Wound Botulism in California, 1951–1998: Recent Epidemic in Heroin Injectors
- Reprints or correspondence: Dr. S. B. Werner, Disease Investigations Section, Division of Communicable Disease Control, California Dept. of Health Services, 2151 Berkeley Way, Rm. 708, Berkeley, CA 94704 (bwerner{at}dhs.ca.gov).
Abstract
California has reported most of the world's wound botulism (WB) cases and nearly three-fourths of the cases reported in the United States. We reviewed the clinical, epidemiologic, and laboratory features of WB. From the first case in 1951, through 1998, a total of 127 cases were identified—93 in the last 5 years. The dramatic increase has been due to an epidemic (of WB) in people who inject black tar heroin. Whereas early cases of WB occurred after gross trauma, all but 1 of the last 102 cases occurred in drug users, primarily those who inject drugs subcutaneously (“skin poppers”). Cases are occurring disproportionately in Hispanics and women. Misdiagnosis and diagnostic delays of up to 64 days have occurred. This unprecedented, ongoing epidemic is now being reported in other states. We discuss the clinical and laboratory features that distinguish botulism from conditions that can mimic it, the relative yield of various diagnostic laboratory tests for botulism, and its treatment.
Botulism was first recognized in the early 19th century and was named for sausage (from the Latin botulus), which was often implicated in early foodborne outbreaks. In 1895, van Ermengem identified the causative bacillus, later renamed Clostridium botulinum. Besides classic foodborne botulism that results from ingesting botulinum toxin in improperly preserved foods, 2 other major forms of botulism are now recognized: wound botulism (WB), first reported in 1951 [1], caused by tissue infection and in situ toxin production by C. botulinum; and infant botulism, first reported in 1976, caused by intestinal colonization by C. botulinum with subsequent in vivo toxin production [2].
Historically, California has accounted for >75% of all US WB cases [3], and US cases have comprised >90% of those known in the world. Between 1951 and 1998, a total of 127 cases of WB were reported from California. We reviewed California's extraordinary series of cases to clarify the rapidly changing epidemiology and clinical presentation of WB. We found a dramatic increase of WB in individuals injecting black tar heroin (BTH), named for its appearance and consistency.
Methods
Clinical and epidemiologic review. Botulism is a reportable condition in California. Information is collected on a standardized national reporting form augmented by information from patient records and physicians who consult with the California Department of Health Services (CDHS) for advice on the diagnosis and care of patients who are suspected to have botulism. Diagnostic testing and the provision of antitoxin are available in the United States only through public health services. California is one of the few states that both tests for botulism and releases botulinum antitoxin for treatment; these activities facilitated our case findings.
All cases of WB reported to the CDHS during 1951–1998 were reviewed for demographic and clinical features. Characteristics of WB patients who were injection drug users (IDUs) were compared with those who were not IDUs, by use of the χ2 test or Fisher's exact test; all P values were 2-tailed. Seasonality of onset was assessed by a generalization of Hewitt's test for seasonality [4]. To assess the economic burden of WB, inpatient hospital charges were obtained for all patients identified in 1995.
Laboratory review. Except for 3 early cases of WB that met a previous national standard of clinical criteria, all cases were confirmed by wound culture or by the mouse neutralization bioassay of sera or of cell-free extracts of homogenated tissue. Heroin samples from 12 patients who were IDUs were submitted for culture at the state laboratory.
Results
Clinical and epidemiologic. We identified 127 cases of WB in California since the first case was recognized in 1951 (figure 1). There have been 2 striking changes in recent years: a dramatically accelerating case count and a change in the types of wounds from unintentional gross trauma to self-injection of illicit drugs, particularly BTH. Specifically, from 1951 through 1987, California averaged 0.5 cases per year. However, since 1988 (when the first case of WB in an IDU was identified in California), there has been a 20-fold increase, to 9.9 cases per year. In 1998 alone, there were 28 cases. All but 1 of 102 cases of WB that occurred since 1990 were present in IDUs. Four types of wounds preceded the onset of WB: (1) traumatic, (2) operative, (3) sinusitis, and (4) injection drug use.
Figure 1
Incidence of wound botulism in California by type of wound, 1951–1998. IDU, injection drug user
Beginning in 1951, traumatic wounds of the extremities caused 15 WB cases. These injuries included lacerations, open fractures, crush injuries, punctures, and gunshot wounds. There was no apparent seasonality to these injuries. Of 10 patients for whom there was information on wound appearance, half were described as infected. Of these 15 patients, 10 (67%) were men. The median age was 26 years (range, 6–44 years). Of the 14 with known outcome, 4 (29%) died. The median interval from injury to onset of neurologic symptoms was 6.5 days (range, 4–13 days), and the median interval from first medical consultation to first clinical consideration of WB was 5.0 days (range, 1–9 days).
Beginning in 1979, there have been 5 cases of WB that occurred as operative complications. One case occurred in a 15-year-old girl who complained of diplopia 5 days after undergoing caesarean section. She was discharged despite diplopia and was much weaker when readmitted 2 days later. Endotracheal intubation resulted in a mediastinal hemorrhage, which led to cardiac arrest and stroke. At follow-up 1 year later, she was institutionalized in a vegetative state. This was the first nosocomial case of WB identified in the United States, and the first patient whose wound was not in an extremity. Three other patients developed symptoms of botulism 2–5 days after emergent laparotomy to resect impacted bowel. All 3 had volvulus associated with adhesions from past appendectomies. The fifth patient with WB presented 1 month after a bone graft and external fixation for a nonhealing tibiofibular fracture sustained 1 year earlier.
Beginning in 1984, there have been 2 cases of WB from sinusitis in young adult men after they sniffed cocaine. One had maxillary drainage; aspirate of the sinuses grew C. botulinum type A.
Beginning in 1988, there have been 105 cases of WB in IDUs. BTH injection was reported by all but 1 injector (who used methamphetamine) for whom information was available. IDUs were older than other patients with WB, with a median age of 40 years versus 28 years (P < .001; table 1). One of the oldest IDUs (64 years old) had been using heroin daily for 50 years. forty-seven (45%) of the IDUs were women. ninety-nine of the IDUs were white, 2 were black, and the race for 4 was unknown. in instances where ethnicity was known, 58 (57%) of 101 IDUs were Hispanic, whereas only 2 (20%) of 10 other patients with WB were Hispanic (relative risk, 2.9; 95% CI, 0.8–10.0; P < .04).
Table 1
Selected features of 105 wound botulism (WB) cases in injection drug users (IDUs) and 22 WB cases in persons not known to have injected drugs (non-IDUs), California, 1951–1998.
There was little geographic clustering of IDU patients. Of California's 58 counties, 24 reported at least 1 patient, and 17 counties reported ⩾2 patients. Instances of WB in IDUs occurred in all months of the year, but 52 (50%) of 105 occurred between October and December (Hewitt's P = .026). Patients did not know one another except for 5 couples. In 1991, a BTH user in southern California developed type A botulism and, 11 months later, so did his girlfriend. In 1995, a man and his 47-year-old wife in central California presented with symptoms of type A botulism within 4 days of each other. Both couples reported sharing BTH but not needles and syringes. In 1995, a third couple in northern California, described in more detail below, became ill after sharing BTH. In 1997, a man and his girlfriend, both from southern California, had onsets of type B botulism 4 days apart after sharing BTH. In 1998, a fifth couple had onsets of type A botulism 4 months apart in northern California.
One IDU developed type A WB twice. In 1995, this BTH injector presented with clinical WB and a fluctuant thigh abscess; culture grew C. botulinum type A. She underwent a 5-week hospitalization requiring intubation, mechanically assisted ventilation, tracheostomy, and incision and drainage of her abscess. She resumed BTH injection after she was discharged from the hospital. She presented again in 1997 with clinical botulism and multiple abscesses; type A toxin was found in pretreatment serum.
The wounds of IDUs with WB appeared to be grossly infected in 80 (85%) of 94 people for whom this information was available versus 12 (71%) of 17 patients who had other types of WB (P = .17). “Abscess” was the most common description, often without further elaboration. Occasionally, there were additional comments, such as fluctuation, spontaneous draining of pus, cellulitis, and, in one instance, necrosis. The appearance of infection was corroborated by studies of aspirated pus and of incisional and excisional biopsies that were recorded in the laboratory results. Although unusual injection sites (e.g., the vulva in one woman and the base of the tongue in another) were infected, the overwhelming majority of infected wounds involved the extremities or the buttocks. Some infections were identified only by close examination of the patient's customary injection sites and not by history.
The interval from injection to onset of neurologic symptoms could not be identified because most IDUs injected frequently, commonly several times a day, often in the same anatomic areas that later became infected, and so could not identify which particular injection (and when) was the inciting event.
Among IDUs, the mean interval from first medical consultation for signs and symptoms of WB and a physician's first consideration of that diagnosis was 3.1 days (range, 0–64 days). Extended delays resulted from initial misdiagnosis. The most extreme examples were delays of 45 and 64 days after clinical presentation. One of these was a 35-year-old homeless IDU who was misdiagnosed as having myasthenia gravis by her attending neurologists at a university-affiliated medical center. Six weeks after admission, a new resident rotated on service and questioned the prevailing diagnosis. He submitted a fresh serum sample for testing at the state laboratory, where it was found to be positive for botulinum toxin; only then was antitoxin administered. The other patient who was diagnosed very late was a 41-year-old woman who had been managed as a case of Guillain-Barré syndrome and was later transferred to a chronic care facility; she was dependent on a ventilator. When her husband, with whom she had shared BTH, was hospitalized for clinical botulism 9 weeks later, he questioned whether WB could also explain his wife's protracted illness. Serum that had been taken from her on the fifth day of hospitalization was then retrieved for study, tested, and found to contain type A botulinum toxin. Diagnostic delays declined from a mean of 4.9 days to 1.6 days after we publicized the epidemic in late 1995 (P < .001, see table 1).
The cost for inpatient medical care was high. All 23 patients with WB who were identified in 1995 were hospitalized, some for months. Total hospital charges were $3.78 million (median, $154,000; range: $19,000–$448,000). These hospital charges did not include convalescent or outpatient care or other indirect costs. Because no patient had private medical insurance, all hospital charges were paid at public or hospital expense.
Laboratory findings. Of the 127 total cases of WB, 107 (84%) were due to type A botulinum toxin, 15 (12%) to type B, and 1 (1%) to both A and B. One (1%) had botulinum toxin that could not be typed because of inadequate serum volume, and in 3 (2%) of the earliest patients tests for toxin type were not done. Of the 123 cases of WB that could be typed, 89% of the IDUs and 78% of the non-IDUs were type A (P not significant).
Serologic testing. The clinical diagnosis of WB was most commonly confirmed by detecting toxin in sera by use of the standard mouse bioassay. This test was positive in 99 (95%) of 104 IDUs and in 15 (83%) of 18 non-IDUs confirmed to have WB.
Wound testing: culture. C. botulinum was isolated from 41 (65%) of 63 patients whose cultures were known to have been taken. The frequency of recovery of this organism from the wounds of IDUs was comparable to non-IDUs with WB: 30 (61%) of 49 versus 11 (79%) of 14 patients.
Wound testing: toxin in situ. Free toxin was detected in 18 (32%) of 56 IDU patients who had abscessed wound tissue resected.
Heroin testing. We were able to obtain only 12 very small (pea-sized) samples of BTH (<0.5 g each) from patients with WB. These were found to be negative for C. botulinum by the state laboratory.
Discussion
To our knowledge, this is the largest series of WB cases ever examined, largely because of an ongoing epidemic of WB in IDUs [5, 6]. The first case of WB identified in an IDU in the United States occurred in New York City in 1982 [7]; California's first case was not identified until 1988. Through 1997, the latest year for which national figures are available, California reported 99 (87%) of the nation's 114 patients with WB in IDUs. The remaining 15 patients were reported from the states of Washington (n = 5), Arizona (n = 3), Oregon (n = 2), New York (n = 2), New Mexico (n = 2), and Texas (n = 1) (figure 2) (J. T. Brooks, CDC, personal communication). There were no cases of WB reported outside of California in 1990–1994, but there were 2 in 1995, 3 in 1996, and 5 in 1997.
Figure 2
Wound botulism (WB) in injection drug users, United States, cumulative through 1997. California's 1998 WB cases are also shown (hatched boxes).
Nearly half of California's 105 IDUs with WB were women. In contrast, women comprised only 23% of those who reported ever using heroin in a 1994 national survey [8] and accounted for only 35% of enrollees in California methadone clinics in 1991–1995 (S. Jew, personal communication). In a study of tetanus cases reported in New York City, the risk to female IDUs was estimated to be 8–12 times greater than that for male IDUs [9]. One reason that female IDUs may be more likely than male IDUs to develop WB or tetanus is their greater tendency to inject drugs into soft tissue (“skin pop”) than into veins [9]. The resulting abscess formation and devitalized tissue are thought to provide a favorable anaerobic milieu for the growth of neurotoxin-producing clostridia (C. tetani and C. botulinum). Many men with WB reported becoming skin poppers only after they had “used up” (sclerosed) their veins by years of injection. This may explain the relatively advanced age (median, 40 years) of IDUs with WB.
The drug used almost exclusively by patients with WB has been BTH. IDUs heat BTH in water, typically in teaspoons, primarily to dissolve the heroin. Although ordinary nonsporeforming bacteria and botulinum toxin itself are readily destroyed by boiling, the spores of C. botulinum are not. In fact, any dormant spores that are present may be activated to germinate by such heating [10].
We gathered the following information about BTH from officials of the federal Drug Enforcement Administration, which was corroborated by state and local drug enforcement agencies. BTH is relatively pure heroin produced in Mexico in small, makeshift factories next to opium poppy fields. It is brown to black in color and can be sticky (like roofing tar) or hard (like coal). Typically, it is injected. BTH was first introduced to the United States in the 1970s as a cheaper alternative to cocaine from Colombia and “China White” heroin from southeast Asia. It became the predominant type of heroin in California in the late 1980s, and its market share increased in the 1990s. BTH is sold in at least 27 states, primarily west of the Mississippi River. Its potency is variable because it is commonly contaminated with by-products of the manufacturing process; adulterated with chemicals such as lidocaine, amphetamine, and diphenhydramine; and diluted with inert absorbent materials such as cornstarch, lactose, mannitol, instant coffee, powdered milk, clay, banana peels, and even dirt. These materials are added not only to increase bulk and profitability but also to make the BTH less tacky and more manageable.
The potency of heroin dictates how many times it can be diluted (“cut,” “hit on,” or “stepped on”). BTH cut in California tends to remain in California. The few cases of WB recognized elsewhere in the United States might suggest that most contamination of BTH with C. botulinum is occurring within California, but we suspect that the more likely reason is that the diagnosis is being missed elsewhere. At least one California patient reported purchasing BTH in Mexico. Our inability to grow C. botulinum from 12 small BTH samples studied may mean that these samples were not from the same batch of BTH that led to WB, that spores of C. botulinum are not uniformly distributed in BTH, or that the BTH sample sizes were simply too small. We have, however, cultured C. botulinum from the washings of the inside of a syringe used by a patient with WB in 1996 [11].
According to drug control officials, those who harvest, process, distribute, and sell BTH tend to be Hispanic. These dealers are reportedly reluctant to sell to blacks, whereas Asians tend to buy their heroin from other Asians (who market “China White”). This may explain the virtual absence of instances of WB in patients of races other than white and why most patients have been Hispanic.
The fact that patients with WB in California occur sporadically and rarely, even among those sharing the same BTH, could suggest that C. botulinum contamination in BTH is not uniformly distributed. Alternatively, the risk of WB could relate to behavioral factors. Indeed, our recent study of risk factors demonstrated that the route of administration (e.g., by skin popping) and the amount injected subcutaneously were important behavioral factors. Cleaning the skin or paraphernalia was not protective [12].
Delays in diagnosis (up to 64 days) were not uncommon, even at major medical centers. The diseases most commonly confused with botulism were Guillain-Barré syndrome (especially the Miller Fisher variant) and myasthenia gravis. These conditions are much more common [13]. Botulism can be distinguished from these and other diseases that mimic it by the clinical and laboratory features (including electromyography and CSF studies) outlined in table 2. We emphasize that, in botulism, the following are true: (1) the first neurologic symptoms are typically diplopia, blurred vision, ptosis, or some combination of these; (2) there are no objective sensory abnormalities, nor altered mental status; (3) the CSF protein is not elevated at any point in the illness; (4) electromyography (EMG) will tend to show augmentation of the muscle action potential with repetitive nerve stimulation at 20–50 Hz [14]; and (5) if disease progresses, paralysis tends to occur in a descending, generally symmetrical fashion.
Table 2
Paralytic diseases that may be confused with botulism.
In addition to delays in diagnosis of WB, we believe cases of WB are being missed altogether. The reasons include inadequate volumes of sera submitted for toxin testing; sera taken too late in the course of illness to detect circulating toxin; and lack of consideration of the diagnosis of WB, so sera are not even submitted for testing. For example, unattended deaths may be ascribed to drug overdoses when tests for opiates are positive.
All patients presenting with clinical botulism should be confirmed in a reference laboratory experienced in testing for botulism. The most useful diagnostic specimen is serum (15 mL), which was found to be positive for botulism toxin in 93% of cases. Anaerobic cultures of the wound (best done by placing a specimen in an anaerobic transport pack, refrigerating it promptly, and then inoculating it into cooked meat glucose broth) were positive for 65% of patients studied. We also detected free toxin directly from abscessed tissue taken from 32% of 56 patients studied, without first growing C. botulinum. To our knowledge, ours is the first report on the detection of free botulinum toxin in tissue.
At least 15% of our patients had wounds that did not appear grossly infected. Therefore, WB should be considered in the differential diagnosis of cranial nerve palsy and descending paralysis, even if injection sites or other wound sites appear benign. We also identified unusual and concealed sites (e.g., vulva and base of tongue) for injection. A toxicology screen for opiates may be helpful in detecting unreported use of BTH.
An important distinction between foodborne botulism and WB is that in foodborne botulism exposure is limited to the amount of toxin ingested, whereas in WB toxin can continue to be produced in situ until C. botulinum infection is eliminated. Treatment for WB often includes not only botulinum antitoxin but also to incision or excision, surgical debridement, irrigation, and appropriate antibiotics. Normally, 1 vial of equine trivalent botulinum antitoxin is sufficient, because each vial reportedly contains a level of antitoxin that is >100 times that needed to neutralize the largest amount of circulating toxin ever measured at the Centers for Disease Control and Prevention (CDC). Accordingly, the CDC has recommended that only 1 vial of antitoxin be used [15]. Twice, however, we found toxin in sera taken 12–24 h after intravenous antitoxin administration that necessitated our release of another vial of antitoxin. (Besides obtaining serum before botulinum antitoxin is administered, we routinely request posttreatment sera for testing of IDU patients with WB, to assure complete toxin neutralization.) Ideally, any debridement or irrigation of a wound should be done after antitoxin is administered, so that toxin that enters the bloodstream by these procedures can be neutralized. Penicillin, administered at a dose of 10–20 million units per day, is recommended, although >90% of 224 strains of C. botulinum tested by Swenson et al. [16] were also susceptible to tetracycline, metronidazole, and chloramphenicol. Aminoglycosides should be avoided because they can potentiate neuromuscular blockade [17, 18].
When a clinical diagnosis of botulism is made, physicians should consider immediate administration of antitoxin before laboratory confirmation (which could take days) to prevent disease progression and death. Patients receiving antitoxin on day 1 of their symptoms tend to have fewer days on a respirator and shorter hospitalizations than those who begin treatment later [19]. On the other hand, antitoxin may not be necessary when a patient is clinically stable or improving.
As with tetanus toxin, botulinum neurotoxin may cause life-threatening illness at doses insufficient to immunize. One California IDU had type A WB twice, 2 years apart, just as others have had 2 episodes of foodborne botulism caused by the same botulinum toxin type [20–22]. Protective immunization with botulinum toxoid, as offered to selected laboratory workers, requires multiple doses over many months [23].
Clinically suspected cases of botulism should be reported immediately to local public health agencies to facilitate laboratory confirmation, release of antitoxin, and prompt investigation. If local and state officials are not immediately available, the CDC can be contacted directly at (404) 639–2888.
Clinicians should be on the alert for WB cases associated with injection drug use. The problem is increasing in California and elsewhere. IDUs need to know that in addition to overdoses, HIV, endocarditis, hepatitis B and C, tetanus, and soft tissue infections, including necrotizing fasciitis, there is another potentially lethal consequence of heroin, known as “shooter's botulism.”
Note Added in Proof
The epidemic of wound botulism is continuing in California and, in fact, is increasing. In 1999, 38 laboratory-confirmed cases were identified as compared to a previous high of 28 cases in 1998. All but 1 of the cases in 1999 were injection drug users. Once again, a case presented a second time: a 68-year-old man was a laboratory-confirmed case in 1994 and, again, in 1999.
- Received September 24, 1999.
- Revision received March 28, 2000.
- © 2000 by the Infectious Diseases Society of America
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