Early recovery of botulism: one decade of experience.

BACKGROUND: Botulism is a rare but serious disease, which appears in different forms. In this study, we reviewed the clinical features, laboratory data, and outcomes of patients who referred to our tertiary center. MATERIALS AND METHODS: All confirmed cases of botulism referred to an academic referral center and a teaching hospital during 2009-2019, were retrospectively reviewed. RESULTS: Fifty-three cases of clinical or laboratory-confirmed botulism were examined in this study. Nineteen patients were confirmed by laboratory data (serotype A (89.5%) and serotype E (10.5%)). In seven cases, the cause of botulism was unclear. In two patients, systemic symptoms emerged after the therapeutic injection of botulinum neurotoxin. The majority of cases (83%) were caused by an obvious food source. In 66% of cases, the initial symptoms emerged within less than 36 h, while in 20.8% of cases, the symptoms developed within or after 36 h; however, in seven patients that their botulism sources were unclear, the onset could not be estimated. All patients showed cranial involvement and generalized manifestation, and 49.1% had gastrointestinal symptoms. Except for two patients who were not treated due to immediate drug reactions who manifested severe hemodynamic instability, the rest of the patients were treated with trivalent antitoxin (A, B, and E). The complete resolution of the symptoms during hospitalization was documented in 50.9% of the patients. About 17% of the patients were intubated. Two patients died due to massive bilateral pulmonary thromboembolism and cardiac asystole following respiratory failure. CONCLUSIONS: Although the complete resolution of the symptoms usually takes several weeks, in our experience, most patients showed at least partial resolution upon discharge. Early treatment results in better outcomes.

Human Botulism in France, 1875-2016.

Botulism is a rare but severe disease which is characterized by paralysis and inhibition of secretions. Only a few cases had been reported at the end of the 19th century in France. The disease was frequent during the second world war, and then the incidence decreased progressively. However, human botulism is still present in France with 10-25 cases every year. Food-borne botulism was the main form of botulism in France, whereas infant botulism (17 cases between 2004 and 2016) was rare, and wound and inhalational botulism were exceptional. Type B was the prevalent botulism type and was mainly due to consumption of home-made or small-scale preparations of cured ham and to a lesser extent other pork meat products. In the recent period (2000-2016), a wider diversity of botulism types from various food origin including industrial foods was reported. Severe cases of type A and F botulism as well as type E botulism were more frequent. Albeit rare, the severity of botulism justifies its continued surveillance and recommendations to food industry and consumers regarding food hygiene and preservation practices.

Botulism Outbreak in a Regional Community Hospital: Lessons Learned in Transfer and Transport Considerations.

Botulism is a potentially lethal disease caused by a toxin released by Clostridium botulinum. Outbreaks of botulism from food sources can lead to a Mass Casualty Incident (MCI) involving sometimes hundreds of individuals. We report on a recent outbreak of botulism treated at a regional community hospital with a focus on emergency medical services (EMS) response and transport considerations. Case Presentation: There were 53 patient evaluated for botulism at the sending facility. In total, 11 botulism exposures required intubation at the sending facility. Twenty-four patients were ultimately transported by critical care capable ALS crews with the majority (16) of these transports occurred in the first 24 hours. There was one fatality in the first days of the outbreak and a second death that occurred in a patient who died after long-term acute care (LTAC) placement several months after hospital discharge. Conclusion: Local EMS providers and public safety officers have a critical role in identifying and following up on potentially exposed botulism cases. The organization of transporting agencies and the logistics of transfer turned out to be 2 opportunities for improvement in response to this mass casualty incident.

Foodborne botulism in Poland in 2016

OBJECTIVES: The main aim of the study is to assess the epidemiological situation of foodborne botulism in Poland in 2016 compared to previous years. MATERIALS AND METHODS: In this assessment we reviewed national surveillance data on foodborne botulism cases published in the annual bulletin "Infectious diseases and poisonings in Poland in 2016" and in previous publications, as well as unpublished data retrieved from botulism case reports for 2016 sent from Sanitary-Epidemiological Stations to the Department of Epidemiology NIPH-NIH. RESULTS: In 2016, a total of 26 foodborne botulism cases (including 18 laboratory confirmed) were reported and the annual incidence rate (0.07 per 100,000 population) was slightly lower than both the previous year and the median incidence from 2010-2014. The highest incidence in the country was noted in Lubelskie (0.33), Warminsko-mazurskie (0.28) and Zachodniopomorskie provinces (0.23). The incidence in rural areas (0.10 per 100,000 population) was twice as high as in urban areas (0.05); incidence among men was 8 times as high as among women; the highest incidence (0.36) was observed in men in the age group of 50-59 years. Most cases were associated with consumption of homemade canned fish or pork products and mixed or unknown types of canned meats. All patients were hospitalized. Three deaths related to the disease were reported. CONCLUSIONS: In 2016, the epidemiological situation of foodborne botulism in Poland has not changed significantly. This study suggests the need for training of health care professionals to improve diagnosis of botulism as well as continuous health education with respect to how to safely preserve, store and consume food at home.

Botulism outbreak causes high mortality in Scottish cattle.

SAc C VS disease Surveillance report for july 2017 Botulism in finishing cattleSeasonal dermatitis in Cheviot ewesStreptococcus suis type 2 meningitis and septicaemia in pigletsRodenticide toxicity in chickens.

Wound botulism, its neurological manifestations, treatment and outcomes: A case series from the Glasgow outbreak, 2015.

Background and aims We examined the neurological manifestations, treatment and outcomes of a subset of 25 patients within the largest ever outbreak of wound botulism in Europe. Methods and results All 25 cases were intravenous drug users. The most common presenting symptom was dysarthria in 19/25 (76%), followed by dysphagia in 12/25 (48%), blurred vision in 10/25 (40%) and double vision in 8/25 (32%). Microbiological analysis confirmed the diagnosis in nine cases (36%). Duration of admission positively correlated with time to antitoxin, time to wound debridement and female sex. Conclusion As the outbreak continued, hospital stays shortened, reflecting growing awareness of the outbreak and quicker treatment initiation.

Retrospective survey to evaluate the safety and efficacy of Japanese botulinum antitoxin therapy in Japan.

Japanese botulinum antitoxins have been used for more than 50 years; however, their safety and therapeutic efficacy are not clear. In order to analyze the available data on botulinum antitoxin therapy in Japan, we surveyed published reports about botulism cases in which botulinum antitoxins were used, and retrospectively analyzed the safety and efficacy of the therapy. A total of 134 patients administered botulinum antitoxins were identified from published reports. Two cases of side effects (1.5%) were detected after antitoxin administration, both not fatal. The fatality rate was 9.4%, and more than 70% of the patients showed improvement in their symptoms and better clinical conditions than those not treated with antitoxins. These data suggest that the therapy with Japanese antitoxins is safe and highly effective.

Expression, purification and characterization of the receptor-binding domain of botulinum neurotoxin serotype B as a vaccine candidate.

The receptor-binding domain of botulinum neurotoxins (the HC fragment) is a promising vaccine candidate. Among the HC fragments of the seven BoNT serotypes, the expression of HC/B in Escherichia coli is considered especially challenging due to its accumulation as a non-soluble protein aggregate. In this study, the effects of different parameters on the expression of soluble HC/B were evaluated using a screening assay that included growing the bacterium at a small scale, a chemical cell lysis step, and a specific ELISA. The highest soluble HC/B expression levels were obtained when the bacterium E. coli BL21(DE3)+pET-9a-HC/B was grown in terrific broth media at 18°C without induction. Under these conditions, the yield was an order of magnitude higher than previously reported. Standard purification of the protein using a nickel column resulted in a low purity of HC/B. However, the addition of an acidic wash step prior to protein elution released a major protein contaminant and significantly increased the purity level. Mass spectrometry analysis identified the contaminant as ArnA, an E. coli protein that often contaminates recombinant His-tagged protein preparations. The purified HC/B was highly immunogenic, protecting mice from a 10(6) LD50 challenge after a single vaccination and generating a neutralizing titer of 50IU/ml after three immunizations. Moreover, the functionality of the protein was preserved, as it inhibited BoNT/B intoxication in vivo, presumably due to blockade of the neurotoxin protein receptor synaptotagmin.

Outcome of adult horses with botulism treated at a veterinary hospital: 92 cases (1989-2013).

BACKGROUND: There are no studies evaluating a large population of adult horses treated for botulism. Reported survival rates in outbreak situations are low; however, many horses in outbreaks do not receive treatment. HYPOTHESIS/OBJECTIVES: That adult horses treated at a veterinary hospital would have improved survival compared to outbreak situations. Additional aims included identification of predictors of nonsurvival. ANIMALS: All horses greater than 6 months of age with a final diagnosis of botulism admitted to a veterinary teaching hospital between 1989 and 2013 were included. METHODS: Retrospective study. Historical, admission, and hospitalization data were retrieved from medical records and associations between variables and nonsurvival were identified using logistic regression. Two multivariable models were developed pertaining to (1) information available at admission and (2) clinical findings during hospitalization. RESULTS: Ninety-two records met inclusion criteria. Retained variables for the two models indicated that higher rectal temperature (OR, 1.94; CI, 1.19-3.17) and dysphagia (OR, 4.04; CI, 1.01-16.17) observed at admission increased the odds of survival, as did treatment with antitoxin (OR, 121.30; CI, 9.94-1,480.65). Horses with abnormal respiratory effort or inability to stand had decreased odds of survival. Overall survival was 48% but was significantly higher (67%, P = .011) for horses that arrived standing, and even higher (95%, P < .001) for horses that remained able to stand throughout hospitalization. Complications occurred in 62% of horses but were not associated with nonsurvival. CONCLUSIONS AND CLINICAL IMPORTANCE: Horses that lose the ability to stand have a poor chance of survival. Complications are common in treated horses but do not reduce survival.

Trends in outcome and hospitalization charges of adult patients admitted with botulism in the United States.

BACKGROUND: To assess the impact of new therapeutic strategies on outcomes and hospitalization charges among adult patients with botulism in the United States. METHODS: We determined in-hospital outcomes and charges for patients with botulism hospitalized in 1993-1994 and compared them with those observed among patients hospitalized in 2006-2007. Mortality, length of stay, and hospitalization charges were calculated. Age, sex, race, ethnicity, and discharge status were also reported. RESULTS: There were 66 and 132 admissions of adult patients with botulism in 1993-1994 and 2006-2007, respectively. Men predominance was observed in 2006-2007 compared to women predominance during the 1993-1994 time period. There was no significant difference in the average length of stay and in-hospital mortality rate between the two groups studied. However, in the 2006-2007 group, there was a significant increase in the mean hospitalization charges (USD 126,092 ± 120,535 vs. USD 83,623 ± 82,084; p = 0.0107) and in the proportion of patients requiring mechanical ventilation when compared to 1993-1994 (34 vs. 13.6%; p < 0.0001). CONCLUSION: Botulism continues to be an infrequent cause of hospitalization, with a significant increase in the average hospitalization charges in 2006-2007 when compared to 1993-1994, despite a nonsignificant change in the mortality rate and average length of hospitalization.

Purification and characterization of a novel subtype a3 botulinum neurotoxin.

Botulinum neurotoxins (BoNTs) produced by Clostridium botulinum are of considerable importance due to their being the cause of human and animal botulism, their potential as bioterrorism agents, and their utility as important pharmaceuticals. Type A is prominent due to its high toxicity and long duration of action. Five subtypes of type A BoNT are currently recognized; BoNT/A1, -/A2, and -/A5 have been purified, and their properties have been studied. BoNT/A3 is intriguing because it is not effectively neutralized by polyclonal anti-BoNT/A1 antibodies, and thus, it may potentially replace BoNT/A1 for patients who have become refractive to treatment with BoNT/A1 due to antibody formation or other modes of resistance. Purification of BoNT/A3 has been challenging because of its low levels of production in culture and the need for innovative purification procedures. In this study, modified Mueller-Miller medium was used in place of traditional toxin production medium (TPM) to culture C. botulinum A3 (CDC strain) and boost toxin production. BoNT/A3 titers were at least 10-fold higher than those produced in TPM. A purification method was developed to obtain greater than 95% pure BoNT/A3. The specific toxicity of BoNT/A3 as determined by mouse bioassay was 5.8 × 10(7) 50% lethal doses (LD(50))/mg. Neutralization of BoNT/A3 toxicity by a polyclonal anti-BoNT/A1 antibody was approximately 10-fold less than the neutralization of BoNT/A1 toxicity. In addition, differences in symptoms were observed between mice that were injected with BoNT/A3 and those that were injected with BoNT/A1. These results indicate that BoNT/A3 has novel biochemical and pharmacological properties compared to those of other subtype A toxins.

A novel strategy for development of recombinant antitoxin therapeutics tested in a mouse botulism model.

Antitoxins are needed that can be produced economically with improved safety and shelf life compared to conventional antisera-based therapeutics. Here we report a practical strategy for development of simple antitoxin therapeutics with substantial advantages over currently available treatments. The therapeutic strategy employs a single recombinant 'targeting agent' that binds a toxin at two unique sites and a 'clearing Ab' that binds two epitopes present on each targeting agent. Co-administration of the targeting agent and the clearing Ab results in decoration of the toxin with up to four Abs to promote accelerated clearance. The therapeutic strategy was applied to two Botulinum neurotoxin (BoNT) serotypes and protected mice from lethality in two different intoxication models with an efficacy equivalent to conventional antitoxin serum. Targeting agents were a single recombinant protein consisting of a heterodimer of two camelid anti-BoNT heavy-chain-only Ab V(H) (VHH) binding domains and two E-tag epitopes. The clearing mAb was an anti-E-tag mAb. By comparing the in vivo efficacy of treatments that employed neutralizing vs. non-neutralizing agents or the presence vs. absence of clearing Ab permitted unprecedented insight into the roles of toxin neutralization and clearance in antitoxin efficacy. Surprisingly, when a post-intoxication treatment model was used, a toxin-neutralizing heterodimer agent fully protected mice from intoxication even in the absence of clearing Ab. Thus a single, easy-to-produce recombinant protein was as efficacious as polyclonal antiserum in a clinically-relevant mouse model of botulism. This strategy should have widespread application in antitoxin development and other therapies in which neutralization and/or accelerated clearance of a serum biomolecule can offer therapeutic benefit.

The ripe olive scare and hotel Loch Maree tragedy: Botulism under glass in the 1920's.

Botulism was believed to be a rare disease in both the US and UK in the 1920's, until two deadly outbreaks altered that view and launched public health measures to control it. In the United States, the ripe olive scare of 1920 found glass-packaged olives linked to multiple deaths. In the United Kingdom, eight deaths from glass-potted duck paste, in the summer of 1922 at Loch Maree, Scotland will always be associated with botulism.

Epidemiology of foodborne botulism in Romania 1980-2009.

In 2007, Romania, the largest southeastern European country, reported the highest notification rate of botulism cases in the European Union (0.18 per 100,000 inhabitants), which was 18 times higher than the reported rate in the United States (0.01 per 100,000 inhabitants). This report aims to analyze published and unpublished surveillance data on foodborne botulism in Romania from 1980 to 2009 in the context of political and economical changes that occurred in the former communist countries. The mean annual incidence rate of botulism cases was significantly lower during the late communist period, 1980-1989 (0.06±0.03 cases per 100,000 inhabitants), than during the years 1990-1999 (0.1±0.04 cases per 100,000 inhabitants, p=0.01) and 2000-2009 (0.12±0.04 cases per 100,000 inhabitants, p<0.01). The highest incidence rates were registered in 1998 and 2007 (0.18 cases per 100,000 inhabitants), whereas the lowest incidence rate was registered in 1983 (0.02 cases per 100,000 inhabitants). The disease was usually associated with the consumption of home prepared meat products (mainly raw sausages, smoked-dried meat). Most of the laboratory-confirmed cases tested positive for type B toxin (99%). During 2007-2009, the incidence was particularly high in northwestern and western Romania (0.5 and 0.3 cases per 100,000 inhabitants, respectively). The fatality rate was 60% before 1995 and decreased to 12.2±8.5% during 1999-2009. The general ascending trend of infection rates throughout the period studied demonstrates the need for the implementation of correct public health and educational measures to fully prevent this severe disease.

Clostridium botulinum in the post-genomic era.

Foodborne botulism is a severe neuroparalytic disease caused by consumption of botulinum neurotoxin formed by strains of proteolytic Clostridium botulinum and non-proteolytic C. botulinum during their growth in food. The botulinum neurotoxin is the most potent substance known, with as little as 30-100 ng potentially fatal, and consumption of just a few milligrams of neurotoxin-containing food is likely to be sufficient to cause illness and potentially death. In order to minimise the foodborne botulism hazard, it is necessary to extend understanding of the biology of these bacteria. This process has been recently advanced by genome sequencing and subsequent analysis. In addition to neurotoxin formation, endospore formation is also critical to the success of proteolytic C. botulinum and non-proteolytic C. botulinum as foodborne pathogens. The endospores are highly resistant, and enable survival of adverse treatments such as heating. To better control the botulinum neurotoxin-forming clostridia, it is important to understand spore resistance mechanisms, and the physiological processes involved in germination and lag phase during recovery from this dormant state.

Relationships between local carcass density and risk of mortality in molting mallards during avian botulism outbreaks.

Removal of bird carcasses has been advocated for management of Clostridium botulinum outbreaks on lakes in North America because a reduction in density of toxin-laden maggots produced within bird carcasses is assumed to enhance survival of healthy birds. This inverse relationship between carcass density and survival has been reported in controlled studies with Mallards (Anas platyrhynchos) but has not been verified in wild ducks during naturally occurring botulism outbreaks. Therefore, we radio-marked 204 molting Mallards on seven lakes in western Canada during July-August 1999-2000, and monitored their survival daily for 30 days. Carcass searches were conducted simultaneously at 90 matched locations for freshly dead and randomly selected live radio-marked Mallards. Carcass density (carcasses/ha) averaged about two times greater at dead than at live duck locations (x = 12.4, SE= 1.2 vs. x= 5.0, SE= 0.7). Predicted risk of mortality increased rapidly with carcass density (case-control logistic regression: model-averaged beta(density)= 0.167, unconditional SE= 0.062). Mallards exposed to 5-11 and >11 carcasses/ ha were 3.5 and 13 times more likely to die, respectively, than were Mallards inhabiting carcass-free areas. Mortality risk was more closely related to density of maggot-laden carcasses than to maggot-free carcass densities. Our results are consistent with the assumption that reducing carcass density could enhance survival. However, we caution that survival rates may remain low on lakes in which areas with high carcass densities persist due to incomplete carcass removal.

Survival of radio-marked mallards in relation to management of avian botulism.

Avian botulism outbreaks are frequently perpetuated by type C toxin produced by Clostridium botulinum proliferating in decomposing bird carcasses and consumption of toxic maggots from these carcasses by healthy birds. Therefore, removing bird carcasses has been advocated for disease management because availability of toxic maggots should be reduced, increasing duck survival. However, this management is expensive, and its effect on waterfowl mortality under field conditions is unknown. We radio-marked 419 molting mallards on 11 lakes in western Canada during July-August 1999-2001 and monitored them for 30 days, testing whether survival was higher on lakes with carcass removal. Botulism occurred on 10 lakes. On five carcass removal lakes, greater-than-normal effort was made to conduct early, thorough surveillance and immediately remove carcasses; on six nonremoval lakes, no carcasses were removed. In 1999, estimated 30-day survival probabilities ranged from 0.149 (95% CI=0.065-0.304) on one large lake with carcass removal to 0.466 (95% CI=0.270-0.674) and 0.618 (95% CI=0.443-0.767) on two nonremoval lakes. As a result, we conducted work on smaller wetlands thereafter, reasoning that any management benefit would be easier to detect. In 2000, estimated 30-day survival probabilities were 0.313 (95% CI=0.143-0.556) and 0.794 (95% CI=0.609-0.905) on two carcass removal lakes versus 0.525 (95% CI=0.362-0.682) and 0.743 (95% CI=0.564-0.866) on two nonremoval lakes. In 2001, botulism was detected on two nonremoval lakes where survival probabilities were 0.845 (95% CI=0.630-0.946) and 0.942 (95% CI=0.778-0.987), and on one removal lake where survival probability was 1.0 (95% CI=0.99-1.0), but not detected on the other removal lake where no marked birds died from botulism (1.0, 95% CI=0.99-1.0). Survival tended to be higher on lakes with lower carcass density, but when data were organized by carcass removal versus nonremoval, mallard survival was not consistently greater on lakes where carcasses were removed.

Survival analysis for respiratory failure in patients with food-borne botulism.

INTRODUCTION: Botulism is a rare presynaptic neuromuscular junction disorder caused by potent toxins produced by the anaerobic, spore-forming, Gram-positive bacterium Clostridium botulinum. Food-borne botulism is caused by the ingestion of foods contaminated with botulinum toxin. In March 2006, there was a large outbreak of food-borne botulism associated with the ingestion of home-canned bamboo shoots in Thailand. The survival analyses for respiratory failure in these patients were studied and are reported here. METHODS: A prospective observational cohort study was conducted on this outbreak. The primary outcome of interest was the time to respiratory failure. The secondary outcome was the time to weaning off ventilator. The prognostic factors associated with respiratory failure and weaning off ventilator are presented. RESULTS: A total of 91 in-patients with baseline clinical characteristics were included. Most cases first presented with gastrointestinal symptoms followed by neurological symptoms, the most striking of which being difficulty in swallowing. Common clinical features included ptosis, ophthalmoplegia, proximal muscle weakness, pupillary abnormality, and respiratory failure. Forty-two patients developed respiratory failure requiring mechanical ventilation and the median duration on ventilator was 14 days. The median length of hospital stay for all patients was 13.5 days. Difficulty in breathing, moderate to severe ptosis, and dilated and fixed pupils were associated with respiratory failure. Among patients who were on ventilators, a short incubation period and pupillary abnormality were associated with a longer period of mechanical ventilation. All patients had antitoxin injection and there was no mortality in this outbreak. CONCLUSION: The history of difficult breathing and the findings of moderate to severe ptosis and pupillary abnormality were associated with severe illness and respiratory failure. A long incubation time was associated with a better prognosis. Although botulism is a potentially fatal disease, there was no mortality in this outbreak. All patients had antitoxin injection and good intensive care that resulted in good clinical outcomes.