deaths.^51,101

In India, 22 children were killed after becoming poisoned when eating their school lunch. It was discovered that the cooking oil was being kept in a container previously used for monocrotophos, a water-soluble organophosphate.^92,126

Food products from all over the world find their way into our foods. Increased vigilance by the agencies responsible for food safety, both in countries where the food originates and in countries that import the food, is needed to prevent other events such as the melamine contaminations. Chapter 2 discusses numerous other foodborne toxicologic outbreaks.

Vegetables and Plants

Plants and vegetables produce clinical signs and symptoms that are associated with diverse presentations often are involved in food poisoning.^{91,108,109,115,117} Edible plants and plant products that are poorly cooked or prepared or contaminated result in poisoning. Extensive discussion of this is found in Chap. 118. The development of genetically modified plants has led many to be concerned about both the long- and short-term health effects. Currently, animal data are being collected, and no definitive conclusions about health effects have been made.

FOOD POISONING AND BIOTERRORISM

The threat of terrorist assaults is discussed in Chaps. 126 and 127. The use of food as a vehicle for intentional contamination with the intent of causing mass suffering or death has already occurred in the United States.^46,113,198 In the first report, 12 laboratory workers had GI signs and symptoms, primarily severe diarrhea, after consuming food purposefully contaminated with Shigella dysenteriae type II served in a staff break room.¹¹³ Four workers were hospitalized; none had reported long-term sequelae. This Shigella strain rarely causes endemic disease. Nevertheless an identical strain, identified by pulsed-field gel electrophoresis, was found in eight of the 12 symptomatic workers, as well as in the pastries served in the break room and in the laboratory stock culture of S. dysenteriae. This finding suggests purposeful poisoning of food eaten by laboratory personnel. The person responsible and the motive remain unknown.

The second case series describes a large community outbreak of food poisoning caused by Salmonella typhimurium.¹⁹⁸ The outbreak occurred in the Dalles, Oregon, area during the fall of 1984; a total of 751 people developed Salmonella gastroenteritis. The outbreak was traced to the intentional contamination of restaurant salad bars and coffee creamer by members of a religious commune using a culture of S. typhimurium purchased before the outbreak of food poisoning. A criminal investigation found a Salmonella culture on the religious commune grounds that contained S. typhimurium identical to the Salmonella strain found in the food poisoning victims. It was identified by using antibiotic sensitivity, biochemical testing, and DNA restriction endonuclease digestion of plasmid DNA. Only after more than 1 year of investigation was this Salmonella outbreak linked to terrorist activity. Reasons for the delay in identifying the outbreak as a purposeful food poisoning included (1) no apparent motive; (2) no claim of responsibility; (3) no pattern of unusual behavior in the restaurants; (4) no disgruntled restaurant employees identified; (5) multiple time points for contamination indicated by epidemic exposure curves, suggesting a sustained source of contamination and not a single act; (6) no previous event of similar nature as a reference; (7) the likeliness of other possibilities (eg, repeated unintentional contamination by restaurant workers); and (8) fear that the publicity necessary to aid the investigation might generate copycat criminal activity.

Publication of the event was delayed by almost 10 years out of fear of unintentionally encouraging copycat activity. On the other hand, use of biological weapons by the Japanese cult Aum Shinrikyo appears to have motivated authorities to release this publication in the hopes of quickly identifying similar deliberate food poisoning patterns in the future.

A third report describes a disgruntled employee who contaminated 200 lb of meat at a supermarket with a nicotine-containing insecticide.⁴⁶ Ninety-two people became ill, and four sought medical care. Signs and symptoms included vomiting, abdominal pain, rectal bleeding, and one case of atrial tachycardia.

There are multiple reports of deliberate food poisoning with tetramine.^53,214 In one particular case of human greed, a Chinese restaurant owner poisoned the food in his neighbor’s restaurant with tetramine. Tetramine or tetramethylenedisulfotetramine is a highly lethal neurotoxic rodenticide, once used worldwide, now illegal in the United States. The snack shop owner caused hundreds to become ill and 38 deaths by spiking his competitor’s breakfast offerings (fried dough sticks, sesame cakes, and sticky rice balls). Tetramethylenedisulfotetramine is an odorless and tasteless white crystal that is water soluble. The mechanism of action is noncompetitive irreversible binding to the chloride channel on the γ-aminobutyric acid receptor complex, which blocks the influx of chloride and alters the neurons potential. It is referred to as a “cage convulsant” because of its globular structure. Severe toxicity presents with tachycardia, dysrhythmias, agitation, status epilepticus, and coma. Immediate or early treatment with sodium-(RS)-2,3-dimercaptopropane-1-sulfonate (DMPS) and pyridoxine (vitamin B₆) (A15) appears to be effective in a mouse model.^13,65,208

The capacity of foodborne xenobiotics that are easy to obtain and disburse to infect large numbers of people is clearly exemplified by two specific outbreaks: (1) the purposeful Salmonella outbreak in Oregon and (2) the apparently unintentional Salmonella outbreak that resulted in more than 16,000 culture-proven cases traced to contamination in an Illinois dairy. The probable cause of the outbreak was a contaminated transfer pipe connecting the raw and pasteurized milk containment tanks.¹⁷¹ These events emphasize the vulnerability of our food supply and the importance of ensuring its safety and security.

PREVENTION OF FOODBORNE ILLNESS

The incidence of foodborne disease has increased over the years and has resulted in a major public health problem on the global level. The current methods for detecting foodborne pathogens are inefficient. This has led to the research and development of rapid detection methods.

The three major types of rapid detection methods are biosensor-based, nucleic acid–based, and immunological-based methods. Biosensor detection methods use an analytical device that contains a bioreceptor and transducer. The transducer converts the biological interactions into a measurable electrical signal. Examples of biosensor based methods are optical, electrochemical, and mass-based biosensors. Nucleic acid–based detection methods work by detecting specific DNA or RNA in the pathogen. An example of this test is the PCR, immunological-based methods detect foodborne pathogens based on antibody–antigen interactions, whereby a particular antibody binds to the specific antigen. An example of an immunological based detection method is ELISA.

In general, the rapid detection methods are more efficient and sensitive than the conventional detection methods. Rapid detection methods may be a very useful way of preventing foodborne disease in the future. Currently, implementing special equipment and training personnel along with high costs have thwarted comprehensive application of rapid detection methods at this time.¹²⁰

SUMMARY

• The diverse etiologies of food poisoning involve almost all aspects of toxicology.

• Our concerns center around the natural toxicity of plants or animals, the contamination of which can occur in the field, during factory processing, subsequent transport and distribution, or during home preparation or storage.

• Whether these events are intentional or unintentional, they alter our approaches to general nutrition and society.

• Issues in food safety include the governmental role in food preparation and protection, bacteria such as Salmonella and E. coli 0157:H7, prions in Creutzfeldt-Jacob disease (bovine encephalopathy), and genetically altered materials such as corn.

• Future discussions of food poisonings and interpretations of the importance of these problems may dramatically alter our food sources and their preparation and monitoring.

REFERENCES