Infant Botulism

Pediatric Perspective

Eric M. Ketcham, MD, and Hernan F. Gomez, MD, ACMT

Infant Botulism: A Diagnostic and Management Challenge

A previously healthy 26-day-old Hispanic boy was brought to a community hospital emergency department at midnight with a chief complaint of poor feeding for 3 days and 2 episodes of briefly “turning blue” that evening. He appeared calm and sleepy at triage with unremarkable vital signs: rectal temperature 99.0˚ F, heart rate 120 beats per minute, respiratory rate 30 breaths per minute, pulse O2 saturation of 100% on room air (RA), weight of 4.3 kg. Shortly after being placed on a cardiac monitor, he had a brief cyanotic, apneic episode and desaturated to an O2 saturation of 75% on RA. He initially responded to blow-by oxygen with a measurable improvement in oxygenation. A few minutes later, he desaturated to 55% and was intubated emergently without medication and placed on positive pressure ventilation. The history (obtained after intubation) reveals an uneventful pregnancy, with an uncomplicated term vaginal delivery. His only immunization, hepatitis B, was up to date. However, during the past 3 days, he had not had a bowel movement (he normally had 1-3 stools per day). He had been intermittently fussy, with progressively decreased energy and oral intake. He had 2 cyanotic episodes at home that evening, which prompted the family to seek a medical evaluation. He had no fever, cough, rhinorrhea, or diarrhea. Physical examination immediately after intubation (still without any medication) is notable only for a generalized decreased tone; he was moderately floppy. A septic work-up and empiric treatment were initiated after his airway was stabilized. A complete blood count, electrolytes, blood culture, arterial blood gas, urinalysis, urine culture, and cerebral spinal fluid (CSF) were obtained. He received parenteral ampicillin, cefotaxime, and acyclovir. The laboratory studies were all within normal limits. A chest x-ray film demonstrated normal lungs, cardiac silhouette, and a well-positioned endotracheal tube. He was transferred to a pediatric intensive care unit at a major children’s hospital as an apneic, likely septic infant. By the following morning (approximately 30 hours after presenting to the community hospital), he was afebrile and had normal vital signs, including a respiratory rate of 20 breaths per minute. However, he was not taking any spontaneous breaths. His pupils were fixed and midpoint (approximately 4 mm) bilaterally, with normal fundi. The infant was 6

completely flaccid with no response to painful stimuli except for a slight plantar flexion of his toes bilaterally. He had no response to cold caloric testing. A review of the patient’s hospital course showed he had not received any sedatives, narcotics, or paralytics. A stat head computed tomography and magnetic resonance imaging of the brain were obtained and were normal. A stat electroencephalogram to evaluate for status epilepticus was obtained and was normal. All cultures (CSF, blood, and urine) continued to show no growth, and the CSF herpes simplex virus polymerase chain reaction was negative. A lumbar puncture was repeated and again was unremarkable. The genetics/metabolic disease and infectious disease services were consulted and comprehensive metabolic laboratory tests, as well as nasopharyngeal swabs for respiratory syncytial virus and pertussis, were sent; all were returned normal. Meanwhile, further history was obtained. The child was mostly breastfed. He had no other sick contacts, and family history was unremarkable. His only other episode of illness occurred 1 week earlier and consisted of 1 day of intermittent “fussiness” or “colic.” For this he was fed a small amount of herbal tea for colic (a family remedy). The tea included approximately 1/2 teaspoon of honey that came from a sealed, single-serving packet from a nationwide fast food chain where his father works. The Michigan Department of Community Health and the Infant Botulism Treatment & Prevention Program (IBTPP) of the California Department of Health were contacted for guidance in the diagnostic evaluation of infant botulism. A stool sample to assay for the presence of Clostridium botulinum toxin was sent to Michigan Department of Community Health’s microbiology laboratory. The infant simultaneously was entered into a study protocol for treatment of infant botulism with human botulism immune globulin (BIG). After baseline serum was drawn to assay for botulinum toxin and antibody levels, BIG (delivered within 24 hours from California) was infused. Meanwhile, on Monday morning an electromyogram (EMG) was performed and reported as mostly within normal limits and therefore inconsistent with botulism. Two days after the BIG infusion, movement increased in the boy’s fingers and toes, and his complete paralysis began to resolve very Air Medical Journal 22:5

gradually. On hospital day 12, his stool was reported as having an extremely high concentration of botulinum toxin A. On hospital day 24, the infant was extubated successfully to nasal continuous positive airway pressure. He was discharged home on hospital day 55, and 1 month later, he was well enough to resume full oral feeding as part of his complete recovery.

Historical Perspective Botulism is a rare, often deadly paralytic disease that afflicts humans in 1 of 3 natural forms. Foodborne botulism, the first clinical syndrome to be recognized, takes its name from the Latin term for sausage, botulus, because outbreaks of the disease first were linked to sausage consumption, particularly blood sausage.1,2 In 1897 in Belgium, studying an outbreak of 24 cases (3 fatal) linked to a ham served at a funeral, Emile Van Ermangem isolated the organism, Clostridium botulinum, and its toxin and determined that the disease was toxin mediated.1,3 Botulism first received significant attention in the United States in the early 1900s, especially during World War I. The wartime boom in home and commercial canning lead to epidemics of botulism.1,4 The Department of Agriculture greatly reduced the incidence by setting new commercial food processing standards and leading a massive public education campaign.1,4 The other natural forms of the disease are wound botulism and infant botulism.2,3,5,6 The annual US incidence of botulism is fewer than 200 cases. Foodborne botulism has a variable incidence. Wound botulism, once extremely rare but now primarily a complication of skin popping black tar heroine (BTH), is rapidly becoming more frequent. Infant botulism is the most common current form.5,7-9

the toxin circulates to acetylcholine-dependent synapses of the autonomic nervous system and neuromuscular junctions in skeletal and smooth muscle. The toxin inhibits release of acetylcholine from the presynaptic terminal, thus affecting both nicotinic and muscarinic acetylcholine synapses.3,5,6,15 The toxin does not, however, cross the blood-brain barrier.4 Thus, despite complete paralysis and potentially devastating autonomic nervous system perturbations, mental status and sensory systems remain completely intact.3,4,6 Recovery of normal synaptic function depends on the quantity of toxin absorbed and the rate of new synapse formation.3,6,10,15 Botulinum toxin is the most potent, lethal substance known. It is estimated to be at least 15,000 times more potent than the organophosphate nerve agent Sarin.2,8 The exact minimum lethal dose in humans is not known but can be estimated by primate studies to be < 2 ng per kg intravenously and approximately 1 mcg per kg orally.5,10

Foodborne Botulism

C. botulinum is an obligate anaerobe and spore-forming, Gram-positive, rod-shaped bacterium. It is classified according to the variant of exotoxin it produces. Each strain produces only 1 type of toxin.6 Toxins A, B, and E cause the vast majority of human disease.10 C. botulinum spores are ubiquitous in the soil throughout the world.1,11 It is a common member of the intestinal flora of some birds.12 In this country, type A is found primarily in soil west of the Mississippi and is the cause of most cases in the western US. Type B is more common in the eastern US and throughout Europe and is associated with most cases there.1,2,6,13 The concentration of C. botulinum spores in the soil varies among regions. It is especially high in California and southeastern Pennsylvania.12 Type E is predominantly found in seawater, soil on the ocean floor, coastal areas, and along the Great Lakes.2,6,10 Type E disease usually is associated with contaminated seafood and predominates in the Pacific Northwest, Alaska, and around the Baltic sea.6,13,14

Foodborne or classic botulism is the oldest recognized form. This occurs after ingesting food that contains neurotoxin as a result of inadequately processed food contaminated with C. botulinum spores. The spores are extremely hardy and can tolerate boiling at 100˚C for hours. To destroy the spores, contaminated foods must be heated to 120˚C for 30 minutes (the basis for pressure canning and autoclaving).6,10 In addition, type E C. botulinum spores are capable of germination at temperatures as low as 3˚C and frequently have been associated with refrigerated seafood.6,13 Spore germination in food is promoted in an anaerobic environment (wrapped or sealed foods) where the pH is > 4.5, with a low sodium or nitrate concentration, and a high water content. Preserved meats, particularly sausage, ham, and fish, often are implicated in Europe and Alaska.2,3,6,10,13 In the rest of the United States, home-canned, low-acid vegetables are implicated most commonly, including chili peppers, beets, asparagus, green beans, mushrooms, and some low acid tomatoes.2,3,6,10,14 Several outbreaks have been attributed to baked potatoes wrapped in foil for long periods (often then placed into a potato salad).6,10,14,16,17 The acidic property of vinegar protects most pickled foods, but case reports involving pickled foods also occur, usually a result of an inadequate vinegar concentration.14,18 Most fruits and jams are too acidic to serve as a growth medium for C. botulinum and are not associated with botulism.3,6,10 Germination and growth of the spores leads to toxin release. Ingesting the bacteria or spores usually is harmless (for noninfants). However, the preformed neurotoxin is readily absorbed, and botulism ensues. Fortunately, the toxin, unlike the spores, is heat-labile and can be destroyed by heating the food (immediately before consumption) to 80˚C for 30 minutes or 100˚C for 10 minutes.6

C. botulinum Toxin

Wound Botulism

The bacteria itself has no significant virulence properties other than the production of toxin. The difference between the various forms of the disease is the mode of toxin exposure and transmission to the blood stream. Once in the blood stream,

Wound botulism occurs when a wound or the subcutaneous tissue is inoculated with C. botulinum spores, followed by anaerobic growth, and toxin production.2,6,9 Until recently this entity was very rare. Only 27 cases had been reported in

Clostridium botulinum

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the 40 years since first described in 1943.3,19 Wound botulism has occurred in grossly contaminated crush injuries, puncture wounds (like tetanus), sinusitis, and even in a small number of postoperative wound infections (unrelated to trauma).9,19,20,21 However, in 1982, the first case of wound botulism associated with injection drug use (IDU) was reported. This case was followed by several more in the late 1980s. Since then, the incidence of IDU-associated wound botulism has increased rapidly each year, especially in California, where 29 cases occurred in 1998.9 Although case reports arise of IDU patients developing wound botulism from cocaine injection (and occasionally cocaine inhalation-related sinusitis), the current epidemic of wound botulism clearly is linked to the growing use of Mexican BTH, especially in the southwestern United States, where it has largely replaced Asian china white heroin. 3,7,9,20,22-28 Meticulous epidemiologic case series reviews of wound botulism patients have demonstrated that C. botulinum spores contaminate the BTH.7,9,28 Wound botulism occurs primarily with skin popping, in which the drug is injected subcutaneously or intramuscularly, and only occasionally when the user claims only intravenous injection.7,9,28 Most heroin starts in a solid form that is dissolved in water and heated before injection. However, this period of heating is inadequate to destroy C. botulinum spores.7 According to the Drug Enforcement Agency, BTH is a relatively pure form of heroine produced in Mexico in small makeshift factories next to opium poppy fields.7,9,20 After harvest, a step in the process of conversion to heroin (diacetylmorphine) requires the raw material to be heated to 150˚C for hours (long enough to destroy any C. botulinum spores).7 The final product is brown or black and can be sticky like tar or hard like coal.9,20 As with most illicit drugs, it then is diluted or cut with a variety of inert materials, including cornstarch, lactose, mannitol, shoe polish, coffee grounds, or even clay or dirt.7,9

Infant Botulism Infant botulism affects children up to 1 year of age (cases reported from the first to fifty-second week of life), but the vast majority (95%) of patients are 3 weeks to 6 months of age.4,12,29-31 The disease occurs when the immature infant gut is inoculated with C. botulinum spores and becomes colonized as a result of the higher pH, lack of bile acids, and lack of competing flora. Botulinum toxin is released and steadily absorbed through the gut into the bloodstream, and weakness and paralysis ensue.3,4,12,29,31,32 The first case of infant botulism was not diagnosed until 1976, after the Centers for Disease Control and Prevention (CDC) changed its recommendations for botulism testing to include stool (and serum) assays for botulinum toxin.4,29,32 Reviews of similar cases from as early as 1931, previously diagnosed as an encephalitis or acute infantile polyneuropathy, have been changed to infant botulism.29,32 The condition now is recognized as the most common form of botulism in the United States (approximately 80 cases per year) and worldwide.12,31 The source of the infecting C. botulinum spores usually is 8

not identified.4,12,29 Household investigations of confirmed cases strongly suggest the spores are encountered in the soil and dust in and around the home, houseplants, and parents’ work shoes.4,12,33 In the United States, infant botulism is most common in California, Utah, and the botulism ring around Philadelphia, where the soil has a higher concentration of C. botulinum.4,12,29,31,32 Infant botulism is almost exclusively a result of C. botulinum types A and B.12 As in foodborne botulism, type A disease predominates in the west and type B in the east.4,12,29,31 The only proven food source exposure to infants is honey, and current recommendations are that honey should not be given to infants less younger than 1 year.4,12,29,33 However, infant botulism is linked to honey exposure in probably less than 20% of cases (and 35% at most).4,12,33 Microbiologic surveys of honey throughout the world have found C. botulinum spores present in 4 to 25% of samples.4,12,32-34 Corn syrup also had been identified as a possible source of C. botulism spores. In the early 1980s the Food and Drug Administration detected C. botulinum spores in commercially produced corn syrup. However, after changes in processing, repeat testing by the Food and Drug Administration was negative,35 and commercially produced corn syrup is no longer considered an exposure risk.12,35 This is important because pediatricians occasionally prescribe corn syrup as a laxative.12,35

Presentation of Infant Botulism Constipation is a hallmark of the disease (only rarely absent) and almost universally ensues a few days after inoculation.4,12,29,30,32 The first signs of weakness are noted 0 to 24 days after the onset of constipation.4,29 However, constipation is the presenting complaint in fewer than half of cases and may be revealed only in a review of systems.4,29 More commonly, infants present with complaints of weakness manifested as feeding difficulty, a feeble cry, loss of head control, “lethargy” (describing an increasingly sleepy appearance or lack of spontaneous movement), and occasionally apnea.29,32 On examination, infants usually are afebrile but may have fever and rales from atelectesis or aspiration pneumonia. A weak suck, ptosis, sluggish pupils, decreased tone, and decreased head control are common.4,29,32 Infants frequently are described as lethargic but not septic appearing.29 Dehydration and bladder distention also may be noted.29,32 Once weakness begins, it usually progresses rapidly over 1 to 3 days.32 Many infants (> 75% in one large series) will progress to loss of airway control or respiratory failure and require mechanical ventilation.4,31,36 Because of the potentially rapid onset of respiratory failure, infant botulism has been proposed as a cause of sudden infant death syndrome (SIDS) since 1978.37 The term sudden infant botulism has been suggested.38 Infant botulism is noted to peak in a similar age distribution as SIDS.37-39 Autopsy studies have found C. botulinum organisms and toxin in up to 20% of SIDS cases.39 Furthermore, age-matched healthy carriers of C. botulinum are almost nonexistent.37-39 However, the overall percentage of SIDS cases positive for C. botulinum is extremely variable, from 0% (in a large Australian study) to 4% (California) to 15% (Switzerland) to 20% (Germany).37-40 Air Medical Journal 22:5

Of course, the distribution of C. botulinum in the soil has been demonstrated to be highly variable, and the location of the autopsy series may reflect that.4 Thus, sudden infant botulism as a disease entity, although certainly feasible, remains controversial.

sensitive (far greater than in foodborne botulism).39 Many centers do not attempt to culture the organism unless the toxin assay is negative. Interestingly, infants have been shown to shed toxin in the stool for more than 3 months after symptoms improve.4,29,32

Diagnosing Infant Botulism

Treatment

The differential diagnosis of a floppy infant is very broad. One must always rule out infectious etiologies, such as sepsis, meningitis, encephalitis, and, if apnea is the presenting complaint, respiratory syncytial virus and pertussis. In early infancy, metabolic and endocrine disorders, such as hypothyroidism, organic acidurias, or other inborn errors of metabolism leading to hepatic encephalopathy, must be considered. In newborns, particularly premature infants, central apnea or reflux-associated apnea is a concern. Toxin exposures, including narcotics, alcohol, heavy metals, anticholinergics, and organophosphates, are possible. Other primary neurologic disorders must be considered, such as infantile spinal muscular atrophy, Guillian-Barre Syndrome, congenital myasthenia gravis, poliomyelitis, muscular dystrophy, and tick paralysis. Finally, a diagnosis of nonaccidental trauma should be entertained. Despite the broad differential, the diagnosis remains clinical. These key features, as in other forms of botulism, remain true: •The infant is usually afebrile (unless developing an aspiration pneumonia). •For a neuromuscular disease, the progression is rapid from time of onset. •Deep tendon reflexes can be normal to hypoactive to absent. •Sensation and mental status also should be normal but may be difficult to assess in a profoundly weak infant. • Electroencephalogram and neuroimaging should be normal (barring an arrest). •Cerebrospinal fluid, electrolytes, and creatinine phosphokinase should be normal. • EMG signature is that of disease at the neuromuscular junction only and may or may not show mild posttetanic facilitation. The test is highly suggestive and may be considered confirmatory in the right clinical setting. However, it is not 100% sensitive or specific, and false negatives are reported.31,36,41

The key element of treatment is supportive care (especially airway protection and ventilatory support). In infants, loss of airway control and respiratory fatigue is particularly insidious and can occur suddenly. All infants should be admitted to an ICU for at least 48 hours of intensive monitoring.12,29,31 Continuous pulse oximetry, respiratory rate, and gag reflex should be checked early and serially. Negative inspiratory force and forced or total vital capacity are difficult to measure on unintubated infants and therefore have limited value in predicting need for mechanical ventilation (but are very useful in timing extubation).31 Prophylactive intubation in all infants younger than 2 months old is recommended.4,12,31 If not intubated, infants should be kept inclined to 30˚ to prevent silent aspiration.5,29 Weakness reaches a nadir at about 1 week after onset and may result in complete paralysis.4,29 Experience with equine antitoxin in infants is limited. It has been given to only 2 infants, and neither appeared to benefit.29 One of the infants had an immediate anaphylactic reaction, with bronchospasm and hypotension, after receiving only one-tenth the planned infusion dose.29 The equine antitoxin works in foodborne and wound botulism by binding circulating toxin, but less than 1% of infants have ever had a measurable concentration of toxin in the blood.32,43 Furthermore, it has a half-life of only 5 to 6 days, and infants appear to absorb toxin at a very low but steady rate for weeks to months.4,6,8,12,29,32,44 Thus, given its lack of efficacy, risk of adverse effects, and risk of inducing lifelong hypersensitivity to equine products, equine antitoxin is not recommended in infants.4,29,32 Because of these problems, research was begun in the late 1970s to develop a human-derived botulism immune globulin, now known as BIG, to achieve lower antigenicity and an increased half-life, estimated at approximately 30 days.5,44,45 BIG is obtained by plasmapharesis of pooled plasma, donated from a small group of individuals who have been fully immunized against botulism.44,45 In 1989, the California Department of Health Services received orphan drug designation for the pentavalent BIG.43 In 1997, a 5-year, placebo-controlled, double-masked, randomized clinical efficacy trial of BIG involving 122 infants from 90 participating hospitals was completed.12 The group receiving BIG demonstrated a better than 60% reduction in the rate of intubation and a reduction in hospitalization from 5.5 to 2.5 weeks.12 Furthermore, according to the IBTPP, the average cost of hospital stay (in 1997 dollars) was reduced from $129,500 to $60,000. The IBTPP also asserts that no related adverse events occurred and the only documented reactions were transient, mild, blush-like rashes. To obtain BIG, the IBTPP should be notified through the California Department of Health Services at (510) 540-2646 or www.infantbot.org. The cost to the ordering institution is approximately $1000.

Electromyography results in infant botulism have been very reliable in some institutions and inconclusive in others. Inexperience with the disease in question and the intensive care setting, especially in infant botulism, can both contribute to a decreased sensitivity.4,31,36,41 Furthermore, the EMG, although regarded by some to be essential to an early diagnosis, is considered by some experts to be painful and unnecessary.12 The diagnosis is confirmed definitively when the toxin is isolated from the stool. The serum usually is tested but has a very low yield (positive in < 1%).29,32,42 As in all forms of botulism, the mouse bioassay is the most sensitive assay and remains the current standard.5,12,29 Sensitivity of the mouse bioassay for toxin in stool in infant botulism is 65 to 100% September-October 2003

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Just as early administration of antitoxin is critical in other forms of botulism, the same applies to BIG and infant botulism. Once the diagnosis is reasonably considered, the IBTPP should be notified immediately. BIG should be provided before confirmation of the diagnosis from the stool toxin assay. Finally, BIG, although presumably extensively tested like other blood products, is a pooled human plasma product. Given the potential infectious disease implications and the potential waste of this valuable product, it should not be administered in low probability cases. Additional principles of supportive care (that apply to most forms of botulism) are as follows. Autonomic instability occurs in approximately 12% of infants, including reported deaths from progressive bradycardia.17 Many infants also are dehydrated from poor intake.4,29 Close attention should be paid to fluid resuscitation, and atropine and pressors used as needed.4,29,31,32 Nasoduodenal or nasojejeunal feedings should be started early, even in infants with absent bowel sounds but no radiographic evidence of ileus or obstruction.12,29,31 A regular bowel regimen should be maintained (lactulose and glycerin suppositories are recommended). 29 Close attention should be paid to avoid iatrogenic complications. Urinary retention should be treated with a Foley catheter if necessary. However, catheters should be removed as soon as possible, and the technique of bladder drainage switched to the Crede method.29 In addition, despite the fact that these infants often are paralyzed, unplanned extubations are not uncommon.31 A complication unique to infant botulism is the syndrome of inappropriate secretion of antidiuretic hormone, resulting in fluid retention and hyponatremia, occurring in up to 16% of patients.4,31,32 Seizures have been attributed to hyponatremia.31 Urine output and electrolytes should be monitored. Despite the fact that the gut is colonized with the organism, antibiotics are not recommended. Only a small number of infants have been treated with antibiotics specifically to eradicate C. botulinum. These case reports give no indication that any benefit was yielded. Some anecdotal evidence suggests it may only exacerbate the severity or duration of paralysis by lysing bacteria in the gut and causing more toxin release. In addition, the IBTPP suggests that if antibiotics are needed to treat a complicating infection, such as an aspiration pneumonia or urinary tract infection, antibiotics to which C. botulinum generally is resistant, trimethoprim-sulfamethoxazole should be used. Alternatively, if a second or third generation cephalosporin is indicated, ceftizoxime or cefotaxime (and avoiding aminoglycosides, as in all forms of botulism) are recommended. In addition, although not clearly linked with antibiotic use, unusually severe cases of C. difficile have been reported in infant botulism.12,46 The acquired colonic stasis of infant botulism, similar to the congenital stasis of Hirschsprung’s disease, may contribute to the susceptibility and severity of C. difficile infections, manifesting as toxic megacolon and necrotizing enterocolitis.12,46 With meticulous supportive care, long-term prognosis is excellent. After reaching a nadir approximately 1 week after the onset of weakness, a very gradual course of improvement ensues. However, exacerbations or relapses within 2 weeks after stabilization occur in about 5% of cases, likely related to 10

the persistence of toxin in the gut.36 Despite this prolonged persistence of toxin, the infants somehow either resist further absorption or “tolerate” its effects.4 In the United States, mortality is less than 1% of hospitalized infants, even without the use of BIG.4,31,32 Most deaths occur in rapidly progressive disease as a result of respiratory failure.4,29,31

Conclusion Botulism, although rare, can present in multiple forms. The history and physical examination are essential to making the diagnosis. In turn, early diagnosis and treatment are critical to reducing mortality, morbidity, intensive care unit complications, and length of hospitalization and ventilator dependence. The diagnosis is clinical until proven or disproved and is confirmed by toxin isolation from stool or serum (or a wound or associated food source). If suspecting botulism, call the state department of health or CDC for antitoxin. If suspecting infant botulism, call the IBTPP to discuss the case with a physician investigator. Most of all, remember the ABCs. Loss of airway control or respiratory failure from diaphragmatic weakness is insidious. All patients need intensive airway and respiratory monitoring. Intubate for hypoxia or a weakened gag or cough reflex (or, when measurable, critically decreased negative inspiratory force or forced vital capacity. Consider prophylactic intubation for all infants 2 months of age or younger. When in doubt, intubate. Do not forget fluid resuscitation and hemodynamic monitoring for autonomic instability. The hospital course often is long, but the overall prognosis is good with close, supportive care.

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Eric M. Ketcham, MD, works in the department of emergency medicine at the University of Michigan Health System in Ann Arbor. Hernan F. Gomez, MD, ACMT, is a clinical associate professor in the same department. Copyright 2003 by Air Medical Journal Associates 1067-991X/2003/$30.00 + 0 doi:10.1067/mmj.2003.65

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