Botulism

Botulism (Latin, botulus, "sausage") (pronounced ) also known as botulinus intoxication is a rare but serious paralytic illness caused by botulinum toxin which is a protein produced under anaerobic conditions by the bacterium Clostridium botulinum, and affecting a wide range of mammals, birds and fish.

The toxin(s) enters the human body in one of three ways: by colonization of the digestive tract by the bacterium in children (infant botulism) or adults (adult intestinal toxemia), by ingestion of toxin from foods (foodborne botulism) or by contamination of a wound by the bacterium (wound botulism). Person to person transmission of botulism does not occur.

All forms lead to paralysis that typically starts with the muscles of the face and then spreads towards the limbs. In severe forms, it leads to paralysis of the breathing muscles and causes respiratory failure. In light of this life-threatening complication, all suspected cases of botulism are treated as medical emergencies, and public health officials are usually involved to prevent further cases from the same source.

Botulism can be prevented by killing the spores by pressure cooking or autoclaving at 121 °C for 3 minutes or providing conditions that prevent the spores from growing. The toxin itself is destroyed by normal cooking processes – that is, boiling for a few minutes. Additional precautions for infants include not feeding them honey.

Signs and symptoms
The muscle weakness of botulism characteristically starts in the muscles supplied by the cranial nerves. A group of twelve nerves controls eye movements, the facial muscles and the muscles controlling chewing and swallowing. Double vision, drooping of both eyelids, loss of facial expression and swallowing problems may therefore occur, as well as difficulty with talking. The weakness then spreads to the arms (starting in the shoulders and proceeding to the forearms) and legs (again from the thighs down to the feet). Severe botulism leads to reduced movement of the muscles of respiration, and hence problems with gas exchange. This may be experienced as dyspnea (difficulty breathing), but when severe can lead to respiratory failure, due to the buildup of unexhaled carbon dioxide and its resultant depressant effect on the brain. This may lead to coma and eventually death if untreated.

In addition to affecting the voluntary muscles, it can also cause disruptions in the autonomic nervous system. This is experienced as a dry mouth and throat (due to decreased production of saliva), postural hypotension (decreased blood pressure on standing, with resultant lightheadedness and risk of blackouts), and eventually constipation (due to decreased peristalsis). Some of the toxins (B and E) also precipitate nausea and vomiting.

Clinicians frequently think of the symptoms of botulism in terms of a classic triad: bulbar palsy and descending paralysis, lack of fever, and clear senses and mental status ("clear sensorium").

Infant botulism
Infant botulism was first recognized in 1976, and is the most common form of botulism in the United States. There are 80 to 100 diagnosed cases of infant botulism in the United States each year. Infants are susceptible to infant botulism in the first year of life, with more than 90% of cases occurring in infants younger than six months. Infant botulism results from the ingestion of the C. botulinum spores, and subsequent colonization of the small intestine. The infant gut may be colonized when the composition of the intestinal microflora (normal flora) is insufficient to competitively inhibit the growth of C. botulinum. Medical science does not yet completely understand all factors that make an infant susceptible to C. botulinum colonization. The growth of the spores releases botulinum toxin, which is then absorbed into the bloodstream and taken throughout the body, causing paralysis by blocking the release of acetylcholine at the neuromuscular junction. Typical symptoms of infant botulism include constipation, lethargy, weakness, difficulty feeding and an altered cry, often progressing to a complete descending flaccid paralysis. Although constipation is usually the first symptom of infant botulism, it is commonly overlooked.

Honey is the only known dietary reservoir of C. botulinum spores linked to infant botulism. For this reason honey should not be fed to infants less than one year of age. Due to the success of this public health message, fewer than 5% of recent infant botulism cases have been exposed to honey. The remaining 95% of infant botulism cases are thought to have acquired the spores from the natural environment. Clostridium botulinum is a ubiquitous soil-dwelling bacterium. Many infant botulism patients have been demonstrated to live near a construction site or an area of soil disturbance.

Infant botulism has been reported in 49 of 50 US states, and cases have been recognized in 26 countries on five continents.

Complications
Infant botulism has no long-term side effects, but can be complicated by nosocomial adverse events. The case fatality rate is less than 1% for hospitalized infants with botulism.

Botulism can result in death due to respiratory failure. However, in the past 50 years, the proportion of patients with botulism who die has fallen from about 50% to 7% due to improved supportive care. A patient with severe botulism may require a breathing machine as well as intensive medical and nursing care for several months. Patients who survive an episode of botulism poisoning may have fatigue and shortness of breath for years and long-term therapy may be needed to aid their recovery.

Cause
C. botulinum is an anaerobic, Gram positive, spore-forming rod. Botulin toxin is one of the most powerful known toxins: about one microgram is lethal to humans. It acts by blocking nerve function and leads to respiratory and musculoskeletal paralysis.

In all cases illness is caused by the toxin made by C. botulinum, not by the bacterium itself. The pattern of damage occurs because the toxin affects nerves that are firing more often. Specifically, the toxin acts by blocking the production or release of acetylcholine at synapses and neuromuscular junctions. Death occurs due to respiratory failure.

Four main modes of entry for the toxin are known. The most common form in Western countries is infant botulism. This occurs in small children who are colonized with the bacterium during the early stages of their lives. The bacterium then releases the toxin into the intestine, which is absorbed into the bloodstream. The consumption of honey during the first year of life has been identified as a risk factor for infant botulism; it is a factor in a fifth of all cases. The adult form of infant botulism is termed adult intestinal toxemia, and is exceedingly rare.

Foodborne botulism results from contaminated foodstuffs in which C. botulinum spores have been allowed to germinate in anaerobic conditions. This typically occurs in home-canned food substances and fermented uncooked dishes. Given that multiple people often consume food from the same source, it is common for more than a single person to be affected simultaneously. Symptoms usually appear 12–36 hours after eating, but can also appear within 6 hours to 10 days.

Wound botulism results from the contamination of a wound with the bacteria, which then secrete the toxin into the bloodstream. This has become more common in intravenous drug users since the 1990s, especially people using black tar heroin and those injecting heroin into the skin rather than the veins.

Isolated cases of botulism have been described after inhalation by laboratory workers and after cosmetic use of inappropriate strengths of Botox.

Diagnosis
For infant botulism, diagnosis should be made on clinical grounds. Confirmation of the diagnosis is made by testing of a stool or enema specimen with the mouse bioassay.

Physicians may consider diagnosing botulism if the patient's history and physical examination suggest botulism. However, these clues are often not enough to allow a diagnosis. Other diseases such as Guillain-Barré syndrome, stroke, and myasthenia gravis can appear similar to botulism, and special tests may be needed to exclude these other conditions. These tests may include a brain scan, cerebrospinal fluid examination, nerve conduction test (electromyography, or EMG), and an edrophonium chloride (Tensilon) test for myasthenia gravis. A definite diagnosis can be made if botulinum toxin is identified in the food, stomach or intestinal contents, vomit or feces. The toxin is occasionally found in the blood in peracute cases. Botulinum toxin can be detected by a variety of techniques, including enzyme-linked immunosorbent assays (ELISAs), electrochemiluminescent (ECL) tests and mouse inoculation or feeding trials. The toxins can be typed with neutralization tests in mice. In toxicoinfectious botulism, the organism can be cultured from tissues. On egg yolk medium, toxin-producing colonies usually display surface iridescence that extends beyond the colony.

In cattle, the symptoms may include drooling, restlessness, uncoordination, urine retention, dysphagia, and sternal recumbency. Laterally recumbent animals are usually very close to death. In sheep, the symptoms may include drooling, a serous nasal discharge, stiffness, and incoordination. Abdominal respiration may be observed and the tail may switch on the side. As the disease progresses, the limbs may become paralyzed and death may occur. Phosphorus-deficient cattle, especially in southern Africa, are inclined to ingest bones and carrion containing clostridial toxins and consequently suffer lame sickness or lamsiekte.

The clinical signs in horses are similar to cattle. The muscle paralysis is progressive; it usually begins at the hindquarters and gradually moves to the front limbs, neck, and head. Death generally occurs 24 to 72 hours after initial symptoms and results from respiratory paralysis. Some foals are found dead without other clinical signs.

Pigs are relatively resistant to botulism. Reported symptoms include anorexia, refusal to drink, vomiting, pupillary dilation, and muscle paralysis.

In poultry and wild birds, flaccid paralysis is usually seen in the legs, wings, neck and eyelids. Broiler chickens with the toxicoinfectious form may also have diarrhea with excess urates.

Prevention
Although the botulinum toxin is destroyed by thorough cooking over the course of a few minutes, the spore itself is not killed by the temperatures reached with normal sea-level-pressure boiling, leaving it free to grow and again produce the toxin when conditions are right.

A recommended prevention measure for infant botulism is to avoid feeding honey to infants less than 12 months of age. In older children and adults the normal intestinal bacteria suppress development of C. botulinum.

While commercially canned goods are required to undergo a "botulinum cook" in a pressure cooker at 121 °C for 3 minutes, and so rarely cause botulism, there have been notable exceptions such as the 1978 Alaskan salmon outbreak and the 2007 Castleberry's Food Company outbreak. Foodborne botulism is the rarest form though, accounting for only around 15% of cases (US) and has more frequently been from home-canned foods with low acid content, such as carrot juice, asparagus, green beans, beets, and corn. However, outbreaks of botulism have resulted from more unusual sources. In July, 2002, fourteen Alaskans ate muktuk (whale meat) from a beached whale, and eight of them developed symptoms of botulism, two of them requiring mechanical ventilation. Other, but much rarer sources of infection (about every decade in the US ) include garlic or herbs stored covered in oil without acidification, chilli peppers, improperly handled baked potatoes wrapped in aluminium foil, tomatoes, and home-canned or fermented fish. Persons who do home canning should follow strict hygienic procedures to reduce contamination of foods. Oils infused with fresh garlic or herbs should be acidified and refrigerated. Potatoes which have been baked while wrapped in aluminum foil should be kept hot until served or refrigerated. Because the botulism toxin is destroyed by high temperatures, home-canned foods are best boiled for 10 minutes before eating. Metal cans containing food in which bacteria, possibly botulinum, are growing may bulge outwards due to gas production from bacterial growth; such cans should be discarded. Any container of food which has been heat-treated and then assumed to be airtight which shows signs of not being so, e.g., metal cans with pinprick holes from rust or mechanical damage, should also be discarded. Contamination of a canned food solely with C. botulinum may not cause any visual defects (e.g. bulging). Only sufficient thermal processing during production should be used as a food safety control.

Wound botulism can be prevented by promptly seeking medical care for infected wounds, and by avoiding punctures by unsterile things such as needles used for street drug injections. It is currently being researched at USAMRIID under BSL-434.

Treatment
Most infant botulism patients require supportive care in a hospital setting. The only drug currently available to treat infant botulism is Botulism Immune Globulin Intravenous-Human (BIG-IV or BabyBIG). BabyBIG was developed by the Infant Botulism Treatment and Prevention Program at the California Department of Public Health.

The respiratory failure and paralysis that occur with severe botulism may require a patient to be on a ventilator for weeks, plus intensive medical and nursing care. After several weeks, the paralysis slowly improves. If diagnosed early, foodborne and wound botulism can be treated by inducing passive immunity with a horse-derived antitoxin, which blocks the action of toxin circulating in the blood. This can prevent patients from worsening, but recovery still takes many weeks. Physicians may try to remove contaminated food still in the gut by inducing vomiting or by using enemas. Wounds should be treated, usually surgically, to remove the source of the toxin-producing bacteria. Good supportive care in a hospital is the mainstay of therapy for all forms of botulism.

Furthermore each case of food-borne botulism is a potential public health emergency in that it is necessary to identify the source of the outbreak and ensure that all persons who have been exposed to the toxin have been identified, and that no contaminated food remains.

There are two primary Botulinum Antitoxins available for treatment of wound and foodborne botulism. Trivalent (A,B,E) Botulinum Antitoxin is derived from equine sources utilizing whole antibodies (Fab & Fc portions). This antitoxin is available from the local health department via the CDC. The second antitoxin is heptavalent (A,B,C,D,E,F,G) Botulinum Antitoxin which is derived from "despeciated" equine IgG antibodies which have had the Fc portion cleaved off leaving the F(ab')2 portions. This is a less immunogenic antitoxin that is effective against all known strains of botulism where not contraindicated. This is available from the US Army. On 1 June 2006 the US Department of Health and Human Services awarded a $363 million contract with Cangene Corporation for 200,000 doses of Heptavalent Botulinum Antitoxin over five years for delivery into the Strategic National Stockpile beginning in 2007.

Prognosis
Infant botulism has no long-term side effects, but can be complicated by nosocomial adverse events. The case fatality rate is less than 1% for hospitalized infants with botulism.

Between 1910 and 1919 the death rate from botulism was 70% in the United States, dropping to 9% in the 1980s and 2% in the early 1990s, mainly because of the development of artificial respirators. Up to 60% of botulism cases are fatal if left untreated.

The World Health Organization (WHO) reports that the current mortality rate is 5% (type B) to 10% (type A). Other sources report that, in the U.S., the overall mortality rate is about 7.5%, but the mortality rate among adults over 60 is 30%. The mortality rate for wound botulism is about 10%. The infant botulism mortality rate is about 1.3%.

Death from botulism is common in waterfowl; an estimated 10,000 to 100,000 birds die of botulism annually. In some large outbreaks, a million or more birds may die. Ducks appear to be affected most often. Botulism also affects commercially raised poultry. In chickens, the mortality rate varies from a few birds to 40% of the flock. Some affected birds may recover without treatment.

Botulism seems to be relatively uncommon in domestic mammals; however, in some parts of the world, epidemics with up to 65% mortality are seen in cattle. The prognosis is poor in large animals that are recumbent. Most dogs with botulism recover within 2 weeks.

Epidemiology
Between 1990 and 2000, the Centers for Disease Control reported 263 individual 'cases' from 160 foodborne botulism 'events' in the United States with a case-fatality rate of 4%. Thirty-nine percent (103 cases and 58 events) occurred in Alaska, all of which were attributable to traditional Alaska aboriginal foods. In the lower 49 states, home-canned food was implicated in 70 (91%) events with canned asparagus being the most numerous cause. Two restaurant-associated outbreaks affected 25 persons. The median number of cases per year was 23 (range 17–43), the median number of events per year was 14 (range 9–24). The highest incidence rates occurred in Alaska, Idaho, Washington, and Oregon. All other states had an incidence rate of 1 case per ten million people or less.

The number of cases of food borne and infant botulism has changed little in recent years, but wound botulism has increased because of the use of black tar heroin, especially in California.

Castleberry's Food Company outbreak
Beginning in late June 2007, 8 people contracted botulism poisoning by eating canned food products produced by Castleberry's Food Company in its Augusta, Georgia plant. It was later identified that the Castleberry's plant had serious production issues on a specific line of retorts that had under-processed the cans of food. These issues included broken cooking alarms, leaking water valves and inaccurate temperature devices, all the result of poor management of the company.

All of the victims were hospitalized and placed on mechanical ventilation. The Castleberry's Food Company outbreak was the first instance of botulism in commercial canned foods in the United States in over 30 years.

Bon Vivant incident
On July 2, 1971, the U.S. Food and Drug Administration (FDA) released a public warning after learning that a New York man had died and his wife had become seriously ill due to botulism after eating a can of Bon Vivant vichyssoise soup.

In other species
Botulism can occur in many vertebrates and invertebrates. Botulism has been reported in rats, mice, chicken, frogs, toads, goldfish, aplysia, squid, crayfish, drosophila, leeches, etc.