botulism consensus

8/11/2019 Botulism Consensus

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CONSENSUS STATEMENT

Botulinum Toxin as a Biological WeaponMedical and Public Health ManagementStephen S. Arnon, MD

Robert Schechter, MD

Thomas V. Inglesby, MD

Donald A. Henderson, MD, MPH

John G. Bartlett, MD

Michael S. Ascher, MD

Edward Eitzen, MD, MPH

Anne D. Fine, MDJerome Hauer, MPH

Marcelle Layton, MD

Scott Lillibridge, MD

Michael T. Osterholm, PhD, MPH

Tara OToole, MD, MPH

Gerald Parker, PhD, DVM

Trish M. Perl, MD, MSc

Philip K. Russell, MD

David L. Swerdlow, MD

Kevin Tonat, PhD, MPHfor the Working Group on CivilianBiodefense

THIS IS THE FOURTH ARTICLE IN A

series entitled Medical and Pub-lic Health Management Follow-ing the Use of a Biological

Weapon: Consensus Statements of TheWorking Group on Civilian Biode-fense.1-3 Thisarticle isthe onlyone intheseries to feature a biological toxin ratherthana replicatingagent. Botulinum toxin

poses a major bioweapon threat be-cause of its extreme potency and lethal-ity; itsease of production, transport, andmisuse; and the need for prolonged in-tensive care among affected persons.4,5

An outbreak of botulism constitutes amedical emergencythatrequires promptprovision of botulinum antitoxin and,often, mechanical ventilation,andit con-

stitutes a public health emergency thatrequires immediate intervention to pre-vent additional cases. Timely recogni-tion of a botulism outbreak begins withan astute clinician who quickly notifiespublic health officials.

Botulinum toxin is the most poison-

ous substance known.

6,7

A single gramof crystalline toxin,evenlydispersedandinhaled, would kill more than 1 millionpeople, although technicalfactors wouldmake such dissemination difficult. Thebasis of thephenomenalpotencyof botu-linum toxin is enzymatic; the toxin is azinc proteinase that cleaves 1 or more ofthe fusion proteins by which neuronal

vesicles release acetylcholine into theneuromuscular junction.8

It is regrettable that botulinum toxinstill needs to be considered as a bio-weapon at the historic moment whenit has become the first biological toxinto becomelicensed for treatment of hu-

mandisease. In the United States, botu-linum toxin is currently licensed fortreatment of cervical torticollis, stra-bismus, and blepharospasm associ-

Author Affiliationsare listed at the end of this article.Corresponding Author and Reprints: Stephen S.Arnon, MD, Infant Botulism Treatment and Preven-tion Program, California Department of Health Ser-vices, 2151 Berkeley Way, Room 506, Berkeley, CA94704 (e-mail: [email protected]).

Objective The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health profes-sionals if botulinum toxin is used as a biological weapon against a civilian population.

Participants The working group included 23 representatives from academic, gov-ernment, and private institutions with expertise in public health, emergency manage-ment, and clinical medicine.

Evidence The primary authors (S.S.A. and R.S.) searched OLDMEDLINE andMEDLINE (1960March 1999) and their professional collections for literature con-cerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opin-

ions were sought from the working group and other experts on diagnosis and man-agement of botulism. Additional MEDLINE searches were conducted through April 2000during the review and revisions of the consensus statement.

Consensus Process The first draft of the working groups consensus statement wasa synthesis of information obtained in the formal evidence-gathering process. The work-ing group convened to review the first draft in May 1999. Working group membersreviewed subsequent drafts and suggested additional revisions. The final statementincorporates all relevant evidence obtained in the literature search in conjunction withfinal consensus recommendations supported by all working group members.

Conclusions An aerosolized or foodborne botulinum toxin weapon would cause acutesymmetric, descending flaccid paralysis with prominent bulbar palsies such as diplo-pia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hoursafter exposure. Effective response to a deliberate release of botulinum toxin will de-pend on timely clinical diagnosis, case reporting, and epidemiological investigation.

Persons potentially exposed to botulinum toxin should be closely observed, and thosewith signs of botulism require prompt treatment with antitoxin and supportive carethat may include assisted ventilation for weeks or months. Treatment with antitoxinshould not be delayed for microbiological testing.

JAMA. 2001;285:1059-1070 www.jama.com

2001 American Medical Association. All rights reserved. (Reprinted) JAMA, February 28, 2001Vol 285, No. 8 1059


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ated with dystonia. It is also used offlabel for a variety of more prevalentconditions that include migraine head-ache, chronic low back pain, stroke,traumatic brain injury, cerebral palsy,achalasia, and various dystonias.9-13

CONSENSUS METHODS

The working group included 23 repre-sentatives from academic, government,andprivate institutions with expertise inpublic health, emergency management,andclinical medicine.The2 primary au-thors (S.S.A. and R.S.) conducted a lit-erature searchonuseof botulinum toxinasa bioweapon. TheOLDMEDLINE andMEDLINE databaseswere queried forallarticles publishedbetween January 1960and March 1999 that contained wordsreferring to biological warfare (bioter-

rorism,biowarfare,terrorism,war,war-fare, andweapon) in combination withterms related toClostridium botulinum(bacillus,botulin, botulinal, botulinum,botulinus, botulism, clostridia, clos-tridial, andClostridium). The articlesidentified in the databaseswere fully re-viewed. In addition, published and un-published articles, books, monographs,and special reports in the primary au-thors collections were reviewed. Addi-tional MEDLINE searches were con-ducted through April 2000 during the

review and revisions of the consensusstatement.

The first draft of the consensus state-ment was a synthesis of information ob-tained in the formal evidence-gatheringprocess. Membersof theworking groupprovided written and oral commentsabout the first draft at their meeting inMay 1999. Working group membersthenreviewedsubsequentdrafts andsug-gested additional revisions. The finalstatement incorporates all relevant evi-dence obtained in the literature search

in conjunctionwithfinal consensus rec-ommendations supported by all work-ing group members.

The assessment and recommenda-tions providedherein representthe bestprofessional judgment of the workinggroup based on currently availabledataand expertise. These conclusions andrecommendations should be regularly

reassessed as new information be-comes available.

HISTORY OF CURRENT THREAT

Terrorists havealready attempted to usebotulinum toxin as a bioweapon. Aero-

sols were dispersed at multiple sites indowntown Tokyo, Japan,andat US mili-tary installations in Japan on at least 3occasions between 1990 and1995 by theJapanese cult Aum Shinrikyo. These at-tacks failed, apparently becauseof faultymicrobiological technique, deficientaerosol-generating equipment, or inter-nal sabotage. The perpetrators obtainedtheir C botulinum from soil that they hadcollected in northern Japan.14,15

Development and use of botulinumtoxin as a possible bioweapon began atleast 60 years ago.16,17 The head of the

Japanesebiological warfare group (Unit731) admitted to feeding cultures ofCbotulinumto prisoners with lethal ef-fect during that countrys occupationof Manchuria, which began in the1930s.18 The US biological weaponsprogram firstproduced botulinum toxinduring World War II. Because of con-cerns that Germany had weaponizedbotulinum toxin, more than 1 milliondoses of botulinum toxoid vaccine weremade for Allied troops preparing to in-vade Normandy on D-Day.19,20 The US

biological weapons program was endedin 1969-1970 by executive orders ofRichard M. Nixon, then president. Re-search pertaining to biowarfare use ofbotulinum toxin took place in othercountries as well.21

Although the 1972 Biological andToxin Weapons Convention prohib-ited offensive research and productionof biological weapons, signatories IraqandtheSoviet Union subsequently pro-duced botulinum toxin for use as aweapon.22,23 Botulinum toxin was 1 of

several agents tested at the Soviet siteAralsk-7 on Vozrozhdeniye Islandin theAral Sea.23,24 A former senior scientist ofthe Russian civilian bioweapons pro-gram reported that the Soviets had at-tempted splicing the botulinum toxingenefrom C botulinum into other bacte-ria.25 With the economic difficulties inRussia after the demise of the Soviet

Union, some of the thousands of scien-tists formerly employed by its bioweap-onsprogram have been recruitedby na-tions attempting to develop biologicalweapons.25,26 Four of the countries listedby the US government as state spon-

sors of terrorism (Iran,Iraq, North Ko-rea, and Syria)27 have developed, or arebelieved to be developing, botulinumtoxin as a weapon.28,29

After the1991 Persian Gulf War, Iraqadmitted to the United Nations inspec-tion team to having produced 19000 Lof concentrated botulinum toxin, ofwhich approximately 10000 L wereloaded into military weapons.22,30 These19000 L of concentrated toxin are notfully accounted for and constitute ap-proximately 3 times the amount neededto kill the entire current human popu-

lation by inhalation. In 1990, Iraq de-ployed specially designed missiles witha 600-km range; 13 of these were filledwith botulinum toxin, 10 with afla-toxin, and 2 with anthrax spores. Iraqalso deployed special 400-lb (180-kg)bombs for immediate use; 100 bombscontained botulinum toxin, 50 con-tained anthrax spores, and 7 con-tainedaflatoxin.22,30 It is noteworthythatIraq chose to weaponize more botuli-num toxin than any other of its knownbiological agents.

Some contemporary analyses dis-count the potential of botulinum toxinas a bioweapon because of constraintsin concentrating and stabilizing thetoxin for aerosol dissemination. How-ever, these analyses pertain to militaryuses of botulinum toxin to immobi-lize an opponent (William C. Patrick,unpublished data, 1998). In contrast,deliberaterelease of botulinum toxin ina civilian population would be able tocause substantial disruption and dis-tress. For example, it is estimated that

a point-source aerosol release of botu-linum toxin could incapacitate or kill10% of persons within 0.5 km down-wind (William C. Patrick, unpub-lished data, 1998). In addition, terror-ist use of botulinum toxin might bemanifested as deliberate contamina-tion of food. Misuse of toxin in thismanner could produce either a large

MANAGEMENT OF BOTULINUM TOXIN USED AS A BIOLOGICAL WEAPON

1060 JAMA,February 28, 2001Vol 285, No. 8 (Reprinted) 2001 American Medical Association. All rights reserved.


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botulism outbreak from a single mealor episodic, widely separated out-breaks.31 In the United States, the Cen-ters for Disease Control and Preven-tion (CDC)maintains a well-establishedsurveillance system for human botu-

lism based on clinician reporting thatwould promptly detect such events.32

MICROBIOLOGY ANDVIRULENCE FACTORS

Clostridium botulinum is a spore-forming,obligateanaerobewhose natu-ral habitat is soil, from which it can beisolated without undue difficulty. Thespecies C botulinum consistsof 4 geneti-cally diverse groupsthat would not oth-erwise be designated as a single speciesexcept for their common characteristicof producing botulinum toxin.33,34 Botu-

linum toxin exists in 7 distinct anti-genic types that have been assigned theletters A through G. The toxin types aredefined by their absence of cross-neutralization (eg, anti-A antitoxin doesnotneutralizetoxin typesB-G).Thetoxintypes also serve as convenientepidemio-logical markers. In addition to C botuli-num,uniquestrainsofClostridiumbaratiiand Clostridium butyricum have thecapacityto producebotulinumtoxin.35-37

Botulinum toxin isa simpledichainpoly-peptide thatconsistsof a 100-kdheavy

chain joined by a single disulfide bondto a 50-kd light chain; its 3-dimen-sional structurewas recentlyresolved to3.3 A.38 The toxins light chain is a Zn++-containing endopeptidase that blocksacetylcholine-containing vesicles fromfusingwiththeterminalmembraneofthemotor neuron,resultingin flaccidmuscleparalysis (FIGURE1).8

Thelethaldoseofbotulinumtoxinforhumans is not known but can be esti-mated fromprimatestudies. By extrapo-lation, the lethal amountsof crystalline

type A toxin for a 70-kg human wouldbe approximately 0.09-0.15 g intrave-nously or intramuscularly, 0.70-0.90 ginhalationally, and 70 g orally.10,39-41

Therapeutic botulinum toxinrepresentsan impractical bioterrorist weapon be-causeavialofthetypeApreparationcur-rently licensed in theUnitedStatescon-tains only about 0.3% of the estimated

human lethal inhalational dose and0.005%oftheestimatedlethaloraldose.

PATHOGENESIS AND CLINICALMANIFESTATIONS

Three forms of naturally occurring hu-

man botulismexist: foodborne, wound,andintestinal (infant and adult). Fewer

than 200 cases of all forms of botulismare reported annually in the UnitedStates.42 All forms of botulism resultfrom absorption of botulinumtoxin intothe circulation from either a mucosalsurface (gut, lung) or a wound. Botu-

linum toxin does not penetrate intactskin. Wound botulism and intestinal

Figure 1.Mechanism of Action of Botulinum Toxin

SYNAPTIC

CLEFT

MUSCLE CELL

MUSCLE CELL

SNARE Proteins

Form Complex

Normal Neurotransmitter Release

Vesicle and Terminal

Membranes FuseSynaptobrevin

Synaptic Vesicle

Acetylcholine

SynapticFusionComplex

NERVE TERMINUS

Neurotransmitter

Released

Types B, D, F, G

Light Chain Cleaves

Specific SNARE Proteins

SNARE Complex

Does Not FormType C

Types A, C, E

Muscle Fiber Contracts

Muscle Fiber Paralyzed

Botulinum Toxin

Endocytosed

Light Chain

Heavy Chain

Botulinum

Toxin

Neuromuscular Junction

Muscle Cell

Motor NerveTerminus

Syntaxin

SNAREProteins SNAP-25

Membranes

Do Not Fuse

Exposure to Botulinum Toxin

AcetylcholineReceptor

Neurotransmitter

Not Released

B

A

A, Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion com-plex that allows themembrane of thesynaptic vesiclecontaining acetylcholine to fuse withthe neuronal cellmem-brane. The synaptic fusion complex is a set of SNARE proteins, which include synaptobrevin, SNAP-25, and syn-taxin. After membranefusion, acetylcholine is releasedinto the synaptic cleft andthen bound by receptors on themuscle cell.B, Botulinum toxin binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocy-tosis. Thelight chain of botulinum toxin cleavesspecific sites on the SNARE proteins, preventingcomplete assem-blyof thesynaptic fusion complexand thereby blocking acetylcholine release. Botulinum toxins types B, D, F, andG cleave synaptobrevin; types A, C, and E cleave SNAP-25; and type C cleaves syntaxin. Without acetylcholinerelease, the muscle is unable to contract.SNARE indicates soluble NSF-attachment protein receptor; NSF, N-ethylmaleimide-sensitive fusion protein; andSNAP-25, synaptosomal-associated protein of 25 kd.




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botulism are infectious diseases that re-sult from production of botulinumtoxin byC botulinumeither in devital-ized (ie, anaerobic) tissue43 or inthe in-testinal lumen,37 respectively. Neitherwould result from bioterrorist use ofbotulinum toxin.

A fourth, man-made form that re-sults from aerosolized botulinum toxinis inhalational botulism. This mode of

transmission has been demonstrated ex-perimentally in primates,39 has been at-temptedby bioterrorists,14,15 and hasbeentheintended outcomeof at least1 coun-trys specially designed missiles and ar-tillery shells.22,30 Inhalational botulismhas occurred accidentally in humans. Abrief reportfrom West Germany in 1962described 3 veterinary personnel whowere exposed to reaerosolized botuli-numtoxin whiledisposing ofrabbits andguinea pigs whose fur was coated withaerosolized type A botulinumtoxin.Type

A botulinum toxin was detected in se-rum samples from all 3 affected indi-viduals.21

Oncebotulinum toxin isabsorbed, thebloodstream carries it to peripheral cho-linergic synapses, principally, the neu-romuscular junction, where it binds ir-reversibly. Thetoxin is then internalizedand enzymatically blocks acetylcholine

release (Figure 1).Accordingly,all formsofhumanbotulism display virtually iden-tical neurologic signs. However,the neu-rologicsigns in naturallyoccurringfood-borne botulism may be preceded byabdominal cramps,nausea, vomiting, ordiarrhea.44 These gastrointestinal symp-toms are thought to be caused by otherbacterial metabolites also present in thefood33 and may not occurif purified botu-

linum toxin is intentionally placed infoods or aerosols.

Botulism is an acute, afebrile, sym-metric,descending flaccidparalysisthatalways begins in bulbar musculature. Itis not possible to have botulism with-out having multiple cranial nerve pal-sies. Disease manifestations are similarregardlessofbotulinum toxin type. How-ever, the extent and pace of paralysismay vary considerably among patients.Some patients may be mildly affected(FIGURE 2),while othersmaybe sopara-

lyzed that they appear comatose andrequire months of ventilatory support.The rapidity ofonset and the severity ofparalysis depend ontheamount oftoxinabsorbed into the circulation. Recoveryresults from new motor axon twigs thatsprout to reinnervate paralyzed musclefibers, a process that, inadults, may takeweeks or months to complete.45,46

Patients with botulism typicallypresent with difficulty seeing, speak-ing, and/or swallowing (TABLE1 andTABLE2). Prominent neurologic find-ings in all forms of botulism includeptosis, diplopia, blurred vision, oftenenlarged or sluggishly reactive pupils,dysarthria, dysphonia, and dyspha-gia.5,44,47,48 The mouth may appear dry

andthe pharynx injected because of pe-ripheral parasympathetic cholinergicblockade. Sensory changes are not ob-served except for infrequent circum-oral and peripheral paresthesias fromhyperventilation as a patient becomesfrightened by onset of paralysis.

As paralysis extends beyond bulbarmusculature, loss of head control, hy-

Figure 2.Seventeen-Year-Old Patient With Mild Botulism

A B

A, Patient at rest. Note bilateral mild ptosis, dilated pupils, disconjugate gaze, and symmetric facial muscles.B, Patient was requested to perform his maximum smile. Note absent periorbital smile creases, ptosis, discon-jugate gaze, dilated pupils, and minimally asymmetric smile. As an indication of t he extreme potency of botu-

linum toxin, the patient had 40 1012g/mL of type A botulinum toxin in his serum (ie, 1.25 mouse units/mL)when these photographs were taken.

Table 1.Symptoms and Signs of FoodborneBotulism, Types A and B*

Cases, %

SymptomsFatigue 77Dizziness 51

Double vision 91Blurred vision 65

Dysphagia 96Dry mouth 93Dysarthria 84Sore throat 54

Dyspnea 60

Constipation 73Nausea 64Vomiting 59Abdominal cramps 42Diarrhea 19

Arm weakness 73Leg weakness 69Paresthesia 14

SignsAlert mental status 90

Ptosis 73Gaze paralysis 65Pupils dilated or fixed 44Nystagmus 22

Facial palsy 63

Diminished gag reflex 65Tongue weakness 58

Arm weakness 75Leg weakness 69Hyporeflexia or areflexia 40Ataxia 17

*Data arefromoutbreaksof botulism reportedin theUnitedStates in 1973-1974. Thenumberof patientswith avail-able data varied from 35 to 55. Adapted from Hugheset al44 with permission.




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potonia, and generalized weakness be-come prominent. Dysphagiaandloss ofthe protective gag reflex may requireintubation and, usually, mechanicalventilation. Deep tendon reflexes maybe present initially but diminish or

disappear in the ensuing days, and con-stipation may occur. In untreated per-sons, death results from airway ob-struction(pharyngeal and upper airwaymuscle paralysis) and inadequate tidalvolume (diaphragmatic and accessoryrespiratory muscle paralysis).

Because botulism is an intoxication,patientsremain afebrileunless they alsohaveacquired a secondary infection (eg,aspiration pneumonia). The toxin doesnot penetrate brain parenchyma, so pa-tients are not confused or obtunded.However, theyoften appear lethargic and

have communication difficulties be-cause of bulbar palsies (Figure 2). Botu-lism may be recognized by its classictriad: (1) symmetric, descending flac-cidparalysis with prominent bulbar pal-sies in (2) an afebrile patient with (3) aclear sensorium. The prominent bul-bar palsies can be summarized in partas 4 Ds: diplopia, dysarthria, dyspho-nia, and dysphagia.

EPIDEMIOLOGY

Early recognition of outbreaks of botu-

lism, whether natural or intentional,de-pends on heightened clinical suspi-cion. Aerosol dissemination may not bedifficult to recognize because a largenumber of cases will share a commontemporal and geographical exposureand will lack a common dietary expo-sure. However, identification of thecommon exposure site initially may bedifficult because of the mobility of per-sons exposed during the incubation pe-riod. Botulism and botulinum toxin arenot contagious and cannot be trans-

mitted from person to person. In con-trast, a microbe intentionally modi-fied to produce botulinum toxin mightbe contagious.

No instances of waterborne botu-lism have ever been reported.42,49,50 Al-though the potency of botulinum toxinhas led to speculation that it might beused to contaminate a municipal wa-

ter supply, this scenario is unlikely forat least 2 reasons.51 First, botulinumtoxin is rapidly inactivated by stan-dardpotablewater treatments (eg,chlo-rination, aeration).52 Second, becauseof the slow turnover time of large-capacity reservoirs, a comparably large(and technically difficult to produce anddeliver) inoculum of botulinum toxinwould be needed.53 In contrast withtreated water, botulinum toxin may bestable for several days in untreated wa-

ter or beverages.52,54

Hence, such itemsshould be investigated in a botulismoutbreak if no other vehicle for toxincan be identified.

If food were deliberately used as a ve-hicle for the toxin, the outbreak wouldneed to be distinguished from natu-rally occurring foodborne botulism.Dur-ing the past 20 years, the epidemiologyof foodbornebotulism hasexpanded be-yond its traditional association withhome-preserved foods and now in-cludes nonpreserved foods and public

eating places,

47

featuresthatcould maketerrorist use of botulinum toxin moredifficult to detect.Characteristics of out-breaks of botulism include:

Incubation Period

The rapidity of onset and severity ofbotulismdepend on therate andamountof toxin absorption. Symptoms of food-

borne botulism may begin as early as 2hours or as long as 8 days after inges-tion of toxin.55,56 Typically, cases pre-sent 12 to 72 hours after the implicatedmeal. In1 largefoodborneoutbreak,newcases presented during the ensuing 3

days at a fairly even rate before decreas-ing (FIGURE3).57 The time to onset ofinhalational botulism cannot be statedwith certainty because so few cases areknown. Monkeysshowed signs of botu-lism 12 to 80 hours after aerosol expo-sure to 4 to 7 multiples of the monkeymedian lethal dose.39 The 3 known hu-man cases of inhalational botulism had

Figure 3.Fifty-Nine Cases of Botulism, byInterval Between Eating at a Restaurant andOnset of First Neurologic SymptomMichigan, 1977

25

15

20

10

5

0

Cases,

%

12-Hour Interval

1201089684726048362412

Reproduced from Terranova et al57 with permissionof Oxford University Press.

Table 2.Symptoms and Signs of Inhalational Botulism in Order of Onset

Humans (n = 3)21 Monkeys (n = 9)39*

Third day after exposure 12-18 hours after exposure

Mucus in throat Mild muscular weakness

Diffi culty swall owing solid f ood I nt er mi ttent ptosi s

Dizziness Disconjugate gaze

Fourth day after exposure Followed byDifficulty moving eyes Severe weakness of postural neck muscles

Mild pupillary dilation and nystagmus Occasional mouth breathing

Indistinct speech Serous nasal discharge

Unsteady gait Salivation, dysphagia

Extreme weakness Mouth breathing

Rales

Anorexia

Severe generalized weakness

Lateral recumbency

Second to fourth day after exposure

Death in some animals

*After exposure to 4 to 7 monkey median lethal doses of botulinum toxin. The time to onset and pace of paralysis weredose-dependent. Adapted from Middlebrook and Franz48 with permission.




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onset of symptoms approximately 72hoursafter exposure to an unknown butprobably small amount of reaerosol-ized toxin.21

Age and Sex

Persons of all ages are potentially sus-ceptible to botulism. There are no sexdifferences in susceptibility.

Agent and Vehicles

Botulinumtoxinin solutionis colorless,odorless, and, as far as is known, taste-less. The toxin is readily inactivated byheat(85Cfor5minutes).33,34,52 Thus,

foodborne botulism is always transmit-ted by foods that are not heated, or notheatedthoroughly,beforeeating.Almostevery type of food has been associatedwithoutbreaksofbotulism,butthemostcommonlyimplicatedfoodsintheUnitedStates are vegetables, particularly low-acid (ie, higher pH)vegetables such asbeans, peppers, carrots, and corn.42,50,58

A novel epidemiological develop-ment is the occurrence of foodbornebotulism after eating various nonpre-served foods in restaurants or delicates-

sens. Foil-wrapped baked potatoes arenow known to becapable ofcausing res-taurant-associated foodborne botu-lism59 when held at room temperatureafter baking and then served plain,60 aspotato salad,61,62 or as a Mediterranean-style dip.59 Other outbreaks that origi-nated in restaurants resulted from con-taminated condiments such as sauteed

onions,63 garlicin oil,64 and commercialcheese sauce.65 Additional examples ofnotable commercial foods that havecaused botulism outbreaks include in-adequately eviscerated fish,66 yogurt,67

cream cheese,68 and jarred peanuts.69

Incidence and Outbreak Size

Naturally occurring foodborne botu-lism is a rare disease. Approximately 9outbreaks of foodborne botulism anda median of 24 cases occur annually inthe United States.42,47 The mean out-break size has remained constant overthe years at approximately 2.5cases peroutbreak. The largest outbreak of food-borne botulism in the United States inthe last 100 years occurred in Michi-gan in 1977; 59 cases resulted from eat-ing home-preserved jalapeno peppersat a restaurant.57 However, only 45 ofthe 59 patients had clinically evidentweakness and hypotonia.

Toxin Types

Of the 135 foodborne outbreaks in the16yearsfrom1980 to1996 inthe United

States,the toxin types representedwere:type A, 54.1%; type B, 14.8%; type E,26.7%; type F, 1.5%; and unknown,3.0%.42 Type F foodborne outbreaksarerare in the United States; a 1962 out-break resulted from homemade veni-son jerky,70 while other type F cases ac-tually mayhave hadintestinal botulism.71

Toxin types C and D cause botulism in

wildlife and domestic animals but havenot caused human foodborne disease.However, humansarethought to be sus-ceptibleto thesetoxintypesbecausetheyhave causedbotulism in primates wheningested.72-74 Toxin type G is produced

by a bacteria species discoveredin SouthAmerican soil in 1969 that has nevercaused recognized foodborne botu-lism.75 Aerosol challengestudies in mon-keys have established the susceptibilityof primates to inhaled botulinum toxintypes C, D, and G.48

Distribution

Although outbreaksof foodbornebotu-lism have occurred in almost all states,more than half (53.8%) of the US out-breaks have occurred in just 5 westernstates(California, Washington, Oregon,

Colorado, andAlaska). East of theMis-sissippiRiver,60%ofthefoodborneout-breakshaveresultedfrom type B toxin,whilewest oftheMississippiRiver, 85%have resulted from type A toxin. In the46 years between 1950 and 1996, 20states, mainly in the eastern UnitedStates, did not report any type A botu-lismoutbreaks, while 24 states, mostlyinthe westernUnited States, did not re-port any type B outbreaks.42 In Canadaand Alaska, mostfoodborne outbreaksresulted from type E toxin associated

with native Inuit andEskimo foods.50,76

Bioterrorism Considerations

Any outbreak of botulism should bringto mind the possibility of bioterror-ism, but certain features would be par-ticularly suggestive (BOX 1). The avail-ability and speed of air transportationmandate that a careful travel and ac-tivity history, as well as a careful di-etary history, be taken. Patients shouldalso be asked whether they know ofother persons with similar symptoms.

Absence of a common dietary expo-sure among temporally clustered pa-tients should suggest the possibility ofinhalational botulism.

DIAGNOSIS ANDDIFFERENTIAL DIAGNOSIS

Clinical diagnosis of botulism is con-firmed by specialized laboratory test-

Box 1. Features of an Outbreak That Would Suggest a Deliberate

Release of Botulinum Toxin

Outbreak of a large number of cases of acute flaccid paralysis with prominentbulbar palsies

Outbreak with an unusual botulinum toxin type (ie, type C, D, F, or G, ortype E toxin not acquired from an aquatic food)

Outbreak with a common geographic factor among cases (eg, airport, worklocation) but without a common dietary exposure (ie, features suggestive ofan aerosol attack)

Multiple simultaneous outbreaks with no common source

Note: A careful travel and activity history, as well as dietary history, shouldbe taken in any suspected botulism outbreak. Patients should also be asked ifthey know of other persons with similar symptoms.




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ing that often requires days to com-plete. Routine laboratory test results areusually unremarkable. Therefore, clini-cal diagnosis is the foundation for earlyrecognition of and response to a bio-terrorist attack with botulinum toxin.

Any case of suspected botulism rep-resents a potential public health emer-gency because of the possibility that acontaminated food remains availableto others or that botulinum toxin hasbeen deliberately released. In thesesettings, prompt intervention by civilauthorities is needed to prevent addi-tional cases. Consequently, clinicianscaring for patients with suspectedbotulism should notify their localpublic health department and hospitalepidemiologist immediately to coordi-nate shipment of therapeutic anti-

toxin, laboratory diagnostic testing,and epidemiological investigation(BOX 2). In most jurisdictions of theUnited States, botulism suspected onclinical grounds alone by law must bereported immediately by telephone tolocal public health authorities. Theattending clinician needs to be bothprompt and persistent in accomplish-ing this notification.

Differential Diagnosis

Botulism is frequently misdiagnosed,

most often as a polyradiculoneuropa-thy (Guillain-Barre or Miller-Fisher syn-drome), myasthenia gravis, or a dis-ease of the central nervous system(TABLE3). In the United States, botu-lism is more likely than Guillain-Barresyndrome, intoxication, or poliomyeli-tis to cause a cluster ofcases ofacute flac-cidparalysis. Botulism differs from otherflaccid paralyses in its prominent cra-nial nerve palsies disproportionate tomilder weakness and hypotonia belowthe neck, in its symmetry, andin its ab-

sence of sensory nerve damage.A large, unintentional outbreak offoodborne botulism caused by a res-taurant condiment in Canada pro-vides a cautionary lesson about the po-tential difficulties in recognizing acovert, intentional contamination offood.64 Duringa 6-week period in whichthe condiment was served, 28 persons

in 2 countries became ill, but all weremisdiagnosed (Table 3). The 28 wereidentified retrospectively only after cor-rect diagnoses in a mother and her 2daughters who had returned to theirhome more than 2000 miles away from

the restaurant. Four (14%) of the caseshad been misdiagnosed as having psy-chiatric disease, including factitioussymptoms. It is possible that hysteri-cal paralysis might occur as a conver-sion reaction in the anxiety that would

Box 2. Clinicians Caring for Patients With Suspected Botulism

Should Immediately Contact Their:

(1) Hospital epidemiologist or infection control practitioner

and

(2) Local and state health departments

Consult your local telephone operator; the telephone directory under gov-ernment listings, or the Internet at: http://www.cdc.gov/other.htm#states orhttp://www.astho.org/state.html

If the local and state health departments are unavailable, contact the Centersfor Disease Control and Prevention: (404) 639-2206; (404) 639-2888 [afterhours].

Table 3.Selected Mimics and Misdiagnoses of Botulism*

ConditionsFeatures That DistinguishCondition From Botulism

Common Misdiagnoses

Guillain-Barr syndrome and its

variants, especially Miller-Fishersyndrome

History of antecedent infection; paresthesias; often

ascending paralysis; early areflexia; eventual CSFprotein increase; EMG findings

My asthenia gravis Recurrent paraly sis; EMG f indings ; sustained respons eto anticholinesterase therapy

Stroke Paralysis often asymmetric; abnormal CNS image

Intoxication with depressants(eg, acute ethanol intoxication),organophosphates, carbonmonoxide, or nerve gas

History of exposure; excessive drug levels detected inbody fluids

Lambert-Eaton syndrome Increased strength with sustained contraction; evidenceof lung carcinoma; EMG findings similar to botulism

Tick paralysis Paresthesias; ascending paralysis; tick attached to skin

Other Misdiagnoses

Poliomyelit is Antecedent f ebril e illness; asymmet ric par al ysis; CSFpleocytosis

CNS infections, especially of thebrainstem Mental status changes; CSF and EEG abnormalities

CNS tumor Paralysis often asymmetric; abnormal CNS image

Streptococcal pharyngitis (pharyngealerythema can occur in botulism)

Absence of bulbar palsies; positive rapid antigen testresult or throat culture

Psychiat ric il lness Normal EMG in conver sion par alysi s

Viral syndrome Absence of bulbar palsies and flaccid paralysis

Inf lammatory myopathy Elevated creatine k inas e lev els

Diabetic complications Sensory neuropathy; few cranial nerve palsies

Hyperemesis gravidarum Absence of bulbar palsies and acute flaccid paralysis

Hypothyroidism Abnormal thyroid function test results

Lary ngeal trauma Absence of f laccid paraly sis; dy sphonia without bulbarpalsies

Overexerti on Absence of bulbar palsies and acut e flaccid paralysis

*CSF indicates cerebrospinal fluid; EMG, electromyogram; CNS, central nervous system; and EEG, electroencepha-

logram.Misdiagnoses made in a large outbreak of botulism.64




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follow a deliberate release of botuli-num toxin.

Diagnostic Testing

At present, laboratory diagnostic test-ing for botulism in the United States

is available only at the CDC andapproximately 20 state and municipalpublic health laboratories.42 The labo-ratory should be consulted prospec-tively about specimen collection andprocessing. Samples used in diagnosisof botulism include serum (30 mLof blood in tiger-top or red-toptubes from adults, less from children),stool, gastric aspirate, and, if available,vomitus and suspect foods. Serumsamples must be obtained beforetherapy with antitoxin, which nullifiesthe diagnostic mouse bioassay. An

enema may be required to obtain anadequate fecal sample if the patient isconstipated. Sterile water should beused for this procedure because salineenema solution can confound themouse bioassay. Gastric aspirates and,perhaps, stool may be useful fordetecting inhaled aerosolized botuli-num toxin released in a bioterroristattack.77 A list of the patients medica-tions should accompany the diagnos-tic samples because anticholinester-ases, such as pyridostigmine bromide,

and other medicines that are toxic tomice can be dialyzed from samplesbefore testing. All samples should bekept refrigerated after collection.

The standard laboratory diagnostictest for clinical specimens and foods isthe mouse bioassay,42 in which type-specific antitoxin protects mice againstany botulinum toxin present in thesample. The mouse bioassay can de-tect as little as 0.03 ng of botulinumtoxin10 and usually yields results in 1to 2 days (range, 6-96 hours). Fecal and

gastric specimens also are cultured an-aerobically, with results typically avail-able in 7 to 10 days (range, 5-21 days).Toxin production by culture isolates isconfirmed by the mouse bioassay.

An electromyogram with repetitivenerve stimulation at 20 to 50 Hz cansometimes distinguish between causesof acute flaccid paralysis.78,79 The char-

acteristic electromyographic findingsofbotulism include normal nerve con-duction velocity, normal sensory nervefunction, a pattern of brief, small-amplitude motor potentials, and, mostdistinctively, an incremental response

(facilitation) to repetitive stimulationoften seen only at 50 Hz. Immediate ac-cessto electrophysiological studies maybe difficult to obtain in an outbreak ofbotulism.

Additional diagnostic proceduresmaybe useful in rapidly excluding botulismas the cause of paralysis (Table 3). Ce-rebrospinal fluid (CSF) is unchanged inbotulism but is abnormal in many cen-tral nervous system diseases. Althoughthe CSF protein level eventually is el-evated in Guillain-Barre syndrome, itmay be normal early in illness. Imaging

of the brain, spine, and chest may re-veal hemorrhage, inflammation, or neo-plasm.A testdose of edrophonium chlo-ridebriefly reversesparalytic symptomsin many patients with myastheniagravisand, reportedly, in some with botu-lism.64 A close inspection of theskin,es-pecially the scalp, may reveal an at-tached tick that is causing paralysis.80

Other tests that require days for resultsinclude stool culture for Campylobacterjejunias a precipitant of Guillain-Barresyndrome and assays for the autoanti-

bodies that cause myasthenia gravis,Lambert-Eaton syndrome, and Guillain-Barre syndrome.

Foods suspected of being contami-nated should be refrigerated untilretrieval by public health personnel.The US Food and Drug Administra-tion and the US Department of Agri-culture can assist other public healthlaboratories with testing of suspectfoodsby using methods similar to thoseapplied to clinical samples.

THERAPY

The mortality and sequelae associatedwith botulism have diminished withcontemporary therapy. In the UnitedStates, the percentage of persons whodied of foodborne botulism decreasedfrom 25% during1950-1959 to 6% dur-ing 1990-1996, with a similar reduc-tion for each botulinum toxin type.42

Despite this increase in survival, the pa-ralysis of botulism canpersist for weeksto months with concurrent require-ments for fluid and nutritional sup-port, assisted ventilation, and treat-ment of complications.

Therapy for botulismconsists of sup-portive care and passive immuniza-tion with equineantitoxin. Optimal useof botulinum antitoxin requires earlysuspicion of botulism. Timely admin-istration of passive neutralizing anti-body will minimize subsequent nervedamage and severity of disease but willnot reverse existent paralysis.81,82 An-titoxin should be given to patients withneurologic signs of botulism as soon aspossibleafter clinicaldiagnosis.47 Treat-ment should not be delayed for micro-biological testing. Antitoxin may be

withheld at the time of diagnosis if itis certain that the patient is improvingfrom maximal paralysis.

In the United States, botulinum anti-toxin is available from theCDCvia stateand local health departments (Box 2).The licensed trivalent antitoxin con-tains neutralizing antibodies againstbotulinum toxin types A, B, and E, themost common causes of human botu-lism. If another toxin type was inten-tionally disseminated, patients couldpo-tentiallybetreatedwith aninvestigational

heptavalent(ABCDEFG) antitoxin heldbythe USArmy.83 However, the time re-quired for correct toxin typing and sub-sequent administration of heptavalentantitoxin would decrease the utility ofthis product in an outbreak.

The dose and safety precautions forequine botulinum antitoxin havechanged over time. Clinicians shouldre-view the package insert with publichealth authorities before using anti-toxin. At present, the dose of licensedbotulinum antitoxin is a single 10-mL

vial per patient, diluted 1:10 in 0.9% sa-line solution, administered by slow in-travenous infusion. Onevialprovides be-tween 5500 and 8500 IU of each type-specific antitoxin. The amount ofneutralizing antibody in both the li-censedandtheinvestigationalequine an-titoxins far exceeds the highest serumtoxin levels found in foodborne botu-




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lism patients, and additional doses areusually notrequired. Ifa patient hasbeenexposed to an unnaturally large amountof botulinum toxin as a biologicalweapon, the adequacy of neutralizationby antitoxin canbe confirmed by retest-

ing serum for toxin after treatment.There are few published data on thesafety of botulinum antitoxins. From1967 to 1977, when the recommendeddose was larger than today, approxi-mately 9% of recipientsof equine botu-linumantitoxin in theUnitedStates dis-played urticaria,serumsickness, or otherreactions suggestive of hypersensitiv-ity.84 Anaphylaxis occurred within 10minutes of receiving antitoxin in 2% ofrecipients. When the US Armys inves-tigational heptavalent antitoxin wasgiven to 50 individuals in a large Egyp-

tian outbreak of type E foodborne botu-lism in 1991, 1 recipient (2%) dis-played serumsickness, and 9 (18%) hadmild reactions.83 To screen for hyper-sensitivity, patients are given small chal-lenge doses of equine antitoxin beforereceiving a full dose. Patients respond-ing to challengewith a substantial whealand flare may be desensitized over 3 to4 hours before additional antitoxin isgiven. During the infusion of anti-toxin, diphenhydramine and epineph-rine shouldbe on hand for rapid admin-

istration in case of adverse reaction.Although both equine antitoxins havebeen partially despeciated by enzy-matic cleavage of the allogenic Fcre-gion, each contains a small residual ofintact antibody that may sensitize re-cipients to additional doses.

Botulism patients require support-ive care that often includes feeding byenteral tube or parenteral nutrition,intensive care, mechanical ventila-tion, and treatmentof secondary infec-tions. Patients with suspected botu-

lism should be closely monitored forimpending respiratory failure. In non-ventilated infants with botulism, areverse Trendelenburgpositioningwithcervical vertebral supporthas been help-ful, but applicability of this position-ing to adults with botulism remainsuntested. This tilted, flat-body posi-tioning withnecksupport may improve

ventilation by reducing entry of oralsecretions into the airway and by sus-pending more of the weight of theabdominal viscera from the dia-phragm, thereby improving respira-tory excursion (FIGURE 4). In con-

trast, placing a botulism patient in asupine or semirecumbent position(trunk flexed 45 at the waist) mayimpede respiratory excursion and air-way clearance, especially if the patientisobese.Thedesiredangle ofthereverseTrendelenburg position is 20 to 25.

Botulism patients should be assessedfor adequacy of gag and cough reflexes,controlof oropharyngeal secretions,oxy-gen saturation, vital capacity, and inspi-ratory force. Airway obstruction or as-piration usually precedes hypoventilationin botulism. When respiratory function

deteriorates, controlled, anticipatory in-tubation is indicated. The proportion ofpatients with botulismwho require me-chanical ventilation hasvariedfrom 20%in a foodborne outbreak64 to more than60% in infant botulism.85 In a large out-break of botulism,theneed formechani-cal ventilators, critical care beds, andskilled personnel might quickly exceedlocal capacity and persist for weeks ormonths.Development of a reserve stock-pile of mechanical ventilators in theUnitedStatesis under way86 andwill re-

quire a complement of staff trained intheir use.

Antibiotics have no known direct ef-fect on botulinum toxin. However, sec-ondary infections acquired during botu-lism often require antibiotic therapy.Aminoglycoside antibiotics and clin-damycin are contraindicated because oftheir ability to exacerbate neuromus-cular blockade.87,88 Standard treat-ments for detoxification, such as acti-vated charcoal,89 may be given beforeantitoxin becomes available, but there

are no data regarding their effective-ness in human botulism.

SPECIAL POPULATIONS

Based on limited information, there isno indication that treatment of chil-dren, pregnant women, and immuno-compromised persons with botulismshould differ from standard therapy.

Despite the risks of immediate hyper-sensitivity and sensitization to equineproteins, both children43,90 and preg-nant women91,92 have received equineantitoxin without apparent short-term adverse effects. The risks to fe-tuses of exposure to equine antitoxinare unknown. Treatment with human-derived neutralizing antibody wouldde-crease the risk of allergic reactionsposed by equine botulinum antitoxin,but use of the investigational product,

Botulism Immune Globulin Intrave-nous (Human) (California Depart-ment of Health Services, Berkeley), islimited to suspected cases of infantbotulism.82,93

PROPHYLAXIS

Botulism can be prevented by the pres-ence of neutralizing antibody in thebloodstream. Passive immunity can beprovided by equine botulinum anti-toxin or by specific human hyperim-mune globulin, while endogenous im-

munitycan beinduced by immunizationwith botulinum toxoid.Useof antitoxinfor postexposurepro-

phylaxis is limited by its scarcity and itsreactogenicity. Because of the risks ofequine antitoxin therapy, it is less cer-tain how best to care for persons whomay have been exposed to botulinumtoxin but who are not yet ill. In a small

Figure 4.Preferred Positioning ofNonventilated Botulism Patients

Tightly Rolled Clothfor Cervical Support

Bumpers to Prevent

Downward Sliding

RigidMattressSupport

Tilt

Noteflat,rigid mattresstiltedat 20, tightlyrolledclothto support cervical vertebrae, and bumpers to pre-vent downward sliding. Useof this positionmay post-pone or avoid the need for mechanical ventilation inmildly affected patients because of improved respi-ratory mechanics and airway protection.




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study of primates exposed to aerosol-ized toxin in which supportive care wasnot provided, all 7 monkeys given anti-toxin after exposure but before the ap-pearance of neurologic signs survived,while 2 of 4 monkeys treated with anti-

toxin only after the appearance of neu-rologic signs died.39 Moreover, all mon-keysinfused withneutralizing antibodybefore exposure to toxin displayed nosigns of botulism. In a balance betweenavoiding the potential adverse effects ofequineantitoxin and needing to rapidlyneutralize toxin, it is current practice infoodborne botulism outbreaks to closelymonitor personswhomayhave been ex-posed to botulinum toxin and to treatthempromptlywith antitoxin at thefirstsigns of illness.47 To facilitate distribu-tionof scarce antitoxin following the in-

tentionaluseof botulinum toxin, asymp-tomatic persons who arebelieved to havebeen exposed shouldremain under closemedical observation and, if feasible,nearcritical care services.

In the United States, an investiga-tional pentavalent (ABCDE) botuli-num toxoid is distributed by the CDCfor laboratory workers at high risk ofex-posure to botulinum toxin and by themilitary for protection of troops againstattack.94 A recombinant vaccine is alsoin development.95 The pentavalent tox-

oid has beenused for more than 30yearsto immunize more than 3000 labora-tory workers in many countries. Immu-nization of the population with botuli-numtoxoidcouldin theoryeliminatethehazard posed by botulinum toxins Athrough E. However, mass immuniza-tion is neither feasible nor desirable forreasons that include scarcity of the tox-oid, rarity of natural disease, and elimi-nation of the potential therapeutic ben-efits of medicinal botulinum toxin.Accordingly, preexposure immuniza-

tion currently is neither recommendedfor nor available to the general popula-tion. Botulinum toxoid induces immu-nity over several months and, so, is in-effective as postexposure prophylaxis.

DECONTAMINATION

Despite its extreme potency, botuli-num toxin is easily destroyed. Heating

to an internal temperature of 85C forat least 5 minutes will detoxify con-taminated food or drink.52 All foods sus-pected of contamination should bepromptly removed from potential con-sumers and submitted to public health

authorities for testing.Persistence of aerosolized botuli-num toxin at a site of deliberate re-lease is determined by atmosphericcon-ditions and the particle size of theaerosol. Extremes of temperature andhumidity will degrade the toxin, whilefine aerosols will eventually dissipateinto the atmosphere. Depending on theweather, aerosolized toxin has been es-timated to decay at between less than1% to 4% per minute.96 At a decay rateof 1% per minute, substantial inactiva-tion (13 logs) of toxin occurs by 2

days after aerosolization.Recognitionofa covertreleaseof finely

aerosolizedbotulinum toxinwouldprob-ably occur too late to prevent addi-tional exposures. When exposure is an-ticipated, some protection may beconferred by covering the mouth andnose with clothing such as an under-shirt, shirt, scarf, or handkerchief.97 Incontrast with mucosal surfaces, intactskin is impermeable to botulinumtoxin.

After exposure to botulinum toxin,clothing and skin should be washed

with soap and water.98

Contaminatedobjects or surfaces should be cleanedwith 0.1% hypochlorite bleach solu-tion if they cannot be avoided for thehours to days required for natural deg-radation.33,52,98

INFECTION CONTROL

Medical personnel caring for patientswith suspected botulism should usestandardprecautions. Patientswith sus-pected botulism do not need to be iso-lated, but those with flaccid paralysis

from suspected meningitis requiredroplet precautions.

RESEARCH NEEDSAdditional research in diagnosis andtreatment of botulism is required tominimize its threat as a weapon. Rapiddiagnostic and toxin typing tech-niques currently under development

would be useful for recognizing and re-sponding to a bioterrorist attack. Al-though polymerase chain reaction as-says can detect the botulinum toxingene,99 they are unable, as yet, to de-termine whether the toxin gene is ex-

pressed andwhether theexpressedpro-tein is indeed toxic. Assays that exploitthe enzymatic activity of botulinumtoxin have the potential to supplant themouse bioassay as the standard for di-agnosis.100 Detection of botulinum toxinin aerosols by enzyme-linked immu-nosorbent assay101 is a component of theUS militarys Biological Integrated De-tection System for rapid recognition ofbiological agents in the battlefield.17

The distribution of botulinum anti-toxin to local hospitals from regionaldepots takes several hours. In con-

trast, standard detoxification tech-niques can be applied immediately.Studies areneeded to assesswhether ac-tivated charcoal and osmotic catharsiscan prevent gastrointestinal tract ab-sorption or reduce circulating levels ofbotulinum toxin. Enteral detoxifica-tion may be less useful in inhalationalbotulism than in foodborne disease.

Thecompeting needsforimmunity toweaponizedbotulinumtoxin andforsus-ceptibility to medicinal botulinum toxincouldbereconciled bysupplyinghuman

antibody that neutralizes toxin. With ahalf-life of approximately 1 month,102

human antibody would provide immu-nity for long periods andavoid the reac-togenicity of equine products. Existingin vitro technologies could produce thestockpiles of fully human antibodynec-essaryboth to deter terroristattacks andto avoid the rationing of antitoxin thatcurrently would be required in a largeoutbreakofbotulism.103-106 A singlesmallinjection of oligoclonalhuman antibod-ies could, in theory, provide protection

against toxins A through G for manymonths. Until such a product becomesavailable, the possibilities for reducingthe populations vulnerability to theintentional misuse of botulinum toxinremain limited.

Author Affiliations: Infant Botulism Treatment andPrevention Program (Drs Arnon and Schechter) andViral and Rickettsial Diseases Laboratory (Dr Ascher),




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California Department of Health Services, Berkeley;Center for Civilian Biodefense Studies, Johns Hop-kins University Schools of Medicine (Drs Inglesby,Bartlett, and Perl) and Public Health (Drs Henderson,OToole, andRussell),Baltimore, Md; US ArmyMedi-cal Research Institute of Infectious Diseases, FtDetrick, Md (Drs Eitzen and Parker); Bureau of Com-municable Disease, New York City Health Depart-ment, New York, NY (Drs Fine and Layton); Science

Applications International Corp, McLean, Va (MrHauer); Centers for Disease Control and Prevention,Atlanta, Ga (Drs Lillibridge and Swerdlow); InfectionControl Advisory Network Inc, Eden Prairie, Minn (DrOsterholm); and Office of Emergency Preparedness,Department of Health and Human Services, Rock-ville, Md (Dr Tonat).Ex Officio Participants in the Working Group onCivilian Biodefense: George Counts, MD, NationalInstitutes of Health; Margaret Hamburg, MD, andStuartNightingale, MD, Officeof Assistant Secretaryfor Planning and Evaluation; Robert Knouss, MD, Of-ficeof Emergency Preparedness; andBrian Malkin, USFood and Drug Administration.Funding/Support: Funding forthis study primarily wasprovided by each participants institution or agency.TheJohnsHopkins Centerfor CivilianBiodefenseStud-iesprovidedtravel funds for6 members of thegroup.Disclaimers: In some instances, theindications, dos-ages, andother informationin this articleare notcon-sistent with current approvedlabeling bythe US Foodand Drug Administration (FDA). The recommenda-tions on use of drugs and vaccine for uses not ap-provedby theFDA donot representthe official viewsof the FDA nor of any of the federal agencies whosescientists participated in these discussions. Unlabeleduses of the products recommended are noted in thesections of this article in whichtheseproductsare dis-cussed. Whereunlabeleduses are indicated,informa-tion used as the basis for the recommendation is dis-cussed.The views, opinions, assertions, and findings con-tained hereinare those of theauthors andshould notbe construed as official US Department of Defense orUS Department of Army positions, policies, or deci-sions unless so designated by other documentation.Additional Articles: This article is the fourth in a se-ries entitled Medical and Public Health Manage-ment Following theUse of a Biological Weapon: Con-

sensus Statements of The Working Group on CivilianBiodefense. See references 1 through 3.Acknowledgment: Theworkinggroupwishesto thankChristopher Davis, OBE, MD, PhD, for his participa-tionin theconsensus process; David Franz,DVM, PhD,for helpful information; Ellen Doyle, MPH, for epide-miological assistance; the reference librarians at theSchoolof PublicHealth, Universityof California,Berke-ley,for many years of superbhelp; andMollyDEsopo,for administrative support.

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47. Shapiro RL, Hatheway C, Swerdlow DL. Botu-lism in the United States: a clinical and epidemiologicreview.Ann Intern Med. 1998;129:221-228.48. Middlebrook JL, Franz DR. Botulinum toxins. In:Sidell FR, Takafuji ET, Franz DR, eds. Medical As-pects of Chemical and Biological Warfare.Washing-ton, DC: Office of the Surgeon General; 1997:643-654.Textbook of Military Medicine; part I, vol 3.49. Gangarosa EJ,Donadio JA, Armstrong RW, MeyerKF, Brachman PH, Dowell VR. Botulism in the UnitedStates, 1899-1969. Am J Epidemiol.1971;93:93-101.50. Hauschild AH. Epidemiology of human food-bornebotulism. In:Hauschild AH , DoddsKL, eds. Clos-tridium botulinum:Ecology andControl in Foods.NewYork, NY: Marcel Dekker Inc; 1993:69-104.51. Wannemacher RW Jr,DintermanRE, ThompsonWL, Schmidt MO, Burrows WD. Treatment for re-moval of biotoxins fromdrinkingwater.Frederick, Md:US Army Biomedical Research and DevelopmentCom-mand; September 1993. Technical Report 9120.52. SiegelLS. Destruction of botulinumtoxinin foodand water. In: Hauschild AH, Dodds KL, eds. Clos-tridium botulinum: Ecology and Control in Foods. NewYork, NY: Marcel Dekker Inc; 1993:323-341.53. Burrows WD, RennerSE. Biologicalwarfare agentsas threats to potable water.Environ Health Perspect.1999;107:975-984.54. Kazdobina IS. Stability of botulin toxins in solu-tions and beverages [in Russian with English ab-stract].Gig Sanit.January-February 1995:9-12.55. KoenigMG, DrutzD, Mushlin AI,SchafferW, Rog-ers DE. Type B botulism in man.Am J Med.1967;42:208-219.56. Geiger JC, Dickson EC, Meyer KF.The Epidemi-ology of Botulism. Washington, DC: US Govern-mentPrinting Office;1922. Public Health Bulletin127.57. TerranovaW, BremanJG, LoceyRP, SpeckS. Botu-lism type B: epidemiological aspects of an extensiveoutbreak.Am J Epidemiol. 1978;109:150-156.

58. MeyerKF, Eddie B.Sixty-FiveYearsof HumanBotu-lismin theUnitedStatesand Canada: EpidemiologyandTabulations of Reported Cases 1899 Through1964.SanFrancisco,Calif:G. W. HooperFoundation andUniver-sity of California San Francisco; 1965.59. Angulo FJ, Getz J, Taylor JP, et al. A large out-break of botulism: the hazardous baked potato. J In-fect Dis. 1998;178:172-177.60. MacDonald KL, Cohen ML, Blake PA. Thechang-ingepidemiology of adult botulism inthe UnitedStates.Am J Epidemiol.1986;124:794-799.61. Mann JM, Hatheway CL, Gardiner TM. Labora-tory diagnosis in a large outbreak of type A botulism:confirmationof the valueof coproexamination. Am JEpidemiol. 1982;115:598-695.62. Seals JE, Snyder JD, Kedell TA, et al. Restaurant-associated type A botulism: transmission by potatosalad.Am J Epidemiol. 1981;113:436-444.63. MacDonaldKL, Spengler RF,HathewayCL, Har-

grett NT, Cohen ML. Type A botulism from sauteedonions: clinical and epidemiological observations.JAMA. 1985;253:1275-1278.64. St. Louis ME, Peck SH, Bowering D, et al. Botu-lismfrom chopped garlic: delayedrecognition of a ma-jor outbreak. Ann Intern Med. 1988;108:363-368.65. Townes JM, Cieslak PR, Hatheway CL, et al. An

outbreak of type A botulism associated with a com-mercial cheese sauce. Ann Intern Med. 1996;125:558-563.66. Telzak EE, Bell EP, Kautter DA, et al. An interna-tional outbreak of type E botulism due to uneviscer-ated fish.J Infect Dis.1990;161:340-342.67. OMahonyM, MitchellE, GilbertRJ, etal. Anout-break of foodborne botulismassociatedwith contami-natedhazelnutyoghurt. Epidemiol Infect. 1990;104:

389-395.68. Aureli P, Franciosa G, Pourshaban M. Food-borne botulism in Italy. Lancet. 1996;348:1594.69. Chou JH, Hwant PH, Malison MD. An outbreakof type A foodborne botulism in Taiwan due to com-mercially preserved peanuts. Int J Epidemiol.1988;17:899-902.70. Midura TF, Nygaard GS, Wood RM, Bodily HL.Clostridium botulinumtype F: isolation from veni-son jerky.Appl Microbiol. 1972;24:165-167.71. McCroskey LM, Hatheway CL, Woodruff BA,Greenberg JA, Jurgenson P. Type F botulism due toneurotoxigenic Clostridium baratii from an un-known sourcein an adult.J Clin Microbiol. 1991;29:2618-2620.72. Gunnison JB, Meyer KF. Susceptibility of mon-keys, goats and small animals to oral administrationofbotulinumtoxin typesB, C and D.J InfectDis. 1930;46:335-340.73. Dolman CE, Murakami L. Clostridium botuli-numtype F with recent observations on other types.J Infect Dis. 1961;109:107-128.74. SmartJL, Roberts TA,McCullagh KG,LuckeVM,Pearson H. An outbreak of type C botulism in captivemonkeys.Vet Rec. 1980;107:445-446.75. Gimenez DF, Ciccarelli AS. Another typeof Clos-tridium botulinum.Zentralbl Bakteriol [Orig]. 1970;215:221-224.76. Beller M, Gessner B, Wainwright R, Barrett DH.Botulismin Alaska:A Guide for Physiciansand HealthCare Providers. Anchorage: State of Alaska, Dept ofHealth and Social Services, Division of Public Health,Section of Epidemiology; 1993.77. Woodruff BA, Griffin PM, McCroskey LM, et al.Clinical and laboratory comparison of botulism fromtoxin types A, B, and E in the United States, 1975-1988.J Infect Dis. 1992;166:1281-1286.78. Maselli RA, Bakshi N. American Associationof Elec-trodiagnosticMedicinecase report 16:botulism.MuscleNerve. 2000;23:1137-1144.79. Cherington M. Clinical spectrum of botulism.Muscle Nerve. 1998;21:701-710.80. Felz MW,Smith CD, Swift TR.A six-year-oldgirlwith tick paralysis. N Engl J Med. 2000;342:90-94.81. Tacket CO,ShanderaWX, Mann JM,HargrettNT,Blake PA. Equine antitoxin use and other factors thatpredict outcome in type A foodborne botulism. Am JMed. 1984;76:794-798.82. ArnonSS. Infantbotulism. In:Feigin RD,Cherry JD,eds. Textbook of Pediatric Infectious Diseases. 4th ed.Philadelphia, Pa: WB Saunders Co; 1998:1570-1577.83. Hibbs RG, Weber JT, Corwin A, et al. Experiencewith the use of an investigational F(ab)2heptavalentbotulism immune globulin of equine origin during anoutbreak of type E botulism in Egypt. Clin Infect Dis.1996;23:337-340.84. Black RE, GunnRA. Hypersensitivity reactionsas-sociated with botulinal antitoxin. Am J Med. 1980;

69:567-570.85. Schreiner MS, Field E, Ruddy R. Infant botulism:a review of 12 years experienceat theChildrens Hos-pital of Philadelphia.Pediatrics. 1991;87:159-165.86. KahnAS, Morse S, Lillibridge S. Public-health pre-parednessfor biological terrorismin theUSA. Lancet.2000;356:1179-1182.

87. Santos JI, Swensen P, Glasgow LA. Potentiationof Clostridium botulinumtoxin by aminoglycosidean-tibiotics: clinical and laboratory observations.Pediat-rics. 1981;68:50-54.88. Schulze J, Toepfer M, Schroff KC, et al. Clinda-mycinand nicotinicneuromuscular transmission. Lan-cet. 1999;354:1792-1793.89. Olson KR,ed. Poisoning andDrug Overdose. 3rded. Stamford, Conn: Appleton & Lange; 1999.

90. Keller MA, Miller VH, Berkowitz CD, YoshimoriRN. Wound botulism in pediatrics.Am J Dis Child.1982;136:320-322.91. Robin L, HermanD, RedettR. Botulism in a preg-nant woman.N Engl J Med. 1996;335:823-824.92. St. Clair EH, DiLiberti JH, OBrien ML. Observa-tions of an infant born to a mother with botulism.J Pediatr. 1975;87:658.93. Arnon SS. Clinical trial of human botulism im-mune globulin. In: DasGupta BR, ed. Botulinum andTetanus Neurotoxins: Neurotransmission and Bio-medical Aspects.NewYork,NY: Plenum Press;1993:477-482.94. Siegel LS. Human immune response to botuli-num pentavalent (ABCDE) toxoid determined by aneutralization test and by an enzyme-linked immu-nosorbent assay.J Clin Microbiol. 1988;26:2351-2356.95. Byrne MP, Smith LA. Development of vaccinesfor preventionof botulism. Biochimie. 2000;82:955-966.96. Dorsey EL,Beebe JM,JohnsEE. Responsesof air-borneClostridium botulinumtoxin to certain atmo-spheric stresses. Frederick, Md: US Army BiologicalLaboratories; October 1964. Technical Memoran-dum 62.97. WienerSL. Strategies forthe prevention of a suc-cessful biological warfare aerosol attack. Mil Med.1996;161:251-256.98. Franz DR. Defense Against Toxin Weapons. FtDetrick, Md: US Army Medical Research Institute ofInfectious Diseases; 1997.99. Franciosa G, Ferreira JL, Hatheway CL. Detec-tion of type A, B, and E botulism neurotoxin genes inClostridium botulinum and other Clostridiumspe-cies by PCR: evidence of unexpressed type B toxingenes in type A toxigenic organisms. J Clin Micro-biol. 1994;32:1911-1917.100. Wictome M, Newton K, Jameson K, et al. De-

velopmentof an in vitro bioassay forClostridium botu-linumtype B neurotoxin in foods that is more sensi-tivethan themouse bioassay. Appl EnvironMicrobiol.1999;65:3787-3792.101. Dezfulian M, Bartlett JG. Detection of Clos-tridium botulinumtype A toxinby enzyme-linked im-munosorbent assay with antibodies produced in im-munologicallytolerant animals.J Clin Microbiol. 1984;19:645-648.102. SarvasH, Seppala I, Kurikka S, SiegbergR, MakelaO. Half-life of the maternal IgG1 allotype in infants.J Clin Immunol.1993;13:145-151.103. Amersdorfer P, Marks JD.Phagelibrariesfor gen-eration of anti-botulinum scFv antibodies. MethodsMol Biol. 2000;145:219-240.104. GreenLL, HardyMC, Maynard-Currie CE,et al.Antigen-specific human monoclonal antibodies frommice engineered with human Ig heavy andlight chainYACs. Nat Genet. 1994;7:13-21.

105. Bavari S, Pless DD, Torres ER, Lebeda FJ, OlsonMA. Identifyingthe principal protective antigenic de-terminants of type A botulinum neurotoxin. Vaccine.1998;16:1850-1856.106. MarksC, MarksJD. Phagelibraries: a newrouteto clinically useful antibodies. N Engl J Med. 1996;335:730-733.




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current national point prevalence data are available. In addi-

tion, there are no quantitative data suggesting isotretinoin mis-use, and the informed consent specifically indicates that the

patient has been diagnosed with the FDA-approved indica-tion. It is important to note that Roche Laboratories promotes

the use of isotretinoin exclusively for patients with this ap-

proved indication.Finally, it is important to state that the clinical criteria for

the use of this drug in an individual patient must be left to thejudgment of the physician, who is the only appropriate per-

son to define the treatment plan for that patient.

Russell H. Ellison, MD, MPHEileen Enny Leach, MPH, RNRoche Laboratories IncNutley, NJ

1. Accutane Tracking Survey, Roche Data on File, Accutane/FDA Annual Report2000.2. Hatcher RA.Contraceptive Technology. 17th ed. New York, NY: Ardent Me-dia, Inc; 1998.

RESEARCH LETTER

Persistent Pain in Nursing Home Residents

To the Editor: More than 1.5 million people in the United

States reside in nursing homes and an estimated 43% of adults65 years and older will enter a nursing home prior to death.1

Previous research using an early version of the MinimumData Set (MDS), a nationally mandated nursing home resident

assessment instrument, noted that daily pain was prevalent

among nursing home residents diagnosed with cancer whohad been discharged from a hospital, as well as among the

residents of nursing homes in general.

2

Prior research wasrestricted by a limited MDS pain frequency measure of none

or daily, but since 1998, information on both frequency(none, daily, or less than daily) and severity of pain (mild,

moderate, or excruciating at times) has been collected. We

report the rates of persistent severe pain among US nursinghome residents by analyzing a national repository of MDS

data, which represents all nursing home residents in all 50states.

Methods. We determined the rate of persistent severe pain

among all 2.2 million residents of US nursing homes within60 days of April 1, 1999. The term persistent pain indicates

residents with pain at an assessment around that time who werealso reported to be in daily moderate or excruciating pain at a

second assessment, 60 to 180 days later. Using state as the unitof analysis, we adjusted observed rates of persistent severe pain

for the nursing home discharge rate and the prevalence of se-

vere pain among all 1999 admissions.Results. Nationwide, 14.7% of residents in a nursing home

for 2 assessments were in persistent pain and 41.2% of resi-

dents in pain at first assessment were in severe pain 60 to 180days later. This rate varied from 37.7% (Mississippi) to 49.5%

(Utah). Forty-one states had rates of persistent pain between

39.5% and 46.1%. Individual state reports are available onlineat http://www.chcr.brown.edu/dying/factsondying.htm.

Comment. We believe that these results underestimate thetrue pain burden experienced by nursing home residents be-

cause the data were reported by nursing home staff rather than

by patients. States in which pain is not adequately assessed mayreport lower rates of persistent pain. Although facilities in states

with higher rates of reported pain may be doing a better job ofrecognizing pain, nearly half of these residents were appar-

ently not afforded adequate palliation. The high rate of persis-

tent pain is consistent with previous research noting that painis often not appropriately treated in nursing home resi-

dents.2,3 Untreated pain results in impaired mobility, depres-

sion, and diminishes quality of life.3-5 These population re-sults indicate that pain control represents an often neglectedneed of this vulnerable population.

Joan M. Teno, MD, MSSherry Weitzen, MSTerrie Wetle, PhDVincent Mor, PhDThe Center for Gerontology and Health Care Research

and Department of Community HealthBrown Medical SchoolProvidence, RI

1. Kemper P, Murtaugh CM. Lifetime use of nursing home care.N Engl J Med.1991;324:595-600.2. Bernabei R, Gambassi G, Lapane K, et al. Management of pain in elderly pa-

tients with cancer: SAGE Study Group: Systematic Assessment of Geriatric DrugUse viaEpidemiology [published erratumappears inJAMA. 1999;281:136]. JAMA.1998;279:1877-1882.3. Ferrell BA, Ferrell BR, Rivera L. Pain in cognitively impaired nursing home pa-tients.J Pain Symptom Manage. 1995;10:591-598.4. Sengstaken EA, King SA. The problems of pain and its detection among geri-atric nursing home residents. J Am Geriatr Soc. 1993;41:541-544.5. Parmelee PA, Smith B, Katz IR. Pain complaints and cognitive status amongelderly institution residents.J Am Geriatr Soc. 1993;41:517-522.

CORRECTION

Incorrect Wording and Web Site Address: In the Consensus Statement entitledBotulinum Toxin as a Biological Weapon: Medical and Public Health Manage-ment published in theFebruary 28,2001, issue of THE JOURNAL (2001;285:1059-1070), 3 errors appeared. In the third introductory paragraph on page 1059, theword biologicalshould be microbial.In the paragraph labeled Toxin Types

on page 1064, the word bacteria should be bacterial. Finally, on page 1069,the Web site address for reference 27 should be http://www.state.gov/www/global/terrorism/1999report/1999index.html.

LETTERS

2001 American Medical Association. All rights reserved. (Reprinted) JAMA, April 25, 2001Vol 285, No. 16 2081

botulism consensus

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