https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON450
Situation at a glance
On 7
March 2023, the National IHR Focal Point (NFP) for Germany notified WHO
of five cases of iatrogenic botulism in individuals who underwent
medical procedures with the injection of botulinum neurotoxin type A
(BoNT/A) in health institutions in Türkiye. As of 17 March 2023, a total
of 71 cases were reported in four countries in the European Region,
mainly linked to two hospitals in different locations in Türkiye.The
products used for the treatment were seized and taken for examination
and evaluation by the Turkish Medicines and Medical Devices Agency. No
new symptomatic cases have been reported since 8 March 2023. Outbreaks
of botulism are very rare and can be associated with a natural,
accidental, or potentially deliberate source of infection.
Description of the situation On
7 March 2023, the National IHR Focal Point (NFP) for Germany notified
WHO of five cases of iatrogenic botulism in individuals who underwent
medical procedures with the injection of botulinum neurotoxin type A
(BoNT/A) in health institutions in Türkiye. As of 17 March 2023, a
total of 71 clinical botulism cases were reported from Türkiye (53
cases), Germany (16 cases), Austria (one case) and Switzerland (one
case) linked to the aforementioned medical interventions performed in
Türkiye between 22 February and 1 March 2023.All cases are
adults; most cases are middle-aged women. Among the 69 cases for which
treatment location information is known, two private hospitals in two
locations in Türkiye were identified, with 66 cases linked to one
hospital and three cases to another hospital. The clinical
presentation of the cases ranged from mild to severe. Clinical signs of
BoNT intoxication were observed (including fatigue, headache, blurred
and/or double vision, dizziness, ptosis, dysphagia, dyspnea, neck
weakness, generalized muscle weakness, and swollen tongue). Several
cases were hospitalized. Some cases were treated with botulinum
antitoxin. At least five cases were admitted to intensive care units.
There are no reported deaths. Investigations carried out by
Turkish authorities reported that licensed BoNT products were
administered for a different purpose other than for which the products
were approved (off-label use). The relevant departments of both
hospitals had their activities suspended on 1 March 2023, and
investigations have been launched against the parties involved. The
products used for the treatment were seized and taken for examination
and evaluation by the Turkish Medicines and Medical Devices Agency. No
new symptomatic cases have been reported since 8 March 2023, which was
the date of symptom onset for the last reported case.
Public health response
The Turkish Ministry of Health is working with the Türkish Medicines
and Medical Devices Agency and the Turkish National Poison Solidarity
Center to investigate this event. The Turkish General Directorate of
Public Health, Department of Communicable Diseases and Early Warning. is
conducting an epidemiological investigation with provincial health
centres and related departments. The relevant units of the Ministry of
Health and the Turkish Police Service urgently inspected the two
hospitals mentioned above. The investigation is currently ongoing to
determine if the cause of the intoxication is due to product
quality/safety, medical error, or an overdose. WHO is
collaborating with the European Centre for Disease Prevention and
Control (ECDC), and the affected IHR State Parties, regarding
investigation, risk assessment, information sharing and response for
this event. The Turkish Medicines and Medical Devices Agency published an
announcement on its website
on 10 March 2023. Similarly, the ECDC announced the current situation
regarding this event in their publicly-available Communicable Disease
Threats Report on 10 March 2023, and a news story was
published on the ECDC website on 14 March 2023.
WHO risk assessment
Botulinum neurotoxins are dangerous toxins produced by several species of the genus
Clostridium (e.g.,
C. botulinum,
C. baratii,
C. butyricum, and
C. sporogenes)
under anaerobic conditions. Botulinum neurotoxins are one of the
most
lethal substances known and occur in
eight serotypes (
A to H). Botulinum
neurotoxins
block nerve functions and can lead to
muscular, including
respiratory, paralysis. Human botulism is a naturally occurring rare
disease and may refer to foodborne botulism, infant botulism, wound
botulism, and inhalation botulism. Clostridium botulinum
culture is used to produce pharmaceutical botulinum toxin-containing
products. These pharmaceutical products employ the purified and heavily
diluted botulinum neurotoxin (type A or type B, depending on the
indication) injected for clinical use for the treatment of more than 20
neurological and non-neurological disorders, as well as for cosmetic
use. Treatment is administered in the medical setting, tailored
according to the needs of the patient and desired treatment effect.
The
symptoms of botulism can be very severe, requiring intensive-care
treatment as well as the administration of specific anti-toxins. Even
when such treatments are available, severe botulism cases require
supportive treatment, including mechanical ventilation. Complete
recovery usually takes weeks to months.
This current event is
possibly linked to a specific procedure and/or a medical product in at
least two healthcare settings. Further investigations are ongoing
regarding case ascertainment and notification. The investigation remains
open for other possible hypotheses of intoxication. The respective
departments in the two clinics where the procedures were undertaken have
been closed since 1 March, with no further cases reported.
There
are several clinical indications for the use of botulinum neurotoxin;
however, its off-label use in bariatric cases has increased in many
countries. Depending on the product used, a warning of toxic effects may
be insufficiently worded, and the risks not adequately addressed in the
patient consent process.
WHO advice
Botulism outbreaks are rare, but outbreaks require rapid recognition
to identify the source of the disease, distinguish between types of
outbreaks (natural, accidental or potentially deliberate), prevent
additional cases, and effectively administer treatment to affected
patients.
Successful treatment depends significantly on early
diagnosis and the rapid administration of the botulinum antitoxins.
Iatrogenic botulism should be suspected if a patient has recently
received botulinum neurotoxin, and clinicians should remain mindful of
the risk of systemic botulism with BoNT therapy. The diagnostic
detection of BoNT/A in patients suffering from iatrogenic botulism might
be highly challenging due to the extremely low dose of toxin present
and the potentially suboptimal timepoint of serum sampling. So far, very
few detection methods have been shown to be validated on clinical
specimens with a sensitivity better than the classical mouse bioassay,
which is still regarded as a reference for BoNT detection in clinical
samples. At this time, it cannot be confirmed if the reported cases of
botulism intoxication are due to product quality/safety, medical error,
or an overdose.
Although the source of the outbreak may have been
removed, WHO Member States need to remain vigilant. It is therefore
critically important for the IHR State Parties to identify any
additional possible case, to establish the cause, and to determine if
the product used in the procedure could be substandard or falsified.
Investigation of these cases will assist in rapid containment at the
disease source to prevent additional possible cases.
WHO does not recommend any travel and/or trade restrictions to Türkiye based on the information available for this event.
Further information
Citable reference: World Health Organization (24 March 2023). Disease Outbreak News; Iatrogenic Botulism– European Region
. Available at
https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON450
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