Charles L. Hatheway

Botulism in the united states : A clinical and epidemiologic review

Botulism is a neuroparalytic illness caused by a neurotoxin produced from the anaerobic, spore-forming bacterium Clostridium botulinum [1]. Botulism was recognized as sausage poisoning during the 18th and 19th centuries [2], and the pathogenesis of disease was first described by van Ermengem in 1897 after his investigation of a large outbreak in Ellezelles, Belgium [3]. Because botulinum toxin is so lethal, intensive surveillance and control measures have been mandated in the United States. However, prompt recognition and treatment of botulism by clinicians remain a critical component of surveillance and are the most important steps in reducing rates of death from this disease. Botulism outbreaks are a public health emergency that require rapid recognition to prevent additional cases and to effectively treat patients with mechanical ventilation and early administration of antitoxin. In the event of terrorist use of botulinum toxin, clinicians would also be the first to recognize and treat casualties of intentional botulism poisoning. In this report, we provide a clinical overview of botulism and describe the U.S. Botulism Surveillance System. The Organism Clostridium botulinum is classified as a single species but consists of at least three genetically distinguishable groups of organisms. These are alike in their abilities to produce neurotoxins with similar pharmacologic activities [4] but diverse serologic properties (toxin types A, B, C, D, E, F, and G). Human botulism is primarily caused by the strains of C. botulinum that produce toxin types A, B, and E. Neurotoxigenic strains of C. baratii [5, 6] (which produce type F toxin) and C. butyricum [7] (which produce type E toxin) also have been implicated in human botulism. Strains of C. botulinum that produce type C or type D toxin for the most part cause botulism only in nonhuman species. These neurotoxigenic organisms are anaerobic, gram-positive, spore-forming bacilli and are commonly found in soils throughout the world. Clostridium botulinum organisms cause food poisoning because the heat-resistant spores survive food preservation methods that kill nonsporulating organisms; they subsequently produce a potent neurotoxin under anaerobic, low-acid (pH > 4.6), and low solute conditions [8]. The toxins affect a broad range of vertebrate species, but the evolutionary utility of toxin production to the bacterial host organisms is unclear. The Toxin The seven recognized types of botulinum neurotoxins (types A through G) are distinguished by neutralization of biological activity with type-specific serologic reagents. These types are defined by the International Standards for Clostridium botulinum Antitoxin [9]. The toxins of all types consist of a 100-kd heavy chain joined to a 50-kd light chain by a disulfide bond [10]. After absorption into the bloodstream, botulinum toxin binds irreversibly to the presynaptic nerve endings of the peripheral nervous system and cranial nerves, where it inhibits the release of acetylcholine (Figure 1). The mechanism involves binding to a toxin receptor on the nerve cell membrane at the neuromuscular junction, internalization of a portion (the catalytic portion residing in the light chain) of the toxin molecule [11], and cleavage of protein components of the neuroexocytosis apparatus within the cell [12]. Figure 1. Schematic representation of the action of botulinum toxin (BT) on a neuromuscular junction. Botulinum neurotoxin is considered the most potent lethal substance known. It is 15 000 to 100 000 times more toxic than sarin, the potent organophosphate nerve agent used in a terrorist attack in the subway system in Tokyo [13]. The nucleotide sequences for all seven toxin types have been sequenced [14-22]. Epidemiology Four clinical forms of botulism occur in humans: foodborne botulism; wound botulism; infant botulism (infant intestinal colonization); and, rarely, adult infectious botulism (adult intestinal colonization). Studies in monkeys indicate that, if aerosolized, botulinum toxin also can be absorbed through the lungs [23]; this could occur in the case of a terrorist attack. From 1973 through 1996 in the United States, 724 cases of foodborne botulism (median, 24 cases annually [range, 8 to 86 cases]), 103 cases of wound botulism (median, 3 cases annually [range, 0 to 25 cases]), 1444 cases of infant botulism (median, 71 cases annually [range, 0 to 99 cases]), and 39 cases of botulism of undetermined type were reported to the Centers for Disease Control and Prevention (CDC) (Figure 2) (CDC. Unpublished data). In the United States, approximately half of the cases of foodborne botulism are caused by toxin type A; the remaining foodborne cases are almost equally divided between toxins type E and type B [24]. Among cases of infant botulism, approximately half are caused by toxin type A and half by toxin type B; among cases of wound botulism, approximately 80% are caused by toxin type A and 20% by toxin type B (CDC. Unpublished data). In the United States, type A botulism is most common west of the Mississippi River, and type B is most common east of the Mississippi River [25]. Type E outbreaks are most common in Alaska [26, 27]. Figure 2. Annual incidence of botulism in the United States, 1973 to 1996. Important changes in the epidemiology of botulism have emerged in the past few decades. Recently identified vehicles for foodborne botulism include homemade salsa [24], baked potatoes sealed in aluminum foil [28], cheese sauce [29], sauteed onions held under a layer of butter [30], garlic in oil [31], and traditionally prepared salted or fermented fish [26] (Table 1). From 1976 through 1984, restaurant-associated outbreaks accounted for a large proportion of botulism cases (42%), although only 4% of all outbreaks were restaurant-associated [32]. The largest of these outbreaks were caused by jalapeno peppers in Michigan in 1977, potato salad in New Mexico in 1978, sauteed onions in Illinois in 1983, and skordalia made with baked potatoes in Texas in 1994 [33]. Table 1. Vehicles Associated with Foodborne Botulism In 1995 and 1996, the occurrence of wound botulism increased [34], with a total of 42 cases (CDC. Unpublished data). Most of these cases occurred among heroin users in California who injected the drug subcutaneously. Although it is unclear what factors contributed to this epidemic, a shift to the use of black tar heroin produced in Mexico may have played a role [35]. Purified botulinum toxin is used to treat various medical conditions, such as strabismus, blepharospasm, torticollis, oromandibular dystonia, spasmodic dysphonia, and achalasia. Systemic symptoms of botulism-like illness have been reported after therapeutic administration of botulinum toxin [36] but are unlikely to have resulted from this procedure. It is estimated that for most patients, at least 10 times the treatment dose would be required to enter the circulation for systemic symptoms to result ([37]; CDC. Unpublished data). The potential for intentional poisoning with botulinum toxin has come into clearer focus in recent years. As many as 17 countries are suspected to include or to be developing biological agents in their offensive weapons programs [38]. Botulinum toxin often is one of these agents because it is relatively easy to produce and is highly lethal in small quantities. In August 1995, Iraq revealed that during the Persian Gulf War, 11 200 L of botulinum toxin preparation was loaded into specially designed SCUD missile warheads [39]. In addition, before the Aum Shinrikyo used sarin in the 1995 terrorist attack on the Tokyo subway system, the cult had produced botulinum toxin [40]. Clinical Features Foodborne Botulism Foodborne botulism is caused by ingestion of preformed toxin produced in food by C. botulinum. The most frequent source is home-canned foods, in which spores that survive an inadequate cooking and canning process germinate, reproduce, and produce toxin in the anaerobic environment of the canned food. In the event of intentional foodborne poisoning with botulinum toxin, the signs and symptoms developing after ingestion would probably resemble those of naturally occurring foodborne botulism. If aerosolized toxin was inhaled, the incubation period might be slightly longer [23], and gastrointestinal symptoms might not occur. The clinical syndrome of foodborne botulism is dominated by neurologic symptoms and signs resulting from a toxin-induced blockade of the voluntary motor and autonomic cholinergic junctions (Table 2). Although the syndrome is similar for each toxin type, type A toxin has been associated with more severe disease and a higher fatality rate than type B or type E toxin [41]. Symptoms from any toxin type may range from subtle motor weakness or cranial nerve palsies to rapid respiratory arrest. The initial symptoms of foodborne botulism may be gastrointestinal and can include nausea, vomiting, abdominal cramps, or diarrhea; after the onset of neurologic symptoms, constipation is more typical. Dry mouth, blurred vision, and diplopia are usually the earliest neurologic symptoms. These initial symptoms may be followed by dysphonia, dysarthria, dysphagia, and peripheral muscle weakness. Symmetric descending paralysis is characteristic of botulism; paralysis begins with the cranial nerves, then affects the upper extremities, the respiratory muscles, and, finally, the lower extremities in a proximal-to-distal pattern. Onset usually occurs 18 to 36 hours after exposure (range, 6 hours to 8 days) [42]. In severe cases, extensive respiratory muscle paralysis leads to ventilatory failure and death unless supportive care is provided. Patients have required ventilatory support for up to 7 months before the return of muscular function, but ventilatory support is most commonly needed for 2 to 8 weeks [43]. Table 2. Commonly Reported Clinical Symptoms and Physical Findings in Botulism* Clinical recovery generally occurs over weeks to m

A Large Outbreak of Botulism: The Hazardous Baked Potato

In April 1994, the largest outbreak of botulism in the United States since 1978 occurred in El Paso, Texas. Thirty persons were affected; 4 required mechanical ventilation. All ate food from a Greek restaurant. The attack rate among persons who ate a potato-based dip was 86% (19/22) compared with 6% (11/176) among persons who did not eat the dip (relative risk [RR] = 13.8; 95% confidence interval [CI], 7.6-25.1). The attack rate among persons who ate an eggplant-based dip was 67% (6/9) compared with 13% (241189) among persons who did not (RR = 5.2; 95% CI, 2.9-9.5). Botulism toxin type A was detected from patients and in both dips. Toxin formation resulted from holding aluminum foil-wrapped baked potatoes at room temperature, apparently for several days, before they were used in the dips. Consumers should be informed of the potential hazards caused by holding foil-wrapped potatoes at ambient temperatures after cooking.

An Outbreak of Type A Botulism Associated with a Commercial Cheese Sauce

Botulism is a rare disease; between 1983 and 1992, an average of only 22 cases of food-borne botulism were reported to the Centers for Disease Control and Prevention each year (Unpublished data). Nevertheless, a reported case of food-borne botulism represents a public health emergency because many persons may be affected if the contaminated food is not identified. This is especially true of outbreaks linked to commercial products or restaurants. However, because few clinicians have ever seen a case of botulism, the diagnosis may be delayed or not even considered. Diagnosing botulism is a special challenge when patients present with mild symptoms and do not have a history of exposure to typical food vehicles, such as home-canned vegetables. We describe an outbreak of botulism that was characterized by relatively mild symptoms and subtle physical findings. The outbreak was caused by a food vehicle that was initially considered to be unlikely. The investigation shows the importance of considering the diagnosis of botulism soon after patients present with acute cranial nerve dysfunction and of promptly reporting suspected cases to public health officials. The Outbreak On 4 October 1993, a 42-year-old woman (patient 1) visited her family physician in a small town in southern Georgia. She had had nausea, blurred vision, and loss of balance for 2 days. Results of physical examination were normal except for a possible sixth-nerve palsy. Labyrinthitis was diagnosed, and the patient was sent home. When her physician contacted her the next day, she was too weak to come to the telephone. Her husband reported that her speech was slurred and that she was having difficulty swallowing. He mentioned that their 21-year-old daughter (patient 2) also had nausea and difficulty swallowing. Both patients were referred to a neurologist, who recognized this unusual clustering of neurologic symptoms as possible botulism. The patients were admitted to a hospital, and public health officials were notified. That same day, a 38-year-old woman with a history of hypertension (patient 3) was seen in the emergency department of the same hospital because of blurred vision, slurred speech, and weakness in her right arm. She was admitted to the medical ward with a diagnosis of transient ischemic attack. By coincidence, the family physician of patients 1 and 2 was also attending on the medical ward that night; he recognized that patient 3 might be another case of botulism. Patient 3 mentioned that her friend, patient 4, was having similar symptoms. Patient 4 was notified that her illness might also be botulism, and she too was hospitalized. Two days earlier, her new symptoms had been diagnosed as an allergic reaction to a tranquilizer. Patient 5 had visited an optometrist on 5 October with fatigue and blurred, double vision. She received a diagnosis of mild glaucoma and astigmatism and was given a prescription for eyeglasses. She presented to the emergency department on 7 October after hearing about the outbreak on the radio. None of the patients had eaten any home-canned foods. However, on 1 October, all of them had eaten food from a delicatessen that had re-opened on 23 September after having been closed for 6 months because of the owners family obligations. Local health officials closed the delicatessen on 6 October and seized leftover foods. Methods Clinical and Epidemiologic Investigation Hypothesis-generating interviews were done with the hospitalized patients and the owner of the delicatessen. Each step in the preparation and storage of foods was reviewed. After a standardized questionnaire that addressed food histories and symptoms was developed, investigators attempted to interview (either by telephone or in person) all persons who had eaten food from the delicatessen in the 6 days it was open between 23 September and 2 October 1993. For the purposes of the investigation, a case of botulism was defined as dysphagia, dysphonia, dysarthria, or diplopia that developed after 23 September in any person who had eaten food purchased at the delicatessen. A press release was issued to identify patrons of the delicatessen. The press release asked all persons who had eaten at the delicatessen to call the local health department. The owner and known patrons of the delicatessen were asked to name other patrons, and businesses in the neighborhood around the delicatessen were surveyed as to whether workers had eaten food from the delicatessen. In an attempt to find additional cases, 50 physicians in the area were called and asked whether they had seen any patients since 23 September who reported blurred or double vision, dry mouth, difficulty swallowing, change in voice, or muscle weakness. To identify any cases that may have been mistakenly diagnosed as other conditions, physicians were also asked if they had recently seen any patients with a diagnosis of stroke, transient ischemic attack, the Guillain-Barre syndrome, or myasthenia gravis. Logs from the emergency department of the local hospital were reviewed for these symptoms and diagnoses. All hospitalized patients were examined by the same neurologist, and their hospital and outpatient records were reviewed. No neurologic examination was done on three persons who met the case definition for botulism but did not seek medical attention. These patients were identified by their responses to the standard questionnaire. The delicatessen was inspected by officials of the Georgia Department of Agriculture. Officials of the Food and Drug Administration inspected the canning facility and searched for unused cans of the same batch of cheese sauce. Laboratory Investigation Samples of food taken from the delicatessen were assayed for botulinum toxin and were cultured for Clostridium botulinum as described elsewhere [1]. All persons who ate the implicated food were asked to submit serum and stool specimens. Gastric aspirate specimens were obtained from two hospitalized patients. Serum, stool, and gastric aspirate specimens were assayed for C. botulinum toxin, and stool specimens were cultured for C. botulinum. Inoculation experiments were done in the Food and Drug Administration botulism laboratory to determine the time and temperature needed for C. botulinum to grow and for toxin to be produced in the implicated brand of cheese sauce. Spores harvested from cultures of the outbreak strain of C. botulinum were heat-shocked at 80 C for 10 minutes and then diluted with sterile water to a concentration of 104 spores/mL. Twenty g of the cheese sauce was then added to sterile test tubes that contained 0.1 mL of inoculum; the final concentration was 103 spores/20 g of cheese. The tubes were incubated at 22 C and 5 C; they were then assayed for toxin on day 8 and every 3 to 4 days for 2 months. Toxin testing was also done before incubation to ensure that no toxin was transferred with the inoculum. Toxin was measured in mouse minimum lethal doses using the mouse bioassay [2]. Results Epidemiologic Findings The delicatessen first opened in August 1992 and then closed for 6 months from March to September 1993. It reopened on 23 September 1993, serving lunch 3 days a week (Thursday through Saturday). Food was served at the delicatessen from 23 to 25 September and from 30 September to 2 October (Figure 1). Routine inspections of the delicatessen done on 30 September and after the outbreak showed no violations of state standards for retail food sale establishments. Figure 1. Date of meals eaten by all 52 patrons of the delicatessen and dates of symptom onset in 8 patrons with botulism. Fifty-two persons who ate food from the delicatessen in the 6 days it was open between 23 September and 2 October 1993 were identified and interviewed. Eight (15%) met the case definition for botulism. Their ages ranged from 20 to 48 years; 6 were women. No additional cases were identified through the review of emergency department logs or the physician survey. The owner of the delicatessen estimated that she served about 20 meals each day. Many of the patrons were friends of the owner or members of the owners family and had eaten there more than once. Eight (36%) of 22 persons who ate food from the delicatessen on Friday, 1 October, met the case definition compared with none of the 30 who ate the food only on other days. Among the 22 persons who ate food from the delicatessen on 1 October, all 8 ill persons but none of 14 well persons had eaten a barbecue stuffed potato. Six other persons had eaten barbecue stuffed potatoes before 1 October but remained well. The owner did not recall selling any stuffed potatoes on 2 October. Clinical Findings and Laboratory Confirmation of Botulism The illnesses ranged from mild to severe. Most patients had few, subtle objective neurologic findings despite having many symptoms characteristic of botulism. Symptoms developed a median of 2.5 days after exposure (range, 1 to 6 days). All ill persons had 3 or more symptoms consistent with botulism (median, 8.5 symptoms; range, 3 to 14 symptoms) and, by definition, at least 1 symptom that suggested a cranial nerve abnormality. The most common symptoms were dry mouth, difficulty speaking and swallowing, and change in voice quality (Table 1). All ill persons had neurologic and gastrointestinal symptoms. Three persons had illnesses so mild that they did not seek medical care. Five persons were hospitalized in an intensive care unit after botulism was suspected; in four of these persons, an illness other than botulism was initially diagnosed (Table 2). Patient 3, the most severely affected, developed complete bilateral ptosis, markedly dysarthric speech, weakness of the tongue and palate, arm and leg weakness, and respiratory failure. She died of a pulmonary embolism after being supported by mechanical ventilation for 18 days. Patient 1 was noticeably dysarthric and required nasogastric intubation because of difficulty swallowing. Patients 2, 4, and 5 had few object

Detection And Identification of Clostridium botulinum Neurotoxins

Botulism is a serious neuroparalytic illness that affects humans and various domestic and wild animal and avian species. It is due to the neurotoxic effect of a toxin produced by the anaerobic bacterium Clostridium botulinum. Botulism is most commonly known as a foodborne intoxication of humans; it also can result from growth of the toxigenic organism in a wound or, in the case of infant botulism, from colonization of the intestinal tract.

Bacteriology and Pathology of Neurotoxigenic Clostridia

Neurotoxigenic clostridia are classified in Bergey’s Manual6 as either Clostridium tetani or Clostridium botulinum. The nomenclature has been strictly determined by the kind of neurotoxin that the organisms produce. For C. tetani, the system has been satisfactory because thus far, only one phenotype of organism has been observed to produce the tetanus neurotoxin. It also remains simple in that only one serologic type of tetanus toxin has been identified. With this simplicity, it is possible to refer to organisms which have all of the same characteristics, but lack the ability to produce the neurotoxin, as nontoxigenic C. tetani. The system for naming organisms that produce botulinum neurotoxin, however, is laden with a number of problems because of the multiplicity of phenotypes and genotypes of organisms that must be included.