Pediatric Botulism

Botulism is a broad term encompassing 3 clinical entities caused by botulinum toxin. Propagation of this toxin under different circumstances can lead to food-borne, wound, or infant botulism.

Foodborne botulism was the first of the 3 entities to be described. Byzantine Emperor Leo VI documented cases of fatal food poisoning in the ninth century. In the 1820s, Justinus Kerner, a German physician, and romantic poet scrutinized a number of food-poisoning cases and found that most were caused by improperly prepared sausages.[1, 2] As a result, he named the disease botulism, after the Latin word for sausage, botulus. Kerner correctly deduced the presence of the culpable toxin in the sausages and extracted a compound he termed wurstgift (German for sausage poison).[3]

Kerner continued studying botulism. In an experiment that would surely cause controversy in any modern human investigations committee, Kerner injected himself with the wurstgift extract and demonstrated many of the signs and symptoms so convincingly that the causal relationship was proven. Lastly, Kerner presaged the therapeutic uses of this toxin in individuals with motor over-activity by some 150 years. Despite his contributions to the field, questions remained regarding how the toxin entered the sausages.

In 1897, the microbiologist Emile-Pierre van Ermengen identified a gram-positive, spore-forming, anaerobic bacterium in a ham that caused 23 cases of botulism in a Belgian nightclub.[4] He termed the bacterium Bacillus botulinus; it was later renamed Clostridium botulinum (see the image below).

This is a photomicrograph of Clostridium botulinum stained with Gentian violet. The bacterium, C botulinum, produces a neurotoxin which causes the rare, but serious, paralytic illness, botulism.

Wound botulism was the next type to be described. C botulinum was cultured from the wounds of asymptomatic patients as early as 1942, but wound botulism was not described as it is known today until 1951. In 1973, Merson and Dowell reported the case of a girl who had open leg and ankle fractures.[5] The girl demonstrated clear clinical signs of botulism without any history of food-borne illness or symptomatic family members.

Infant botulism was described separately in 1976 by Midura and Arnon and by Pickett et al.[6, 7] Currently, the infant form is the most common presentation of botulism in the United States, with about 110 cases occurring annually.[8] Although frequently mentioned, raw honey is the apparent cause in only 15% of cases in the US and 58% of cases in Europe. It is more commonly seen in infants of immigrant families.[9, 10, 11] The origin of the spores is unknown in 85% of cases in the US,[12] but may be associated with soil and dust from nearby construction sites, nearby heavy traffic or from caretakers exposed to these risk factors.[13] Other possible sources of infant botulism, include corn syrup, powdered infant milk, infant cereal formulas, natural sweeteners, medicinal plants such as Matricaria chamomilla, and there is even one case report from Japan of infant botulism caused by spores in contaminated well water.[10]  There is also one case report of an infant who developed botulism after a wound, the infant was being treated for was treated with a honey dressing. The authors of this article caution about using honey dressings in infants.[14]

See 5 Cases of Food Poisoning: Can You Identify the Pathogen?, a Critical Images slideshow, to help identify various pathogens and symptoms related to foodborne disease.

C botulinum is a gram-positive, spore-forming anaerobe that naturally inhabits soil, dust, and fresh and cooked agricultural products. Although classified as a single species, C botulinum is better described as a group of at least 3 (possibly 4) genetically unique organisms. All of the organisms share the ability to produce a type of botulinum toxin, although not all produce the same type. There are 7 serotypes of botulinum toxin: A through G.[8] Types A and B are by far the most common types. In the US, Type A is more common on the West Coast and Type B is more common on the East Coast.[10] Clostridium baratii and Clostridium butyricum also produce botulinum toxin. These organisms produce type E and F toxins. Whether Clostridium argentinense is a subgroup of C botulinum or a separate species is currently under debate.

Botulinum toxin is the most potent naturally occurring toxin known to humankind. Botulinum toxin is lethal at a dose of 10–9 g/kg, making botulinum toxin 15,000-100,000 times more potent than sarin gas.

Food-borne botulism is not seen after eating fresh foods. Some methods of food preparation, such as home canning, produce an anaerobic, low-acid (ie, pH >4.6), low-solute environment in which the toxin can be produced. A similar environment exists in wounds, thus providing an opportunity for wound botulism to develop.[15]

Infant botulism is unique. In persons older than 1 year, the spores are unable to germinate in the gut, and therefore food-borne disease is the result of ingesting a preformed toxin. C botulinum spores can germinate in the gut of infants younger than 1 year because of their relative lack of gastric acid, decreased levels of normal flora, and immature immune systems (ie, specifically lacking secretory immunoglobulin A). This environment is conducive to toxin production, and therefore, infant botulism can arise from eating the spores present in unprepared foods, such as honey.[16]

Once produced, several activating steps are required for the toxin to produce deleterious effects. The toxin precursor is produced as a 150-kd protein encoded by a single gene. The precursor is cleaved to a 100-kd heavy chain and a 50-kd light chain, joined by a disulfide bond. The bond is essential for membrane penetration, and reduction of the bond inactivates the toxicity of the polypeptides. The light chain is more toxic than the heavy chain, although both must be present to achieve the full toxic effect.

All botulinum toxins are zinc-metalloproteases that bind to different membrane proteins involved in fusion of the synaptic vesicle to the presynaptic membrane. This fusion allows the release of acetylcholine into the synaptic junction. The toxins are classified as types A through G, although only types A, B, E, and F cause human disease. Types A and E bind to synaptosomal-associated protein 25, type C binds to syntaxin, and types B, D, and F bind to the vesicle-associated membrane protein. Inhibition of the proteins effectively blocks acetylcholine transmission across the synapse and functionally denervates the muscle. This binding to presynaptic cholinergic receptors irreversibly prevents the release of acetylcholine (paper 4). The magnitude of the clinical effect depends on the proportion of synapses blocked and the effects can range from weakness to flaccid paralysis and atrophy. The toxin does not cross the blood-brain barrier, and that is why preservation of CNS and cognitive function is preserved unless complications such as hypoxic brain damage from hypoventilation occur.[8]

Frequency

United States

From 1973-1996, 724 cases of food-borne botulism, 103 cases of wound botulism, and 1444 cases of infant botulism were reported. As noted above infant botulism is the most common type of botulism in the US, with about 110 cases reported annually.[8] The type of botulism was undetermined in 39 cases.[17] Very rare causes of botulism, such as an Adult Enteric type seen in patients with Crohn’s Disease on chronic antibiotics, inhalation of spores nasally in laboratory workers, and overdose of injected toxic for cosmetic purposes, have recently been reported.[8]

Type A accounts for 50% of foodborne cases and the other 50% of cases are evenly split between types B and F. Wound botulism is caused by type A in 80% of cases and type B causes most of the remaining cases. In the 1990s, the US experienced a drastic increase in wound botulism, due to the injection subcutaneously of Heroin contaminated with C. botulinum spores, often referred to as Black Tar Heroin.[15] The cause of infant botulism is evenly split between types A and B.[17] Geographically, type A predominates west of the Mississippi River, whereas type B predominates east of the river.[18] A single case of type E infant botulism has been reported.[19]

International

In Europe, contaminated hams and sausages are the usual modes of transmission. Poland has the highest frequency by far, with 325 outbreaks and 448 cases in a 3-year period. China is a distant second with 39 outbreaks and 234 cases in a 25-year period.[20] Recently, case reports from Australia have appeared.[21] Five cases were recently reported in an 18-month period (2006-2008) in and around Toronto, Canada,[22] and recent epidemiology of foodborne botulism in Canada has been reported.[23] Many countries have recently reported cases of infant botulism, with the notable exception of countries in Africa, which have not yet reported a case of infant botulism, likely because of lack of recognition.[9] There are several excellent recent case reports and reviews of infant botulism from Great Britain and Canada.[16, 13, 8]

Mortality/Morbidity

Around the year 1900, the mortality rate associated with botulism was 70%. Today, the mortality rate approaches 15%.

Race

In Great Britain, infant botulism was found to be more common in immigrant families from Asia, probably due to the tradition of giving honey to infants.[9] In the Southwestern United States, there may be a greater risk of infant botulism among Hispanics, because of the greater use of honey pacifiers and herbals, such as chamomile, in this population.[11]

Botulism has no racial predilection, although foodborne botulism is endemic in Alaskan Natives.[24, 25]

Sex

Gender is not a factor in botulism infection.

Age

Infant botulism usually occurs in children aged 2-6 months, although it can occur in infants aged 3-382 days.

Foodborne botulism

GI tract symptoms usually occur first, beginning 18-36 hours after ingestion (range, 2 h to 8 d) and consist of nausea, vomiting, and diarrhea followed by constipation.

Motor function symptoms follow, with the cranial nerves usually affected first. As a result, many patients present with diplopia (eg, impaired lateral gaze secondary to sixth cranial nerve involvement) and blurred vision secondary to loss of accommodation.

Many patients have dry mouth.

Finally, a rapidly progressive descending weakness or paralysis occurs. Respiratory muscle paralysis and subsequent death may occur.[8, 26] Autonomic dysfunction may lead to orthostatic hypotension, urinary retention, or constipation.

Because the toxin affects only motor and autonomic systems, sensation and mentation remain intact. Patients are usually afebrile.

Wound botulism

Except for the prerequisite history of a wound, this type of botulism presents in the same way as food-borne botulism. The diagnosis of wound botulism should be suspected in any patient with a contaminated wound that presents with neuro-muscular weakness, especially if there is bulbar involvement.[15] Also, wound botulism, as compared to the other types of botulism, is much more like to cause fever.[15]

Wound botulism is the least common type of botulism and may follow a penetrating or blunt injury. Recurrent wound botulism has been reported in injection drug users.[27]

The incubation period is 4-14 days.

Infant botulism

The incubation period is 2-4 weeks. The peak age of incidence is 2-4 months.

Constipation is the usual presenting symptom, often preceding motor function symptoms by several days or weeks.

Other signs of autonomic dysfunction usually present early as well, including those mentioned above. Gag reflexes are frequently impaired, which can lead to aspiration if the airway is unprotected.

Infants with botulism are afebrile, suck poorly, and are lethargic and listless. They often are described as being floppy.[9] Constipation is almost always the first sign of infant botulism.[28] Constipation, poor feeding, ptosis, facial and generalized weakness are considered to be the classical signs of infant botulism.[16] They develop the same descending weakness and paralysis that occurs in those with food-borne disease. About 25% of babies with infant botulism present with hypoventilation,[13] but 60% of patients with infant botulism may develop hypoventilation, and require ventilatory support as the disease progresses.[8] Awareness of the symptoms of botulism, and a high degree of clinical suspicion is needed to make a prompt diagnosis of infant botulism and prevent death.[26] Initially, infant botulism may be confused with an infection or may exist concomitantly with a respiratory infection, and if the potentially fatal diagnosis of infant botulism is not thought of, it will be missed with dire consequences.[28] Breastfeeding may protect infants from lethal fulminant infant botulism, but exclusive breastfeeding is a risk factor for the disease, presumably because the relatively pristine bowel flora of the exclusively breastfed infant is more permissive for spore germination and toxin production.

Suspect botulism in patients with autonomic dysfunction (eg, dry mouth, blurred vision, orthostatic hypotension), cranial nerve involvement (eg, ptosis, mydriasis, decreased ocular motility, dysphagia, dysarthria),[29] and muscle weakness or flaccid paralysis.

Frequencies of the most common symptoms and signs of food-borne and wound botulism are as follows:

• Dysphagia - 96%

• Dry mouth - 93%

• Diplopia - 91%

• Dysarthria - 84%

• Extremity weakness - 73%

• Constipation - 73%

• Blurred vision - 65%

• Nausea - 64%

• Dyspnea - 60%

• Vomiting - 59%

• Abdominal cramps - 42%

• Diarrhea - 19%

Frequencies of the most common symptoms and signs of infant botulism are as follows:

• Poor ability to suck - 96%

• Poor head control - 96%

• Hypotonia - 93%

• Weak crying - 84%

• Constipation - 83%

• Lethargy - 71%

• Facial weakness - 69%

• Irritability - 61%

• Hyporeflexia - 52%

• Sluggish pupils - 50%

• Respiratory difficulty - 43%

It is important to maintain a high degree of suspicion of the diagnosis of infant botulism, in any infant presenting with acutely acquired hypotonia.[13] The history of constipation, hoarse cry, progressive weak suck, and symmetric descending weakness, and the physical exam findings of bilateral extremity weakness, truncal weakness, marked head lag and decreased gag reflex point very strongly to the diagnosis of infant botulism.[13] The combination of ptosis, bilateral facial weakness, and poor respiratory effort should make the physician very suspicious of the diagnosis of infant botulism complicated by respiratory failure.[28]

See Pathophysiology.

Although clinical suspicion should be sufficient to prompt supportive therapy for botulism, other differential diagnoses must be excluded.

Obtain stool cultures in all patients, adding wound cultures if wound botulism is suspected.

Approximately 60% of food-borne cases yield positive stool culture results. Cultures may be enriched to enhance the growth of C. botulinum.[15] A positive culture finding in the presence of flaccid paralysis is diagnostic. Currently, specific assays for the toxin, including enzyme-linked immunoassays and polymerase chain reaction, are under investigation.

Currently, the mouse inoculation test is the best test available and can be performed by the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. In the assay, mice are injected with a serum sample or stool sample[8, 12] from the patient and test results are considered positive for toxin if the mice die of respiratory arrest within 24 hours. The exact type of toxin is determined through pretreating each mouse in a set of mice with a different type-specific antitoxin, then injecting the serum. The mouse left alive the next day is the one pretreated with the antitoxin to the toxin affecting the patient. The sensitivity of this test in the diagnosis of wound botulism has been questioned; strong clinical suspicion should outweigh a negative mouse inoculation test.[31, 32]

Serum testing for toxins is a less sensitive test than is testing feces for toxins, especially for infant botulism, and serum should be used only if stool samples cannot be obtained.[8, 12] When collecting samples of stool for botulinum toxin and spores, one must be very careful and use protective equipment, because of the great toxicity of the toxin. A sample of 25-50 grams of stool should be collected, although, sometimes smaller amounts in infants have yielded positive results.[12] Infants with botulism often have severe constipation and an enema may be necessary to obtain stool samples for spores and toxins.[8] Stool samples should be refrigerated in a leak proof container and shipped out to the testing laboratory as soon as possible. If possible stool samples should be collected prior to starting treatment with immune globulin, however this treatment should not be delayed waiting for the results of confirmatory testing.[12]

For infant botulism detecting botulism toxins or spores in stool is the best way to confirm the diagnosis. Detecting toxin in stool is much less sensitive. For food borne botulism detection of toxin in feces, serum, gastric aspirate or contaminated food is the best way to confirm the diagnosis. Also, cultures should be sent. For wound botulism detecting toxin in serum and culturing tissue from the wound are the best ways to confirm the diagnosis. For the rare cases of adult enteric botulism, detection of toxin in the feces and culture of the feces are the best ways to confirm the diagnosis. For the very rare case of iatrogenic botulism caused by the injection of too much toxin, detecting the toxin in the serum is the only way to confirm the diagnosis. Finally in the extremely rare case of inhalation botulism, the detection of toxin from a nasal swab is the way to confirm the diagnosis.[8]

It must be emphasized again that treatment with immune globulin should not be delayed waiting for confirmatory tests, but should be given based on a strong clinical suspicion. Delays in initiating treatment increase mortality and morbidity.

A Multiplex polymerase chain reaction test (PCR) has been described.[33, 34]

PCR testing for spores in stool has been done successfully. Results may be available before the results of mouse bioassays are. However, this testing is not widely available yet, and the sensitivities are yet to be determined. Local and state public health departments should be contacted for advice and assistance in getting specimens tested.[8]

Perform CT scanning or MRI as clinically indicated to exclude stroke.

See the list below:

• Perform an edrophonium chloride test to exclude myasthenia gravis, if indicated, although transient responses have been reported with botulism.

• Electromyelography (EMG) demonstrates a non-specific, decreased amplitude of action potentials. Rapid repetitive EMG at frequencies of 20-50 Hz is more specific for botulism and useful in excluding Guillain-Barré syndrome, but this response does not distinguish botulism from Lambert-Eaton syndrome. Infant botulism is characterized by a pattern known as brief, small, abundant motor-unit action potential on EMG in clinically affected muscles.

• The classical electromyography finding is neuro-muscular junction blockade with normal axonal conduction. However, the lack of this finding should not preclude the clinician from initiating treatment with immune globulin, if there is strong clinical suspicion of botulism.[15]

See the list below:

• Lumbar puncture findings can usually exclude Guillain-Barré syndrome, a condition that tends to elicit a higher protein level in cerebrospinal fluid (especially later in the course of the disease) than does botulism. Also, lumbar puncture can help exclude the diagnosis of meningitis or encephalitis, as Botulism does not cause an increase in WBCs in the CSF.

• In wound botulism, wounds should be debrided and any foreign bodies removed as deemed necessary by the physician.[15]

In patients with botulism, supportive care, especially ventilatory support, is essential.[35]

• Promptly initiate ventilatory support, because respiratory muscle weakness rapidly progresses and the gag reflex is frequently impaired, which predisposes patients to respiratory failure and/or aspiration. Patients need continued suctioning and may require intubation or tracheostomy.

Antitoxin (see Medication) dramatically alters the course of the disease, especially if administered within the first 24 hours.

• As of 2010, Heptavalent antitoxin active against all 7 types of botulism toxin (A-G) has been available from the CDC for treatment for food borne and wound botulism. It is very effective and safe, and should be started as soon as possible, as longer periods of ventilation were needed if the antitoxin was started more than 12 hours after hospitalization.[15]

  • A joint task force that analyzed the allergy risk of botulinum antitoxin treatment reported that anaphylaxis incidence was low at 1.64% (5/305 patients) for HBAT and 1.16% (8/687 patients) for all other botulinum antitoxins (relative risk, 1.41 [95% confidence interval, .47-4.27]; P = .5).[36]

• Human Botulism Immune Globulin Intravenous (BabyBIG) should be administered for infant botulism. It is effective if given within 7 days of onset of symptoms. It can only be obtained from the California Department of Public Health by calling the Infant Botulism Treatment and Prevention Program (IBTPP) (Telephone #510-231-7600). It is given as an IV drip of 50 mg/kg over 1 hour and has to be reconstituted 2 hours before use in 5% sucrose and 1% albumin solutions. It is very safe and not associated with the anaphylactic reactions that were previously seen with antitoxins derived from horse serum. Without treatment with BabyBIG, infants have prolonged symptoms and an increased number of complications, including longer hospitalizations, longer ICU stays and higher overall costs. Although the cost of BabyBig is $45,300 per infant, this cost is more than made up by decreased hospital costs when BabyBIG is used.[12]  Although one study showed an increase in hospital charges for infants that received treatment with BabyBIG, even in that study there was a decrease in morbidity, the number of days spent on a ventilator and length of hospital stay.[37] In a comprehensive review of infant botulism, the authors found that treatment with BabyBig decreased both morbidity and hospital costs, and the high cost of BabyBIG was justified by these results. The authors strongly felt that both supportive therapy and the use of BabyBIG should be initiated as early as possible based on clinical findings, and not wait for laboratory confirmation.[37]

• In general, antibiotic therapy to clear clostridial GI infection in infant botulism is contraindicated, because the treatment increases toxin release and worsens the condition. Antibiotics may be used to treat secondary bacterial infections, but if possible this should be done after BabyBIG has been given.[13]

• Aminoglycosides, such as gentamicin or tobramycin, may potentiate the neuromuscular blockade caused by the botulinum toxin, and therefore are contraindicated. It is recommended that aminoglycosides not be administered for the next 6 months.[13]

• Many experts recommend antibiotic therapy after antitoxin administration in wound botulism. Penicillin G and Metronidazole are most commonly used, but Clindamycin has also been shown to be effective. Aminoglycosides, Nalidixic acid and Trimethoprim-sulfamethoxazole have not been shown to be effective against C. botulinum, and should not be used.[15]

• Cathartics containing Magnesium should not be used.[15]

In patients with wound botulism, surgical debridement of the wound is indicated to remove the source of toxin production.

Consultations with an infectious diseases specialist and a neurologist are frequently beneficial.

Consultations with the local public health and state health departments are very useful, and will often facilitate obtaining antitoxin and getting confirmatory testing done. Also, the CDC may be called directly at 770-488-7100 to obtain management advice and antitoxin. For management advice for infant botulism and for obtaining BabyBig, the IBTPP should be called at 501-231-7600.

Tube feeding may be useful if GI tract motility is intact. If motility is not intact, consider parenteral feeding.

In addition to the equine-derived heptavalent botulinum antitoxin available from the CDC and FDA approved for use in non-infant botulism cases (Cangene's botulism antitoxin [BAT] heptavalent),[38] a human-derived antitoxin is currently under an Investigational New Drug (IND) treatment protocol; the treatment IND protocol is only for infant botulism and only for infants aged 1 year or younger.[39, 40] For infants who meet these criteria, the human-derived antitoxin may be obtained from the California Department of Health Services at (510) 231-7600. Information regarding treatment of older children can be obtained at http://www.bt.cdc.gov/agent/botulism.

Class Summary

These agents are used for food-borne and wound botulism. They are produced from horse serum stimulated with specific antibodies directed against C botulinum and provide passive immunity.

Botulism immune globulin, human (BabyBIG)

Solvent-detergent–treated and viral-screened immune globulin. Derived from pooled adult plasma from persons immunized with botulinum toxoid who developed high neutralizing antibody titers against botulinum neurotoxins type A and B. Indicated to treat infant botulism caused by type A or B. C botulinum.

Botulinum antitoxin, heptavalent (HBAT)

Investigational antitoxin indicated for naturally occurring non-infant botulism. Equine-derived antitoxin that elicits passive antibody (ie, immediate immunity) against Clostridium botulinum toxins A, B, C, D, E, F, and G.

Each 20-mL vial contains equine-derived antibody to the 7 known botulinum toxin types (A through G) with the following nominal potency values: 7500 U anti-A, 5500 U anti-B, 5000 U anti-C, 1000 U anti-D, 8500 U anti-E, 5000 U anti-F, and 1000 U anti-G.

Available from CDC as treatment IND protocol. Replaces licensed bivalent botulinum antitoxin AB (BAT-AB) and investigational monovalent botulinum antitoxin E (BAT-E). To obtain, contact CDC Emergency Operations Center; telephone: (770) 488-7100.

See the list below:

• Avoid administration of sedatives or CNS depressants in patients with botulism.

• Stool softeners and adequate hydration are useful in patients with constipation.

See the list below:

• Transfer the patient to an institution able to provide antitoxin and adequate supportive care, if necessary.

See the list below:

• Instruct patients to adhere to safe methods of food handling and preparation.

• Thoroughly cleanse and debride potentially contaminated wounds.

• Instruct parents to avoid feeding honey to infants in the first year of life.[9, 11]

• Early studies of a vaccine against botulinum toxin are underway.[41, 42]

See the list below:

• Aspiration pneumonia

• Respiratory failure

• Secondary urinary tract infections, respiratory tract infections, and sepsis

• Subglottic stenosis (following intubation)

See the list below:

• Timing of antitoxin administration greatly influences the prognosis. Studies with the new Heptavalent botulinum antitoxin show that if it is administered longer than 12 hours after hospitalization longer periods of assisted ventilation were required and there was greater mortality. Retrospective analysis has shown that use of antitoxin within 24 hours is associated with a 10% mortality rate, antitoxin administered more than 24 hours later is associated with a 15% mortality rate, and failure to administer antitoxin carries a 46% mortality rate. Timing of administration also affects length of hospital stay, with a median stay of 10 days when antitoxin is administered within 24 hours, 41 days if administered after 24 hours, and 56 days if not used at all. In infants with botulism, treatment with BabyBig within 7 days markedly improves the prognosis (papers 1,3,4,7).

• Prompt and vigorous supportive care, especially respiratory care, greatly improves the prognosis (paper 3).

• After recovery from acute illness, late symptoms may remain, primarily muscle weakness including diplopia and fatigue with exertion. Although some patients have reported feeling breathless, pulmonary function test results demonstrate that results in lung volumes, forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC), maximum inspiratory and expiratory pressures, and ventilatory response to exercise fall within reference ranges.

• There have been reported episodes of relapse within 13 days in infants with botulism, therefore close observation for recurrence of symptoms is necessary.[26]