Botulism in Children: Clinical Guidelines

List of Abbreviations

ALT - alanine aminotransferase

AST – aspartate aminotransferase

ATA – atmosphere absolute (pressure of air mixture)

BA – botulinum antitoxin

WHO – World Health Organization

HBO – hyperbaric oxygenation

GI – gastrointestinal tract

IMV – invasive mechanical ventilation

CK-MB – creatine kinase MB isoenzyme

LD – lethal dose

LDH – lactate dehydrogenase

ICD-10 – International Statistical Classification of Diseases and Related Health Problems 10th Revision

MUAP – motor unit action potential

ESR – erythrocyte sedimentation rate

CNS – central nervous system

ECG – electrocardiography

ENMG – electroneuromyography

Cl. botulinum – Clostridium botulinum

Cl. butyricum – Clostridium butyricum

Cl. boratti – Clostridium boratti

SNAP-25 – synaptosomal-associated protein 25

pH – measure of hydrogen ion activity

Zn – zinc

Terms and Definitions

Clinical guidelines— documents containing scientifically based structured information on prevention, diagnostics, treatment, and rehabilitation, including patient management protocols (treatment protocols), medical intervention options, and a description of the sequence of actions of a medical professional taking into account the course of the disease, presence of complications and comorbid conditions, and other factors influencing medical care outcomes (Federal Law No. 323-FZ).

Nosological entity – a set of clinical, laboratory, and instrumental diagnostic features that allow the identification of a disease (poisoning, trauma, physiological state) and its classification into a group of conditions with a common etiology and pathogenesis, clinical manifestations, and general approaches to treatment and condition correction.

Disease – a disturbance of bodily activity, working capacity, and the ability to adapt to changing environmental and internal conditions arising from the impact of pathogenic factors, accompanied by simultaneous alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Primary disease – a disease that, by itself or due to complications, creates the primary need for medical care owing to the greatest threat to working capacity, life, and health, or leads to disability, or becomes the cause of death.

Concomitant disease – a disease that has no causal relationship with the primary disease, is secondary to it in terms of the need for medical care, impact on working capacity, and danger to life and health, and is not the cause of death.

Severity of a disease or condition – a criterion determining the degree of damage to human organs and/or body systems or the impairment of their functions caused by the disease, condition, or their complications.

Disease outcomes – the medical and biological consequences of a disease.

Consequences (results) – disease outcomes, as well as the social and economic results of applying medical technologies.

Disease complication – the addition to a disease of a physiological process impairment syndrome: violation of the integrity of an organ or its wall; hemorrhage; developed acute or chronic failure of an organ function or organ system.

Condition – bodily changes arising from the impact of pathogenic and/or physiological factors that require medical care.

Clinical situation – a case requiring the regulation of medical care regardless of the disease or syndrome.

Syndrome – a condition developing as a consequence of a disease and defined by a set of clinical, laboratory, and instrumental diagnostic features that allow its identification and classification into a group of conditions with different etiologies, but a common pathogenesis, clinical manifestations, and general approaches to treatment, which nevertheless depend on the underlying diseases forming the basis of the syndrome.

Symptom – any sign of a disease that can be determined regardless of the method used for this purpose.

Patient – an individual receiving medical care or applying for medical care, regardless of the presence of a disease and their condition.

Medical intervention – a, performed by a medical worker in relation to a patient, affecting the physical or mental state of a person and having a preventive, exploratory, diagnostic, therapeutic, or rehabilitative orientation, types of medical examinations and/or medical manipulations, as well as artificial termination of pregnancy.

Medical service – a medical intervention or a complex of medical interventions aimed at the prevention, diagnosis, and treatment of diseases, and medical rehabilitation, and having an independent completed significance.

Quality of medical care – a set of characteristics reflecting the timeliness of medical care provision, the correctness of the choice of prevention, diagnostic, treatment, and rehabilitation methods during the provision of medical care, and the degree of achievement of the planned result.

Physiological process – an interrelated aggregate activity of various cells, tissues, organs, or organ systems (an aggregate of functions) aimed at satisfying a vital need of the entire organism.

Function of an organ, tissue, cell, or group of cells – a property constituting a physiological process that implements an action specific to the corresponding structural unit of the organism.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Botulism – an acute infectious-toxic disease caused by the action of a neurotoxin produced by vegetative forms of the causative agent Clostridium botulinum (Cl. botulinum) and clinically characterized by paresis and paralysis of striated and smooth muscles, sometimes combined with a gastroenteritis syndrome in the initial period [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Etiology. Cl. botulinum (phylum Firmicutes, genus Clostridium) is a Gram-positive, spore-forming anaerobe whose pathogenicity is determined by its ability to secrete an exotoxin (botulinum toxin) with neurotoxic effects. The optimal temperature for growth and toxin production of Cl. botulinum is +28 to +35 °C, with a medium pH of 7.2–7.4. Under unfavorable conditions of an oxygen-containing atmosphere, Cl. botulinum transforms into a spore that resembles a tennis racket under microscopy. Cl. botulinum type A bacterial spores can remain viable for 6–8 years in fresh water, 2 months in saltwater, withstand sunlight and deep freezing, and are capable of reproduction after drying for 347 days and more than a century of soil residence. Viable spores are found in vegetables and fruits, fly larvae, and earthworms, and colonize the gastrointestinal tract of fish, birds, and mammals. Spore destruction can be achieved by boiling in water (for 6 hours at 100 °C or 20 minutes at 120 °C), treatment with 20% formalin for at least 24 hours, or heating in 10% hydrochloric acid for 1 hour. Under favorable conditions, spores germinate within 30–40 minutes into a vegetative bacterial form capable of reproduction. Bacterial reproduction is possible only under anaerobic conditions. Bacteria can use any protein products as a nutrient medium: insufficiently salted meat, improperly processed canned meat, fish, legumes, or mushrooms, predominantly of home preparation [2–4].

Botulinum toxin (botulinum neurotoxin) is an organic neurotoxin of protein nature (C6760H10447N1743O2010S32, M: 149,322 g/mol). Its mass is about 150,000 atomic mass units, which is three times the typical size of a protein chain [2-4]. Botulinum toxin is colorless, tasteless, and odorless. It is a poison of biological origin. In addition to pronounced neurotoxic activity, various types of Cl. botulinum exhibit leukotoxic, hemolytic, and lecithinase activity [4, 5]. Depending on the antigenic structure of the exotoxins, 8 serotypes of the pathogen are distinguished: A, B, C1 (α), C2 (wβ), D, E, F, G [6, 7]. A new serotype H has recently been discovered [8-10].

Botulinum toxins of all types are similar to each other in the nature of their damaging effect, although they differ in primary structures (composition and number of amino acids, sequence of their linkage), degree of toxicity, and immunogenic properties: (important!) botulinum antitoxin of each type does not neutralize toxins of other types. The most pathogenic for humans are serotypes A, B, E, and less commonly F. Currently, there is data on the possibility of botulinum toxin synthesis not only by Cl. botulinum, but also by some other representatives of the clostridial flora (Cl. botulinum produces all types of toxins, while Cl. butyricum and Cl. boratii produce only types E and F, respectively) [11]. Relative toxicity for humans via inhalation LD₅₀ = 0.00002 mg×min/L, upon ingestion LD₅₀ = 0.0000057 mg/kg [3]. Botulinum toxin is stable in acidic and neutral media and is not inactivated by digestive enzymes in the stomach and intestine when ingested with food. The pathogenic properties of botulinum toxin type E under the influence of trypsin in the stomach can increase hundreds of times. Botulinum toxin withstands high concentrations of sodium chloride (up to 18%) and is not destroyed in products containing various spices. Botulinum toxin is thermolabile (destroyed by boiling for 25–30 minutes, autoclaving for 10 minutes), and is destroyed by the action of alkalis, potassium permanganate, chlorine, or iodine within 15–20 minutes, and formalin within a few minutes. [12, 13].

Pathogenesis. The initial link in the pathogenesis of foodborne botulism is the absorption of the toxin from the upper gastrointestinal tract into the blood, with its subsequent penetration through the blood-brain barrier into the central nervous system. Botulinum toxin selectively affects the cholinergic structures of various parts of the nervous system: motor neurons of the anterior horns of the spinal cord and nerve endings. The mechanism of action of botulinum toxin is realized by blocking the transmission of impulses from the nerve ending to the muscle by blocking the release of the neurotransmitter acetylcholine from vesicles by the nerve ending. Botulinum toxin does not cross the placenta and does not cause specific fetal damage [1, 14].

The action of botulinum toxin is conventionally divided into three stages [4]:

- the first stage of the action of botulinum toxin consists in the specific binding of the molecule to the presynaptic membrane;

- the second stage is the penetration of the bound toxin into the cytoplasm of neurons by endocytosis. Inside the cell, the light chain exhibits Zn²⁺-dependent protease activity, selectively degrading the SNAP-25 enzyme

- the third stage is the blockade of acetylcholine release from the presynaptic terminals of cholinergic neurons [28].

1.3 Epidemiology of the Disease or Condition

The epidemiology of botulism is extremely peculiar and does not fit into the classical concepts of the epidemiology of infectious diseases due to the polymorphism of clinical manifestations, severity of the course, and specific features of spread. Cl. botulinum have been discovered on all continents. However, the incidence rate varies, which is explained by the dietary habits of the population, food preparation methods, and the thoroughness of disease detection and diagnosis. The infectious nature of the disease is clearly manifested only in cases of infant botulism and in extremely rare cases of botulism in adults when the incubation period exceeds 4-5 days. In most cases, infant botulism is provoked by types A and B toxins [1, 13, 15]. In recent years, sporadic cases of botulism have been registered in the territory of the Russian Federation.

1.4 Features of Coding the Disease or Condition

A05.1 Botulism

1.5 Classification of the disease or condition

According to the WHO classification [4]:

1) Foodborne botulism – the disease develops as a result of consuming foods that have accumulated botulinum toxin;

2) Wound botulism – develops when a wound is contaminated with soil, creating conditions for the germination and subsequent toxin production of Cl. botulinum introduced from the soil;

3) Infant botulism – occurs in children, predominantly under 6 months of age, upon infection with Cl. botulinum;

4) Botulism of unspecified nature – it is not possible to establish a link between the disease and a food product.

I. By severity:

1) mild form of botulism – characterized by low severity of all symptoms;

2) moderate form of botulism – cases of the disease with pronounced neurological manifestations without signs of decompensated acute respiratory failure, with fully preserved swallowing ability.

3) severe form of botulism – characterized by the maximum severity of all symptoms of the disease with signs of decompensated acute respiratory failure, impaired swallowing of liquids of any degree of severity.

Comments: Foodborne botulism accounts for over 99% of all botulism cases. Infant botulism in children under 6 months of age develops as a result of intraintestinal toxin production by vegetative Cl. botulinum spores.

The clinical presentation of botulism is specific and consists of several leading syndromes: paralytic, gastrointestinal, and intoxication. Even minimal patient complaints of "respiratory discomfort" (labored inspiration, feeling of air hunger) allow the patient's condition to be assessed as severe, regardless of the severity of all other neurological manifestations of botulism, with the immediate initiation of all appropriate therapeutic (resuscitation) measures. When the disease debuts with neurological symptoms, the process develops so rapidly that the phase of accelerated gastrointestinal motility is almost immediately replaced by its depression. Such a course of the disease is subsequently assessed as severe [28, 29].

1.6 Clinical presentation of the disease or condition

The incubation period is variable, ranging from 2-4 hours to 2-3 or even 5 days, usually a few days (up to seven days), and in botulism in children can reach 30 days [12].

As a rule, the onset of the disease is acute; patients can even pinpoint the exact hour of onset. Less commonly, a prodromal period may occur, when patients are bothered by malaise, fatigue, weakness, and headaches. However, this period is short-lived and usually does not exceed 12-24 hours.

The clinical presentation of botulism is specific and consists of several leading symptoms: paralytic, gastrointestinal, and intoxication. The true severity of the disease can only be established during dynamic observation of the patient.

The gastrointestinal syndrome is caused by concomitant anaerobic flora present simultaneously with Cl. botulinum in the food product. The intoxication syndrome in botulism (without gastrointestinal syndrome) is not accompanied by symptoms of infectious intoxication (malaise, body aches, fever, etc.). The true severity of the disease can only be established during dynamic observation of the patient.

In foodborne botulism, early clinical manifestations are most often symptoms of gastrointestinal tract damage: nausea, vomiting up to 3-5 times, 2-4 loose stools. Retrosternal pain and burning, belching, bloating, and abdominal pain are possible [16-18].

Diarrhea and vomiting in botulism are not profuse or prolonged (within 6-24 hours) and disappear by the time neurological symptoms appear; diarrhea is replaced by persistent constipation and depression of intestinal peristalsis, and vomiting by a distinct slowing of the evacuation of food masses from the stomach, in severe cases – up to stasis. In some cases, diarrhea and vomiting may be absent, and neurological symptoms are predominant.

A typical feature is the involvement of motor cranial nerve nuclei located at the brainstem level. The severity of neurological disorders in classical cases correlates with the severity of the process. A distinctive feature of the paralytic syndrome in botulism is its symmetry and bilaterality [19]. As a rule, the first complaint of most botulinum patients is visual impairment – the appearance of "fog" and/or a "veil" before the eyes, blurred contours of objects, and diplopia that worsens when looking sideways. In mild cases, patients' general well-being may hardly suffer, as a result of which some of them repeatedly seek help from an ophthalmologist.

In children, overall disease symptoms are identical to those in foodborne botulism in adults, taking into account the specifics of childhood. The diagnosis of botulism is most difficult in infants, as the initial symptoms of the disease may be nonspecific: weakness, lethargy during sucking or refusal to breastfeed, and a decrease in active movements develop, manifesting as the clinical picture of a "floppy infant". Infants also experience alterations in voice timbre (up to aphonia), swallowing disorders, diminished pupillary reactions, persistent mydriasis, and ophthalmoplegia. Botulism in children is characterized by constipation (lasting more than 3 days) combined with paresis and paralysis starting from the muscle groups innervated by cranial nerves and spreading to the periphery, including the respiratory muscles [20]. Against the background of these symptoms, sudden respiratory arrest may occur. The severity of the clinical picture ranges from mild drowsiness to severe hypotonia and respiratory failure. The sick child stops holding their head up, crying becomes rare and hoarse, and sucking lethargy is noted [21]. A feature of acute respiratory failure in botulism is the predominant depression of external respiration reserve capacities, i.e., a decrease in vital capacity (VC) and a hypoventilatory nature of acute respiratory failure.

Pathognomonic for botulism is the development of infectious-allergic myocarditis, especially on the 10th-15th day of the disease [28, 29].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

The diagnosis of botulism is established based on the epidemiological history and the identification of a combination of symptoms caused by impaired contractility of various muscle groups, primarily small ones, leading to characteristic disorders of vision, swallowing, voice changes, and in severe cases, respiration.

2.1 Complaints and Anamnesis

An important part of diagnosis is clarifying the epidemiological history: consumption of canned goods (vegetables, meat, fish, mushrooms), smoked or dried fish, homemade sausage or ham, honey/grape molasses (for children under one year old) in the period from a few hours to 2-3 (less often 5-7) days before the onset of the disease. Simultaneous illness of several individuals is possible. From a diagnostic standpoint, it is very important to obtain information about the time of onset of clinical signs from the moment of food intake.

Visual impairment: to varying degrees, restricted mobility of the eyeballs in all directions, pupil dilation (mydriasis), and sluggish or absent pupillary reflexes (to light, convergence, and accommodation) [19]. Sometimes nystagmus is detected in extreme gazes, usually horizontal; corneal and conjunctival reflexes are depressed. In severe cases of the disease, complete external and internal ophthalmoplegia may occur — immobility of the eyeballs with absent pupillary reflexes, resulting from paralysis of all extraocular and intraocular muscles (the constrictor pupillae and ciliary muscles). Visual impairment is further aggravated by narrowing of the palpebral fissures due to eyelid ptosis — the latter can be so pronounced that patients have to lift their eyelids manually.

Swallowing disorders and dry mouth: an early symptom; the degree of severity varies significantly [15, 16]. In the mildest cases, there may only be complaints of a «lump» in the throat or minor difficulty swallowing solid, dry food. As the disease progresses, swallowing soft and liquid foods is impaired. The ability to drink liquids is limited last of all. In severe forms of botulism, there is a complete inability to swallow, which necessitates tube feeding in a hospital setting. In fact, swallowing disorders caused by pharyngeal muscle paresis in botulism are inextricably linked with impaired salivation, and paresis of the muscles of the tongue, epiglottis, and soft palate. Paresis of the epiglottis and soft palate leads to swallowed liquids partially entering the trachea, causing choking, and partially escaping through the nose. The atropine-like effect of botulinum toxin on the autonomic nervous system causes hyposalivation [22, 23].

Voice changes: hoarseness, a nasal tone to speech («nasality»), slurred and indistinct articulation appear. These complaints are due to paresis of the muscles of the soft palate, tongue, and larynx. The extreme degree of these disorders is manifested by aphonia and anarthria [15, 16].

Weakness is an obligatory complaint of patients even with mild forms of botulism. It is caused by both intoxication and the paralytic effect of the toxin on skeletal muscles. This effect is most pronounced in the proximal muscle groups, but overall the lesion is generalized, a striking example of which is the easily detectable decrease in grip strength in the hands during physical examination. Of particular danger is the involvement of the intercostal muscles, abdominal muscles, and diaphragm, which leads to impaired external respiration and, consequently, to acute respiratory failure [15, 16].

2.2 Physical Examination

Comments: The clinical picture of botulism at the height of the disease is quite specific and characterized by polymorphic complaints:

- nausea, recurrent vomiting (if gastroenteritis is present);

- dry mouth;

- diplopia, worsening with lateral gaze;

- «fog», «mesh», «floaters» before the eyes;

- difficulty reading normal print;

- difficulty swallowing solid, dry food; as the disease progresses — impaired swallowing of soft and liquid food; in severe forms — complete inability to swallow;

- feeling of a «lump» in the throat;

- choking;

- frequent loose stools (if gastroenteritis is present);

- belching, abdominal distension;

- feeling of heaviness, epigastric pain;

- by the beginning of the 2nd day, diarrhea is replaced by persistent constipation (if gastroenteritis was present on days 1–2);

- voice — hoarse, slurred, nasal; in severe cases — aphonia, anarthria;

- dizziness, increasing headache, muscle weakness, fatigue, insomnia;

- feeling of air hunger, chest tightness, and chest pain.

- decreased chest excursion and reduced effectiveness of the cough reflex.

In addition, attention should be paid to the presence and severity of intoxication syndrome (headache, weakness, decreased appetite, nausea, vomiting) and fever.

The diagnosis of botulism is most difficult in infants, since the initial symptoms of the disease may be nonspecific: weakness, lethargy during suckling or breast refusal develop, and the range of active movements decreases, manifesting as the clinical picture of a «floppy» infant. Infants also experience voice timbre changes (up to aphonia), swallowing disorders, decreased pupillary reflexes, persistent mydriasis, and ophthalmoplegia. Botulism in infants is characterized by constipation (lasting more than 3 days) combined with paresis and paralysis starting from muscle groups innervated by cranial nerves and spreading to the periphery, including the respiratory muscles. Against the background of these symptoms, sudden respiratory arrest may occur. The severity of the clinical picture ranges from mild drowsiness to profound hypotonia and respiratory failure. The sick infant stops holding their head up, crying becomes rare and hoarse, and suckling is sluggish. In general, the symptoms of the disease are identical to those of foodborne botulism in adults, taking into account the specifics of infancy [1, 4, 12, 13, 15, 16, 24].

2.3 Laboratory Diagnostics

Specific laboratory diagnostics must be performed for all patients with suspected botulism to confirm the diagnosis.

Comments: The detection of botulinum toxin in the blood serves as absolute confirmation of the diagnosis. Detection of botulinum toxin in laboratories is carried out by performing a biological assay and a toxin biological neutralization reaction in white mice using diagnostic poly- and monovalent antitoxic sera of serotypes A, B, E, and F. In the assay, the test material is injected intraperitoneally into laboratory animals in a mixture with one of the monospecific or polyvalent botulinum antitoxic sera. The sensitivity of the method is 30–40 pg/ml of botulinum toxin.

Comments: The material for microbiological examination includes vomit, gastric lavage fluid, feces, blood, urine, and food leftovers cultured on special nutrient media (Kitt-Tarozzi, casein-fungal, Hottinger broth, etc.). If culture growth is present, smears are prepared and Gram-stained. In the case of detecting typical clostridia with terminally located oval spores resembling a «tennis racket», subculturing on blood agar is performed to obtain individual colonies and isolate a pure culture [15, 23]. This method confirms the diagnosis 4–5 days after specimen collection.

All procedures related to attempts to detect the toxin or the pathogen itself must be performed by specially trained personnel. The patient's blood, feces, vomit, or gastric lavage fluid are sent for laboratory diagnostics. Sample collection for laboratory testing is carried out at the first suspicion of botulism, prior to administering type A and/or B and/or E botulinum antitoxin to the patient**.

All patients with botulism undergo screening laboratory diagnostics as part of a clinical minimum to assess the involvement/preservation of various organs and systems [1, 3, 15, 24].

Comments: Moderate leukocytosis with neutrophilia, lymphopenia (of toxic origin), and elevated ESR are noted.

Comments: In toxic renal injury, a decrease in specific gravity, microhematuria, and isolated leukocytes may occur. Hyaline and granular casts may appear.

Comments: In moderate and severe cases liver damage is possible

Comments: In moderate and severe cases, an increase in the activity of "cardiospecific" enzymes (CK-MB, AST, and LDH-1,2) and troponin T levels is recorded.

2.4 Instrumental Diagnostics

Comments: ENMG examination can provide significant diagnostic assistance. Studying the state of motor unit action potentials (MUAPs) using concentric needle electrodes in the acute period of botulism reveals a significant decrease in the mean duration of MUAPs, most pronounced in clinically affected muscles.

Comments: Performing an ECG in patients to detect infectious cardiopathy, myocarditis, and select therapy tactics, as well as to early detect potential complications associated with the use of botulinum antitoxin type A, botulinum antitoxin type B, and botulinum antitoxin type E.

The ECG shows sinus tachycardia, indications of hypoxic myocardial changes, and non-specific ST-segment and T-wave changes.

Comments: chest X-ray is performed when auscultatory changes in the lungs characteristic of pneumonia are detected, or when pneumonia is suspected.

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

When botulism is suspected, emergency hospitalization in an infectious diseases hospital or infectious diseases department of a multidisciplinary medical organization is recommended for all patients, and in severe cases, admission to an intensive care unit [1, 15, 20, 26].

Level CLevel 3Level of recommendation evidence C (reliability level of evidence – 3).

Comments: To provide medical care, only those methods, medical devices, materials, and medications that are approved for use in the established manner are used. Treatment tactics are influenced by the following factors: disease severity; patient age; presence and nature of complications; availability and feasibility of treatment in accordance with the required type of medical care. Treatment of botulism in infants does not differ from that in adults.

Treatment goals:

- prevention of the further development of the pathological process caused by the disease;

- prevention of complications;

- prevention of residual effects.

Medication treatment methods:

- etiotropic therapy agents;

- pathogenetic therapy agents;

- symptomatic therapy agents.

3.1 «Conservative treatment»

Comments: Enteral nutrition is carried out via a nasogastric feeding tube using high-energy nutritional formulas (in the absence of a swallowing reflex) or parenteral nutrition with concentrated dextrose** solutions (10–40%), amino acid mixtures, and fat emulsions, with mandatory partial enteral nutrition (in the absence of a swallowing reflex and impaired consciousness) For infants, formulas are prescribed according to age or for additional indications depending on concomitant diseases [1, 15, 26].

Etiotropic therapy

Comments: botulinum antitoxin (BtA) contains toxin-neutralizing antibodies. When performing serotherapy, a number of fundamentally important points must be considered:

- BtA is capable of neutralizing only the toxin freely circulating in the blood.

- The severity of the paralytic syndrome may increase even after BtA administration, which does not indicate the ineffectiveness of serum therapy.

- To treat diseases caused by an unknown type of botulinum toxin (pathogen), a mixture of polyvalent sera is used.

- Regardless of the severity of clinical symptoms, only a single therapeutic dose of the drug is administered intravenously as an infusion.

- BtA is administered once.

- Increasing single doses or repeated administrations of BtA are not recommended.

- For prophylactic purposes, BtA in a half-dose is administered to people who simultaneously consumed products with the patients that caused the botulism outbreak.

Detoxification therapy

3.2 Subsection Surgical Treatment

Comments: Nasotracheal intubation can be performed for a long time (in the case of botulism - up to 80 days) without any pronounced side effects and avoids tracheostomy. Re-intubation is performed every 3-5 days. Final extubation is carried out only upon complete recovery of respiration and the act of swallowing liquids. Under conditions of preventive nasotracheal intubation, considering that botulinum patients are fully alert and communicative, the slightest subjectively noted impairments in spontaneous ventilation serve as an indication to initiate mechanical ventilation in this patient cohort, which patients evaluate as a "feeling of air hunger," occurring before blood gas composition and acid-base balance (ABB) parameters begin to change. The same applies to mechanical ventilation modes, which in botulism are determined and dynamically adjusted not only and not so much by laboratory parameters, but by the subjectively noted feeling of "respiratory comfort" by patients.

3.3 Other Treatment

Comments: The rationale for its use is based on data regarding the development of tissue hypoxia in patients with botulism. HBOT is used for all severity grades, but its efficacy is maximal in the early stages of the pathological process. There are no absolute contraindications to HBOT sessions. Relative contraindications include inflammatory changes in the lungs, the presence of pulmonary cavities, cysts, or abscesses, as well as severe forms of arterial hypertension, epilepsy, and a history of other convulsive seizures. The frequency of sessions and their parameters (oxygen pressure, session duration) are selected individually. However, the best effect is achieved at an oxygen pressure within 1.5–2.0 ATA (1.3 ATA for myocarditis) and an exposure duration of 45–60 minutes.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no specialized rehabilitation programs for patients who have recovered from botulism.

Rehabilitation is carried out by specialist physicians depending on the developed complications.

5. Prevention and Dispensary Observation

In the prevention of botulism, strict adherence to state standards (GOST/TU) in the commercial production of canned food and sanitary education of the population regarding the rules of preparing foods that may cause poisoning are of essential importance.

Meat and fish are allowed to be canned only when fresh. Vegetables and fruit must be thoroughly washed before canning to remove soil particles. Canning overripe fruit is also unacceptable. The guaranteed sterilization regimen must be strictly observed. Sterilization should be carried out in autoclaves, since elevated pressure and high temperature (120 °C) destroy not only bacterial cells and toxin, but also spores. At home, plant-based products can only be preserved for future use by pickling or salting with the addition of a sufficient amount of acid and salt, and necessarily in containers open to the air. Botulism prevention in the retail network is of great importance. The most important point is compliance with storage conditions for perishable foods. Spoiled (swollen/bombaged) canned food and products with expired shelf-life must not be allowed into the retail network. Educational work among the population plays an important role.

Dispensary follow-up care for convalescents is organized individually depending on the severity of the past illness and the presence of complications.

6. Organization of Medical Care

Treatment of patients is carried out in a hospital setting upon referral by a district pediatrician, general practitioner (family doctor), infectious disease specialist, emergency physician, or other medical workers who identified botulism.

Indications for emergency hospitalization:

• emergency hospitalization in an infectious disease hospital, infectious disease department (infectious disease beds) in a multidisciplinary clinic having an intensive care unit and critical care department in its structure is indicated for all patients with suspected botulism

• in case of a severe form, admission to the intensive care unit or critical care department.

Specialized medical care is provided in a hospital setting by infectious disease physicians and other specialist physicians and includes the prevention, diagnosis, treatment of diseases and conditions requiring the use of special methods and complex medical technologies, as well as medical rehabilitation.

Possible outcomes of botulism and their characteristics are presented in Table 1.

The outcome of the disease depends on early diagnosis and the initiation of prompt treatment, including etiotropic therapy.

Disease outcome classifier

Table 1

Discharge of patients with botulism from the hospital is possible after stable vital functions; with spontaneous breathing, swallowing, absence of diplegia and dysphagia [1, 15, 24].

Criteria for recovery:

· absence of intoxication;

· absence of complications;

· normalization or improvement of the functions of all affected organs.

7. Additional Information

Not applicable

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lobzin, Yuri Vladimirovich – MD, DSc, Academician of the Russian Academy of Sciences, President of the Federal State Budgetary Institution "Children's Research and Clinical Center of Infectious Diseases of the Federal Medical-Biological Agency", Chief Freelassie Specialist in Pediatric Infectious Diseases of the Russian Ministry of Health and the Federal Medical-Biological Agency, President of the Interregional Public Organization "Euro-Asian Society of Infectious Diseases"

2. Zhdanov, Konstantin Valerievich – MD, DSc, Corresponding Member of the Russian Academy of Sciences, Professor, Director of the Federal State Budgetary Institution "Children's Research and Clinical Center of Infectious Diseases of the Federal Medical-Biological Agency", Chief Freelance Specialist in Infectious Diseases of the Health Committee of Saint Petersburg, Deputy President of the Interregional Public Organization "Euro-Asian Society of Infectious Diseases"

3. Uskov, Alexander Nikolaevich – MD, DSc, Associate Professor, Advisor to the Director of the Federal State Budgetary Institution "Children's Research and Clinical Center of Infectious Diseases of the Federal Medical-Biological Agency", Member of the Euro-Asian Society of Infectious Diseases and the Association of Infectious Disease Physicians of Saint Petersburg and Leningrad Oblast

4. Skripchenko, Natalia Viktorovna – MD, DSc, Professor, Honored Scientist of the Russian Federation, Deputy Director for Research at the Federal State Budgetary Institution "Children's Research and Clinical Center of Infectious Diseases of the Federal Medical-Biological Agency", Member of the Euro-Asian Society of Infectious Diseases

5. Zakharenko, Sergei Mikhailovich – MD, PhD, Associate Professor, Deputy Director of the Federal State Budgetary Institution "Children's Research and Clinical Center of Infectious Diseases of the Federal Medical-Biological Agency", Member of the Euro-Asian Society of Infectious Diseases and the Association of Infectious Disease Physicians of Saint Petersburg and Leningrad Oblast

6. Rychkova, Svetlana Vladislavovna – MD, Associate Professor, Head of the Medical Care Organization Department, Pediatric Research and Clinical Center of Infectious Diseases under the Federal Medical-Biological Agency, Pediatrician

7. Sidorenko, Sergei Vladimirovich – MD, DSc, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Medical Microbiology and Molecular Epidemiology, Federal State Budgetary Institution "Children's Research and Clinical Center of Infectious Diseases of the Federal Medical-Biological Agency", Member of the Euro-Asian Society of Infectious Diseases and the Association of Infectious Disease Physicians of Saint Petersburg and Leningrad Oblast

8. Vilnits, Alla Aronovna – MD, DSc, Leading Researcher at the Research Department of Vaccinology and Post-Vaccination Complications, Neurologist

Conflict of interest: none

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• anesthesiologist-intensivist;

• bacteriologist;

• virologist;

• disinfectologist;

• health station physician;

• infectious disease physician;

• clinical laboratory diagnostics physician;

• clinical pharmacologist;

• laboratory physician;

• neurologist;

• general practitioner (family physician);

• pediatrician;

• municipal (district) pediatrician;

• primary care pediatrician;

• medical prevention physician;

• medical rehabilitation physician;

• admitting department physician;

• internist;

• adolescent therapist;

• district general practitioner;

• epidemiologist;

• surgeon.

Table 1.Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2.Levels of Evidence (LoE) grading scale for prevention, treatment and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3.Grades of Recommendation (GoR) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 25, 2023) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" (with rev. and add., effective from April 1, 2024)1.

2. Federal Law No. 52-FZ dated March 30, 1999 (as amended on July 24, 2023) "On the Sanitary and Epidemiological Welfare of the Population"

3. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021 (as amended on May 25, 2022) "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases'" (together with "SanPiN 3.3686-21. Sanitary Rules and Norms...") (Registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500)

4. Order of the Russian Ministry of Health No. 1122n dated December 6, 2021 "On Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations According to Epidemiological Indications, and the Procedure for Administering Preventive Vaccinations" (Registered with the Ministry of Justice of Russia on December 20, 2021, No. 66435)

5. Order of the Ministry of Health and Social Development of Russia No. 521n dated May 5, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to Children with Infectious Diseases" (Registered with члена the Ministry of Justice of Russia on July 10, 2012, No. 24867)

6. Order of травосмеси the Ministry of Health and Social Development of Russia No. 69n dated January 31, 2012 (as amended on February 21, 2020) "On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases" (Registered with the Ministry of Justice of Russia on April 4, 2012, No. 23726)

7. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on September 24, 2020, with amendments dated October 26, 2022) "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808)

8. Order of the Russian Ministry of Health No. 302n dated May 16, 2019 (as amended on November 19, 2020) "On Approval of the Procedure for Minors Undergoing Dispensary Observation, Including During the Period of Education and Training in Educational Organizations" (Registered with the Ministry of Justice of Russia on June 7, 2019, No. 54887)

9. Order of the Russian Ministry of Health No. 168n dated March 15, 2022 "On Approval of the Procedure for Conducting Dispensary Observation of Adults" (Registered with the Ministry of Justice of Russia on April 21, 2022, No. 68288)

10. State Report "On the State of Sanitary and Epidemiological Welfare of the Population in the Russian Federation in 2022" Moscow: Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 2023 https://www.rospotrebnadzor.ru/documents/

Clinical criteria for early diagnosis of botulism* in crisis and emergency situations^# Afebrile (<38 °C)^§

• Acute onset with at least one of the following symptoms:

  • Blurred vision

  • Double vision (diplopia)

  • Difficulty speaking, including slurred speech

  • Any change in voice quality, including hoarseness

  • Dysphagia, pooling of secretions, or drooling

  • "Thick" tongue

• At least one of the following signs:

  • Ptosis

  • Extraocular paralysis or fatiguability (the latter manifested by the inability to keep eyes away from light repeatedly shining into the eyes [usually used in infants])

  • Facial paresis (manifested, for example, by loss of facial expression or pooling of secretions, and in young children by poor breast or bottle sucking or fatigue during feeding)

  • Fixed pupils

  • Descending paralysis starting from cranial nerves

Source: 21. Rao AK, Lin NH, Griese SE, Chatham-Stephens K, Badell ML, Sobel J. Clinical criteria to trigger suspicion for botulism: an evidence-based tool to facilitate timely recognition of suspected cases during sporadic events and outbreaks. Clin Infect Dis 2017; 66(suppl_1): S38–S42.

* Suspected botulism when all three criteria are met. All patients with botulism are expected to have an unaltered mental status. If a patient presents with an altered mental status, this may be due to other causes (e.g., respiratory failure, drug or alcohol use, a pre-existing condition, or a concomitant infection).

^# Although this tool can also be used in routine clinical care settings, a more detailed evaluation of the criteria is required. Under crisis standards of care, meeting these criteria alone may be sufficient for the treatment of suspected botulism.

^§ Fever combined with the acute onset of botulism in adults is extremely rare; fever is also rare in infants and young children, but may occur more frequently than in adults.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Botulism – an acute infectious-toxic disease caused by the action of a neurotoxin produced by vegetative forms of the pathogen Cl. botulinum and clinically characterized by paresis and paralysis of skeletal muscles and internal organ muscles, sometimes combined with gastroenteritis syndrome.

Etiology. Cl. botulinum is a spore-forming microorganism capable of multiplying only in an oxygen-free environment; its pathogenicity is due to the ability to secrete a specific botulinum toxin that exerts a neurotoxic effect. The optimal temperature for growth and toxin production of Cl. botulinum is +28–35 °C, with a slightly alkaline medium pH. Under unfavorable oxygen-containing atmospheric conditions, Cl. botulinum transforms into a spore. Bacterial spores of Cl. botulinum type A are able to remain viable for 6–8 years in fresh water, 2 months in salt water, withstand sunlight and deep freezing, are capable of reproduction after drying, and can survive in the soil for more than a century. Viable spores are found in vegetables and fruit, in fly larvae and earthworms, and colonize the gastrointestinal tract of fish, birds, and mammals. Under favorable conditions, spores germinate within 30–40 minutes into a vegetative bacterial form capable of reproduction. Bacterial multiplication is possible only in the absence of oxygen. Bacteria can use any protein-rich products as a nutrient medium: insufficiently salted meat, improperly processed meat, fish, legume, or mushroom canned goods, predominantly homemade.

Destruction of spores can be achieved by boiling in water for 6 hours at a temperature of 100 °C or 20 minutes at 120 °C, or by special processing methods.

Botulinum toxin is an organic protein-based neurotoxin that is colorless, tasteless, and odorless. It is a poison of biological origin. Botulinum toxin is thermolabile (destroyed by boiling for 25–30 minutes, autoclaving for 10 minutes), and is destroyed by alkalis, potassium permanganate, chlorine, or iodine within 15–20 minutes, and formalin within several minutes.

The initial link of damage in foodborne botulism is the absorption of the toxin from the upper gastrointestinal tract into the blood, with its subsequent penetration through the blood-brain barrier into the central nervous system. The mechanism of action of botulinum toxin is realized by blocking impulse transmission from the nerve terminal to the muscle. Botulinum toxin does not cross the placenta and does not cause specific fetal damage. Treatment is possible only in a hospital setting with the administration of a special antibotulinum serum **. In severe cases, fatal outcomes are possible.