Botulismo del lactante: estudio descriptivo en una unidad de cuidados intensivos pediátricos / Infant botulism: a descriptive study in a pediatric intensive care unit

Introducción. El botulismo del lactante (BL) es la forma más frecuente de botulismo humano en Argentina. El objetivo es describir aspectos esenciales del diagnóstico y tratamiento de pacientes con BL internados en el servicio de terapia intensiva pediátrica (STIP). Métodos. Estudio observacional, descriptivo y retrospectivo. Se utilizó la base de datos del STIP con diagnóstico de BL en el período 2005-2020. Se registraron variables demográficas, métodos de diagnóstico, días de asistencia respiratoria mecánica convencional (ARMC), de ventilación no invasiva (VNI), estadía en STIP, mortalidad al alta hospitalaria. Resultados. Se registraron 21 pacientes con BL; 14 pacientes fueron varones, con una mediana de edad de 5 meses (RIC 2-6 m). El diagnóstico se realizó mediante técnica de bioensayo y se detectó la toxina en suero en 12 pacientes. Uno solo no requirió ARMC; 1 paciente fue traqueostomizado; 18 pacientes recibieron antibióticos; 5 recibieron VNI. Ningún paciente recibió antitoxina y no hubo fallecidos. La mediana de estadía hospitalaria fue 66 días (RI: 42-76); de internación en STIP, 48 días (RI: 29-78); y de ARMC, 37 días (RI: 26-64). La demora en la confirmación diagnóstica fue 15,8 ± 4,8 días. Conclusiones. La totalidad de los pacientes fueron diagnosticados con la técnica de bioensayo, que generó un tiempo de demora diagnóstica que excede los lapsos recomendados para la administración del tratamiento específico. Ningún paciente recibió tratamiento específico. El BL presentó baja mortalidad, pero tiempos de ARM e internación prolongados, que se asocian a infecciones sobreagregadas y uso frecuente de antibióticos.

Introduction. Infant botulism (IB) is the most common form of human botulism in Argentina. Our objective was to describe the main aspects of diagnosis and management of patients with IB admitted to the pediatric intensive care unit (PICU). Methods. Observational, descriptive, and retrospective study. The PICU database with IB diagnosis in 2005­2020 period was used. Demographic variables, diagnostic methods, days of conventional mechanical ventilation (CMV), non-invasive ventilation (NIV), length of stay in the PICU and mortality upon hospital discharge were recorded. Results. In total, 21 patients with IB were recorded; 14 were male, their median age was 5 months (IQR: 2­6 m). Diagnosis was made by bioassay, and the toxin was identified in the serum of 12 patients. Only 1 patient did not require CMV; 1 patient had a tracheostomy; 18 patients received antibiotics; 5 received NIV. No patient was administered antitoxin and no patient died. The median length of stay in the hospital was 66 days (IQR: 42­76); in the PICU, 48 days (IQR: 29­78); and the median use of CMV, 37 days (IQR: 26­64). The delay until diagnostic confirmation was 15.8 ± 4.8 days. Conclusions. All patients were diagnosed using the bioassay technique, which resulted in a diagnostic delay that exceeds the recommended period for the administration of a specific treatment. No patient received a specific treatment. IB was related to a low mortality, but also to prolonged use of MV and length of hospital stay, which were associated with cross infections and frequent antibiotic use.

Pathogenicity and virulence of Clostridium botulinum.

Clostridium botulinum, a polyphyletic Gram-positive taxon of bacteria, is classified purely by their ability to produce botulinum neurotoxin (BoNT). BoNT is the primary virulence factor and the causative agent of botulism. A potentially fatal disease, botulism is classically characterized by a symmetrical descending flaccid paralysis, which is left untreated can lead to respiratory failure and death. Botulism cases are classified into three main forms dependent on the nature of intoxication; foodborne, wound and infant. The BoNT, regarded as the most potent biological substance known, is a zinc metalloprotease that specifically cleaves SNARE proteins at neuromuscular junctions, preventing exocytosis of neurotransmitters, leading to muscle paralysis. The BoNT is now used to treat numerous medical conditions caused by overactive or spastic muscles and is extensively used in the cosmetic industry due to its high specificity and the exceedingly small doses needed to exert long-lasting pharmacological effects. Additionally, the ability to form endospores is critical to the pathogenicity of the bacteria. Disease transmission is often facilitated via the metabolically dormant spores that are highly resistant to environment stresses, allowing persistence in the environment in unfavourable conditions. Infant and wound botulism infections are initiated upon germination of the spores into neurotoxin producing vegetative cells, whereas foodborne botulism is attributed to ingestion of preformed BoNT. C. botulinum is a saprophytic bacterium, thought to have evolved its potent neurotoxin to establish a source of nutrients by killing its host.

Lambert-Eaton Myasthenic Syndrome and Botulism.

PURPOSE OF REVIEW: This article reviews the pathophysiology, epidemiology, clinical features, diagnosis, and treatment of Lambert-Eaton myasthenic syndrome (LEMS) and botulism, presynaptic disorders of neuromuscular transmission in which rapid diagnosis improves long-term outcomes. RECENT FINDINGS: Therapy for LEMS has seen significant advances in recent years due to the approval of amifampridine-based compounds. LEMS is likely still underdiagnosed, particularly when no underlying malignancy is identified. Clinicians must have a strong suspicion for LEMS in any patient presenting with proximal weakness and autonomic dysfunction. Botulism is another rare disorder of presynaptic neuromuscular transmission that is most commonly associated with improper storage or preservation of food products. Over the past 2 decades, wound botulism has been increasingly reported among users of black tar heroin. A high degree of clinical suspicion and electrodiagnostic studies can be beneficial in distinguishing botulism from other acute neurologic disorders, and early involvement of state and federal health authorities may assist in confirming the diagnosis and obtaining treatment. When botulism is suspected, electrodiagnostic studies can provide clinical evidence of disordered neuromuscular transmission in advance of serologic confirmation, and providers should not wait for confirmation of the diagnosis to initiate treatment. SUMMARY: A targeted clinical history and a thorough neurologic examination with support from serologic and electrodiagnostic studies are key to early diagnosis of LEMS and botulism. Early diagnosis of both conditions creates opportunities for therapy and improves outcomes.

Open Tibial Fracture Complicated by Wound Botulism: A Case Study.

Botulism is a neuroparalytic disease most commonly caused by foodborne ingestion of neurotoxin types A, B, and E, and is often fatal if untreated. Clinicians should be able to recognize the classic symptoms of botulinum intoxication (12). Owing to its rarity, there are a limited number of studies evaluating the clinical care of patients with wound botulism (10). We present an infected tibial non-union with botulism who underwent a successful radical excision and bone transport. The patient tolerated the procedure well.

Adult Intestinal Toxemia Botulism.

Intoxication with botulinum neurotoxin can occur through various routes. Foodborne botulism results after consumption of food in which botulinum neurotoxin-producing clostridia (i.e., Clostridium botulinum or strains of Clostridiumbutyricum type E or Clostridiumbaratii type F) have replicated and produced botulinum neurotoxin. Infection of a wound with C. botulinum and in situ production of botulinum neurotoxin leads to wound botulism. Colonization of the intestine by neurotoxigenic clostridia, with consequent production of botulinum toxin in the intestine, leads to intestinal toxemia botulism. When this occurs in an infant, it is referred to as infant botulism, whereas in adults or children over 1 year of age, it is intestinal colonization botulism. Predisposing factors for intestinal colonization in children or adults include previous bowel or gastric surgery, anatomical bowel abnormalities, Crohn's disease, inflammatory bowel disease, antimicrobial therapy, or foodborne botulism. Intestinal colonization botulism is confirmed by detection of botulinum toxin in serum and/or stool, or isolation of neurotoxigenic clostridia from the stool, without finding a toxic food. Shedding of neurotoxigenic clostridia in the stool may occur for a period of several weeks. Adult intestinal botulism occurs as isolated cases, and may go undiagnosed, contributing to the low reported incidence of this rare disease.

Therapeutic Plasma Exchange in a rare case myasthenic crisis after Botox injection.

BACKGROUND AND AIMS: Botulinum toxin (Botox) injections are used as a cosmetic treatment to decrease wrinkles in face and chin. Being a neurotoxic agent it minimizes muscle activity, while side effects are usually rare. This article subsequently presents one case of these rare effects. CASE: A 30-year-old woman presenting with ptosis, diplopia, dysarthria, dysphagia and muscle weakness was admitted to our hospital. She had no history of disease. For cosmetic reasons, she had three Botox injections during the preceding months. On physical examination, muscle weakness 4/5 (cervical extensor, ocular and pharynx) was detected and a diagnosis of myasthenia gravis was made. Protective artificial ventilation was necessary. As a consequence, eight sessions of 2.5 L volume Therapeutic Plasma Exchange (TPE) were applied using normal saline/albumin as substitute. Due to TPE, her muscle force and clinical condition improved. Artificial ventilation could be stopped. CONCLUSIONS: Clinical symptoms of myasthenia gravis and systemic Botox effects are very similar. This should be taken into consideration during medical history taking. The injection of high doses of Botox (more than 200 units in every injection) or boostering within less than one month is dangerous. (Botox BCC2024). Systemic side effects can be treated using TPE to lower the circulating dose of Botox.

Effective and rapid treatment of wound botulism, a case report.

BACKGROUND: The latest news shows several cases of contaminated heroin that is found in different parts all over Europe. This information can be helpful for the emergency doctors to find the correct diagnosis of wound botulism in patients who are intravenous drug users. CASE PRESENTATION: We describe a case of a 40-year-old man who presented to the emergency department in 2016. He suffered from mild dysarthria, diplopia, dysphagia and ptosis since two days. The CT-scan of the cerebrum and the liquor were without any pathological results. We found out that the patient is an intravenous drug user and the clinical examination showed an abscess in the left groin. So we treated him with the suspected diagnosis of wound botulism. In the emergency operation we split the abscess, made a radical debridement and complementary treated him with a high dose of penicillin g and two units of botulism antitoxin. The suspected diagnosis was confirmed a few days later by finding the Toxin B in the abscess and in the patient's serum. In the following days the neurological symptoms decreased and the wound healing was without any complications. The patient left the hospital after nine days; the antibiotic therapy with penicillin g was continued for several days. In a following examination, 14 days after the patient's discharge of the hospital, no further symptoms were found and the abscess was treated successfully without any problems. CONCLUSION: Because wound botulism is a very rare disease it can be challenging to the attending physician. This case shows a fast treatment with full recovery of the patient without any further disabilities, which can be used for the future.

Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin.

A short half-life in the circulation limits the application of therapeutics such as single-domain antibodies (VHHs). We utilize red blood cells to prolong the circulatory half-life of VHHs. Here we present VHHs against botulinum neurotoxin A (BoNT/A) on the surface of red blood cells by expressing chimeric proteins of VHHs with Glycophorin A or Kell. Mice whose red blood cells carry the chimeric proteins exhibit resistance to 10,000 times the lethal dose (LD50) of BoNT/A, and transfusion of these red blood cells into naive mice affords protection for up to 28 days. We further utilize an improved CD34+ culture system to engineer human red blood cells that express these chimeric proteins. Mice transfused with these red blood cells are resistant to highly lethal doses of BoNT/A. We demonstrate that engineered red blood cells expressing VHHs can provide prolonged prophylactic protection against bacterial toxins without inducing inhibitory immune responses and illustrates the potentially broad translatability of our strategy for therapeutic applications.The therapeutic use of single-chain antibodies (VHHs) is limited by their short half-life in the circulation. Here the authors engineer mouse and human red blood cells to express VHHs against botulinum neurotoxin A (BoNT/A) on their surface and show that an infusion of these cells into mice confers long lasting protection against a high dose of BoNT/A.

mRNA mediates passive vaccination against infectious agents, toxins, and tumors.

The delivery of genetic information has emerged as a valid therapeutic approach. Various reports have demonstrated that mRNA, besides its remarkable potential as vaccine, can also promote expression without inducing an adverse immune response against the encoded protein. In the current study, we set out to explore whether our technology based on chemically unmodified mRNA is suitable for passive immunization. To this end, various antibodies using different designs were expressed and characterized in vitro and in vivo in the fields of viral infections, toxin exposure, and cancer immunotherapies. Single injections of mRNA-lipid nanoparticle (LNP) were sufficient to establish rapid, strong, and long-lasting serum antibody titers in vivo, thereby enabling both prophylactic and therapeutic protection against lethal rabies infection or botulinum intoxication. Moreover, therapeutic mRNA-mediated antibody expression allowed mice to survive an otherwise lethal tumor challenge. In conclusion, the present study demonstrates the utility of formulated mRNA as a potent novel technology for passive immunization.

Informe especial de brote: Brote intrafamiliar de botulismo alimentario / Outbreak special report: Intrafamily outbreak of food botulism

Presentación de dos casos notificados el 24 de diciembre de 2016 a la Gerencia Operativa de Epidemiología de la Ciudad de Buenos Aires por la Dirección de Epidemiología Nacional, sospechosos de botulismo alimentario en integrantes de una familia, e internados en efectores públicos y privados de la Ciudad de Buenos Aires. Se describen el cuadro clínico y el tratamiento recibido, la evolución de los pacientes, la patología de la enfermedad, y acciones de vigilancia epidemiológica: definición de casos sospechosos, de casos notificados, y notificación de la enfermedad. Incluye datos de instituciones de referencia en la Ciudad de Buenos Aires, para atención de esta patología

Presynaptic Disorders: Lambert-Eaton Myasthenic Syndrome and Botulism.

Lambert-Eaton myasthenic syndrome (LEMS) and botulism are acquired presynaptic nerve terminal disorders of the neuromuscular junction. Lambert-Eaton myasthenic syndrome is an idiopathic or paraneoplastic autoimmune syndrome in which autoantibodies of the P/Q-type voltage-gated calcium channel play a role in decreasing the release of acetylcholine, resulting in clinical symptoms of skeletal muscle weakness, diminished reflexes, and autonomic symptoms. Paraneoplastic LEMS is most often associated with small cell lung cancer. Diagnosis is confirmed by positive serologic testing and electrophysiological studies, which display characteristic features of low compound muscle action potentials, a decrement at 3Hz repetitive nerve stimulation, and facilitation with exercise or high-frequency repetitive stimulation. Treatment involves cancer monitoring and treatment, 3,4-diaminopyridine, immunosuppressive medications, and acetylcholinesterase inhibitors. Botulism is another presynaptic disorder of neuromuscular transmission. Clinical features classically involve cranial and bulbar palsies followed by descending weakness of the limbs, respiratory failure, and autonomic dysfunction. Electrodiagnostic testing is important in the evaluation and diagnosis. Treatment is supportive, and administration of antitoxin is beneficial in selected cases.

Invaginación intestinal en un lactante con diagnóstico de botulismo: Reporte de un caso / Intussusception in infant with diagnostic botulism: A case report

El botulismo es un importante problema de salud pública en Argentina. Es una enfermedad potencialmente letal y de difícil diagnóstico. Existen casos de presentación infrecuente de dicha enfermedad, como el abdomen agudo. Exponemos el caso de un niño de 4 meses, que consultó por constipación de 3 días de evolución, asociada a decaimiento y regular actitud alimentaria de 12 horas de evolución. Presentaba tono muscular conservado, sin alteraciones en la succión ni deglución, según la referencia materna. Se constató sensorio alternante y abdomen agudo, por lo que ingresó a quirófano con sospecha de invaginación intestinal, la cual fue confirmada mediante desinvaginación neumática. Durante la internación, el paciente evolucionó desfavorablemente y presentó llanto débil, hipotonía progresiva e insuficiencia respiratoria, por lo que requirió cuidados intensivos. Se aisló Clostridium botulinum en la muestra de materia fecal y toxina botulínica tipo A en el suero. Recibió toxina antibotulínica equina como tratamiento, con recuperación total a los 25 días de haber ingresado.

Botulism is an important public health problem in Argentina. It is a potentially fatal disease, and its diagnosis may be difficult. There are rare presentation forms of the disease, such as acute abdomen. We present a 4-monthbaby with a 3-day constipation condition, associated with weakness and abnormal eating attitude in the last 12 hours. The baby presented preserved muscle tone, with no changes in sucking or deglutition according to the mother's observations. Altered sensorium and acute abdomen were found; the patient was entered into the operating room with presumptive diagnosis ofintussusception, which was confirmed by pneumatic desinvagination. During hospitalization, the patient did not make good progress and presented weak cry, progressive hypotonia and respiratory failure requiring intensive care. Clostridium botulinum was isolated from the stool sample and botulinum toxin type A was isolated from serum. The patient was treated with equine botulinum toxin. Twenty five days after admission, he was totally recovered.

Sublingual immunization with adenovirus F protein-based vaccines stimulates protective immunity against botulinum neurotoxin A intoxication.

Sublingual (s.l.) vaccination is an efficient way to induce elevated levels of systemic and mucosal immune responses. To mediate mucosal uptake, ovalbumin (OVA) was genetically fused to adenovirus 2 fiber protein (OVA-Ad2F) to assess whether s.l. immunization was as effective as an alternative route of vaccination. Ad2F-delivered vaccines were efficiently taken up by dendritic cells and migrated mostly to submaxillary gland lymph nodes, which could readily stimulate OVA-specific CD4(+) T cells. OVA-Ad2F + cholera toxin (CT)-immunized mice elicited significantly higher OVA-specific serum IgG, IgA and mucosal IgA antibodies among the tested immunization groups. These were supported by elevated OVA-specific IgG and IgA antibody-forming cells. A mixed T(h)-cell response was induced as evident by the enhanced IL-4, IL-10, IFN-γ and TNF-α-specific cytokine-forming cells. To assess whether this approach can stimulate neutralizing antibodies, immunizations were performed with the protein encumbering the ß-trefoil domain of C-terminus heavy chain (Hcßtre) from botulinum neurotoxin A (BoNT/A) as well as when fused to Ad2F. Hcßtre-Ad2F + CT-dosed mice showed the greatest serum IgG, IgA and mucosal IgA titers among the immunization groups. Hcßtre-Ad2F alone also induced elevated antibody production in contrast to Hcßtre alone. Plasma from Hcßtre + CT- and Hcßtre-Ad2F + CT-immunized groups neutralized BoNT/A and protected mice from BoNT/A intoxication. Most importantly, Hcßtre-Ad2F + CT-immunized mice were protected from BoNT/A intoxication relative to Hcßtre + CT-immunized mice, which only showed ∼60% protection. This study shows that s.l. immunization with Ad2F-based vaccines is effective in conferring protective immunity.

Surto familiar de botulismo no estado do Ceará: relato de caso / Familiar outbreak of botulism at Ceará state, Brazil: case report

Relato de surto familiar de botulismo por intoxicação alimentar, envolvendo um óbito, onde foram encontradas lacunas no preenchimento do prontuário. O objetivo foi descrever a patologia chamando a atenção dos profissionais de saúde para o fornecimento adequado de informações relevantes para a investigação epidemiológica de doenças de notificação compulsória.

Report of a family outbreak of botulism food poisoning involving a death, where gaps in the completion of medical records were identified. The study aimed to describe the pathology and emphasize to health professionals the need to provide adequate information relevant to epidemiological investigation of compulsory notification diseases.

Single-Breath-Count Test: an important adjunct in the triaging of patients in a mass-casualty incident due to botulism.

Clostridium botulinum toxins, the most poisonous substance known to humankind, are considered to be a [US] Centers for Disease Control and Prevention Category A bioterrorist agent. Despite this concern, little has been published with regard to the tactical aspects of triaging a mass-casualty event involving botulism victims arriving at an emergency department. Because neuromuscular-ventilatory failure is a principal reason for botulism's early morbidity and mortality, using a quick and sensitive test to evaluate this possibility is imperative. The purpose of this article is to propose the adoption of the Single-Breath-Count Test (SBCT). The ease and validity of the use of the SBCT in evaluating complications associated with various neuromuscular disorders make it an attractive adjunct for triage during a mass-casualty incident due to botulism. While education, immune globulin, antitoxin, and invasive airway techniques are well-recognized steps in treating botulism, incorporating a time-honored technique such as the SBCT, will be an important addition to the triage process.

Myasthenia and related disorders of the neuromuscular junction.

Our understanding of transmission at the neuromuscular junction has increased greatly in recent years. We now recognise a wide variety of autoimmune and genetic diseases that affect this specialised synapse, causing muscle weakness and fatigue. These disorders greatly affect quality of life and rarely can be fatal. Myasthenia gravis is the most common disorder and is most commonly caused by autoantibodies targeting postsynaptic acetylcholine receptors. Antibodies to muscle-specific kinase (MuSK) are detected in a variable proportion of the remainder. Treatment is symptomatic and immunomodulatory. Lambert-Eaton myasthenic syndrome is caused by antibodies to presynaptic calcium channels, and approximately 50% of cases are paraneoplastic, most often related to small cell carcinoma of the lung. Botulism is an acquired disorder caused by neurotoxins produced by Clostridium botulinum, impairing acetylcholine release into the synaptic cleft. In addition, several rare congenital myasthenic syndromes have been identified, caused by inherited defects in presynaptic, synaptic basal lamina and postsynaptic proteins necessary for neuromuscular transmission. This review focuses on recent advances in the diagnosis and treatment of these disorders.

Antibody protection against botulinum neurotoxin intoxication in mice.

Adulteration of food or feed with any of the seven serotypes of botulinum neurotoxin (BoNT) is a potential bioterrorism concern. Currently, there is strong interest in the development of detection reagents, vaccines, therapeutics, and other countermeasures. A sensitive immunoassay for detecting BoNT serotype A (BoNT/A), based on monoclonal antibodies (MAbs) F1-2 and F1-40, has been developed and used in complex matrices. The epitope for F1-2 has been mapped to the heavy chain of BoNT/A, and the epitope of F1-40 has been mapped to the light chain. The ability of these MAbs to provide therapeutic protection against BoNT/A intoxication in mouse intravenous and oral intoxication models was tested. High dosages of individual MAbs protected mice well both pre- and postexposure to BoNT/A holotoxin. A combination therapy consisting of antibodies against both the light and heavy chains of the toxin, however, significantly increased protection, even at a lower MAb dosage. An in vitro peptide assay for measuring toxin activity showed that pretreatment of toxin with these MAbs did not block catalytic activity but instead blocked toxin entry into primary and cultured neuronal cells. The timing of antibody rescue in the mouse intoxication models revealed windows of opportunity for antibody therapeutic treatment that correlated well with the biologic half-life of the toxin in the serum. Knowledge of BoNT intoxication and antibody clearance in these mouse models and understanding of the pharmacokinetics of BoNT are invaluable for future development of antibodies and therapeutics against intoxication by BoNT.