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Case 1
A 6-month-old infant was admitted to the intensive care unit of our centre with a 2-day history of poor feeding, decreased movement of all limbs and respiratory distress. The patient was hypotonic and cold peripherally with a metabolic acidosis. Treatment for presumed sepsis was commenced. On day 4 of illness the child became unconscious and bradycardic, necessitating ventilation.
Cranial MRI was normal. Electromyography (EMG) was suggestive of Guillian–Barre syndrome but there was no improvement despite intravenous immunoglobulin therapy. Infantile botulism was queried, and a faecal sample sent for analysis to the regional Health Protection Laboratory confirmed the presence of toxin A producing Clostridium botulinum on PCR. Botulism immune globulin (BabyBIG) was given on day 16 of the illness. Improvement was notable but still slow, requiring continued ventilation for 6 weeks through a tracheostomy.
Case 2
A 2-month-old infant presented with a 5-day history of constipation, poor feeding, lethargy, poor respiratory effort and hypotonia. Within hours the child deteriorated, requiring intubation and ventilation and remained floppy, with dilated pupils despite minimal sedation. The infant was mixed breast and bottle fed and the parents reported giving a commercial brand of honey as a remedy for constipation. The cranial CT scan was normal. Clinical suspicion of botulism was raised and confirmed on day 4 of intensive care admission with faecal sample positive for C botulinum toxin type A. EMG was compatible with this clinical picture of botulism. BabyBIG was given on day 11 of illness, after which neurological and respiratory improvement was noted. Successful extubation occurred on day 16 with a slow but full recovery. The milk formula and honey were negative for C botulinum.
Case 3
A 3-month-old infant presented to the local hospital with a 2-week history of poor feeding, decreased social interaction and constipation. The mother reported using honey to pacify her infant. This child was noted to be globally hypotonic with evolving bilateral ptosis, a weak cry and had one episode of apnoea. Cranial MRI and EEG were normal but EMG indicated a neuromuscular junction abnormality. Both honey and rectal washout samples were culture positive for C botulinum type A. In addition, toxin A was isolated by PCR from the faecal sample. BabyBIG was administered 2 days after molecular diagnosis was made (day 17 of illness) and there was clinical improvement in tone, with no further respiratory compromise.
Case 4
A 4-month-old infant presented to the local hospital with a 3-day history of weak cry, lethargy, poor feeding and increased work of breathing. The mother reported giving honey to the child for constipation. Examination noted global hypotonia, bilateral ptosis and a weak cry. Treatment for presumed sepsis was commenced; but by day 5, intubation was required for respiratory failure. MRI scan of brain and spine were normal. EMG indicated a neuromuscular transmission disorder with ‘no particular neurophysiological signature of botulism’. Faecal samples were negative by PCR for C botulinum toxin on day 6 of illness but on day 8, faecal cultures were positive. This child did not receive BabyBIG and remained intubated for several weeks.
Discussion
Infantile botulism is a rare but treatable cause of paralysis in infants. The Health Protection Agency reported six cases of infant botulism in England and Wales between 1975 and 2007.1 Since 2007, seven cases are documented (including those described here)2 which raises the concern that the incidence is increasing. Mild cases may be missed and underreported.
Clinicians should be alerted that, as in our cohort, the constellation of constipation, poor feeding, ptosis, facial muscle paralysis and generalised weakness are classic signs of infant botulism. The three infants who were given BabyBIG once the diagnosis was confirmed went on to make a good recovery.
Infantile botulism occurs when spores of the organism C botulinum are ingested and colonise the gut. Toxin is then produced and absorbed into the bloodstream.3 Botulism is a neuroparalytic illness caused by one of four genotypically and phenotypically distinct groups of C botulinum (groups I–IV). These antigenically distinct toxins vary in the spectrum of clinical illness they cause: only toxin types A, B, E and F are known to cause illness in humans. Infantile disease is generally due to toxins type A and B. The toxins exert their action by preventing acetylcholine transmission at the neuromuscular junction, thereby resulting in blockade. Neurotoxin A is the most potent, with the longest lasting effects.4,–,6
Onset of symptoms may occur from 6 h to 8 days after ingestion of the toxin. The clinical manifestations range from subclinical infection and mild disease possibly to sudden infant death. It has been postulated that poor host microflora defences in young infants may worsen the disease. Antibiotic therapy given empirically for sepsis may aggravate toxin release and potentiate its effects. Complete recovery may take several weeks to months and is dependent on the regeneration of new neuromuscular end plates.
In the USA, pooled human immunoglobulin specific to botulinum toxin (containing antibodies to toxin A and B) was first trialled in 1992, with routine use since 2003. BabyBIG is only available on a case-by-case basis from the Infant Botulism Treatment and Prevention Programme in California.4 5 7 It is a single intravenous infusion and costs approximately £50 000.00 for a treatment dose in a 5-kilogram infant.
BabyBIG has been used in three patients in the UK, and all three cases are reported here.2 Unfortunately, in all cases significant delay occurred to administration of the drug, due to time needed for diagnostic confirmation, requirement for hospital drug and therapeutic board approval and shipping from California. Response to treatment is thought to be optimal if initiated within 3 days of onset of the initial illness4 5 but can, if given within 7 days, significantly reduce the inpatient course, in particular the duration of intensive care support. In our cohort BabyBIG was given even after this period, but despite this, we saw favourable results. Our rationale for treatment in these cases was the potential prolonged intensive care and neuro-rehabilitation to which all three infants could have been subjected to if supportive care alone had been used. In cases 2 and 3 at least, we believe this may have been prevented.
Botulism is usually associated with the use of honey, powdered infant formula or dust. It classically affects infants at the time of weaning but may also occur in the neonatal and early infancy period. Diagnostic confirmation is by toxin isolation from faecal samples. Our cases were confirmed on PCR performed by the HPA.1 2 Three of the four infants in this series had been given honey, which was the major risk factor and presumed to be the source of the infection (with only one positive honey sample). Public health guidance advises against the use of honey in children less than 1 year of age. Commercial honey distributors also issue such guidance on their products, but with new cases reported since 2007; this advice needs to be highlighted.8 This will encourage earlier recognition of botulism when these infants present with symptoms and also further discourage parents and caregivers from giving honey to infants.
Clinicians should be vigilant as the incidence of infantile botulism appears to be rising in the UK, diagnostic delay is common and early treatment with BabyBIG significantly improves outcome.
Acknowledgments
The authors acknowledge the support of Dr K Grant of the Foodborne Pathogen Reference Unit, Health Protection Agency (HPA), Centre for Infections, London.
Footnotes
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Competing interests None.
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Provenance and peer review Not commissioned; externally peer reviewed.