Dangerous weight loss trend triggers Iatrogenic botulism outbreak in Europe

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Jun 11 2023

A recent Euro Surveillance study documents relevant laboratory and epidemiological data on travel-associated iatrogenic botulism (IB) outbreaks in Europe. 

Study: A large travel-associated outbreak of iatrogenic botulism in four European countries following intragastric botulinum neurotoxin injections for weight reduction, Türkiye, February to March 2023. Image Credit: Kateryna Kon / Shutterstock.com

The recent European botulism outbreak

Botulism is caused by botulinum neurotoxins (BoNTs) produced by the Clostridium species. Exposure to this neurotoxin causes flaccid descending paralysis. In the European Union (EU), around 94 human botulism cases were reported between 2012 and 2021.

On March 3, 2023, the German National Consultant Laboratory (CL) for neurotoxin-producing clostridia at the Robert Koch Institute (RKI) in Berlin was notified by a German hospital about a clinical case of botulism. The patient in question received intragastric botulinum neurotoxin injections (IBNI) during a gastroscopic procedure in Istanbul, Turkey, at the end of February 2023.

Soon after that, more cases were reported. Subsequently, the European Union notified the European Centre for Disease Prevention and Control (ECDC) and World Health Organization’s Regional Office for Europe (WHO/ Europe) of this botulism outbreak.

What are neurotoxins?

Neurotoxins are categorized into eight serotypes ranging from A to H. Serotypes A, B, E, and F commonly cause human botulism.

Each serotype is further divided into subtypes or mosaic forms. Each serotype can cleave a particular amino acid bond in synaptic synaptosomal-associated protein (SNAP-25), syntaxin, and vesicle-associated membrane protein (VAMP). These are essential components of the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment receptor (SNARE) complex.

SNARE-complex formation is crucial for the fusion of neurotransmitter-loaded vesicles with the synaptic membrane. Therefore, cleavage of SNARE-complex proteins by BoNT stops the release of neurotransmitters, ultimately paralyzing the innervated muscle.

What is botulism?

A key feature of botulism is paralysis of the facial muscles, which causes blurred vision, ptosis, dysarthria, diplopia, and dysphagia. This paralysis descends and causes hypotonia of the extremities and dyspnoea.

The clinical symptoms of botulism aggravate rapidly and can become life-threatening if left untreated. Botulism antitoxins prevent further uptake of BoNTs at the motoneurons. 

BoNTs are produced by different Clostridium species, such as C. butyricum, C. baratii, and C. sporogenes. Botulism can be caused by contaminated food, which is the most common source of botulism in Europe.

Another type of botulism occurs in infants due to bacterial colonization in the infant’s intestine and toxin release. Botulism can also occur through wound infection.

Both (BoNT)/A and BoNT/B are used in many pharmaceutical formulations to treat neurological and non-neurological diseases. However, only licensed companies can use this neurotoxin for specific formulations. 

To date, no pharmaceutical company has received approval to use BoNT/A to treat obesity; however, many clinics are offering intragastric injections with BoNT/A between 100-500 units/injection for the treatment. Recently, IB has been observed in some individuals where nerves and muscles adjacent to the injection site are affected with mild to moderate symptoms.

About the study

It is essential to report suspected or confirmed botulism in humans to the local health departments, as RKI is subsequently notified. Although the German case of botulism was laboratory-confirmed, the clinical botulism cases reported in Austria, France, and Switzerland were not confirmed in the laboratory.

A total of 53 cases of apparent IB had been reported in Turkey between February 28, 2023, and March 8, 2023, 31 of whom required hospitalization. Notably, all IB cases were linked to IBNI performed by the same physicians in Hospital X (50 cases) and Hospital Z (3 cases).

Upon discovery of the outbreak, BoNT products were seized. It was noted that product D of brand E was approved for import but used off-label. Currently, there is an ongoing investigation regarding these products.

BoNT/A could be traced in patients’ sera for up to eleven days post-administration. This indicates that BoNT/A was still circulating in the blood in trace amounts.

It is possible that additional IB cases in Germany may not have been identified through physician reporting. In comparison to other serotypes, BoNT/A could trigger the longest paralysis times of up to six months. Most patients included in the current analysis did not completely recover by mid-April 2023. 

During this outbreak, most cases clustered in a single hospital (Hospital X) where all patients were treated with a similar IBNI treatment. It remains unclear which product was used in late February. To date, no pharma companies have been approved to market BoNT-preparation for IBNI use.

Conclusions

The current outbreak reports on an unrecognized potential for large IB outbreaks linked to a procedure using BoNT. Thus, patients must be provided with information on the consequence of BoNT overdoses and subsequent botulism. More robust surveillance is required to detect counterfeit BoNT/A products, particularly in Turkey. More clinical trials are also needed to elucidate the sustainable benefit of IBNI. The current study underscores the importance of modern endopeptidase assays that can detect minute amounts of BoNT remaining in serum.