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Botulism: An update
Abstract
Botulism is a paralytic illness caused by the action of a neurotoxin elaborated by Clostridium botulinum. Other clostridial bacteria, like C.butyricum and C.baratii can also produce the toxin leading to signs and symptoms of botulism. Though rare, the illness is potentially fatal and can masquerade as other illnesses making diagnosis difficult. Physicians need to familiarize themselves with the disease as prompt recognition and early treatment can considerably curtail the fatal outcome in the affected and prevent additional cases in the unaffected. New diagnostic, therapeutic and preventive modalities to tackle the disease have come into focus. Botulinum toxin, generally considered a potent poison, is successfully being used for treatment of various neuromuscular disorders representing one of the most dramatic role reversals of modern times.
... Botulinum toxin is modified to alter its toxicity without changing its penetrability, specificity, or immunogenicity, which would be safe, effective, and easy to administer. Even if more than 10,000 lethal doses of unmodified toxin tested, it was evoked a striking response-protection against subsequent challenge against C. botulinum infection (Mohanty et al., 2001). Moreover, botulinum toxin derivatives (Botox®, Botox Cosmet-ic®, Dysport® and Xeomin®) are approved as commercial therapeutic and cosmetic preparations by the United States Food and Drug Administration (Guaita and Hogl, 2016;Patil et al., 2016;Sundaram et al., 2016). ...
Pain afflicts more than 1.5 billion people worldwide, with hundreds of millions suffering from unrelieved chronic pain. Despite widespread recognition of the importance of developing better interventions for the relief of chronic pain, little is known about the mechanisms underlying this condition. However, transient receptor potential (TRP) ion channels in nociceptors have been shown to be essential players in the generation and progression of pain and have attracted the attention of several pharmaceutical companies as therapeutic targets. Unfortunately, TRP channel inhibitors have failed in clinical trials, at least in part due to their thermoregulatory function. Botulinum neurotoxins (BoNTs) have emerged as novel and safe pain therapeutics because of their regulation of exocytosis and pro-nociceptive neurotransmitters. However, it is becoming evident that BoNTs also regulate the expression and function of TRP channels, which may explain their analgesic effects. Here, we summarize the roles of TRP channels in pain, with a particular focus on TRPV1 and TRPA1, their regulation by BoNTs, and briefly discuss the use of BoNTs for the treatment of chronic pain.
BASICS BEFORE THE INTRODUCTION The critical care team is entrusted with patients with the severest pathology. Victims of bioterrorism are often not immediately recognized, and present special and daunting challenges. However, before these challenges can be addressed, basic precepts must be followed. The U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) Handbook for the Management of Biological Casualties (1) recommends the following: 1. Maintain an index of suspicion. 2. Protect yourself. 3. Assess the patient. 4. Decontaminate as appropriate. 5. Establish a diagnosis. 6. Render prompt treatment. 7. Practice good infection control. 8. Alert the proper authorities. 9. Assist in the epidemiologic investigation and manage the psychological consequences. 10. Maintain proficiency and spread the word (1).
The transient receptor potential vanilloid 1（TRPV1） channels are members of the transient receptor potential (TRP) superfamily. Members of this family are expressed in primary sensory neurons and are best known for their role in nociception and sensory transmission. Multiple painful stimuli can activate these channels. In this review, we discussed the mechanisms of different types of venoms that target TRPV1, such as scorpion venom, botulinum neurotoxin, spider toxin, ciguatera fish poisoning (CFP) and neurotoxic shellfish poisoning (NSP). Some of these toxins activate TRPV1; however, some do not. Regardless of TRPV1 inhibition or activation, they occur through different pathways. For example, BoNT/A decreases TRPV1 expression levels by blocking TRPV1 trafficking to the plasma membrane, although the exact mechanism is still under debate. Vanillotoxins from tarantula (Psalmopoeus cambridgei) are proposed to activate TRPV1 via interaction with a region of TRPV1 that is homologous to voltage-dependent ion channels. Here, we offer a description of the present state of knowledge for this complex subject.
The persisting interest around neurotoxins such as vanilloids and botulinum toxin (BoNT) derives from their marked effect on detrusor overactivity refractory to conventional antimuscarinic treatments. In addition, both are administered by intravesical route. This offers three potential advantages. First, intravesical therapy is an easy way to provide high concentrations of pharmacological agents in the bladder tissue without causing unsuitable levels in other organs. Second, drugs effective on the bladder, but inappropriate for systemic administration, can be safely used as it is the case of vanilloids and BoNT. Third, the effects of one single treatment might be extremely longlasting, contributing to render these therapies highly attractive to patients despite the fact that the reasons to the prolonged effect are still incompletely understood. Attractive as it may be, intravesical pharmacological therapy should still be considered as a second-line treatment in patients refractory to conventional oral antimuscarinic therapy or who do not tolerate its systemic side effects. However, the increasing off-label use of these neurotoxins justifies a reappraisal of their pharmacological properties.
Botulism is an important public health problem in Argentina, but obtaining antitoxin rapidly has been difficult because global supplies are limited. In January 1998, a botulism outbreak occurred in Buenos Aires.
To determine the source of the outbreak, improve botulism surveillance, and establish an antitoxin supply and release system in Argentina.
Cohort study in January 1998 of 21 drivers of a specific bus route in urban Buenos Aires.
Occurrence of botulism and implication of a particular food as the vehicle causing this outbreak.
Nine (43%) of 21 bus drivers developed botulism, presenting with gastroenteritis, symptoms of acute cranial nerve dysfunction including ptosis, dysphagia, blurred vision, and motor weakness. One driver experienced respiratory failure. Type A toxin was detected from 3 of 9 patients' serum samples. All drivers received botulism antitoxin; there were no fatalities. Consumption of matambre (Argentine meat roll) was significantly associated with illness. Among 11 persons who ate matambre, 9 developed illness, compared with none of those who did not eat it (P<.001). The matambre had been cooked in water at 78 degrees C to 80 degrees C for 4 hours, sealed in heat-shrinked plastic wrap, and stored in refrigerators that did not cool adequately. Subsequently, a botulism surveillance and antitoxin release system was established.
Insufficient cooking time and temperatures, storage in heat-shrinked plastic wrap, and inadequate refrigeration likely contributed to Clostridium botulinum spore survival, germination, and toxin production. A rapid-response botulism surveillance and antitoxin release system in Argentina should provide more timely distribution of antitoxin to patients and may serve as a model for other nations.
Type F botulism was confirmed in a 54-year-old male with signs compatible with botulism who reported to the emergency unit of a hospital. Botulinal neurotoxin was detected in the patient's serum and fecal specimens, and a neurotoxigenic organism whose physiologic characteristics correspond to those of Clostridium baratii was isolated. The toxin produced by the isolate was neutralized by type F botulinal antitoxin and cross-neutralized with lower efficiency by type E antitoxin. The patient's food history was not suggestive of botulism, and it seems likely that the illness was due to colonization of the gut.
Although botulism is rare, recognition of a possible case of this illness represents a public health emergency. To prevent more cases, prompt investigation must be done to determine whether illness is linked to commercial product or restaurant. Botulism can masquerade as other illnesses, and seemingly unlikely foods can harbor botulinum toxin.
To confirm the diagnosis and determine the cause and extent of an outbreak of botulism associated with food served at a delicatessen.
Retrospective cohort study of patrons of the delicatessen; laboratory analysis of food, serum samples, and stool samples; and traceback of implicated food.
Community in Georgia.
Patrons of the delicatessen.
Botulinum toxin in food, serum, or stool and Clostridium botulinum in food and stools.
8 of 52 patrons (15%) met the case definition for botulism. In 4 of the 8 patrons, and illness other than botulism was initially diagnosed. Five of the 8 were hospitalized, and 1 died. Stool cultures from 4 patrons yielded type AC. botulinum, and two serum samples contained botulinum toxin. All ill persons ate food from the delicatessen on 1 October 1993. Of the 22 persons who ate at the delicatessen that day, all 8 ill persons but none of the 14 well persons ate a potato stuffed with meat and cheese sauce. An open can of cheese sauce contained type A botulinum toxin and yielded C botulinum on culture. Cheese sauce experimentally inoculated with C botulinum spores became toxic after 8 days at a temperature of 22 degrees C (room temperature).
A commercial, canned cheese caused a botulism outbreak. This product readily becomes toxic when contaminated by C botulinum spores and left at room temperature. Mild botulism caused by unusual vehicles may be misdiagnosed. Botulism should be included in the differential diagnosis of persons with signs or symptoms of acute cranial nerve dysfunction.
Neurotoxigenic Clostridium butyricum was isolated from the food implicated in an outbreak of clinically diagnosed type E botulism in China. PCR assay showed that the isolate (LCL 155) contained the type E botulinum toxin gene. This appears to be the first report of neurotoxigenic C. butyricum causing food-borne botulism.
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% (24/189) 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.
Cases of botulism in the northern province of Iran were studied in March and April 1997. A total of 27 patients were affected; 1 patient died. The samples were sent to the Department of Bacteriology, Pasteur Institute of Iran, for investigation. To identify the food source, several patients were interviewed and a case control investigation was conducted among families of hospitalized patients. Clinical and food specimens were tested. Toxin testing was positive for 37% of serum and stool specimens. Type A botulinal toxin was detected in cheese and Clostridium botulinum type A was isolated from cultures of clinical specimens and the cheese. This is the first documented outbreak of botulism due to Clostridium botulinum type A following consumption of cheese in Iran.
Indiscriminate use of organophosphates without public education on safety increases the potential threat of foodborne outbreaks of poisoningFoodborne diseases have a major impact on public health. Early and correct identification of the cause of an outbreak of food poisoning enables specific treatment to be started as soon as possible, and this can be life saving. We report an outbreak of fatal food poisoning caused by the pesticide malathion. Case reports On 6 July 1997, 60 men aged 20-30 years attended a communal lunch at which they ate chapatti, cooked vegetables, pulses, and halva. They all developed nausea, vomiting, and abdominal pain over the next three hours. The men were taken to a local primary healthcare centre where they received treatment for their symptoms. Fifty six responded to the treatment and were discharged home the same day. However, the condition of the remaining four patients deteriorated. Their level of consciousness fell, and they developed respiratory distress and generalised muscular weakness. The next day they were moved to an urban emergency hospital. Case 1 A 20 year old man presented with miosis, sweating, impaired consciousness, and hypotension. The muscle power in his arms and legs was graded as 3/5. Reflexes in the arms and legs were reduced, but he did not have sensory impairment. He had noticeable weakness of neck flexion, to the extent that he could not raise his head off the pillow. Initial treatment included intravenous fluids, antiemetics, and antibiotics. On the second day after admission to the urban emergency hospital, he developed respiratory insufficiency. Because he needed endotracheal intubation and intermittent positive pressure ventilation, he was transported immediately to a tertiary care hospital. Over the next 24 hours he developed type II respiratory failure with paralysis of thoracic, neck, and diaphragmatic muscles. He underwent tracheostomy and was ventilated mechanically for the next few days. He was treated with atropine and pralidoxime (1 g intravenously), but his neurological status did not improve appreciably, nor did his muscle strength improve much over the nine days after admission to hospital. On day 10 he had a cardiac arrest and could not be revived.
Two unconnected cases of type E botulism involving a 19-year-old woman and a 9-year-old child are described. The hospital
courses of their illness were similar and included initial acute abdominal pain accompanied by progressive neurological impairment.
Both patients were suspected of having appendicitis and underwent laparotomy, during which voluminous Meckel's diverticula
were resected. Unusual neurotoxigenic Clostridium butyricum strains that produced botulinum-like toxin type E were isolated from the feces of the patients. These isolates were genotypically
and phenotypically identical to other neurotoxigenic C. butyricum strains discovered in Italy in 1985–1986. No cytotoxic activity of the strains that might explain the associated gastrointestinal
symptoms was demonstrated. The clinical picture of the illness and the persistence of neurotoxigenic clostridia in the feces
of these patients suggested a colonization of the large intestine, with in vivo toxin production. The possibility that Meckel's
diverticulum may predispose to intestinal toxemia botulism may warrant further investigation.
Botulism occurring in patients with wounds has been thought of as a rare disease. A patient with a lacerating wound of his hand and wrist and an avulsion of his fourth finger developed diplopia, dizziness, and slurred speech one week later, followed by generalized weakness and difficulty in swallowing. Repetitive nerve stimulation studies showed signs of neuromuscular block consistent with the diagnosis of botulism. Results of bacteriologic and immunologic tests were not revealing, but the subsequent course of progressing, and retrogressing, bulbar signs and symptoms with eventual nearcomplete recovery confirmed the diagnosis. Increasing awareness and employment of electrophysiologic studies are uncovering increasing numbers of cases.
Botulism is caused by a neurotoxin produced from the anaerobic, spore-forming bacterium Clostridium botulinum. Botulism in humans is usually caused by toxin types A, B, and E. Since 1973, a median of 24 cases of foodborne botulism, 3 cases of wound botulism, and 71 cases of infant botulism have been reported annually to the Centers for Disease Control and Prevention (CDC). New vehicles for transmission have emerged in recent decades, and wound botulism associated with black tar heroin has increased dramatically since 1994. Recently, the potential terrorist use of botulinum toxin has become an important concern.
Botulism is characterized by symmetric, descending, flaccid paralysis of motor and autonomic nerves, usually beginning with the cranial nerves.Blurred vision, dysphagia, and dysarthria are common initial complaints. The diagnosis of botulism is based on compatible clinical findings; history of exposure to suspect foods; and supportive ancillary testing to rule out other causes of neurologic dysfunction that mimic botulism, such as stroke, the Guillain-Barre syndrome, and myasthenia gravis. Laboratory confirmation of suspected cases is performed at the CDC and some state laboratories. Treatment includes supportive care and trivalent equine antitoxin, which reduces mortality if administered early. The CDC releases botulism antitoxin through an emergency distribution system. Although rare, botulism outbreaks are a public health emergency that require rapid recognition to prevent additional cases and to effectively treat patients. Because clinicians are the first to treat patients in any type of botulism outbreak, they must know how to recognize, diagnose, and treat this rare but potentially lethal disease.
A completely synthetic gene encoding fragment C, a approximately 50-kDa fragment, of botulinum neurotoxin serotype A was constructed from oligonucleotides. The gene was expressed in Escherichia coli, and full-sized product was produced as judged by Western blot (immunoblot) analysis. Crude extracts of E. coli expressing the gene were used to vaccinate mice and evaluate their survival against challenge with active toxin. Mice given three subcutaneous vaccinations were protected against an intraperitoneal administration of 10(6) 50% lethal doses (ID50) of serotype A toxin. The same mice survived when challenged with 3 LD50 of botulinum toxin serotype E but died when challenged with 10 LD50 of serotype E or 3 LD50 of serotype B. Purified fragment C was compared with the botulinum toxoid vaccine in a vaccination and challenge study. Fragment C was as efficacious in protecting against challenge with active botulinum neurotoxin serotype A as the toxoid vaccine. This recombinant protein product has many properties that make it a good candidate for human use to protect against botulinum toxin.
Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/66984/2/10.1177_000992289303201105.pdf
The seven serotypes of botulinum toxin (BTX) produced by Clostridium botulinum exert their paralytic effect by inhabiting acetylcholine release at the neuromuscular junction. Each of these zinc encopeptidases cleaves one or more proteins involved in vesicle transport and membrane fusion. The extent of paralysis depends on both doese and volume; the duration of paralysis is further dependent on the serotype employed. Restoration of neuromuscular function follows axon terminal sprouting. The two major commercial preparations of BTX-A appear to differ in their relative potencies, despite a commmon unit labeling system. Adverse effects are a consequence of the drug's mechanism of action, and can usually be tolerated or mitigated through dosing changes. Patients who are pregnant or lactating, or who have a neuromuscular disease, may not be appropriate candidates for BTX therapy. Development of resistance to BTX-A therapy, characterized by absence of any beneficial effect and by lack of muscle atrophy following the injection, is an important clinical issue. The incidence of antibody-mediated resistance as determined by the mouse lethality assay, ks reported between 3% and 10%. Use of the smallest possible effective dose and longer treatement intervals may reduce the likelihood of antibody development. Other serotypes may benefit those who have developed antibody resistance. © 1997 John Wiley & Sons, Inc. Spasticity: Etiology, Evaluation, Management, and the Role of Botulinum Toxin Type A, MF Brin, editor. Muscle Nerve 1997;20(suppl 6):S146-S168.
Botulinum toxin (BTX), a purified form of the neurotoxin responsible for botulism, is used worldwide for the treatment of abnormal muscle contractions. The ability of BTX to block acetylcholine release in a long-lasting but reversible fashion with few side effects has made it an important tool in a wide variety of neuromuscular disorders, including the dystonias, tremor, tics, and spasticity. There are seven antigenically distinct toxins. BTX-A has been in clinical use for almost two decades, with an outstanding efficacy and safety profile. Clinical effects are often seen within 1 week of injection, and benefits typically last from 3-6 months. Patient selection and the proper choice of dose and administration site are the most important determinants of a favorable response to BTX treatment. © 1997 John Wiley & Sons, Inc.. Inc. Spasticity: Etiology, Evaluation, Management, and the Role of Botulinum Toxin Type A, MF Brin, editor, Muscle Nerve 1997; 20(suppl 6):S129-S145.
Botulism is a well recognized clinical syndrome that is usually the result of eating food contaminated with botulin, a toxin derived from Clostridium botulinum. Rarely, botulism is caused by the toxin produced within a wound infected with that organism. The majority of such cases have been in open fractures, but nevertheless, it has been mentioned as a complication only infrequently. The present case is reported to alert orthopaedic surgeons to this complication in a healthy six-year-old white girl.
The recent development and evaluation of procedures for examination of fecal specimens for botulinal toxin and Clostridium botulinum have provided the means by which infant botulism can be recognized. The toxicity for mice of fecal extracts containing botulinal
toxin can be neutralized with specific botulinal antitoxin. The presence of C. botulinum in the feces is detected by demonstrating the presence of botulinal toxin in enrichment culture supernatant by means of toxicity
tests in mice. C. botulinum is isolated by streaking enrichment cultures on egg yolk agar and picking typical lipase-positive colonies. The experience
of both the Center for Disease Control (CDC) Botulism Laboratory and other laboratories has been that botulinal toxin and
C. botulinum are rarely, if ever, found in the feces of humans (infants or older people) not afflicted with botulism. Results of the examination
in the CDC laboratory of specimens from 24 babies with infant botulism are given.
Although botulism is characterized by weakness and hypotonicity, it is rarely considered in the diagnosis of the hypotonic infant. We report on two infants whose clinical course and electrophysiological findings were consistent with botulism and from whom botulinal toxin was identified in stool. Case Reports Case 1. A two-month-old boy had diffuse weakness of short duration. He was the product of an unremarkable gestation, labor, and delivery. At birth, examination was normal; he had a vigorous suck. He was breast-fed and received only vitamin preparations. Growth and development were normal until he was six weeks old, when over a period . . .
Cases of adult botulism (n = 309) were studied to identify clinical differencesbetween toxin types and to evaluate the sensitivity of diagnostic laboratory
testing. Patients with illness from type E toxin had the shortest incubation periods. Sporadic case-patients were more severely
ill: 85% required intubation compared with only 42% in multiperson outbreaks. Of patients with type A botulism, 67% required
intubation compared with 52% with type Band 39% with type E. Toxin testing was positive for 40%–44% of serum and stool specimens
obtained within 3 days of toxin ingestion and for 15%-23% of specimens obtained thereafter, while 37% of stool specimens obtained
>3 days after toxin ingestion were positive by culture. Patients with type A botulism have more severe illness. In general,
specimens obtained early are more likely to be positive by toxin assay, and stool cultures are more sensitive than toxin detection
for specimens obtained later in the illness.
Sixty-one outbreaks of food-borne botulism involving a total of 122 cases, of which 21 were fatal, were recorded from 1971 to 1984 in Canada. Most occurred in northern Quebec, the Northwest Territories or British Columbia. Of the 122 victims 113 were native people, mostly Inuit. Most of the outbreaks (59%) were caused by raw, parboiled or "fermented" meats from marine mammals; fermented salmon eggs or fish accounted for 23% of the outbreaks. Three outbreaks were attributed to home-preserved foods, and one outbreak was attributed to a commercial product. The causative Clostridium botulinum type was determined in 58 of the outbreaks: the predominant type was E (in 52 outbreaks), followed by B (in 4) and A (in 2). Renewed educational efforts combined with a comprehensive immunization program would significantly improve the control of botulism in high-risk populations.
The first two confirmed cases of type E infant botulism occurred in two 16-week-old girls in Rome, Italy. The original diagnosis
for the first patient was intestinal blockage due to an ileocecal invagination, which was treated surgically. Postoperatively,
the patient became unresponsive and required ventilatory assistance. A diagnosis of infant botulism was then made. The second
infant presented to the same hospital 7½ months later with profound weakness, hypotonicity, mydriasis, and areflexia. This
case was recognized as possible botulism at admission. Both cases were confirmed by detection and identification of type E
botulinal toxin in stool specimens and in enrichment cultures of those specimens. The toxigenic organisms isolated were quite
different from Clostridium botulinum type E. The apparent causative organism in each case resembles Clostridium butyricum but produces a neurotoxin that is indistinguishable from type E botulinal toxin by its effects on mice and by its neutralization
with type E botulinal antitoxin.
Isolation of lipase-positive Clostridium botulinum from fecal specimens establishes the diagnosis of infant botulism, contributes to the diagnosis of food-borne botulism, and is most easily accomplished by use of selective media. Modification of an available selective medium, C. botulinum inhibitory medium (CBI), enabled more rapid isolation of C. botulinum. The modified medium (botulinum selective medium [BSM] contained (per liter) 25 g of dehydrated heart infusion broth, 20 g of agar, 30 ml of egg yolk suspension, 250 mg of cycloserine, 76 mg of sulfamethoxazole, 4 mg of trimethoprim, and 100 IU of thymidine phosphorylase at pH 7.4. The two media were compared by using 15 fresh fecal specimens from infant botulism patients (10 type A and 5 type B) and a C. botulinum isolate that had been obtained from an infant botulism patient and that was mixed into a fresh stool specimen from a healthy human infant. In comparison to CBI, BSM always provided better suppression of the nonbotulinum fecal flora and earlier emergence of lipase-positive colonies. Diagnosis of infant botulism was accomplished sooner with BSM than with CBI because isolation of lipase-positive C. botulinum was easier.
All reported cases of infant botulism except one have been caused by proteolytic strains (group I) of Clostridium botulinum, toxin types A or B. We describe the cultural and biochemical characteristics of the causative organism of this singular case of infant botulism, caused by type F botulinal toxin. Although this organism produces type F botulinal toxin, it is quite different from proteolytic (group I) C. botulinum, being more closely related to Clostridium barati.
An electron microscopic study was made of the motor innervation of slow (soleus) and fast (superficial gastrocnemius) skeletal muscle fibres of the mouse after a single local injection of a sublethal quantity of botulinum toxin. The muscles became paralysed within 24 hr of the injection and recovered only after several weeks. Sprouting from nerve terminals in motor end-plates was seen in soleus at 4 days but in gastrocnemius nerve sprouts were found only after about 4 weeks. Nerve sprouts were always enclosed in processes of Schwann cells. New nerve-muscle contacts were formed and were at first loose and irregularly interrupted by Schwann cell processes. Later the nerve-muscle contacts became close and uninterrupted. There were no subneural folds of the sarcolemmal membrane at the new nerve-muscle junctions for the first few weeks after their formation but with longer survival subneural folds were formed. Degenerative changes occurred in some sole-plate nuclei. In the animals surviving 4 months or longer the end-plates of soleus fibres were similar to the normal for that muscle though nerve terminals were scattered along muscle fibres and many had no sole-plate nuclei near them. In gastrocnemius some end-plates were normal in appearance but others had unusually few and shallow subneural folds.
Botulism is rare in both developing and developed countries. During 1980 only 89 cases (18 food borne, 68 infant, 2 wound,
1 unspecified) were reported in the United States. Coproexamination is essential for laboratory confirmation of infant botulism.
Botulinal antitoxins of equine origin are used for treating food-borne and wound botulism but are usually not recommended
for infant cases. Tetanus is much more common in some developing countries than in developed countries. During 1980 only 95
cases of tetanus were reported in the United States; in 68 (72%) of these cases, the patient was 50 years or older, and in
only two (2.1%) cases was the patient younger than one year. Tetanus neonatorum is a major problem in some developing countries.
Diagnosis of tetanus is based primarily on clinical findings, but laboratory studies can be helpful, especially in epidemiologic
investigations. Human hyperimmune immunoglobulin is now used in the treatment of tetanus.
An enzyme-linked immunosorbent assay (ELISA) for Clostridium botulinum type A and type B toxins was assessed for diagnostic accuracy in cases of infant botulism. This test was positive in all 22 cases confirmed by the conventional tests, which included the mouse lethality assay and stool culture. Stool specimens from five cases were positive by culture, but the mouse lethality bioassay was either negative or toxicity was judged nonspecific since it could not be neutralized by specific antitoxin. The positive ELISA results in these specimens suggested that this assay may be more reliable, in some cases, than the mouse bioassay. Of the 21 fecal specimens from suspected foodborne cases, 2 contained botulinal toxin demonstrable by the mouse assay and the ELISA. With regard to specificity, 35 fecal specimens from infants and 19 from suspected foodborne cases which were negative in the bioassay for botulinal toxins A and B were also negative in the ELISA. Only two fecal specimens with negative bioassay gave positive ELISA readings, providing a specificity rate of 96%. These results suggest that the ELISA may serve as a useful screening test to detect C. botulinum toxin in clinical specimens.
Clostridium botulinum type G has not been identified until now from humans or animals; it has been isolated only twice, from soil samples in Argentina.
Type G organisms were isolated from necropsy specimens in four adults and an 18-week-old infant. Type G botulinal toxin was
demonstrated in the serum of three of these individuals. The toxic dose in mice ranged from 2 to 750% lethal doses/ml. These
persons died suddenly and unexpectedly at home, without any pathologic evidence to account for the cause of death in four
cases. Symptoms in two individuals were similar to those observed in food-borne botulism. Thus, a prompt postmortem search
for toxin and organisms of C. botulinum in blood and feces may be worthwhile in determining the etiology of unexplained deaths. More microbiologic, physiologic,
and toxicologic data are needed to clarify the role of C. botulinum in the pathogenesis of sudden unexpected death in infants and adults.
Medical records of 55 patients with type A and type B food-borne botulism reported to the Centers for Disease Control during 2 years were reviewed to assess the clinical features and severity of illness, diagnostic test results, nature of complications, amd causes of death. Some patients had features not usually associated with botulism including paresthesia (14%), asymmetric extremely weakness (17%), asymmetric ptosis (8%), slightly elevated cerebrospinal fluid protein values (14%), and positive responses to edrophonium chloride(26%). Several observation suggest that type A was more severe than type B disease. Although the case-fatality ratio was not significantly greater, patients with type A disease saw a physician earlier in the course of illness, were more likely to need ventilatory support, and were hospitalized longer. Patients who died were older than those who survived. Deaths within the first 2 weeks resulted from failure to recognized the severity of the disease or from pulmonary or systemic infection whereas the three late deaths were related to respirator malfunction.
The botulinal neurotoxins (BoNT) associate with non-toxic proteins (ANTP) by non-covalent bonds to form large complexes. In C. botulinum C, the BoNT/C1 locus consists of six genes which are organized in three clusters. Cluster 1 encompasses the genes of BoNT/C1 and ANTP/139 which could be involved in the resistance of the BoNT/C1 to the acidic pH and protease degradation. The second cluster consists of three genes which encode hemagglutinin components. The last gene encodes a DNA binding protein (Orf22) which might regulate the BoNT/C1 complex gene expression. BoNT and tetanus toxin (TeTx) display similar structure and mechanism of action at the molecular level. Their identity at the amino acid level range from 34 to 96.8%, indicating that the clostridial neurotoxin genes probably derive from a common ancestor. The fact that Clostridium other than C. botulinum such as C. butyricum and C. baratii can produce a BoNT suggests that the BoNT genes can be transferred between Clostridium strains. The toxigenic C. butyricum strains seem to derive from originally non-toxic strains by neurotoxin gene transfer from C. botulinum E, probably including a mobile DNA element. In C. botulinum C and D the gene encoding the exoenzyme C3 has been localized in a transposon-like element of 21.5 kbp. Transposons could be involved in BoNT gene transfer in C. botulinum.
The genetic structure of neurotoxin genes in a Clostridium botulinum strain producing both type A and B neurotoxins (type AB) was investigated. Analyses by polymerase chain reaction (PCR) using type-specific primers corresponding to the coding regions for N-terminals of light-chains and C-terminals of heavy-chains of type A and type B neurotoxins, and Southern hybridization of total DNA showed that the type AB strain I.P.7212 carries at least one copy each of type A and B neurotoxin genes. Partial nucleotide sequences obtained by direct sequencing of the PCR products indicate that the type A and B genes carried by this strain are not classical type A and non-proteolytic type B genes, but are similar to the type A gene present in a strain which had caused infant botulism in Kyoto and the type B gene present in a proteolytic type B strain.
Clostridium botulinum type G produces a toxin complex that is composed of neurotoxin, hemagglutinin, and nontoxic nonhemagglutinin. The three genes encoding these proteins were closely linked on a plasmid of about 114 kb (76 MDa) but not on chromosomal DNA. In contrast to the genes of other C. botulinum serotypes, the genes encoding type G toxin are on a plasmid.
Botulism, a food-borne toxin-mediated disease caused by Clostridium botulinum is still a common disease, which is most frequent in the rural environment; 108 cases, 66 males and 42 females, average age 32 years, were recorded from 1965 to 1990 in the infectious disease department of the University Hospital of Poitiers (France). In 83% of patients, the food responsible was home-cured ham. Mean incubation time was 3.4 days; digestive symptoms were observed in 93% of cases, ocular symptoms in 92% and urinary tract dysfunction in 22%. A scale of severity was used to classify the patients into those suffering from severe (6), intermediate (50) and mild (52) forms of the disease. Botulinum toxin type B was found in 36 (52%) of 69 blood samples and in 41 (51%) of 81 samples of the suspected food. From 1965 to 1976, 44 patients were treated with both toxoid and heterologous equine serotherapy. Since 1976, 29 patients have been treated with guanidine hydrochloride (35 mg/kg daily) and 35 patients with guanidine hydrochloride plus heterologous serotherapy. All 108 patients recovered without any sequelae.
Constipation in children is rarely thought of as a serious health condition. It is, however, one of the leading symptoms of the pathologic sequence in infantile botulism. The pathogenesis, common clinical manifestations, and common grounds in treatment and prognosis in infant botulism are summarized. The nursing role is presented, focusing on airway management, nutritional needs, environmental support, and parental role in an intensive care unit. An exemplar case study is presented.
Two Clostridium butyricum strains from infant botulism cases produce a toxic molecule very similar to C. botulinum type E neurotoxin. Chromosomal, plasmid, and bacteriophage DNAs of toxigenic and nontoxigenic strains of C. butyricum and C. botulinum type E were probed with (i) a synthesized 30-mer oligonucleotide encoding part of the L chain of type E botulinum toxin and (ii) the DNA of phages lysogenizing these cultures. The toxin gene probe hybridized to the chromosomal DNA of toxigenic strains but not to their plasmid DNA. All toxigenic and most nontoxigenic strains tested were lysogenized by a prophage on the chromosome. Prophages of toxigenic strains, irrespective of species, had related or identical DNAs which differed from the DNAs of prophages in nontoxigenic strains. The prophage of toxigenic strains was adjacent or close to the toxin gene on the chromosome. Phage DNAs purified from toxigenic strains did not hybridize with the toxin gene probe but could act as the template of the polymerase chain reaction to amplify the toxin gene. The toxin gene was not transferred between C. botulinum and C. butyricum (either direction) when different pairs of a possible gene donor and a recipient strain were grown as mixed cultures. Nontoxigenic C. butyricum or C. botulinum type E-like strains did not become toxigenic when grown in broth containing the phage induced from a toxigenic strain of the other species.(ABSTRACT TRUNCATED AT 250 WORDS)
We describe a case of wound botulism associated with a tooth abscess in a 5-year-old boy. We reviewed the literature and reports
to the Centers for Disease Control and Prevention (Atlanta) of laboratory-confirmed cases of wound botulism. From 1943 through
1990, 47 cases were reported. Type A botulinus toxin was identified in 32 cases, type B in 13, types A and B in 1, and an
unknown type in 1. Botulism was associated with wounds from trauma, use of injectable drugs, and surgery. Sinusitis after
use of intranasal cocaine has also been associated with botulism. Treatment for wound botulism includes prompt debridement
of the wound for eliminating anaerobic conditions, intensive care, and treatment with antitoxin.
Tetanus and botulinum neurotoxins are produced by bacteria of the genus Clostridium and cause the paralytic syndromes of tetanus and botulism with a persistent inhibition of neurotransmitter release at central and peripheral synapses, respectively. These neurotoxins consist of two disulfide-linked polypeptides: H (100 kDa) is responsible for neurospecific binding and cell penetration of L(50 kDa), a zinc-endopeptidase specific for three protein subunits of the neuroexocytosis apparatus. Tetanus neurotoxin and botulinum neurotoxins serotypes B, D, F, and G cleave at single sites, which differ for each neurotoxin. VAMP/synaptobrevin, a membrane protein of the synaptic vesicles. Botulinum A and E neurotoxins cleave SNAP-25, a protein of the presynaptic membrane, at two different carboxyl-terminal peptide bonds. Serotype C cleaves specifically syntaxin, another protein of the nerve plasmalemma. The target specificity of these metallo-proteinases relies on a double recognition of their substrates based on interactions with the cleavage site and with a non contiguous segment that contains a structural motif common to VAMP, SNAP-25 and syntaxin.
A polymerase chain reaction (PCR)-based method was established to detect each type of neurotoxin genes of Clostridium botulinum types A to F by employing the oligonucleotide primer sets corresponding to special regions of the light chains of the neurotoxins. In this procedure, the PCR products were easily confirmed by restriction enzyme digestion profiles, and as little as 2.5 pg of template DNAs from toxigenic strains could be detected. The specific PCR products were obtained from toxigenic C. botulinum types A to F, a type E toxin-producing C. butyricum strain, and a type F toxin-producing C. baratii strain, but no PCR product was detected in nontoxigenic strains of C. botulinum and other clostridial species. The neurotoxin genes were also detected in food products of a seasoned dry salmon and a fermented fish (Izushi) which had caused type E outbreaks of botulism. Therefore, it is concluded that this PCR-based detection method can be used for the rapid diagnosis of botulism.
On January 16, 1997 two Germans got botulism after eating hot-smoked Canadian whitefish produced in Finland. The serum sample of one of the patients contained 6 MLD/ml of botulinum toxin. The type of toxin was identified as E by the toxin neutralization test and the botulinum neurotoxin type E (BoNT/E) gene was also amplified from the serum by polymerase chain reaction (PCR), but C. botulinum could not be isolated from the positive serum sample. The remains of the hot-smoked whitefish eaten by the patients contained botulinum toxin detected by the mouse bioassay and the BoNT/E gene as determined by PCR. C. botulinum was isolated from the fish sample and it was confirmed to be type E by the mouse bioassay and by PCR. Eleven other fish samples from the same lot did not contain botulinum toxin nor any BoNT gene. The incriminated food was processed on the 9th and 10th of January, 1997 from frozen whitefish imported to Finland from Canada. The pulsed-field gel electrophoretic pattern of the isolated C. botulinum strain resembled a reference strain of North American origin. It did not match any C. botulinum strains isolated from the Baltic sea-bottom or from the fish caught in the area indicating that the fish was contaminated by C. botulinum in Canada. The conditions resulting in toxin production could not be identified. The safety problems associated with vacuum-packaged hot-smoked fish seem to be of utmost concern and the product is one of the most important botulism food vehicles processed on an industrial scale. Temperature monitoring and the use of time-temperature indicators are to be recommended in order to ensure adequate storage temperature from processing through to consumption. Allowing the use of nitrate and nitrite together with sufficiently high NaC1 concentration in this particular product should also be considered.
Botulinum toxin is now used to treat a wide variety of cholinergic disorders, ranging from mild tics to more disabling forms of dystonia. The demonstrated safety of such treatments has encouraged further exploitation of the toxin's unique properties. With genetic manipulation of structural features, this poisonous substance could turn out to be an efficient carrier of oral medications and vaccines.
Food poisoning syndromes caused by four different bacteria are described. For all types, food kept at a permissive temperature allows growth of the vegetative forms of the bacteria and production of a toxin or toxins. The key features of these syndromes, as well as possible new trends of concern, are summarized in Table 1.
Where Marco polo meets Meckel: Type E botulism from Clostridium butyricum
- Schechter