Grassley Seeks Improvements to Anti-bioterrorism Network

WASHINGTON – Sen. Chuck Grassley, ranking member of the Committee on Finance, todayasked Homeland Security Director Tom Ridge to review expert critiques of the nation’s response tothe anthrax attack last fall and make improvements as needed. Grassley’s letter to Ridge comes onthe six-month anniversary of the opening of the anthrax-laced letter to Sen. Tom Daschle. Grassley’sletter to Ridge follows.

April 15, 2002
The Honorable Tom Ridge
Director, Office of Homeland Security
The White House
1600 Pennsylvania Avenue
Washington, D.C. 20502

Dear Governor Ridge:

Today marks the six-month anniversary of the opening of a letter containing anthrax toSenator Tom Daschle. The anthrax threat to postal workers and congressional staff in Washington,D.C., to media professionals in Florida and New York, and to two individuals in New York andConnecticut required a comprehensive, investigative response from various local, state and federalagencies. The unprecedented anthrax exposure prompted responding agencies to marshal untestedresources. Given the newness of the situation, policymakers and public health experts must analyzethe response, identify its strengths and weaknesses, and use the findings to inform future responsesto similar threats and to circumvent tragedy.

I asked several public health experts to lend their expertise to this cause and provide a writtencritique of the local, state and federal agencies' response to the anthrax attacks. I asked them tocomment on any aspect of the response as they saw fit, with an eye toward identifying strengths andweaknesses that could prove useful in the future. I also asked them to touch on, if they could, theinteractions between responding agencies, including the Centers for Disease Control (CDC), theFederal Bureau of Investigation and the U.S. Army Medical Research Institute on InfectiousDiseases.

Three of the experts provided critiques. They raise several points that highly concern me.For example, one expert feels the CDC failed to recognize that “a tape-sealed letter could leak(anthrax) spores.” Another expert believes the Federal Bureau of Investigation wrongly reassured theCDC that the anthrax had limited potential to spread. I am not in a position to verify these experts’contentions, but I hope everyone in the public health community who dealt with last fall’s anthraxoutbreak will consider these responses, analyze their relevance, and make any necessary changes tosecure public safety in the event of another bioterrorism attack. Five people died in last fall’s anthraxoutbreak. We have an obligation to them, to their families, and to the public to prevent any futureloss of life.

Please let me know how your office processes these responses and ensures that the relevantagencies correct any applicable shortcomings. Thank you for your work to protect the public. Pleasecall Jill Gerber of my staff at 202/224-6522 if you have any questions.

Sincerely,

Chuck Grassley
Ranking Member
Attachments: Critiques from Public Health Experts

TO: Senator Chuck Grassley
Senate Finance Committee
135 Hart Senate Building
Washington, DC 20510-1501
FROM: David S. Perlin, Ph.D.
Scientific Director
Public Health Research Institute
Newark, NJ 07103
DATE: March 17, 2002

RE: Evaluation of the CDC's response to the October 2001 anthrax outbreak

CC. John Drake______________________________________________________________________Executive Summary
The October 2001 anthrax outbreak resulted in 18 documented cases of disease with fivedeaths. More than 32,000 people were prescribed antibiotics, 10,000 persons were recommendedto take at least 60 days antibiotic prophylaxis, and additional individuals with high-level exposurewere offered a further course of antibiotic and the anthrax vaccine. Anthrax is not a new disease inthe United States. It is endemic to some parts of the country and it is an occupational hazard in someindustries. The CDC was faced with the task of managing the deliberate transmission of anthraxspores through the mail. The overall management of the outbreak was successful. But along the way,errors in judgment, poor communication, and a reluctance to modify approaches and outlook basedon current findings led to the appearance of an agency that was not in full control. Most notable wasthe failure of CDC to recognize that a tape-sealed letter could leak spores. This was most seriousbecause the spores emerging from those envelopes were potentially more deadly than those leftbehind. It was also surprising given the CDC's experience with previous threats of this nature.
Furthermore, the CDC did not have a good handle on the surface properties of anthrax spores, whichallowed them to adhere to mail and mail sorting machines, and be distributed through a complex mailsystem. Limitations on the use of nasal and environmental sampling were not explained to the public,which provided a false sense of security. Finally, assumptions about the infectious dose of sporesrequired to cause disease and spore germination were too firmly cast in stone. Although morbidityand mortality was limited during this past outbreak, the lessons learned are critical to our ability torespond more successfully to future outbreaks.

Background
Anthrax cases: Rare but not absent
Bacillus anthracis is a spore-forming soil organism that commonly infects domesticated andwild animals, such as cattle, sheep, horses, mules, and goats. Humans become infected incidentallywhen brought into contact with diseased animals, which includes their flesh, bones, hides, hair andexcrement. For this reason, anthrax has been a common source of disease in the textile industry,"Woolsorters Disease." It is found throughout the world causing sporadic and endemic disease. Inthe United States, areas of infection include South Dakota, Nebraska, Arkansas, Texas, Louisiana,Mississippi and California. Naturally occurring anthrax cases are uncommon but not absent in theUnited States.

Anthrax spores
The spore-forming characteristic of Bacillus anthracis has made it a desirable agent forbiological warfare. Anthrax spores contain the genetic material of the bacteria encased in a toughprotein coat. They are dormant and highly resistant to a variety of stress conditions including extremeheat and cold, ultraviolet radiation, and chemical treatment; they can retain viability in soils for morethan 50 years. When environmental conditions are favorable, the spores germinate and develop intothe disease-producing form of the organism. The Bacillus spores have surface properties that causethe spores to be attracted to one another, as well as to various solid surfaces. This well knownproperty is a major hurdle in developing anthrax as an offensive weapon because clumping of sporesresults in large aggregates. Various substances, like bentonite, which neutralize surface charges onthe spore, significantly reduce attractive forces between spores and promote relatively free dispersal.

Since the start of offensive weapons programs in the United States and Soviet Union in the 1940s,it was presumed that a successful attack with anthrax would require the rapid dispersal of substantialquantities of free spores in a so-called "weapons-grade" form. For this reason, it is generally assumedby specialists that suspicious powders presumed to be anthrax are of weapons-grade caliber andtherefore contain freely dispersed spores. Such freely dispersed spores would be either individualspores in the 1-2 micron range or aggregated spores mechanically milled to produce spores in thesame range. Such spores in sufficient quantities in the right host would be capable of producing theinhalation form of disease.

Disease pathology
Anthrax infection results in three clinically distinct diseases: cutaneous (skin), gastrointestinaland inhalation disease. Cutaneous anthrax is initiated when spores of B. anthracis are introduced intothe skin through cuts or abrasions. Spores germinate within hours, and the cells multiply and produceanthrax toxin with ensuing edema and necrosis. Gastrointestinal anthrax occurs following theingestion of contaminated meat. The bacteria move to mesenteric and other regional lymph nodeswhere they multiply and disseminate. The most feared of the three clinical states is inhalation anthrax.Normally, large clusters of anthrax spores (greater than 5 microns) are deposited in the upper airways(pharynx, larynx, and trachea) and are effectively trapped or cleared by the mucociliary system.

However, small individual spores (1-2 microns) can reach the alveolar ducts and alveoli where theyare engulfed by pulmonary macrophages and transported to mediastinal and peribronchial lymphnodes. Following germination, a large amount of anthrax toxin is produced. Edema factor and lethaltoxin produced by the vegetative organism causes massive hemorrhagic mediastinitis that is typicalof inhalation anthrax. Regional lymph nodes are quickly overwhelmed and the toxin enters thesystemic circulation resulting in edema, hemorrhage, necrosis, septic shock and death.

October 2001 Outbreak Issues: CDC response
Mail as a vector for spore dispersal
Unlike bioterrorism-related exposures in Japan and the former Soviet Union, the US Mailsystem was used as a vector to spread disease in the October 2001 outbreak. The outbreak wasalmost certainly exacerbated by the CDC's slow recognition that anthrax could permeate a tape-sealedletter and that spores could effect ively "hitch-hike" through the mail. The CDC's lack ofpreparedness for mail-based biological terrorism was surprising given their experience with previousthreats of this nature. The CDC was fully aware that mail could be used as a potential vehicle todeliver fatal anthrax spores. From October 30 through December 23, 1998, CDC received reportsof threats of anthrax-laden letters sent to health clinics in Indiana, Kentucky, and Tennessee, as wellas a letter in California sent to a private business. All threats were hoaxes and were investigated byFBI and local law enforcement officials (MMWR 1999, Feb 5). Certainly, the CDC and FBI analyzedthese letters for anthrax contamination and were aware of their potential to deliver anthrax spores.

Most disturbing was the failure of CDC to recognize that individual anthrax spores, with a welldocumentedsmall spore of 1-2 microns (e.g. Shafazand et al. 1999), could easily penetrate astandard cellulose-based envelope. The of spores was well known because a debate had alreadyemerged over the best type of particle respirator to use in the event of an attack (Nicaset al. 2000)or to protect workers in the textile industry (see http://www.3m.com/occsafety/html/anthrax_notice.html). Clearly, spore and its challenges were a safety issue for some time.

If there was any question about the containment properties of an envelope, a quick call topaper industry experts or a simple search through the internet would have revealed that standardenvelopes have numerous micro-channels of 5 microns or greater. Such channels not only serve asan exit point for anthrax spores but also serve as a selective filter to allow the smallest and mostdeadly spores to be released while retaining the largest and least virulent clumps. High-speed postalequipment, which places letters under high pressure, further served to force spores through theseopenings. Thus filtered spores emerging from the so-called "sealed letters" resulted in large numbersof small, freely dispersed (unclumped) spores being deposited on mail machines, mail, and in mailrooms. The release of deadly free spores through an inadvertent pressurized filtering process mayhave accounted for the high degree of inhalation anthrax in postal workers, and for the deadlyconsequences of contaminated mail.

Anthrax and cross-contamination of the mail
Once it was known that anthrax was being distributed through the mail, it should have comeas no surprise to the CDC that Bacillus spores could adhere to pieces of mail emerging from highspeedsorters. The sorters impart an electrostatic charge to the letters, which serves to attract thespores and hold them tightly. A great deal is known about environmental conditions and physicalproperties of surfaces that promote spore adherence (e.g Husmark and Ronner (1990); Dragon, 1995;Ronner et al. (1990); Matz et al. 1970). The high-speed sorters and mail-processing units shouldhave been expected to act as electrostatic generators, attracting and holding spores like magnets. Itis for this reason that the spores were not released into the air until postal workers used high-pressureair to clean sorting machines. Once aerosolized, the spores became deadly. For this reason, crosscontaminationof the mail from an initial inoculum produced by one or more spore-laden pieces ofmail should have been expected. Tight adherence of spores to cross-contaminated letters could easilyhave allowed contaminated mail to be distributed through a complex mail delivery system, and couldwell account for fatal exposures of susceptible hosts such as 61 year-old Kathy T. Nguyen (NewYork City, NY) and 94 year-old Ottilie Lundgren (Oxford, CT). If free spores were dislodged fromthe mail to produce a fatal dose, then it might be reasonable to expect that spores adhering tightly tothe letters were more likely to be small and individual rather than clumped. This would be consistentwith cross-contaminated mail resulting from freely dispersed spores (smallest and most deadly)emerging from the original letters after being filtered through micro-channels in the envelopes. Sporeshitch-hiking through the mail by surface adherence is not surprising. The tight adherence of sporesto other charged surfaces, such as protein in wool from imported raw fabrics, was a frequent causeof inhalation anthrax disease (Woolsorters Disease) in textile mills in the 1940s and 1950s (Gold,1955). Clearly, tightly bound spores can be dislodged and cause disease. Approximately 85 millionpieces of mail were processed on the days after the implicated envelopes passed through the NJ andthe District of Columbia (DC) sorting facilities until they were closed. Both of these facilities hadevidence of widespread environmental contamination with B. anthracis. Certainly, anthrax sporeswere moving in many directions.

Spores are everywhere
Once released, Bacillus spores will move rapidly through air currents and contaminateextensive exposed surfaces. Offices, lab complexes (e.g. Fort Detrick's infamous Building 470) oreven whole islands (e.g. Britain's Gruinard Island) can be extensively contaminated following highlevelexposures. The CDC recognized quickly that HVAC systems and nearly all surfaces had thepotential to be contaminated. Academic researchers, especially those engaged with tissue culture,know that spore-forming organisms like Aspergillus are a nightmare to contain. Entire buildings canbecome infected from a single lab engaged in routine experimentation. Thus, it is not at all surprisingthat a letter leaking spores could contaminate thousands of pieces of mail, nearly all exposed surfaces,and could be carried into buses, cars and homes by workers with inadvertent exposure. Environmentalsampling results in this investigation indicated widespread contamination from the letters processedfor delivery to the offices of two U.S. senators. Although sampling with surface wipes has been thestandard sampling method and has advantages for sampling some small surfaces, surface wipes haveseveral limitations. Wipe samples might miss minimally contaminated surfaces or smaller, discretecontaminated areas. In fact, some confusion arose early because some simple wipe tests werenegative, while a more thorough use of HEPA filtered vacuum sampling was positive. This reflectedthe ubiquitous nature of dispersed spores and either their tight adherence to certain surfaces orinadequate sampling material used in the environmental swabs.

In order to certify that Senator Daschle's office in the Hart Senate Office building was clean,several thousand surface samples were taken. This was probably a prudent measure given theunreliability of routine environmental swabs to detect anthrax from surfaces known to be exposed.However, far fewer swabs were taken from postal facilities. For example, when tracking down crosscontaminationof the letter(s) believed to be responsible for infecting Mrs. Otillie Lundgren inConnecticut, only 117 samples from the Wallingford facility, 29 samples from Seymour facility, and43 samples taken at Lundgren's home were used to declare those building free of anthrax. Whendealing with trace amounts of a biological agent, more samples, not fewer, relative to a largeexposure are needed. How does the CDC reconcile the number of samples taken from those facilities,and others, with that of the Hart Building? If they know more now, have they gone back and resampledthose facilities? Has the EPA been involved with those facilities?

Nasal sampling and surface wipe tests
Early in the anthrax outbreak, nasal swabs were being used as an indicator of human exposureto aerosolized anthrax spores. While the intent was right, it became clear quickly that thismethodology was highly flawed and was not a reliable predictor of exposure. Several of theindividuals that died from inhalation anthrax had negative nasal swabs. The CDC readilyacknowledged that a negative nasal swab did not mean that a person was not exposed. "Nasal swabcultures should not be used to diagnose cases of anthrax or to evaluate whether a person had beenexposed" (MMWR 2001 Nov. 9). Nasal swabs can occasionally document exposure, but cannot ruleout exposure to B. anthracis. As an adjunct to epidemiologic evaluations, nasal swabs may provideclues to help assess the exposure circumstances" (MMWR 2001 Oct. 26). If nasal swabs were ofmarginal value, then why so much emphasis on them and why wasn't the limitation of this testpublicized more readily. More than 5000 nasal swabs were taken from employees at the Hart SenateOffice building, which had extensive anthrax exposure. Nearly all were negative. The CDC regularlyreported that workers suspected of exposure had negative nasal swab tests suggesting that they hadno exposure. In fact, the nasal swab test is unreliable at best. Given the affinity of anthrax spores forprotein in hair, it is surprising that hair sampling was not used as a better indicator of environmentalexposure. Human hair presents a far greater surface area than the nose and does not have clearancesystems operating to cleanse mucosal surfaces. Surgeons know far too well the potential for hair toretain airborne microorganisms. Why wasn't this approach used? It is difficult to believe that CDCdid not consider this possibility. The October 2001 outbreak was a perfect time to evaluate theeffectiveness of such a sampling technique. In the end, a highly flawed sampling methodologyremains the only option for a new outbreak.

How many spores are needed to cause inhalation anthrax?
In the early phase of the outbreak, the CDC maintained that the "textbook" infectious doseof anthrax required to produce inhalation disease was at least 8,000-12,000 spores. For this reason,as spores were detected in offices, workers were told that the number of spores detected fell belowthe threshold level required to cause disease. However, as the outbreak continued two fatal cases ofinhalation anthrax and a case of cutaneous anthrax were documented in which there was no directevidence of any spore exposure. The most likely explanation was incidental exposure through crosscontaminatedmail or other environmental sources whereby small numbers of spores caused disease.

It should be recognized that several academic researchers, myself included, publicly challenged thethreshold value because of the way it was derived. An infectious dose has never been established forhumans. Rather, the number was inferred indirectly from animal model studies and from an evaluationof human disease documented in U.S. textile mills and through naturally-occurring outbreaks anddeliberate (accidental?) releases such as in Sverdlovsk in 1979.

Published lethal doses of anthrax spores that cause 50% death (LD50s) range from less than10 spores for the guinea pig, 3,000 for the rhesus monkey, 1,000,000 for the rat, 1,000,000,000 forthe pig and 5,000,000,000 for dog (Watson and Keir, 1994). LD50s in non-human primates rangefrom 2,500 to 760,000 spores (Meselson et al.,1994; Watson and Keir, 1994). It is generally assumedin humans that substantial exposure was necessary before the risk of inhalation anthrax becomessignificant. However, in Namibia, where anthrax is epidemic, a recent study found that the highestlevels in air sampled downwind from disturbed dry, dusty anthrax carcass sites were 20 to 40 colonyformingunits of spores per cubic meter. It would take about 2.5 minutes for an average humanundergoing moderate activity to inhale 1 spore (Turnbull et al., 1998). It was suggested that suchlevels would be unlikely to contribute to infection. Yet disease is prevalent in the area. This mayindicate that either a smaller dose can cause disease or inhaled spores are accumulating with time.

The likelihood and severity of an infection depends on multiple factors including route ofinfection, nutritional and other health states of the host, and relative virulence of the infecting strain.It should also be recognized that infectious doses generally follow a bell-shaped curve in which mostpeople fall on the flat portion of the curve. In essence, the majority of cases will require a broadminimum and maximum range of spores to cause disease. However, a much smaller population willdevelop disease following exposure at the extremes of the bell curve, representing low and high sporelevels. The implication of such an infection model is that in order for several individuals to havecontracted inhalation anthrax without documented exposure, small numbers of spores were mostlikely involved and many thousands of people had to be exposed. The CDC reluctantlyacknowledged this inevitable conclusion in late December 2001 following months of denying thispossibility. It was this recognition that placed an additional burden on the EPA to clean-up "everylast spore" in the Hart Senate Office Building. While the textbooks were mostly right, the CDC failedto recognize that a subset of the population was highly susceptible to infection. In addition, they weretoo slow to modify their risk assessment for a spore threshold for active disease. In light of theCDC's current position on the dangers of small numbers of spores for certain populations, such asimmunosuppressed elderly, chemotherapy or HIV patients, have they re-tested postal facilities orother buildings deemed safe because they were below the previous spore threshold for causingdisease?

Spore germination: incomplete assumptions.
The original decision to provide 60 days of antibiotic prophylaxis following potential anthraxexposure was based mostly on case emergence in outbreaks, so-called epidemic curves. However,little or nothing is known about spore latency (delayed germination) in humans. In some diseases,such as tuberculosis, where microorganisms are also taken up by macrophages in the lungs, latencymay be months or years. There is no definitive data in humans. In model animal systems, factorsaffecting spore germination have been extensively studied (Titball et al.1987; Guidi-Rontani et al.

1999). Numerous host conditions will impact spore germination. Like TB, immunosuppression maybe an important factor. In addition, the affects of antibiotics like ciprofloxacin or doxycycline onspore germination in a prolonged exposure model has not been addressed. Some 32,000 people wereprescribed antibiotics for 60 days and probably hundreds of thousands of people took antibiotics asa prophylactic measure. These considerations forced CDC to acknowledge after the 60 day periodexpired that individuals with suspected exposure were still at risk. In addition, CDC offered thatspores could be detected in the lungs 100 days following exposure. They then recommended anadditional course of antibiotics and or investigational use of the anthrax vaccine as a post-exposureprophylactic. Why did it take so long to inform the public about the uncertainty of the germinationtime. In this outbreak, short-term latency was not observed. Many, perhaps thousands of peoplewere exposed to anthrax spores at some level. These people are not sick. But, it would not besurprising in the future to see one or more cases of inhalation anthrax resulting from latent sporegermination because an infected host's immune status has changed. Time will tell.

Identifying anthrax in clinical and environmental samples: more obstacles.
A definitive diagnosis of anthrax requires culturing of live organisms from specimens such asblood, tissue, exudates, sputum and environmental surfaces. Certain immunological and biochemicaltest are available to confirm the identification once an organism grows, usually after 12-24 hours.Final testing requires several days for confirmation. Molecular-based polymerase chain reaction(PCR) techniques can be used to rapidly identify the organism. PCR analysis is fast, often producingresults within hours. Yet, PCR alone can be unreliable (MMWR December 7, 2001). However, whencoupled with state-of-the-art probes such as TaqMan, Light-cycler or Molecular Beacons, PCR is notonly fast, but nearly 100% accurate. The CDC developed such an approach several weeks after theinitial outbreak. But they have systematically refused to provide non-infectious reference DNA tostate health departments or academic labs seeking to develop alternative strategies. PCR-basedapproaches are not only essentially because they are fast, but they can also be developed in a highthrough-put automated capacity. Such an approach is critical for analyzing numerous (thousands)environmental samples from a suspected outbreak in a timely fashion. Without such approaches,health department labs will be overrun with samples in short time in a future outbreak where multiplesources occur.

Vaccination: a good decision not well received
Approximately 10,000 persons potentially exposed to anthrax in Connecticut, Florida, NewJersey, New York City, and Washington, D.C., were recommended to take at least 60 days ofpostexposure antibiotic prophylaxis. Those with high level exposure are eligible to receive theanthrax vaccine (MMWR 2002, Jan. 25). But public health officials have a perceived credibilityproblem created by a well-documented series of miscues in the anthrax outbreak of the past fewmonths. The abrupt change in thinking about spore persistence and germination, and the potentialfuture health risk prior exposures posed, has eroded the public' s confidence in health officials toproperly guide management of a deadly disease. To further complicate matters, the use of the anthraxvaccine was being described as experimental, falling in the category of an investigational new drug(IND) requiring informed consent of patients. This was necessary because the vaccine is not FDAapprovedfor prophylaxis following pathogen exposure. Patients would be advised to consult theirprimary care physician for guidance and monitoring of side effects. In an atmosphere alreadyconsumed with doubt about the CDC's knowledge about anthrax and the nuances of its health risks,the public reacted with skepticism over the latest CDC recommendation. A vaccine is almost alwayspreferred over antibiotic prophylaxis when considering side effects and the loss of an antibiotic classthrough emergence of drug resistance. At a different time, perhaps even six months ago, acontroversial recommendation from the CDC would have been well received. But public confidencehas been shaken during the latest public health emergency. Too often statements of fact wereretracted or qualified weeks or months later. This is truly an unfortunate turn of events because abeleaguered CDC made the right decision. An assertive preemptive approach utilizing a vaccine isthe best way to protect the public's safety. Yet, the public has not embraced the CDC's view. Tomany, it requires a leap of faith to embrace such an approach given their shaken confidence. A smallnumber of federal employees did agree to take the vaccine. But many balked. D.C. Mayor AnthonyWilliams flatly recommended against the vaccine citing side effects and a lack of clinical data tosupport its use. Similarly, William Smith, President of the New York Metro Area Postal Unionrejected the vaccine as a solution to lingering spore counts at the Morgan postal facility in New Yorkand demanded that the facility be thoroughly cleaned and tested.

In principle, the anthrax vaccine should be safe. Unlike other types of vaccines, it does notuse killed organisms to induce immunity. Rather, it is a subunit vaccine consisting of a culturepurifiedprotein, "protective antigen," as the principal determinant of immunity. Limited clinical data,mostly in the textile industry, supports its value in preventing disease. Even though local minorreactions at the injection site are observed in 30% of the people that receive the vaccine, serious sideeffects are rare. In a comprehensive review published in the CDC's MMWR, 1,859,000 doses of thevaccine were distributed in the United States from January 1, 1990 through August 31, 2000(MMWR 2000 December 15). During this period, 1544 adverse events, those requiring medicalattention, were noted but only 76 were deemed as potentially life threatening. As vaccines go, thesafety profile appears quite good.

So why the outcry? First, the public was concerned about substituting one risk, anthraxexposure, for another, vaccine-related complications. Second, the anthrax vaccine has been linkedby some advocacy groups to the multisymptom "Gulf War Syndrome." Although epidemiologicaldata does not support this linkage, many remain skeptical. In October, 2000, the General AccountingOffice stated that 25 percent of the 176,000 pilots and crew in the US Air Force and Air NationalGuard left their jobs or asked to be reassigned to avoid anthrax vaccinations. Third, the sole U.S.manufacturer of the anthrax vaccine, BioPort Corporation (Lansing, Michigan), has had consistentquality control issues related to the vaccine production. The FDA only recently reinstated themanufacturer. In addition, the FDA complained in the past that reports of adverse reactions to thevaccine from members of the armed services were not being tracked or investigated by BioPort, asrequired. These lingering issues have cast a cloud over the anthrax vaccine program. Regrettably,public health officials have not adequately addressed these issues, which has further eroded thepublic's confidence. Public confidence in the CDC may be shaken, but their leadership is needed nowand in the future. They should press forward with this difficult decision in a firm and decisive manner.If safety questions persist, then they should be addressed openly.

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Cheng SM, Streifel AJ, 2001, Infection control considerations during construction activities: landexcavation and demolition. Am J Infect Control Oct; 29(5):321-328

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Franz DR, Jahrling PB, Friedlander AM, McClain DJ, Hoover DL, Bryne WR, Pavlin JA,Christopher GW, Eitzen EM Jr. 1997 Clinical recognition and management of patients exposed tobiological warfare agents. JAMA Aug 6; 278(5):399-411

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Husmark U, Ronner U, 1990, Forces involved in adhesion of Bacillus cereus spores to solid surfacesunder different environmental conditions. J Appl Bacteriol Oct; 69(4):557-562

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MMWR, 1999, Feb 5; 48(4):69-74 Bioterrorism Alleging Use of Anthrax and Interim Guidelines forManagement -- United States, 1998

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MMWR, 2001, Dec. 21; 50(50):1129-1133. Evaluation of Bacillus anthracis Contamination Insidethe Brentwood Mail Processing and Distribution Center ---District of Columbia, October 2001MMWR, 2002, Jan. 25; 51(03):59 Evaluation of Postexposure Antibiotic Prophylaxis to PreventAnthrax

Nicas M, Neuhaus J, Spear RC, 2000, Risk-based selection of respirators against infectious aerosols:application to anthrax spores. J Occup Environ Med Jul;42(7):737-748Ross, JM, 1957, The pathogenesis of anthrax following the administration of spores by the respiratoryroute. J Pathol Bacteriol 73,485-494

Shafazand S, Doyle R, Ruoss S, Weinacker A and Raffin, TA, 1999, Inhalational Anthrax:Epidemiology, Diagnosis, and Management, Chest 116:1369-1376.

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3/13/02

Senator Charles Grassley
Ranking Member
United States Senate
Committee on Finance
Washington, D.C. 20510-6200

Dear Senator Grassley,

Thank you for requesting my analysis on the handling of last Fall'sbioterror crisis. I will direct my comments to the official response and itsrelevance to future threats.

The anthrax mailings revealed a lack of integration among the variousagencies that were called upon to defend against the threat. Specifically,the FBI led the investigation, and acting with strict criminal protocol,conducted experiments using the USAMRIID lab, but excluded CDC scientistsfrom directly examining the envelopes.

Nor did the Army perform the appropriate tests right away; in fact DNAtracers to check seepage from the envelopes, and quantitative tests todetermine airborne potential, were not conducted until late October, whenseveral people had already gotten sick and two had died.

The CDC, in turn, spread faulty information to the local health agenciesand the US Postal Service based on epidemiological speculation. Not seeingthe evidence, and being wrongly reassured by the FBI, the CDC guessed thatthe anthrax had limited potential to spread. Then when the two postal workersdied in Brentwood, the CDC overreacted, not by closing facilities, but byadministering antibiotics to 30,000 postal, media, and government workers whowere anywhere near where the anthrax had been found. This overuse ofantibiotics (only eighteen people actually acquired anthrax overall), causedneedless expense (millions of dollars), and side effects from the medication(diarrhea, insomnia, rashes).

The antibiotic authorized for use, Cipro ($300 for a month's supply), isten times more expensive than generic equivalents (doxycycline - $30 for amonth's supply) that have been tested and found to be equally effectiveagainst the anthrax bacillus. Examination of the anthrax itself revealed nodrug resistance to any of these antibiotics, yet the more expensive Ciprocontinued to be used.

The FBI only showed photos of the anthrax letters to the CDC's scientistsand epidemiologists. No one from the CDC examined the actual envelopes thatwere sent to Tom Brokaw, Senators Daschle and Leahy, and the NY Post. TheArmy Infectious Disease lab, which has the same top level D clearance as theCDC lab, had control of the letters. But the Army lab is oriented tobiowarfare whereas the CDC targets public health. According to CDC's DeputyDirector for Infectious Disease, Julie Gerberding, the Army worked directlywith the FBI, and the CDC was informed of the results by conference callsorganized by the National Security Council. At first the Army downplayed therisk to postal workers and the media, and the CDC relayed this reassurance.On October 15th, the letter to Senator Daschle was received in his officeand opened by his assistant. According to Dr. Gerberding, Army scientists didnote that the anthrax in the Daschle letter had "a high concentration ofspores, and that the powder would poof, indicating it was easily aerosolizedand could float around in a more dangerous way." Yet the FBI continued torelay that the letter had been well sealed, only a risk to the person whoopened it, (though only Daschle's assistant had seen it unopened), andtherefore none of the other agencies including the CDC and the Postal Serviceexpected the anthrax to escape the envelope.

It was only after workers got sick that the CDC began closing governmentbuildings and postal facilities, and under pressure from the media began tohand out antibiotics to everyone who was in a contaminated building. Theinitial underreaction was followed by a costly overreaction. This anthrax wasdeadlier than expected, but it was still not contagious and the mail was aninefficient way to spread it. In the end, many more people probably got sickfrom taking Cipro than from anthrax.

Had the FBI integrated its team with the Army and the CDC, had this teamworked together with state and local agencies, the reaction to the anthraxcould have been earlier, more appropriate, and more to scale.

Deborah K. Willhite, Senior Vice President of the Postal Service forGovernment Relations, in a letter to you dated November 14th, wrote that thePostal Service "received critical information through the media, not fromother agencies. The different focuses of various law enforcement and healthorganizations resulted in parties speaking different languages. And, absentan established protocol, lines of authority could be unclear."

Even after a postal task force was organized, the CDC only provided guestexperts, and was no direct imput to the Postal Service from the FBI.

Here in New York, state and city health departments relied on theguidance and the presence of the CDC. Resources were marshaled to test largenumbers of the population, without knowing whether this would be necessary ornot. Labs were readied to perform nasal swab testing of all who might beexposed to anthrax, and blood cultures on those who might already be sickwith inhalation anthrax. (the blood cultures could help distinguish anthraxfrom flu). At first, nasal swabs were felt to be adequate screening, untilthe CDC reversed itself in late October and indicated that the test wasuseful for epidemiological purposes only. But the NY State epidemiologist,Dr. Perry Smith, told me that nasal swabs did in fact have clinical value ifit detected the presence of anthrax - whereupon treatment could potentiallyprevent the onset of the disease.

The confusion about testing; who to test, how to test, how many to test,typified the lack of knowledge and the lack of communication between the CDCand the local agencies it was asked to inform. This problem would have beenless significant if the CDC had seen the anthrax and been better able to makepredictions about its potential for spread.

Going forward, if a team of experts in public health is integrated with ateam of nose-to-the-ground law enforcement agents, the result could be atight web of educated defenders. In fact, Dr. Mitchell Cohen, the CDC'sDirector of Bacterial Diseases and liason to the FBI, admitted to me thatthese "different cultures are not used to working together," but that apartnership is crucial to fight bioterror. He said, "we will be going to FBIheadquarters. Our different approaches can complement each other. We look atinformation in different ways, Scientists collect data, develop hypotheses,and test them. Law enforcement examines the data for patterns to developleads. One side might find what the other side is missing."

Now that 11 billion dollars has been budgeted to protect the publicagainst future threats of bioterror, consideration must be given to where themoney will be spent. Antibiotics, vaccines, and beefing up state and localhealth care agencies are considered primary targets for the funding. But thereal protection against bioterror, the safety net that can be built ofepidemiologists, scientists, and co-operating federal agencies, has still notbeen established. And massive stores of antibiotics and vaccines areperishable, if not used within a few years, they will have to be discardedRecently, truckloads of antibiotics were sent to Salt Lake City to coverthe Olympics. Given how difficult it is to spread anthrax, those antibioticswere due to be wasted, and now, after they expire in two years, discarded.

Bioterror money is better spent in integrating agencies and in making sure anatrocity the magnitude of crop dusting a stadium doesn't happen. A moreeffective public defense against bioterror attack would be public educationrather than antibiotics. Conferences and lectures could be given informingdoctors and the public about tools of bioterror. A relevant medical data basethat could be drawn from in the event of an impending attack would be worththe money spent. Accurate information about smallpox, other viruses, anthrax,plague, could go a long way towards calming fears and preparing a defense.I believe large scale purchases of antibiotics should be avoided. For onething, antibiotics convey the message that bioterror may be in the offing.

For another, since a bacteria cannot possibly spread to thousands of peopleovernight, such a display of drugs is purposeless. Mass stores of antibioticswithout the doctors ready to prescribe them for a disease that doesn'tcurrently exist is a significant waste of funds. As was evidenced last Fallwith the anthrax scare, public perception of a potential catastrophe caneasily necessitate an additional expenditure just to combat hysteria.

Money is better spent on scientists, epidemiologists, and liaisonservices between federal and local agencies. The best return for the moneywould be in establishing a framework of expertise that could be mobilized butcould also be used to reassure the public. But integrating agencies requiresa spirit of co-operation. More than that there must be a structure, adesignated bioterror agency under the auspices of the Office of HomelandSecurity with power over all the other agencies on issues of bioterror.

Though the FBI controls its turf and is not used to co-operating excepton its own terms, still, I believe interagency liaison and the formation of abioterror agency would be a good place to start when considering how to spendthe money that's been allocated. A good epidemiologist or public healthoriented microbiologist working in conjunction with an on-the-scene FBI agentmight know exactly when a particular group of citizens is at risk. Asuspected pathogen of bioterror could be subject to meticulous measurementsto quantify its risk of spread. Vectors such as envelopes could bescrutinized with DNA probes to make exact predictions. Found spores could besent right away to spore specialty labs. The information acquired fromcareful CDC supervised experiments could then be spread responsibly to statesand counties perceived to be in danger.

Just assigning millions of dollars to a particular region will by nomeans assure that the response there is effective or integrated. Whereas aresponse team of high priced scientists would be worth the money spent.

Respectfully submitted,

Marc K. Siegel, MD
Asst. Professor of Medicine
NYU Medical School

February 26, 2002
Senator Chuck Grassley
U.S. Senate
135 Hart Senate Building
Washington, D.C. 20510

Dear Senator Grassley:

I am responding to your request of January 25 to critique the response by government agencies tothe anthrax bioterrorism event that began in September 2001. As a former epidemiologist on the staffof the Centers for Disease Control and Prevention (CDC) for thirty-two years, I was in charge of theanthrax activities during the 1950s, 1960s, and 1970s and am acquainted with anthrax as well as withthe responsibilities that CDC has been given related to bioterrorism. I am also well acquainted withthe Epidemic Intelligence Service (EIS) that I directed for 11 years while at CDC. My comments arebased on information from CDC's Morbidity and Mortality Weekly Report (MMWR), reports fromvarious media sources, and by attending meetings both in Atlanta and in Washington, D.C. I feel thatI can respond to your queries with objectivity.

Several years ago CDC had been given responsibility for developing a response plan for bioterrorismto be implemented at all levels of government i.e. federal, state, and local which in my judgment theycarefully accomplished. It was previously acknowledge that CDC would be the lead federal agencyin directing the public health response to a bioterroristic event. This was not what happened. Therewere problems with the release of information for the public and is conducting some of the fieldinvestigations. Whereas, CDC's normal actions would include daily public briefings reporting thecurrent data developed from the investigations, it was reported that all briefings would come fromWashington. One result of the inability of CDC to put out daily briefings was that state healthdepartments were unable to obtain up to date information about the investigations. When informationwas released from Washington, it was not always correct information due to nonfamiliarity withanthrax and with all the investigations in progress. When CDC wished to investigate certainpotentially contaminated environments, they were told to stand aside, as others (the FBI) would bein charge of that activity. In determining the degree of environmental contamination of variousbuildings, CDC's expertise was not found useful, which resulted in confusion and inappropriatestatements.

These are examples that I am aware of, when CDC's leadership was subverted. Initially datadeveloped by other agencies were not shared with CDC, and yet CDC was supposed to makerecommendations for control and prevention. If there is a criminal element to a bioterroristic event,then the Federal Bureau of Investigation (FBI) will be involved which is appropriate. It is obviousthat the FBI needs to work with a certain amount of secrecy in order to conduct the criminalinvestigation in the manner in which they have expertise. However, CDC is sensitive to their publichealth responsibilities to keep the public aware of what is being done to try to determine the causationfactors in a bioterroristic event and to help alleviate the fear and hysteria that is associated with suchan event. But when they are not able to provide daily briefings, those who look to CDC forinformation will be frustrated, as was the case in this event. From what I observed, the relationshipbetween CDC and the U.S. Army Medical Research Institute on Infectious Diseases wascollaborative, cordial, and very important.

CDC, with its primary mission to control and prevent disease, with a dedicated, competent,experienced staff that is ready to travel on a moments notice must be given the authority to operateas it always has in times of emergency. To put dampers on its actions, can only lead to problems, andI suggest this is what led to some of the problems that occurred during the recent bioterroristic event.I was concerned over several problems within CDC. It appeared that there was no one person atCDC who was directing all of CDC's activities. Though they held daily meetings within CDC, no oneperson was fully knowledgeable about all of the activities in progress nor the results of various fieldand laboratory investigations. CDC did place some of their staff as liaison persons in cities of majorinvolvement, but these persons were not always adequately informed of the current investigation data.

Use of a retrospective scope is dangerous. We must not forget that this is the first such majorbioterroristic event to occur in the United States. No matter how carefully plans are developed forhandling bioterroristic events, once an event has occurred, and the plan is implemented, problems willbe identified. Each bioterroristic event will differ from a previous such event and it is not possibleto foresee what will happen. Thus flexibility has to be part of any plan directed at reacting to abioterrorist event.

It has been said that CDC did not advise the postal service early enough about the dangers ofprocessing contaminated mail. Since this was the first known actual use of the mail to distribute B.anthracis, who would have thought that the environment in post offices could become contaminatedfrom processing these letters. Also, CDC was not in charge of culturing the environments of the postoffice and of the government buildings so they did not immediately have all the necessary data uponwhich recommendations should be made. Some of the results reported by other agencies were ofculture results from unproven field kits, whose sensitivity and specificity had not been determined.The current bioterroristic event has clearly pointed out the significant need CDC has for additionalresources. It has been reported that some new monies have been made available to CDC so that itwill now be possible for the Epidemic Intelligence Service to be expanded in order that there may beEIS officers located in every state health department and in some of the larger municipal healthdepartments. EIS officers represent the first line of involvement in investigating bioterroristic events.

It is important that the support staff for the EIS officers also be expanded and given permanent status.The fabric of CDC needs to be strengthened and expanded. The original buildings are old and needrefurbishing. They have been forced to rent additional facilities throughout northeast Atlanta and thisleads to inefficiency in operation as a team. CDC has developed plans to upgrade their currentfacilities and to build additional offices and laboratories on their current two primary sites, but thisoverdue development should be expedited so that it can be completed within five and not ten orfifteen years. The current facilities are an embarrassment and inhibiting especially when CDC is beinggiven important new bioterrorism prevention responsibilities. If the government is serious aboutstrengthening our ability to adequately respond to such events, there needs to be better support forthe prevention activities and this should be given immediate and primary attention.

Education and training are an important aspect of bioterrorism preparedness and to this end CDC hasdeveloped plans for constructing a cutting edge training center on their primary campus in Atlanta.This facility should be given the highest possible priority so that training both within the facility aswell as for developing and implementing a full range of distant learning activities can provide as soonas possible.

Once the physical facilities and program strengthening actions have been taken, it will be apparentthat the practice of prevention in general will be strengthened. Not only will we improve our abilityto handle a bioterroristic event but many public health prevention programs will also be strengthened.It is also necessary that CDC have the necessary authority and financial support to conduct researchappropriate to their mission, which is control and prevention of disease whether it is related tobioterrorism or natural phenomenon. This includes operational research, which is exceedinglyimportant for the vitality of their activities.

It is unfortunate that it takes this type of an event to empha the additional needs of support forCDC but let us not dwell upon the traumatic nature of the bioterroristic event but on the opportunityto have learned what deficiencies there are in the system so that corrections can be made prior to thenext bioterroristic event. No matter what we as a country or what specific agencies do, we cannotprevent bioterroristic events but we can certainly reduce the quantitation of that event by beingprepared to respond. This is the responsibility of CDC and I do hope that the resources will be madeavailable to them so that they can operate in the manner in which they are well suited to function inthese critically important emergency situations as well as during normal times.

I hope you find these comments useful.

Sincerely,

Philip S. Brachman, M.D.
Professor, Emory University
PSB/mjc

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