Efficacy of Antitoxin Therapy in Treating Patients With Foodborne Botulism: A Systematic Review and Meta-analysis of Cases, 1923–2016

Clinical Infectious Diseases, Jan 2018

Botulism is a rare, potentially severe illness, often fatal if not appropriately treated. Data on treatment are sparse. We systematically evaluated the literature on botulinum antitoxin and other treatments.

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Efficacy of Antitoxin Therapy in Treating Patients With Foodborne Botulism: A Systematic Review and Meta-analysis of Cases, 1923–2016

Systematic Review of Botulism Treatment • CID Efficacy of Antitoxin Therapy in Treating Patients With Foodborne Botulism: A Systematic Review and Meta- analysis of Cases, 1923-2016 John C. O'Horo 0 1 2 Eugene P. Harper 5 Abdelghani El Rafei 2 Rashid Ali 0 1 Daniel C. DeSimone 2 Amra Sakusic 0 1 Omar M. Abu Saleh 2 Jasmine R. Marcelin 2 Eugene M. Tan 2 Agam K. Rao 4 Jeremy Sobel 3 Pritish K. Tosh 2 0 Department of Medicine, Division of Pulmonary and Critical Care Medicine 1 Multidisciplinary Epidemiology and Translational Research in Critical Care, Emergency and Perioperative Medicine Group 2 Department of Medicine, Division of Infectious Diseases 3 DFWED, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia 4 Enteric Diseases Epidemiology Branch, Division of Foodborne , Waterborne, and Environmental Diseases, DFWED 5 School of Medicine, Mayo Clinic , Rochester, Minnesota , USA Background. Botulism is a rare, potentially severe illness, often fatal if not appropriately treated. Data on treatment are sparse. We systematically evaluated the literature on botulinum antitoxin and other treatments. Methods. We conducted a systematic literature review of published articles in PubMed via Medline, Web of Science, Embase, Ovid, and Cumulative Index to Nursing and Allied Health Literature, and included all studies that reported on the clinical course and treatment for foodborne botulism. Articles were reviewed by 2 independent reviewers and independently abstracted for treatment type and toxin exposure. We conducted a meta-analysis on the effect of timing of antitoxin administration, antitoxin type, and toxin exposure type. Results. We identified 235 articles that met the inclusion criteria, published between 1923 and 2016. Study quality was variable. Few (27%) case series reported sufficient data for inclusion in meta-analysis. Reduced mortality was associated with any antitoxin treatment (odds ratio [OR], 0.16; 95% confidence interval [CI], .09-.30) and antitoxin treatment within 48 hours of illness onset (OR, 0.12; 95% CI, .03-.41). Data did not allow assessment of critical care impact, including ventilator support, on survival. Therapeutic agents other than antitoxin offered no clear benefit. Patient characteristics did not predict poor outcomes. We did not identify an interval beyond which antitoxin was not beneficial. Conclusions. Published studies on botulism treatment are relatively sparse and of low quality. Timely administration of antitoxin reduces mortality; despite appropriate treatment with antitoxin, some patients suffer respiratory failure. Prompt antitoxin administration and meticulous intensive care are essential for optimal outcome. - Botulism is a rare neuroparalytic illness characterized by bilateral cranial nerve palsies and descending paralysis, which may lead to respiratory failure. Disease can be fatal, particularly without treatment. Botulinum neurotoxin (BoNT) mediates the effects of disease [ 1, 2 ]. Foodborne botulism occurs following ingestion of toxin found in contaminated foods; outbreaks occur periodically, and contamination of a widely consumed food could cause many illnesses. BoNT is the most toxic substance by weight known, and various countries with biologic warfare programs have weaponized it as a biological weapon. The Centers for Disease Control and Prevention classifies BoNT as a category A biological agent [ 3, 4 ]. Seven botulism toxin serotypes, A–G, were described between 1919 and 1970. Most human botulism is caused by serotypes A, B, E, and F, but others have pathogenic potential as well. Paralysis induced by BoNT can last weeks to months. In cases in which the respiratory tract or respiratory muscles are impaired, mechanical ventilation is life-saving. Botulinum antitoxins can neutralize circulating botulinum toxin, preventing toxin binding to the neuromuscular junction, but does not reverse existing paralysis. The mainstays of treatment are supportive care and botulinum antitoxin. These measures have been credited with reducing botulism mortality in the United States from >60% in the early 20th century to <5% at present [ 5 ]. Additionally, other targeted treatments have been attempted to ameliorate the effects of botulism, such as cathartics and enemas to clear toxin from the gastrointestinal tract, and guanidine and 3,4-diaminopuridine to stimulate acetylcholine release [ 6 ]. Equine-source botulism antitoxins of varying valencies (anti-A, anti-B, anti-AB, etc) and neutralizing capacities have been used over the past century. Currently, the sole botulinum antitoxin product licensed for treatment of noninfant botulism in the United States is equine-source botulism antitoxin heptavalent [ 7 ]. A human-source antitoxin, botulism immune globulin intravenous (BIG-IV), is licensed in the United States solely for the treatment for infants with botulism type A or type B. Botulism is rare, with <100 noninfant cases and approximately 100 infant cases reported annually in the United States [ 8 ]. Consequently, peer-reviewed studies on the efficacy of botulinum antitoxin are sparse. In nearly a century, only 1 study, involving a retrospective cohort, examined the effectiveness of equine-origin botulinum antitoxin, finding reduced mortality and other measures of severity associated with early treatment [ 9 ]. For infant botulism, 1 randomized controlled trial found that use of BIG-IV was associated with reduced duration of mechanical ventilation and hospitalization without reported adverse events [ 10–13 ]. A large botulism outbreak, either naturally occurring or intentionally created, may strain resources, and at present, no evidence-based guidance exists to prioritize antitoxin administration. Data-based treatment recommendations are needed to ensure an effective and efficient public health response. We sought to systematically review all published reports and studies on the treatment of foodborne botulism. The questions that guided our systematic review were (1) what benefit should be expected from botulinum antitoxin? (2) Is there a window of time beyond which administration of antitoxin is no longer beneficial? (3) Do any patient demographic or clinical characteristics predict greater benefit from antitoxin administration? METHODS This study was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42015024327). Our systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 14 ]. Search Strategy With the assistance of an expert research librarian, we queried PubMed via Medline, Web of Science, Embase, Ovid, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) using keywords such as botulism, Clostridium botulinum, botulinum antitoxin, botulism, botulinum, BoNT, antibacterial agents, antitoxins, botulinum antitoxin, respiration artificial, activated charcoal, cholinergic antagonists, drugs investigational, disaster planning, immunoglobulins, cholinergic, guanidine, anticholinergic, ventilation, antitoxin, antisera, antiserum, antibody, antibiotic, charcoal, pharmaceutical, germine, immunoglobulin, intubation, experimental animal, and nonhuman; the search strategy is detailed in Supplementary Appendix 1. Embase, Scopus, Medline, CINAHL contain conference proceedings and dissertations). Additionally we searched National Technical Information Service, Defense Technical Information Center, and Google Scholar for government documents, and manually included article references for additional studies. S44 • CID 2018:66 (Suppl 1) • O’Horo et al Inclusion and Exclusion Criteria We included any article in the English language including case report, series, cohort, controlled trial, and animal study that reported patient-level data on the natural history of foodborne botulism or the effect of a directed treatment such as antitoxin. Botulism was defined by clinical diagnosis, epidemiologically (reported exposure known source with neurologic symptoms of botulism), or based on laboratory assays. Because of different pathophysiology, human cases of iatrogenic, infant, and wound botulism were excluded. Animal cases were excluded if they did not describe both controlled toxin exposure and antitoxin treatment. Case reports and series of <3 cases were abstracted for descriptive analysis, including specific rare treatments and outcomes, and excluded from meta-analysis and formal statistical analyses. Article Screening and Abstraction Articles were screened independently by 2 investigators (J. C. O. and P. K. T.) using Covidence (www.covidence.org), an online tool for systematic reviews. Initial screening entailed abstract review, followed by review of all potentially relevant full text articles. Reviewers determined if cases reported a case of foodborne botulism with discussion of both treatment strategies and clinical outcomes; if these criteria were met, the study was included. In both phases, disagreements were resolved by discussion and consensus was reached on all articles. Articles were abstracted using a standardized form developed on Research Electronic Data Capture (REDCap) (Supplementary Appendix 2). Study data were collected and managed using REDCap electronic data capture tools hosted at Mayo Clinic. REDCap is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources [ 15 ]. Primary abstraction was completed by 1 of 8 reviewers (E. H., A. G. E. L., R. A., D. D., A. S., O. A., J. M., or E. T.) trained in use of the abstraction tool and definitions by 1 investigator (J. C. O.). All articles were independently abstracted and reviewed by a second reviewer (J. C. O. or P. K. T.). Disagreements were resolved through discussion at weekly meetings. Data Abstraction Articles were reviewed for outcomes including mortality, hospital length of stay, duration of mechanical ventilation, and longterm neurologic sequelae. Articles were grouped first by the article type (case series, cohorts and trials, animal studies) and then by the intervention (eg, monovalent, bivalent, heptavalent antitoxin). Meta-analysis For meta-analytic purposes, we combined cohort studies, outbreak reports, or case series with N ≥3 to estimate the effect of antitoxin on mortality, ventilation, and hospital length of stay. In studies in which both the toxin type and antitoxin type were reported, only patients who received antitoxin which matched identified toxin exposures were considered “treated.” For mortality analysis, the odds of death were calculated as a proportion of the total number of treated vs not-treated patients in a given report. Because in smaller studies the binomial distribution may not approximate the normal distribution, we performed a double arcsine Freeman-Tukey transformation to stabilize the variance and restore assumptions of normalcy. We calculated estimated variance by adding a proportionality constant to the observed number of deaths to adjust for zero values; this was equal to the reciprocal of the total number of subjects in the study. Resultant data were combined using the random-effects model prescribed by DerSimonian and Laird [ 16 ]. Subgroup analyses were performed by antitoxin type and toxin types. The odds of death for each type was calculated and compared. Heterogeneity was assessed using I2, where 0% indicates low heterogeneity and 100% high heterogeneity. Publication bias was assessed using visual inspection of a funnel plot using the method prescribed by Egger et al [ 17 ]. Statistical analysis was performed using Stata (StataCorp, College Station, Texas) and Review Manager 5 (Nordic Cochrane Center, Copenhagen, Denmark) software. Duration of hospitalization and ventilation were modeled using mean and standard deviation data from cohorts and case series providing sufficient data to determine patients’ duration of treatment. On meta-analysis, only studies including both treated and untreated patients were analyzed, as interhospital ventilation and extubation practices were too great for indirect comparison. Early vs late administration of antitoxin, defined by report authors, was analyzed relative to mortality, duration of ventilation, and duration of hospitalization using the methods described above. Subgroups were defined by (1) definitions given in the study for early vs late (Supplementary Appendix 8) or (2) patients who received antitoxin within 24 hours of presenting for medical care vs all others. Additional sensitivity analyses were performed on studies with sufficient patient-level data to exclude those who died when calculating length of stay and duration of hospitalization. This was performed to determine the effect of any survivor bias on these time-dependent variables. Finally, using study evidence ratings, we conducted an additional sensitivity analysis excluding the 50% lowest-scoring studies as rated by the evidence-rating tool described below. Results from these sensitivity analyses were compared to the main outcomes to identify confounding by reporting and publication bias. Meta-regression was performed on all studies by year of publication to determine the role that evolving supportive care techniques have played over time in each of these domains. Individual Study Evidence Rating Each publication was assessed by both reviewers for quality of evidence using a tool developed by the authors (Supplementary Appendix 3). This tool evaluates articles for design quality, level of certainty, and completeness of reporting. Study design and evidence were modified from the criteria used by the US Preventive Services Task Force. The risk-of-bias tool was modified from the Newcastle-Ottawa Scale. Completeness was assessed based on the presence of 15 pieces of information deemed pertinent to a botulism treatment article (Supplementary Appendix 3). RESULTS The search strategy yielded 13 055 distinct abstracts for screening. One abstract could not be obtained; 13 069 were screened, of which 12 455 studies were excluded. Full text evaluation was performed on 599 articles, of which 223 met inclusion criteria (Figure 1). Characteristics of the comparative studies included are described in Supplementary Appendix 7. Outcomes are summarized in Table 1. Additional details on the method of diagnosis are shown in Supplementary Appendix 8. Individual studies and case reports unsuitable for quantitative analysis are summarized in Table 2. Patient Characteristics Data tying individual outcomes to age, gender/sex, comorbidities, and severity of illness at time of initial contact with medical care were reported inconsistently. While we cannot exclude that some populations may receive greater benefit from antitoxin treatment, we could not identify such a subpopulation on the basis of the highly limited data set. Supportive Care All articles that described survival alluded to the importance of high-quality supportive care, particularly respiratory critical care. However, insufficient detail (eg, modes of mechanical ventilation and nutritional support) in these publications precluded evaluation of specific intensive care components on clinical outcomes. Relationship Between Type of Toxin and Clinical Outcome Mortality among patients treated and not treated with antitoxin, by toxin type, is presented in Figures 2–5. Overall, antitoxin reduced mortality (odds ratio [OR], 0.22; 95% confidence interval [CI], .17–.29); a high degree of heterogeneity was observed (I2  =  69.3%). Heterogeneity was largely due to studies not reporting toxin type (Figure 2). Subset analyses by toxin type were significantly less heterogeneous as described below. On meta-regression modeling, study year, design, selection, comparability, and completeness variables were not substantial contributors to heterogeneity (P = 0.86). Egger test identified no evidence of publication bias (P = 0.26). Systematic Review of Botulism Treatment • CID 2018:66 (Suppl 1) • S45 The greatest reduction in botulism-related mortality was associated with the use of type E antitoxin (OR, 0.13; 95% CI, .06–.30; I2 = 10%; Figure 5), followed by type A antitoxin (OR, 0.57; 95% CI, .39–.84; I2 = 81.2%; Figure 3); reduction in mortality was not statistically significant for type B antitoxin (OR, 0.74; 95% CI, .27–1.97; Figure 4). Key data on the impact of type E antitoxin come from Dolman and Iida, who examined Canadian mortality rates of botulism type E before (baseline) and after introduction of type E antitoxin therapy [ 18 ]. Baseline mortality in this study was derived from secondary data and was thus excluded from the meta-analysis. Dolman and Iida’s baseline was derived from 75 outbreaks with 374 patients in 6 countries; case fatality rate was 30%. In Canada, in 28 outbreaks, 85 of 220 patients were treated with anti-E antitoxin. S46 • CID 2018:66 (Suppl 1) • O’Horo et al Among patients not treated with antitoxin, 28.9% died, compared with 3.5% of those treated [ 18 ]. Use of Different Antitoxin Formulations Studies that reported both toxin type and administered antitoxin type were less heterogeneous overall and demonstrated a survival benefit to antitoxin (OR, 0.16; .09–.30; I2  =  0%; Figure 6). Fifteen studies reported use of trivalent antitoxin, 10 bivalent antitoxin, and 2 heptavalent antitoxin. Use of anti-ABE trivalent antitoxin was most commonly reported [ 19–34 ]. Trivalent antitoxin, when administered in cases of botulism types A, B, or E, reduced mortality (OR, 0.13; 95% CI, .04–.38; I2  =  0%). Side effects from this formulation were less commonly reported than all other antitoxins with side effects reported. Anti-ABE antitoxin was generally reported as effective and well tolerated. Case series reported occasional residual neuromuscular deficits persisting up to several months after therapy (Table 2). Bivalent AB antitoxin was the second most commonly reported formulation [ 25, 35–43 ]; its use was not significantly associated with reduction in mortality (OR, 0.37; 95% CI, .10– 1.31; I2 = 0%). Information on heptavalent antitoxin includes 2 reports of foodborne botulism outbreaks. One was caused by toxin type A–contaminated canned bamboo in Thailand [ 43– 45 ] and affected 137 patients, of whom 20 were treated with heptavalent antitoxin, and the others with bivalent AB or quadrivalent ABEF antitoxin. No deaths were reported. The second outbreak, caused by type A toxin, affected 8 prison inmates in Utah [46]. All received heptavalent antitoxin; none died. Low mortality in both outbreaks was attributed to excellent critical and supportive care of the patients [ 45 ]. The largest available data source on heptavalent antitoxin was the unpublished Centers for Disease Control and Prevention’s expanded-access Investigational New Drug application. Data included mostly foodborne botulism cases and several cases of wound botulism, infant botulism, and other syndromes. Of 249 patients treated under this protocol, 105 were confirmed as having botulism. One child experienced hemodynamic instability after administration, comprising the only serious adverse event seen with heptavalent antitoxin. Allergic reactions, typically rash, were noted in 6 patients, all of whom recovered without sequelae. Seven deaths were observed in confirmed botulism cases treated with heptavalent antitoxin; none were attributed to the antitoxin [ 47 ]. A variety of other antitoxin combinations are reported in Figure  6, including quadrivalent ABEF [ 43 ], monovalent A  [ 48 ], monovalent E [ 18, 49 ], and a combination of bivalent AB formulation and monovalent E formulation [ 50, 51 ]. The small number of deaths from botulism reported in patients treated with these agents precludes a statistical assessment of their impact on clinical outcomes. tor dependence compared with those receiving it on day 6 [ 44 ]. Sheth et al reported on 6 patients in a botulism type B outbreak associated with bottled carrot juice. Five patients received antitoxin: 3 within 24 hours, 1 on day 13, and 1 on day 45. At the time of publication, 2 patients had been ventilator dependent for >1 year [ 52 ]. We treated these patients as having 365 ventilator-days, demonstrating some reduction in ventilator time in those who had early treatment. mechanical ventilation was significantly reduced and there were no deaths, compared with 7 deaths among patients treated later. Overall, earlier antitoxin administration reduced mortality, compared with later administration (OR, 0.12; 95% CI, .03–.41; I2 = 0%; Figure 7). Animal Studies In general, animal studies showed some benefit to antitoxin treatment (Supplementary Appendices 5 and 9). Therapeutic Agents Other Than Antitoxin We identified no improvement with several agents reported in the literature (Supplementary Appendix 6). Yu et al also reported a benefit from heptavalent antitoxin Study Quality Assessments given within 48 hours compared with later administration [ 47 ]. Most studies were rated as level III evidence (case reports and In patients treated early, the proportion of patients requiring series, opinions of expert authorities) (Supplementary Appendix S48 • CID 2018:66 (Suppl 1) • O’Horo et al 4). Outcome assessments were not consistently high quality, with a mean of 5/12 on our scoring rubric. Completeness of reporting was generally good, with an average score of 11/16. Study design was not a major contributor to interobserver variability (P = .50). Study outcome assessments were similarly not a major contributor (P  =  .54). Completeness was also not significantly associated on meta-regression (P = .31). DISCUSSION In this systematic, comprehensive literature review of botulism treatment, we examined all relevant publications since the early 20th century. Our findings support the routine administration of botulinum antitoxin to botulism patients. Antitoxin treatment reduces mortality, and the available data show that earlier antitoxin administration reduces both mortality and ventilation time, compared with later administration. However, there are reports of benefit even with late antitoxin administration, defined by the authors as anywhere from >24 hours after illness onset to 48 hours after presentation. We found no clear indication of a point in the course of illness at which antitoxin administration was no longer beneficial. Although the nature of the data did not allow for quantitative analysis of the benefits of supportive care, this modality is doubtless essential to survival of patients with severe botulism, as evidenced by decreased mortality since the introduction of ventilator care in the 1960s. Despite some early promising studies for guanidine, we did not identify clear or sustained benefit to any alternative treatment modalities applied to botulism patients. Qualitative studies and case reports broadly supported treatment with botulinum antitoxin. Several older studies dating to the first half of the 20th century reported dramatic clinical resolution following antitoxin administration with all types (Table 2); the significance of these observations is unclear. It is worth noting that while mortality in patients not treated with antitoxin was high, often these patients did not have access to advanced life support. Therefore, these poor outcomes were likely influenced by the lack of supportive care. Available data do not suggest any patient characteristics that predict a response to therapy. Because the data do not provide evidence of demographic or clinical indicators for predictors of better outcome, we cannot recommend any specific criteria for prioritizing antitoxin treatment when its availability is limited. Further study is needed to risk-stratify patients and identify patients likeliest to benefit from antitoxin treatment. Correspondence between toxin types and antitoxin serotype corresponded with clinical outcome. The currently licensed heptavalent antitoxin provides appropriate treatment for botulism caused by serotypes A–G. Data available to us were limited to unpublished prelicensure surveillance. Therefore, treatment outcomes should be monitored and analyzed on an ongoing basis. Recently, reports of new toxin types have been published, including a novel toxin subsequently shown to be a hybrid type A/F fully neutralized by HBAT [ 53, 54 ] and a novel toxin S52 • CID 2018:66 (Suppl 1) • O’Horo et al identified and assembled from the published gene sequence of a C.  botulinum isolate [55]. These reports illustrate important challenges in the field of botulism. New botulinum toxins of clinical significance may be discovered. The routine analysis and dissemination of clostridial gene sequences can accelerate such discoveries, and likely facilitate assembly of toxins, for purposes hopefully benign but possibly nefarious. Preparedness requires careful laboratory investigation of all suspected botulism cases and ongoing research and development of new countermeasures. Appropriate supportive care is considered a cornerstone in survival and recovery from botulism [ 56, 57 ]. It must be borne in mind that a substantial proportion of botulism patients suffer respiratory compromise, some despite prompt diagnosis and early antitoxin treatment; therefore, survival of some botulism patients, treated or untreated with antitoxin, depends on high-quality intensive care. Longstanding experience shows that deaths from botulism can be averted by providing meticulous intensive care, including ventilator care when required [52]. Antitoxin should be given as soon as possible along with meticulous intensive care. Likewise, mortality in case series and reports was highest in patients remote from hospital or emergency care facilities. Early recognition and best intensive care unit practices are an important part of the comprehensive care of the botulism patient. In a situation of limited antitoxin availability, the availability of critical supportive care will determine survival for patients experiencing respiratory compromise. Critical care is an essential component of emergency preparedness for botulism events, both naturally occurring and intentionally created. Our study has several limitations. We did not include reports of wound botulism in the review, so our findings may not fully apply to that syndrome. Although we made every effort to separate outbreaks and case reports to avoid analyzing the same individual twice, the way that outbreaks are reported and analyzed, particularly in older literature, makes this nearly impossible. For example, several patients are likely reported in each of 2 case series reported by Dolman [ 18, 58 ] likely, but it is impossible to determine which. We attempted to account for this with several sensitivity analyses serially excluding these and other high overlap studies; we did not see a substantial change in our overall results. Our review includes publications spanning 8 decades. Aside from improvements in antitoxin manufacture, types, and valence, this period encompasses dramatic improvements in supportive care technology and techniques and the rise of critical care as a specialty. The effect of these on outcomes is profound, but we could not methodologically account for it in our results. We must therefore accept that some of the benefit attributed to antitoxin may in fact be due to some of these advances. Thus, we cautiously interpret our results to suggest that appropriate antitoxin therapy in conjunction with high-quality supportive care produce the best outcomes in botulism patients. A final limitation is our inability to adjust for the effect of disease progression and timing. Although we did observe some benefit from early antitoxin administration as defined by the report authors, several confounders are inherent in this finding. First, early administration may have been a marker for early recognition and initiation of other interventions. Second, early administration in several studies may have reflected early Systematic Review of Botulism Treatment • CID 2018:66 (Suppl 1) • S53 treatment of clinically milder cases that presented after delayed diagnosis of a severely ill outbreak index case. However, a beneficial effect of early antitoxin administration was reported in nearly all studies examining this measure. Overall, this would support a benefit of earlier administration, but we may have overestimated the degree of benefit. Another significant limitation is our focus on foodborne botulism. This was done primarily because of the different physiology involved in foodborne, infant, and iatrogenic botulism, and allowed us to focus on a less heterogenous population experiencing the most common form of botulism. We do not know how these findings may apply to other forms of botulism. In conclusion, we found that early administration of antitoxin of serotype-appropriate antitoxin, along with high-quality supportive care, was consistently associated with reduced mortality in botulism patients. No demographic or clinical predictors of the response to antitoxin were identified. Notes Acknowledgments. We gratefully acknowledge the contribution of Joanne Taliano, CDC librarian, for her role in developing and executing the systematic review literature search; and Elliott Churchill, for expert editorial advice. Disclaimer. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health (NIH) or the Centers for Disease Control and Prevention (CDC). The inclusion of commercial product or entity names is for identification purposes only and does not constitute endorsement by NIH or CDC. Financial support. This work was supported in part by the National Center for Advancing Translational Sciences (grant number UL1 TR000135). J.  C. O.’s time was supported by the Robert D.  and Patricia E. Kern Center for the Science of Health Care Delivery at Mayo Clinic. S54 • CID 2018:66 (Suppl 1) • O’Horo et al Supplement sponsorship. This article appears as part of the supplement “Botulism,” sponsored by the Centers for Disease Control and Prevention. Potential conflicts of interest. All authors: No potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. 1. Montecucco C , Molgó J . Botulinal neurotoxins: revival of an old killer . Curr Opin Pharmacol 2005 ; 5 : 274 - 9 . 2. Chaudhry R , Dhawan B , Kumar D , et  al. Outbreak of suspected Clostridium butyricum botulism in India . Emerg Infect Dis 1998 ; 4 : 506 - 7 . 3. Arnon SS , Schechter R , Inglesby TV , et al.; Working Group on Civilian Biodefense. Botulinum toxin as a biological weapon: medical and public health management . JAMA 2001 ; 285 : 1059 - 70 . 4. Biological and chemical terrorism: strategic plan for preparedness and response. Recommendations of the CDC Strategic Planning Workgroup . 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O’Horo, John C, Harper, Eugene P, El Rafei, Abdelghani, Ali, Rashid, DeSimone, Daniel C, Sakusic, Amra, Abu Saleh, Omar M, Marcelin, Jasmine R, Tan, Eugene M, Rao, Agam K, Sobel, Jeremy, Tosh, Pritish K. Efficacy of Antitoxin Therapy in Treating Patients With Foodborne Botulism: A Systematic Review and Meta-analysis of Cases, 1923–2016, Clinical Infectious Diseases, 2018, S43-S56, DOI: 10.1093/cid/cix815