No 17 - 2015

Three cases of infant botulism

From December 2014 to March 2015, three children in the Copenhagen area aged 5-6 months were diagnosed with infant botulism. All three cases presented with classic symptoms of infant botulism. Nevertheless, the diagnosis was not made immediately, probably because the clinical image may be hard to distinguish from other causes of infant hypotonia.

Botulism is a rare, but potentially life-threatening, neuro-paralytic syndrome caused by neurotoxins that are produced by the anaerobe, spore-forming, gram-positive bacterium Clostridium botulinum. Botulism is divided into three clinical variants; food-borne botulism, wound botulism and infant botulism/intestinal botulism.

Infant botulism includes botulism in children aged 0-12 months, but is seen most frequently in infants aged from 6 weeks to 6 months. The disease is caused by ingestion of spores which turn into toxin-producing bacteria in the intestinal tract of infants. This occurs because infants have yet to develop a stable normal intestinal flora capable of protecting them against this bacterial colonisation and growth.

The ensuing paralysis is due to uptake of botulinum toxins in the axons of motor nerve cells. Thereby, pre-synaptic release of acetylcholine is inhibited and neuromuscular blockade occurs. Infant botulism is nearly always caused by botulinum toxin A or B.

The condition is characterised by a broad clinical spectrum, but the most classic symptoms include several days of obstipation followed by sub-acute progression of symmetric, descending neurologic deficits with cranial nerve involvement. Hypotonia, laboured sucking and swallowing function, aphonic voice and crying, reduced facial expression, particularly ptosis, dilated pupils and lacking control of the head and lethargy are the classic findings that typically present in the course of the disease.

Disease progression may be prevented through administration of botulism antitoxin-containing antibodies that inactivate the toxins.

Once paralyses have presented, patients can be cured only through regeneration of nerve endings. Treatment should therefore be initiated as soon as motivated suspicion has been established and should not await the results of microbiological diagnostics. Any additional management is supportive, depending on disease severity.

Typically, laxatives and tube-feeding will be needed; and in more severe cases, respiratory support and parenteral nutrition may be indicated due to intestinal paralysis. Antibiotics are not indicated for treatment of infant botulism, and some antibiotics are contraindicated (e.g. aminoglycosides) because they may potentiate the neuromuscular blockade. Generally, the prognosis is good with a mortality rate < 2%. After discharge, there may be a need for prolonged tube-feeding and physiotherapy.

Diagnostics

Suspicion of infant botulism is primarily based on the typical clinical symptoms. The final diagnosis may be confirmed through detection of C. botulinum and/or botulinum toxin in the faeces. Faeces culture of the bacterium is the "gold standard". In addition to culture, Statens Serum Institut (SSI) also has a more sensitive, PCR-based method for the detection of the more common botulinum toxin genes in faeces (A, B, E and F).

Botulinum toxin may also be detected in serum, but this is more relevant in cases of classic botulism that is caused by foods containing pre-formed botulinum toxin, EPI-NEWS 5/03 and EPI-NEWS 5/13. In this case, botulinum toxin is detected in serum through a so-called neutralisation bioassay in mice.

All of the above analyses can be performed at the SSI. If paralytic ileus makes it impossible to take a faeces sample, a rectal swab or collection using rectal irrigation solution may be used.

Case 1

A 6-months-old child is admitted with the diagnosis of dehydration after 4 days of fatigue and reduced ability to suckle and swallow. The physical examination shows that the child is hypotonous with weak crying and aphonic voice. During the admission, the child increasingly lacks facial expressions and develops bilateral ptosis. Initially, acute disseminated encephalomyelitis (ADEM), encephalitis and polyradiculitis are suspected.

The child is investigated with blood samples, urine-metabolic screening, lumbar puncture, EEG and MRI, which all have normal results, but imaging of the abdomen shows considerable dilatation of the colon and signs of obstipation. On suspicion of infant botulism, faeces samples are submitted to the SSI for PCR and culture. Six days after admission, the diagnosis of infant botulism is made as PCR tests positive to botulinum toxin B and growth of C. botulinum in the faeces is seen.

The condition of the child improves spontaneously on conservative management including tube, laxatives and physiotherapy.

Intensive care is not required. As the child is improving when the test results are received, no antitoxin is given. The child is discharged after 20 days of admission. At an outpatient check-up after a month, only modest symptoms persist in the form of discrete hypotony and ptosis. The child has not ingested honey, but had initiated spoon-feeding and had ingested commercial porridge products and soft vegetables.

Case 2

A 6-months-old child is admitted to a Norwegian hospital with increasing symptoms in the form of obstipation, weakness and reduced ability to suckle and swallow. Symptoms developed in the course of one week. Objectively, the child is assessed as being hypotonous, with bilateral ptosis, a raspy aphonic voice and pronounced obstipation. Blood tests, lumbar puncture and MRI all show normal results. A nerve conduction test shows lower motor amplitude in the extremities. On suspicion of atypical polyradiculitis, the child receives a total of 5 days of IVIG treatment with only a modest effect.

The child is transferred to a Danish hospital after 5 days of admission, and on suspicion of infant botulism faeces samples are submitted to the SSI for PCR and culture. Eight days after admission, the diagnosis of infant botulism is made as PCR tests positive to botulinum toxin B, and growth of C. botulinum is observed in faeces. The child receives conservative treatment with laxatives and physiotherapy. Owing to spontaneous improvement, there is no indication for antitoxin treatment.

The child is discharged after a total of 14 days of admission, and the child is without symptoms at an outpatient check-up three weeks after discharge. The child has not ingested honey, but had initiated spoon-feeding and had ingested commercial porridge products and soft vegetables.

Case 3

A 5-month-old child is admitted due to anorexia, weakness and lack of stools through several days. Vesicles are observed in the child's mouth. The abdomen is distended and bowel sounds are scarce. The child is investigated with blood samples, tracheal secretion for culture, CT of the cerebrum and lumbar puncture, all of which are normal. Imaging of the abdomen shows considerable dilatation of the colon.

On suspicion of intestinal paralysis, the child undergoes surgery, but no surgical explanation of intestinal paralysis is found. Postoperative complications arise in the form of atelectasis and possible pulmonary infiltration, and the child is initiated on antibiotic treatment on suspicion of pneumonia. The child briefly needs respiratory support in the form of C-PAP. Additionally, aciclovir treatment is initiated on suspicion of a herpes infection.

The patient develops increasing symptoms in the form of fixed, dilated pupils; reduced ability to swallow; sparse, spontaneous movements of the extremities; and weak deep tendon reflexes. The child needs parenteral nutrition, laxatives, rectal tube and analgesics. Later in the disease course, physiotherapy is initiated. On suspicion of infant botulism, faeces samples are submitted to the SSI with a view to PCR and culture. Three days after admission, the diagnosis of infant botulism is made as PCR tests positive to botulinum toxin B, and growth of C. botulinum is observed in faeces.

Shortly before symptom onset, the child was introduced to spoon-feeding, including commercial baby mash and porridge products. The child was not treated with antitoxins owing to spontaneous recovery. The child was discharged after 28 days, but still receives tube-feeding, physiotherapy and ergotherapy due to a reduced ability to suckle and swallow.

Results of diagnostic tests and investigation of foods

As stated above, faeces cultures from all three patients returned growth of C. botulinum and PCR showed botulinum toxin B. Nevertheless, whole genome typing of the C. botulinum isolates from the three patients was not identical. This indicates that these were isolated cases with no epidemiological connection. Remains of commercial baby mash and porridge products from two of the three families were tested for the presence of C. botulinum through culture , but tested negative. It was this not possible to establish the sources of infection.

Commentary

Since 1995, a total of 9 cases of infant botulism have been reported in Denmark, but the real incidence is probably higher. Clusters have also been observed previously, probably because the detection of one case increases subsequent attention to the diagnosis, EPI-NEWS 5/13.

Assessed on the basis of whole genome typing, the three described cases were isolated and did not form part of an outbreak. C. botulinum spores are found naturally in, e.g., soil and dust. Natural products, including honey, may contain these spores, and ingestion of honey is considered the primary risk factor for the development of infant botulism even though honey is the cause of infection in only 20% of cases. In the remaining 80% of cases, the source of infection is typically unknown.

On this basis, honey is not recommended for children below 1 year of age. Testing of relevant food aims to exclude foodborne botulism or find contaminated foods that may put other people at risk. In some cases, C. botulinum spores have been found in pasteurised products for infants; but unless honey is suspected, the source of infection for infant botulism will generally remain unknown.

Reverse tracking to determine the source of infection is hampered by the fact that the diagnosis is frequently made late, and parents have typically discarded glasses of baby mash or any remains of baby porridge. Empty packaging may be of considerable value to the investigations as the information stated on the packaging may help the Danish Veterinary and Food Administration when they contact manufacturers. Manufacturers often keep sample items from each produced batch, which may subsequently be subjected to testing.

On clinical suspicion of botulism, including infant botulism, the case shall be reported immediately by phone to the Medical Officers of Health. The on-call officer at the Department of Infectious Disease Epidemiology can provide advice on the diagnostics and on the issue of antitoxin outside of normal working hours on phone: +0045 41317404. During the daytime, the SSI's Clinical Microbiology Reference Laboratory can be contacted by phone: +0045 20161993 for relevant diagnostics.

In the USA, a human-derived immunoglobulin product has been produced specifically for treatment of infant botulism, and the product includes antitoxin A and B (BabyBIG®). The product should be given as early in the disease course as possible. In an American blinded, randomised trial including 120 children, BabyBIG®/placebo was given to infants a maximum of three days after acute paralysis had presented. Microbiological confirmation was not awaited. The study found a significantly shorter admission period in the treatment group (2.6 weeks versus 5.7 weeks) and fewer children needed intensive care.

Botulism antitoxin, BabyBIG®, should be given on motivated clinical suspicion without awaiting microbiological confirmation. The hospital may order the product directly from the producer (www.infantbotulism.org). The cost is approx. 45,000 USD, not including transport costs. It takes approx. 48 hours to ship BabyBIG® to Denmark; the SSI can provide advice concerning transport. (B. Drivenes, M.L. Børresen, The Paediatric Department, Hvidovre Hospital, T.G. Krause, L. Müller, Department of Infectious Disease Epidemiology, K. Fuursted, Diagnostics and Infection Control, T. Jensen, Danish Veterinary and Food Administration)

Link to previous issues of EPI-NEWS

22. April 2015