Type F Botulism Due to Clostridium baratii

This paper summarizes a case of botulism in a 69-year-old man caused by Clostridium baratii (C. baratii) type F toxin and the resultant investigation conducted at a local health department. The case is suspected to have been one of adult intestinal colonization botulism, about which little is known. The intention of this case report is to increase the amount of information available to clinicians and health officials about an extremely rare pathogen, as well as a rare form of botulism.

Case description. A 69-year-old man presented to the emergency department (ED) early in the morning after having awoken with diplopia, loss of facial expression, dry mucous membranes, difficulty swallowing, difficulty speaking, gait problems, weakened reflexes, facial paralysis, and descending weakness/paralysis. 

His past medical history was significant for chronic gastroesophageal reflux disease (GERD), obesity, hypercholesterolemia, hypertension, alcohol use, obstructive sleep apnea, impaired fasting glucose, spinal stenosis, and lumbar radiculopathy. His daily prescription medications prior to admission included amlodipine 10 mg, atenolol 50 mg, atorvastatin 40 mg, fenofibrate 134 mg, gabapentin 300 mg three times daily, hydrochlorothiazide 12.5 mg, omeprazole 20 mg, ramipril 10 mg, and tramadol 50 mg every 6 hours as needed.

The patient’s symptoms were initially suggestive of a stroke, so a computed tomography (CT) scan of the head was done which did not reveal any intracranial hemorrhage, infarct, or any other acute intracranial pathology. After arrival in the ED, the patient developed sudden dyspnea and hypoxia and was placed on supplemental oxygen (4 L nasal cannula). Further testing, including a CT angiogram and chest radiograph, did not reveal the etiology of his illness. On his first day of hospitalization the patient continued to decline and developed an acute change in mental status, becoming unresponsive with fixed gaze, pupillary asymmetry, and rhythmic motion of the arms with some mild rigidity in the upper extremities. A stat arterial blood gas revealed hypercapnic neck respiratory failure with profound acidemia, so the patient was transferred to the intensive care unit and intubated. Intravenous lorazepam 2 mg was administered for concern for seizure activity, as well as ceftriaxone 1 g and azithromycin 500 mg for concern for pneumonia. 

Approximately 15 hours following presentation, the patient was transferred to a tertiary hospital for a higher level of care. The second hospital performed a workup for a likely thromboembolic or epileptic etiology. An electroencephalogram (EEG), two CTs, and magnetic resonance imaging (MRI) were all within normal limits. A CT angiogram showed significant stenosis at the origin of the left vertebral artery, so norepinephrine was started for pressor support. Antibiotic coverage was expanded to include ampicillin 2 g every 4 hours, acyclovir 10 mg/kg every 8 hours, as well as doxycycline 100 mg and vancomycin 1,000 mg, both every 12 hours. Ceftriaxone 2 g was increased and administered every 12 hours, though azithromycin was not continued.

On the third day of illness and hospitalization, an infectious disease physician consulted on the progressive neurological weakness. The differential diagnosis was expanded to include encephalitis, viral infection, and botulism. Plasmapheresis was ordered, along with further testing including a meningoencephalitis winter panel, cryptococcal antigen, serologies for West Nile virus and Lyme disease, a cerebrospinal fluid venereal disease research laboratory test (CSF-VDRL), a cerebrospinal fluid gram stain and workup, and testing for heavy metals, all of which were negative.

The second hospital notified the New York State Department of Health (NYSDOH) that they had a patient whose signs and symptoms were consistent with botulism. Later on day 3 of hospitalization, the CDC authorized the release of heptavalent antitoxin from John F. Kennedy International Airport in Queens, New York, more than 350 miles away. Inclement weather complicated the transport of the antitoxin, which ultimately was administered on the evening of day 4. 

A rectal swab and stool were collected from the patient on day 8 for testing for the presence of both the toxin and organism. The rectal swab tested positive by reverse transcription polymerase chain reaction (RT-PCR) for C. baratii possessing the type F toxin gene, although it tested negative for active toxin, which is likely because the antitoxin had been administered 4 days prior to the sample collection. The laboratory was subsequently able to enrich the rectal swab sample, and tests of the enrichment were positive for both C. baratii producing type F toxin by RT-PCR and for toxin type F by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The stool sample also tested positive for both C. baratii possessing the type F toxin gene and for the type F neurotoxin itself. C. baratii was later isolated from cultures of the day 8 rectal swab and stool sample and identified by biochemical analysis. Serum that was initially collected on day 3 and sent to NYSDOH’s laboratories returned negative on day 10 for botulinum toxins A, B, E, and F.

In the 4-day period following the administration of the heptavalent antitoxin, the patient made small neurological improvements. Due to prolonged and difficult ventilator weaning, a tracheostomy was performed on the patient on day 12. The patient also underwent six sessions of plasmapheresis, completing the final session on day 15. He was decannulated on day 26 and was discharged to an acute rehabilitation facility 31 days after symptom onset and hospital admission. After making functional gains, the patient was discharged home from rehab 51 days after presentation, with instructions for at-home physical therapy and recuperation.

Epidemiological investigation. A NYSDOH epidemiologist notified the county health department the day following patient presentation about the differential diagnosis of botulism or myasthenia gravis.

The case interview was conducted with the patient’s partner on day 10 of the patient's illness and hospitalization, after the first laboratory result confirming botulism (C. baratii possessing the type F toxin gene detected by RT-PCR in a rectal swab) was reported by NYSDOH. The partner reported that the patient had gone to bed the night before presentation feeling well, but the patient had woken early the following morning complaining of blurry vision, dry mouth, and slurred speech. He was transported to the local hospital that morning for evaluation.

The patient works for a packaging company, and he had no recent history of injuries, wounds, gastrointestinal procedures, antibiotics, or injection drug use. The patient and his partner traveled to Florida to visit a relative the week prior to symptom onset, and an additional interview was conducted with the Florida relative on day 10.

The patient only eats once per day because of his GERD. During the 3 days prior to his illness onset the patient ate all his meals at restaurants, which consisted of cooked vegetables, potatoes, pickles, steak, a tossed salad, a Reuben sandwich, macaroni salad, and a roast beef sub sandwich with peppers, onions, and lettuce.

Two days prior to symptom onset, the patient worked outdoors opening soffits and replacing posts on the front of the Florida relative's house. No injuries to the patient while working on the outdoor project were identified. 

The case was classified as botulism of unknown type because of the patient’s positive stool and rectal sample laboratory results, combined with his being over 1 year of age, his lack of history of suspect food ingestion during the foodborne botulism incubation period, and his lack of wounds. As there was a lack of evidence of botulism of other etiologies, he was suspected of having adult colonization with C. baratii, although this form of botulism is difficult to diagnose with certainty.¹ The patient did not undergo repeat testing for viable C. baratii spores or neurotoxin in his stool, the prolonged excretion of which can help to distinguish adult intestinal colonization from foodborne botulism.¹ Since there is little known about the epidemiology of C. baratii and because adult intestinal colonization botulism in general is poorly understood (including its pathogenesis and incubation period), we were limited in our ability to determine any likely sources of exposure.

Discussion. Botulism is a rare but clinically severe disease caused by intoxication from botulinum toxin-producing types of clostridia.²  These clostridia are spore-forming bacteria that are ubiquitous in the environment.³ While botulism can be caused by nine recognized serotypes of botulinum neurotoxins, types A, B, E, and F are most commonly implicated in cases of human botulism.^3,4 Botulinum toxin is most commonly produced by Clostridium botulinum (C. botulinum), but also by some strains of Clostridium butyricum, C. baratii, and Clostridium argentinense.³ C. botulinum and C. baratii can both produce type F toxin. C. baratii was first identified in 1985 and is an uncommon cause of botulism.⁵

Intoxication can result from exposure to clostridia or the botulinum toxins it produces through various routes.¹ Foodborne botulism is caused by ingestion of preformed botulinum toxin in food in which clostridia grew and produced botulinum toxins.¹ Conversely, infant botulism and intestinal colonization botulism occur when an individual consumes clostridia, which then grow and produce botulinum toxin within the patient’s intestines.¹ Wound botulism is caused by the growth of clostridia producing botulinum toxin within a wound, and is often associated with injection drug use as well as soil or gravel contamination of open traumatic injuries.³  

Foods most commonly implicated in foodborne botulism include inadequately processed home-preserved foods with a low content of sugar, salt, and acid, or foods that have suffered time-temperature abuse.³ Infant botulism is thought to occur because incomplete establishment of normal intestinal flora enables colonization by toxin-producing clostridia.³ Adult intestinal colonization botulism is poorly understood, although it has been found to occur most often in individuals who have gastrointestinal risk factors that are thought to increase susceptibility to colonization.^1,3-6

The incubation period of botulism varies depending on the mode of transmission, with the onset of neurological symptoms in foodborne botulism ranging from 2 hours to 8 days (typically 12 to 72 hours) following toxin ingestion, whereas onset of symptoms in infant botulism can be up to 30 days following clostridia ingestion.³  Although its pathogenesis is thought to be similar to that of infant botulism, the incubation period for intestinal colonization in adults has not been determined.³

In individuals older than 1 year of age, signs and symptoms of botulism may include bilateral cranial nerve palsies, bilateral descending flaccid paralysis, ptosis, diplopia, blurred vision, dysphagia, dysarthria, and ophthalmoplegia, while maintaining typical mental status.³

Reported cases of botulism caused by type F toxin are very rare. From 1950 to 2000, there were six reported cases of botulism caused by type F toxin in the United States.^7,8 From 2001 to 2018 (the most recent year for which US botulism surveillance data is available) 31 cases of botulism caused by type F toxin were reported, accounting for just over 1% of all reported botulism cases during that period.⁹

Cases of confirmed or suspected foodborne botulism due to type F toxin in the US and Europe have often been traced back to meat or poultry products, including homemade liver pâté, homemade venison jerky, tomato meat sauce, meat pot pies, ground beef in restaurant-prepared Bolognese sauce, and homemade turkey soup.^{2, 9-13}

Adult intestinal colonization botulism (also called infectious botulism in adults, adult intestinal toxemia botulism, or infant botulism in adults) of any toxin type is itself quite rare, and occurs when ingested neurotoxigenic clostridia colonize the intestines of individuals where they produce botulinum toxin.¹ Typical sources of exposure for adult intestinal colonization botulism caused by any type of clostridia are presently unknown; food sources of spores are rarely identified in these cases, and it has been suggested that spores present in dust that is inhaled into the mouth and swallowed may also be a route of transmission in intestinal colonization.¹ There are, however, several known risk factors that may predispose individuals to intestinal colonization, including prior bowel or gastric surgery or wounds, anatomical or functional intestinal abnormalities, Crohn or inflammatory bowel disease, or recent use of antibiotics, which may result in altered gastrointestinal flora that enables colonization.^1,3,5,6 The case profiled herein took omeprazole 20 mg daily for GERD, which may have altered his gut microbiome.^14,15 However, more research is necessary to determine whether omeprazole can predispose individuals to intestinal colonization botulism.

Type F botulism is more regularly implicated in adult intestinal colonization than its relative rarity as a cause of botulism would otherwise suggest, and one prevalent hypothesis currently is that it often causes intestinal toxemia.⁵ From 2001 through 2018, among the 50 cases of “other” botulism (a classification that includes adult intestinal colonization, iatrogenic, and unknown forms of botulism) reported in the United States, 13 cases (26%) were caused by type F toxin, despite the fact that this toxin caused only 1% of all reported botulism cases within the same period.⁹ This would suggest that C. baratii or C. botulinum producing type F toxin are more likely to cause adult intestinal colonization botulism—or less likely to cause infant, foodborne, or wound botulism—than clostridia producing other toxin types.

Clinicians need to consider botulism in their differential diagnoses early in their workup because botulism in individuals older than 1 year of age can be difficult to clinically differentiate from other neurological disorders (such as myasthenia gravis and Guillain-Barré syndrome) and because hospital laboratories typically cannot make a diagnosis of botulism.³ Clinicians may also not suspect botulism in cases of adult intestinal colonization as it is much less common than the other types, which also have more easily identifiable risk factors. However, the early administration of antitoxin is critical to limiting the progression of disease (particularly in type F botulism, which often rapidly progresses) and prompt access to intensive care and mechanical ventilation can ensure the early detection and management of respiratory failure.^3,5 Additionally, timely coordination with reference laboratories and the CDC can ensure rapid testing and antitoxin treatment for patients suspected of having botulism.¹

Reported cases of botulism caused by C. baratii are extremely rare. There is currently a small amount of published information available about this particular pathogen, and this case helps to add to the current literature available.