The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2003 second edition, Dr. Andrew K. Feng. This current third edition chapter is a revision and update of the original author’s work.
A 1 month old boy presents to the pediatrician's office with a chief complaint of decreased activity, poor feeding, and constipation for 2 days. Pertinent past medical history reveals that the infant was born at 39 weeks gestation, with no complications during the pregnancy or birth. The infant is exclusively breastfed, up-to-date on immunizations and has not suffered from any previous illness. On further questioning, his mother reports her baby has not been himself for the past week. He has had no fever and there are no sick contacts. He has been less active and has a weak cry during this time. His mother also notes her baby has not been as interested in feeding and has recently become constipated. His urine output is decreased with only four wet diapers in the last 24 hours. Typically, he has 3 to 4 soft stools per day, usually after feeds, but has had no bowel movement in the past 4 days. The infant is referred to the pediatric inpatient service for hospitalization.
Exam: VS T37.0, P 144, R 42, BP 75/50, Weight 4.5 kg (50%), Height 55 cm (50%), HC 37 cm (50%). He is awake, lethargic appearing, with an expressionless face. His mouth is open and he has a weak hoarse cry. His anterior fontanel is flat and soft. He has poor head control with marked head lag. His eyes appear sleepy with slight bilateral ptosis. He has a weak suck and gag reflexes with increased oral secretions. His neck is supple without adenopathy. Heart and lungs are normal. Aeration is good. His abdomen is soft, non-tender, with decreased bowel sounds throughout. No hepatosplenomegaly. His extremities are slightly cool with capillary refill time of 3 seconds. His skin shows no rash or petechiae. He has decreased muscle tone throughout and diminished deep tendon reflexes. He was not able to roll over and slumped forward with poor head control when placed in a seated position.
A sepsis work up is done and he is started on IV fluids and empiric antibiotics of ampicillin and gentamicin for possible sepsis. After 6 hours in the hospital, his overall condition deteriorates, and a code blue is called for apnea. He is bag mask ventilated, but he continues to be apneic, therefore he is intubated and placed on mechanical ventilatory support.
His neurological clinical condition worsens such that he becomes completely flaccid. His cultures remain negative for bacterial growth. Viral studies are negative. An electromyography study is done which shows brief, small, abundant, motor unit potentials, known by the acronym BSAP, a characteristic pattern associated with infant botulism (1). Botulinum immunoglobulin (BIG) is administered. He gradually improves, and he is weaned off the ventilator after 12 days. His stool assay returns positive for botulinum toxin. He continues to gradually improve over the next two weeks such that he is able to feed on his own, and he is then discharged from the hospital.
Clostridium botulinum is a gram positive, spore forming obligate anaerobe that can be normally found in the soil worldwide. It is found in a wide variety of fresh and cooked agricultural products including fruits, vegetables, and honey (1). Historically, a significant number of cases were linked to ingestion of honey in infants. Since then, it has been recommended to avoid honey in infants (2). Could the honey have caused the infant botulism, or could the honey be merely associated with botulism since it was a common treatment for infant constipation which is a known symptom of infant botulism? Honey is longer given to infants, yet cases of infant botulism still occur.
Infant botulism has been reported from all inhabited continents continents including most recently Africa (3). In the United States, there are approximately 100 reported cases every year, with more than 50% of the new cases reported in California (4). Risk factors include breastfed infants with high birth weights, consumption of honey, residence in a region with high spore densities and potential soil exposure, and advanced maternal age (1,4). Epidemiologically, 95% of all cases are reported in patients between 6 weeks and 6 months of age. Once ingested, the bacteria produce a neurotoxin within the gastrointestinal tract. The toxin is subsequently absorbed and carried by the blood stream to peripheral cholinergic synapses, in particular the neuromuscular junction, where it binds irreversibly and blocks acetylcholine release from neuromuscular junctions in cranial and peripheral nerves. This results in generalized weakness and hypotonia, and the clinical findings may present with large variability, on a spectrum from milder feeding difficulties and failure to thrive to a sudden infant death syndrome (SIDS) like presentation. The most common clinical manifestation is constipation, which is seen in over 95% of all cases.
The classic picture of infant botulism is an initial presentation of constipation (defined as 3 or more days without defecation in a previously regular infant), listlessness, and poor feeding (resulting in maternal breast engorgement for breast fed infants). The typical patient often has an expressionless face, weak/hoarse cry, ptosis, poor head control, generalized weakness, and hypotonia. Patients are most often afebrile (unless a secondary infection is present), and most initial laboratory tests are normal. The differential diagnosis includes sepsis (the most common admitting diagnosis), dehydration, viral syndrome, constipation, hypothyroidism, Lambert-Eaton myasthenic syndrome, Guillain-Barre syndrome, meningitis, other neurologic diseases, inborn errors of metabolism, and poisoning. The diagnosis is made clinically and confirmed with isolation of C. botulinum neurotoxin or organisms identified in the stool. Importantly, the described BSAP pattern is not specific and thus electromyography (EMG) is not diagnostic, nor is it necessarily required for the clinical diagnosis (1).
Treatment of infant botulism is fundamentally supportive and depends on the anticipation and avoidance of potentially fatal complications. Antibiotics are not routinely recommended as they have not been shown to affect the course of the illness or recovery times, except in treatment of secondary complications, including pneumonia and urinary tract infections (UTI).
Aminoglycosides, which are weak pharmacologic neuromuscular blocking agents, may even potentiate the neuromuscular weakness caused by the released toxin and should be particularly avoided to prevent acutely worsening paralysis and potential respiratory complications if infant botulism is suspected (1,2). Note that in this chapter’s case presentation, the patient undergoes an evaluation for sepsis, then empiric treatment with ampicillin and gentamicin, which is followed by a respiratory arrest, possibly from the gentamicin. Human botulinum immunoglobulin (BIG), which acts by interrupting the neuromuscular blockade, has been approved for the treatment of infant botulism. A single intravenous dose of BIG has been shown to reduce the typical course of hospitalization from 5.7 to 2.6 weeks with a mean reduction of intensive care unit time of 3.2 weeks, and mechanical ventilation time of 2.6 weeks (5).
Most infants will show gradual improvement over a period of 10 days to 2 months with rare cases of relapse. Common complications including respiratory failure (requiring mechanical ventilation), secondary infections (e.g., pneumonia and UTI), and SIADH (syndrome of inappropriate anti-diuretic hormone). Infant botulism requires an appropriate management to optimize the ultimate prognosis, which is potentially excellent with a full neurologic recovery.
"Infant botulism" differs from "botulism" in that food-borne botulism results from the ingestion of a food in which C. botulinum has produced pre-formed toxin, so its onset is more rapid compared to infant botulism. It is more commonly seen in older children and adults and often occurs in outbreaks traced to spoiled, low acidity canned foods. While all forms of botulism produce disease through a similar pathway, food-borne botulism often begins acutely with gastrointestinal symptoms such as nausea, vomiting, and diarrhea. A characteristic pattern of dysarthria, dysphagia, dry mouth, diplopia, and blurred vision with ptosis, evolves during the onset of disease. Fulminate and extensive paralysis, respiratory distress and apnea are more likely to be experienced with food-borne botulism. Wound botulism is an exceptionally rare disease but is important in pediatrics since adolescents and children are disproportionately affected.
Questions
1. The mother of a 3-month-old infant asks if it is okay to coat a pacifier with honey to soothe her baby. What is your response?
2. What is the basic mechanism of action of botulinum toxin?
3. Describe the typical clinical presentation of infant botulism. Why may the diagnosis be unclear initially? What is the classic age distribution?
4. What are the principal methods that can be used to confirm infection by C. botulinum?
5. What are the indications for antibiotic treatment in an infant with infant botulism? Why are aminoglycoside antibiotics relatively contraindicated?
6. What is the role of human botulinum immunoglobulin in the treatment of infant botulism?
7. What is the prognosis for an infant infected with infant botulism?
8. Describe the basic difference between "botulism" and "infant botulism”.
References
1. Brook I. Infant botulism. J Perinatol. 2007;27(3):175-180. doi:10.1038/sj.jp.7211651
2. Chapter 31. Botulism and Infant Botulism. In: Baker CJ (ed). Red Book Atlas of Pediatric Infectious Diseases, 4th edition. 2020, American Academy of Pediatrics, Itasca, IL, pp: 113-118. doi:10.1542/9781610023511-31
3. Vosloo MN, Opperman CJ, Geyer HDW, et al. First confirmed case of infant botulism in Africa, caused by a dual-toxin-producing Clostridium botulinum strain. Int J Infect Dis. 2021;103:164-166. doi:10.1016/j.ijid.2020.11.131
4. Van Horn NL, Street M. Infantile Botulism. Treasure Island (FL): StatPearls Publishing; 2022. https://www.ncbi.nlm.nih.gov/books/NBK493178/
5. Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL. Human Botulism Immune Globulin for the Treatment of Infant Botulism. N Engl J Med. 2006;354(5):462-471. doi:10.1056/NEJMoa051926
Answers to questions
1. It is recommended that infants should avoid honey.
2. Botulinum toxin is released by bacteria within the infant's gastrointestinal tract. From here, the toxin is absorbed and carried by the bloodstream to cholinergic receptors where it binds irreversibly, preventing the release of acetylcholine. Clinically, the most important of the cholinergic receptor is the neuromuscular junction. Here the toxin's action results in flaccid paralysis and hypotonia, which are the classic clinical signs of infant botulism.
3. Initially, infected infants often present with a history of poor feeding, decreased activity, and constipation. The diagnosis may not be considered initially because signs of an evolving bulbar palsy, flaccid paralysis, and hypotonia may be subtle. Additionally, the infant may be evaluated for sepsis if he appears toxic or lethargic, or for constipation until the classic manifestations of infant botulism become apparent. The classic age distribution for infant botulism is 3 weeks to 6 months of age.
4. Isolation of the clostridium botulinum organism in stool can be accomplished in the early stages of disease. It is rarely isolated in blood. The most common method for proving infection is to isolate botulinum toxin in blood or stool samples. Toxin can be detected in the stool of infected infants for up to 4 months. Electrophysiological testing, specifically electromyography, can aid in ruling out other neurologic disorders such as Guillain-Barre syndrome, congenital myopathies, and myasthenic conditions.
5. The use of antibiotics in infant botulism should be reserved only for proven secondary infections such as pneumonia or urinary tract infections. Aminoglycosides should be avoided as they are weak pharmacologic neuromuscular blocking agents which may worsen paralysis acutely or cause respiratory failure in an unsuspected infant with botulism being treated for sepsis.
6. Human botulinum immunoglobulin (BIG), which acts by interrupting the blockade of nerve receptors by botulinum toxin, has been shown to reduce the need for mechanical ventilatory support and shorten overall duration of hospitalization.
7. If recognized early and given appropriate supportive care minimizing complications, a full recovery and normal neurologic function can be expected.
8. Classic "botulism" is a food borne disease in which high levels of toxin in spoiled canned foods can be ingested. It often occurs in outbreaks linked to a particular source, and typically afflicts older children and adults. Wound botulism is are but is seen disproportionately in adolescents and children. Infant botulism has a more gradual onset. All types of botulism produce disease through a similar pathogenesis.