Year: 2017
Type: article
Abstract: Botulism is a rare disease that affects a few hundred persons each year in the United States. The vast majority of clinicians have never seen a patient with botulism [1]. Yet, botulism’s potential to be severe and to cause large outbreaks renders it a constant preoccupation for public health practitioners [1]. The US Centers for Disease Control and Prevention’s (CDC) Botulism Clinical Consultation Service provides round-the-clock consultation to physicians who suspect botulism in a patient and is the sole source of equine botulinum antitoxin in the United States [1]. Our CDC team is preparing clinical guidelines for noninfant botulism. This supplement contains systematic reviews and studies that marshal the limited available data to provide an evidence base for these guidelines. Botulism is a disease of contradictions. Its distinct presentation is described as unmistakable [2], yet the diagnosis is often missed or delayed [3, 4]. Its foodborne form should have disappeared along with the foods classically associated with it—rustic blood sausages and shoddy commercially canned foods from the early twentieth century—yet outbreaks caused by homemade foods, foods mishandled by consumers, and, occasionally, modern industrially produced foods continue to this day [3–8]. While an explosive growth in the therapeutic and cosmetic use of botulinum toxins has taken place over the past 2 decades [9], diagnosis and treatment of botulism retain elements of the 1930s. The only currently validated laboratory diagnostic test is the time-consuming mouse bioassay; critical clinical management decisions must be based on clinical diagnosis; and the sole specific therapeutic medication for noninfant botulism, botulinum antitoxin, is produced from the serum of toxoid- and toxin-immunized horses [1, 10]. Botulism’s role in the history of modern food safety is barely known to the public today, but large outbreaks of the disease a century ago instigated the development of and regulatory requirement for retort canning methods and formulation of state and federal canning standards and their enforcement through regulation and inspection [11]. Whereas the persistence of foodborne botulism testifies to the human capacity for error as well as the inevitability of close encounters with the ubiquitous microbial world, another potential cause of botulism lies in what Winston Churchill termed “perverted science” [12]. Botulinum toxin has been weaponized for battlefield use by the biological weapons programs of various countries, and purified botulinum toxin, the most deadly substance known, could be used to poison many persons deliberately by the foodborne or aerosolized routes [13]. Thus, to the public health professional’s eternal preoccupation with the possibility of a large botulism outbreak from an inadvertent error in food preparation or handling is added the specter of the toxin’s use as an agent of bioterror. Despite its historical role as a driver of the modern food safety regulatory structure and the toxin’s status as a tier 1 select agent [14], the published literature on botulism and its treatment is sparse and characterized by disparate, low-quality data, some of it many decades old. Gaps exist in our knowledge of basic facets of botulism. The clinical syndrome of botulism is said to be distinctive, yet because of the rarity of the disease, a high index of suspicion is needed to make the diagnosis, and some sporadic cases and even cases in outbreaks are initially misdiagnosed [3, 4]. Common misdiagnoses include Guillain-Barré syndrome and myasthenia gravis, which also manifest flaccid paralysis. Sometimes misdiagnosis may be due to not performing a thorough neurological examination in the emergency room, an examination that should uncover the cranial nerve palsies of botulism. In some cases, the neurological exam may be deferred because rapidly progressing or advanced respiratory symptoms and the need for respiratory support become the focus of clinicians. In some cases, the neurological findings, which are classically described as symmetric, bilateral, and descending, are described as initially or persistently asymmetric [15, 16]. In some cases, the report likely reflects an incomplete neurological exam, whereas in others true asymmetry might be due to causes yet to be elucidated. Respiratory symptoms from upper airway compromise, not diaphragmatic paralysis, may precede observable paralysis of more skeletal musculature [1]. In this supplement, several articles examine clinical presentation [17–20], and we offer a diagnostic aid for clinicians based on presenting symptoms and patient age [21]. Two reports highlight diagnostic challenges in an outbreak setting [3, 22]. Intensive medical care with respiratory support can be life-saving. The only specific therapy approved for noninfant botulism is equine-origin botulinum antitoxin. Botulism can be caused by any of several immunologically distinct botulinum toxins. Treatment consists of administering an antitoxin that contains antibodies specific to the toxin type present in the patient’s circulation. The currently licensed antitoxin available in the United States (heptavalent botulinum antitoxin [BAT®]) contains antibodies to the 7 serotypes described between 1919 and 1970 and designated A, B, C, D, E, F, and G. The effectiveness of botulinum antitoxin has been an article of faith for more than a century. This teaching rests on human data limited to a handful of case series and outbreak-related cohorts, which included few children and pregnant women [23]. Published animal data have been sparse as well. Few articles have been published on hypersensitivity to equine-source botulinum antitoxin formulations, yet the potential for antitoxin-induced anaphylaxis, especially in a mass-casualty setting, is an important concern. In this supplement, 4 systematic reviews and the report of the currently licensed heptavalent antitoxin clinical monitoring data marshal the evidence on antitoxin treatment effectiveness. It is reassuring that the data, imperfect as they are, support the effectiveness of antitoxin [5, 19, 20, 24, 25]. A separate systematic review presents the data available in the published literature on allergic reactions to botulinum antitoxins [26]. The relatively low rate of anaphylactic reactions documented is reassuring for the individual patient treated in a modern hospital but concerning for a mass-casualty scenario. Fortunately, large outbreaks of up to several dozen cases are rare in the United States [5, 8]. Several aspects of large botulism outbreaks present difficult questions, for which data in the published literature and elsewhere do not offer clear answers. As described by Harvey et al. in this supplement, cases of botulism may be misdiagnosed and the occurrence of an outbreak missed even when multiple patients with classic symptoms present to the same hospital. The insight of astute clinicians is key to recognizing outbreaks [3]. How can we improve recognition? A moderate size, for example, 29 cases, botulism outbreak can exceed the resources of a local hospital and strain those of the surrounding major metropolitan area [6]. Outbreaks with hundreds or thousands of cases would present far greater challenges. In a mass event, many worried asymptomatic persons and those with symptoms that might be due to botulism may seek care. Triaging patients to quickly identify those in danger of respiratory failure and to reassure others will present challenges; this was apparent even in an outbreak with 8 cases [22]. An antitoxin shortage, even if temporary, will compel clinicians to prioritize some patients for treatment. How should antitoxin be allocated in a shortage situation? Available data are insufficient to provide clear answers [24]. In situations that involve resource scarcity that mandates allocation decisions, ethical principles must be rigorously incorporated in clinical decision-making, and this is all the more important when the scientific data do not allow rapid identification of patients who would most benefit from therapy. Further studies would help close important knowledge gaps in the diagnosis and treatment of botulism. Thorough, standardized real-time assessment of patients starting as soon as possible in the course of botulism could refine our understanding of early presentation and the frequency of variations of the classic symptoms. Prospective assessment of patients over months or years could better define long-term complications, some of which are subtle [27]. Prospective standardized evaluation would also expand our limited understanding of botulism and its treatment in children and pregnant women. Detection of botulinum toxin genes by polymerase chain reaction is in routine use in public health laboratories [28], and great promise has been shown for use of mass spectrometry methods in laboratory confirmation of botulism [29]. The 7 botulinum toxin serotypes A–G were described between 1919 and 1970. Recently, reports of new toxin types have been published, including a novel toxin subsequently shown to be hybrid type A/F fully neutralized by BAT® [30, 31] and a novel toxin identified and assembled from the published gene sequence of a Clostridium botulinum isolate [32]. 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 research and development of new countermeasures. Meanwhile, clinicians and the public may take comfort in knowing that diagnosis and treatment of botulism in the United States are buttressed by a robust public health infrastructure. Physicians who suspect botulism in a patient should immediately contact their state health department’s emergency phone number. The physician will be put in touch with an expert from CDC’s Botulism Clinical Consultation Service or, in California and Alaska, at the state health department. When indicated, CDC will urgently dispatch BAT® from the large federal stockpiles at no charge, and the state health department will facilitate collection of specimens and their testing at a specialized public health laboratory. State health departments will quickly initiate an epidemiologic investigation to identify and control the source of botulinum toxin and determine if there are other cases [1]. Production of this supplement was the result of great effort on the part of public health and other government officials, clinicians, and academic investigators, often in addition to their assigned duties. We thank them all. We also gratefully extend our thanks to the many students, fellows, and research assistants who contributed to this project, particularly while some staff were engaged in the CDC responses to the outbreaks of Ebola and Zika virus. Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Supplement sponsorship. This article appears as part of the supplement “Botulism,” sponsored by the Centers for Disease Control and Prevention. Potential conflicts of interest. Both authors: No reported conflicts of interest. Both 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.
Source: Clinical Infectious Diseases
DOI: 10.1093/cid/cix829
Authors: Jeremy Sobel, Agam K Rao
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,763
OpenAlex ID: W2776864536