Am. J. Trop. Med. Hyg., 77(2), 2007, pp. 386-389
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene
Signs and Symptoms Predictive of Respiratory Failure in Patients with Foodborne Botulism in Thailand
Manas Wongtanate,
Niwatchai Sucharitchan,
Kanit Tantisiriwit,
Petchdee Oranrigsupak,
Aphinya Chuesuwan,
Sukumal Toykeaw, AND
Yupin Suputtamongkol*
Department of Medicine, Nan Hospital, Nan, Thailand; Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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ABSTRACT
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We conducted a clinical study of 137 patients with home-canned bamboo shoot botulism at Nan Hospital, northern Thailand. The median age of the patients was 44 years (range = 14–74 years) and 36.2% were male. The median incubation period was 2 days (range = 1–8 days). Forty-three patients (31.4%) developed respiratory failure, but there were no deaths. Patients who did not have either nausea or vomiting and did not have urinary retention that required Foley catherization was less likely to develop respiratory failure. This clinical predictor rule had a sensitivity of 75.5% and a specificity of 90.7%. The clinical syndrome most predictive of respiratory failure was nausea or vomiting and any cranial neuropathy with urinary retention or difficulty swallowing. This clinical syndrome had a sensitivity of 69.8% and a specificity of 93.6%. These clinical characteristics could help triage large numbers of patient in the event of a future outbreak.
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INTRODUCTION
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Foodborne botulism is a severe, potentially fatal disease. It is caused by the consumption of food contaminated with botulinum toxin, which is produced by the gram-positive, anaerobic, spore-forming bacterium Clostridium botulinum. Botulinum toxin is the most potent biologic toxin known.1 C. botulinum produces seven potent neurotoxins (type A–G), of which types A, B, and E are responsible for most cases of foodborne botulism.2 Ingested toxin absorbed from the intestine inhibits the release of acetylcholine at the neuromuscular junction, leading to acute flaccid paralysis.3 The clinical syndrome of botulism is characterized by cranial neuropathies and symmetric descending flaccid paralysis, and in severe cases, respiratory muscle weakness. Therapy for botulism includes equine botulinal antitoxin and intensive supportive care.3 The mortality rate of foodborne botulism varies between 5% and 15%, and respiratory failure is a major cause of death.4,5 Botulinum toxin is categorized as a class A biologic agent by the Centers for Diseases Control and Prevention (CDC, Atlanta, GA). In addition, an increase in the number of botulism outbreaks has been reported. Little is known about clinical features that predict severe outcomes. Identifying predictive characteristics for respiratory failure could help triage large number of patients during a large outbreak. This is especially critical in resource-limited countries such as Thailand.
Nan Province is located in the northern Thailand (668 km from Bangkok). A large outbreak of foodborne botulism occurred between March 15 and March 21, 2006, in this province.6 This outbreak was caused by consumption of home-canned bamboo shoots that were shared at a religious rite held in Ban Luang District, Nan Province, Thailand on March 14, 2006. A total of 209 persons, 59% of those who ate at that festival, had illness consistent with botulism. A total of 190 patients came to the hospital, 53 patients (who developed only gastrointestinal symptoms) were treated at Ban Luang Hospital, and 137 patients were referred to Nan Hospital. Overall, respiratory failure developed in 43 patients and 25 patients were referred to 7 other hospitals in Thailand that had advance respiratory support facilities. The details of treatment and clinical outcome of 18 patients in this group has been described.7 Samples of the leftover canned bamboo shoots grew C. botulinum and toxin A was found. We describe the clinical presentations, risk factors for respiratory failure, and safety of 3 types of antitoxin given to 137 patients treated at Nan Hospital.
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MATERIALS AND METHODS
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We reviewed medical records of 137 patients treated at Nan Hospital for foodborne botulism during the outbreak period. This was defined as an individual who participated in the common meal shared at the annual rite at Nawaimai village, Pakaluang Subdistrict, Banluang District, Nan Province on March 14, 2006, and who developed gastrointestinal symptoms or cranial neuropathies. Demographic data, time course of admission, clinical presentation, treatment, and outcome were recorded using standard data record forms. All records were reviewed by one physician who was involved with the treatment of these patients during the outbreak.
Statistical analysis.
Patients were classified according to presence or absence of respiratory failure that necessitated endotracheal intubation and mechanical ventilation. Descriptive statistics were used to summarize the demographic and baseline data in each group. Differences between groups were analyzed by the chi-square test for categorized variables and the Kruskal-Wallis H test for continuous variables. All P values were two-sided, and values < 0.05 were considered significant. Analyses were conducted with SPSS version 11.5 (SPSS Inc., Chicago, IL). We performed classification and regression tree (CART) analysis to identify clinical syndromes at the time of initial presentation that were predictive of respiratory failure. The CART analysis progressively classifies patients into subgroups on the basis of patient’s characteristics and the proportion within the subgroup that has the outcome of interest.8 In this analysis we included age, symptoms, and signs that were recorded at admission to the hospital. We did not include variables associated with inhospital care, such as antitoxin treatment or antibiotic treatment, because the objective of this analysis was to assess the clinical predictors of the respiratory failure on admission. Analysis was conducted with CART version 6.0 extended edition (California Statistical Software Inc., Lafayette, CA). Partitions were chosen on the basis of large values of the likelihood-ratio chi-square (i.e., G2) statistic. The minimum partition size was 10 in this analysis.
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RESULTS
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The median age of patients was 44 years (range = 14–74 years), 36.2% of whom were males. The median incubation period, defined as the interval between consumption of home-canned bamboo shoots and symptom onset, was two days (range = 1–8 days). Of these, 115 patients (83.6%) were admitted to Nan Hospital and mechanical ventilation was initiated in 43. Age and sex were similar between the out-patient and in-patient treated groups. The duration between home-canned bamboo shoot consumption and hospital visit was 5 days (range = 2–8 days) for the out-patient group and 2 days (range = 1–6 days) for the in-patient group, respectively (P < 0.001).
The distribution of age and sex was similar in patients who required mechanical ventilation and those who did not. The median age in both groups was 43 years (range = 14–74 years). Overall, 15 patients had an underlying diseases such as diabetes mellitus (10 in patients who did not required mechanical ventilation and 5 patients in patients who required mechanical ventilation, respectively, P = 0.86). The median incubation period was 2 days (range = 1–8 days) in patients without mechanical ventilation and 2 days (range = 1–3 days) in patients with mechanical ventilation (P < 0.001). The median duration between exposure and mechanical ventilation was 4 days (range = 2–7 days), and the median duration of intubation was 14 days (range = 1–44 days). The median duration of admission was 6 days (range = 1–19 days) in patients without mechanical ventilation and 25 days (range = 10–49 days) in patients with mechanical ventilation (P < 0.001). Clinical characteristics of these two groups are shown in Table 1
. Twenty-five of 43 patients who developed respiratory failure were referred to other hospitals in Thailand for intensive care support. Detailed clinical manifestations and management of these patients have been described.7 Overall, nosocomial pneumonia and urinary tract infection occurred in 42 patients (in 40 patients with mechanical ventilation and in 2 patients without mechanical ventilation). No deaths occurred as a result of this outbreak.
In univariate analysis, a large number of patient characteristics were associated with increased odds of respiratory failure requiring endotracheal intubation and mechanical ventilation (Tables 1
and 2). In a CART analysis restricted to patient age, symptoms, and signs, we found that initial presentation with either nausea and vomiting was a strong predictor of respiratory failure and a requirement for endotracheal intubation and mechanical ventilation (Figure 1). Patients who did not have this symptom and did not have urinary retention that required Foley catherization were less likely to develop respiratory failure that required endotracheal intubation and mechanical ventilation (odds ratio [OR] = 0.03, 95% confidence interval [CI] = 0.01–0.10). For identifying patients who subsequently did not develop respiratory failure and required endotracheal intubation and mechanical ventilation, this clinical predictor rule had a sensitivity of 75.5% and a specificity of 90.7%. The clinical syndrome most predictive of respiratory failure and required endotracheal intubation and mechanical ventilation was nausea and vomiting and any cranial neuropathy with urinary retention or difficulty swallowing (OR = 33.8, 95% CI = 11.8–96.9). For identifying patients who subsequently required endotracheal intubation and mechanical ventilation, this clinical syndrome had a sensitivity of 69.8% and a specificity of 93.6%.
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FIGURE 1. Classification and regression tree analysis of clinical syndrome predictive of mechanical ventilation in patients with botulism at Nan Hospital in northern Thailand. Arrows pointing to the left indicate factors predictive of no endotracheal intubation (ET) that did not require mechanical ventilation; arrows pointing to the right indicate factors predictive of ET that required mechanical ventilation.
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Ninety-one (66.4%) patients received antitoxin injections; 20 patients received heptavalent antitoxin (A–G), provided by the United Kingdom Department of Health (London, United Kingdom) on March 19, 61 patients received bivalent antitoxin (A and B) provided by CDC on March 20 and March 21, and 10 patients received quadrivalent antitoxin (A, B, E, and F) provided by the National Institute of Infectious Diseases (Tokyo, Japan) on March 23–24, 2006. All patients who required mechanical ventilation received antitoxin (20 patients received heptavalent antitoxin and 23 patients received bivalent antitoxin). The median duration between onset of symptom and antitoxin treatment was 5 days (range = 4–6 days). The efficacy of antitoxin in patients who developed respiratory failure has been reported.7 The antitoxin was given to patients with severe botulism. Among patients who did not develop respiratory failure, the median duration of admission was 9 days (range = 2–19 days) in patients treated with antitoxin and 1 day (range = 1–6 days) in patients who were not treated with antitoxin. Therefore, the efficacy of antitoxin treatment was not evaluated in this study.
Skin testing was not performed in every patient prior to antitoxin injection. An allergic reaction developed in 11 patients (12%), anaphylaxis developed in 2 patients, urticarial rash developed in 4 patients, and maculopapular rash developed in 10 patients. There was no correlation between results of skin tests and prevalence of these allergic reactions (Table 3). However, anaphylaxis occurred only in patients who had positive skin reactions or no skin test.
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DISCUSSION
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Botulism is a rare disease, but its incidence has increased substantially over the past decade. Respiratory failure is a major cause of morbidity and mortality in foodborne botulism. Only few reports of foodborne botulism9,10 and only one report of black tar heroin–associated wound botulism11 have focused on pulmonary complications. However, the sample sizes of the study populations in these reports were too small to identify predictive factors for respiratory failure. The large outbreak described here confirmed that botulism can be an important cause of medical casualty. Cases were diagnosed and patients were hospitalized promptly because this was the third outbreak in northern Thailand12,13 and physicians were well aware of clinical presentations of foodborne botulism. However, previous outbreaks occurred in small numbers of people. In this outbreak, 115 patients were hospitalized and respiratory failure that required endotracheal intubation and mechanical ventilation in 43 patients. Twenty five of these patients were referred to other hospitals because of limited intensive care facilities. Although no clinical features were 100% predictive, patients who did not have vomiting and no urinary retention were at lower risk of severe respiratory involvement requiring endotracheal intubation. Using these clinical features to identify low-risk patients could help in a resource-poor setting, such as Nan Hospital, Thailand. Similarly, patients with vomiting and any cranial neuropathy with either urinary retention or difficulty swallowing, a clinical syndrome predictive of respiratory failure, could be triaged immediately to intensive care facilities.
Although not all cases in this outbreak were laboratory confirmed, misclassification was unlikely because the clinical syndrome of botulism is highly distinctive; all patients had characteristic features and reported consuming home-canned bamboo shoots on the same occasion. Another limitation of this study was that we only included 72% of cases that were treated at two hospitals during this outbreak. All cases that were not included in this analysis did not develop respiratory failure. Therefore, ORs calculated in this study could be overestimated. Additional studies to validate these prediction rules are needed to confirm their usefulness in treating patients triaged during future outbreaks.
The efficacy of antitoxin could not be evaluated in this study population because antitoxin was given to all patients with respiratory failure as soon as the antitoxin was available. A detailed study in a subgroup of 18 patients with severe respiratory failure showed that patients receiving antitoxin on day 4 had decreased ventilator dependency compared with those receiving antitoxin on day 6.7 Results of this study showed that skin testing prior to antitoxin administration was not a useful predictor of allergic reaction. The incidence of allergic reaction was similar for the three types of antitoxin used in this outbreak. Anaphylaxis occurred in 5–10% of the patients.
Received January 22, 2007.
Accepted for publication May 1, 2007.
Acknowledgments: We thank the doctors, nurses, and medical technologists of Nan Hospital for their cooperation and help during the study, and Dr. Sumalee Kiatboonsri (Faculty of Medicine Ramathibodi, Mahidol University) for her help in management of patients during the outbreak.
* Address correspondence to Yupin Suputtamongkol, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Bangkok-noi, Bangkok 10700, Thailand. E-mail: siysp{at}mahidol.ac.th 
Authors’ addresses: Manas Wongtanate, Niwatchai Sucharitchan, Kanit Tanisiriwit, Petchdee Oranrigsupak, Aphinya Chuesuwan, and Sukumal Toykeaw, Department of Medicine, Nan Hospital, 1 Worawichai Road, Amphur Mueng, Nan 55000 Thailand, Telephone: 66-54-751-865, Fax: 66-54-710-977, E-mails: manas wongtanate{at}hotmail.com, ni_watchai{at}yahoo.co.th, kanit_tantisiriwit{at}hotmail.com, krai{at}krairoek-wsanook.com, aphinya{at}yahoo.com, and sukumal2508{at}yahoo.com. Yupin Suputtamongkol, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Bangkok-noi, Bangkok 10700, Thailand, Telephone: 66-2-419-7203, Fax: 66-2-412-5994, E-mail: siysp{at}mahidol.ac.th.
Reprint requests: Yupin Suputtamongkol, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Bangkok-noi, Bangkok 10700, Thailand.
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ABSTRACT
INTRODUCTION
