BW-ch03.pdf

Epidemiology of Biowarfare and Bioterrorism

Chapter 3

EPIDEMIOLOGY OF BIOWARFARE AND

BIOTERRORISM

ZYGMUNT F. DEMBEK, P h D, MS, MPH*; JULIE A. PAVLIN, MD, MPH † ; and MARK G. KORTEPETER, MD, MPH ‡

INTRODUCTION

THE EPIDEMIOLOGY OF EPIDEMICS

Definition

Recognition

Potential Epidemiological Clues to an Unnatural Event

Outbreak Investigation

EPIDEMIOLOGICAL CASE STUDIES

Bioterrorism Events

Accidental Release of Biological Agents

Studies of Natural Outbreaks for Potential Bioweapon Use

EPIDEMIOLOGICAL ASSESSMENT TOOL

IMPROVING RECOGNITION AND SURVEILLANCE OF BIOTERRORISM

SUMMARY

* Lieutenant Colonel, Medical Service Corps, US Army Reserve; Chief, Biodefense Epidemiology and Education and Training Programs, Operational

Medicine Department, Division of Medicine, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Maryland

21702

† Lieutenant Colonel, Medical Corps, US Army; Graduate Student, Uniformed Services University of the Health Sciences, Department of Microbiology

and Immunology, 4301 Jones Bridge Road, Room B4109, Bethesda, Maryland 20814; formerly, Chief, Department of Field Studies, Division of Preven-

tive Medicine, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland

‡ Colonel, Medical Corps, US Army; Fellow, Department of Infectious Diseases, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Wash-

ington, DC 20307; formerly, Chief, Division of Medicine, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick,

Maryland

A portion of this chapter has been published as: Dembek ZF, Kortepeter MG, Pavlin JA. Discernment between deliberate and natural infec-

tious disease outbreaks. Epidemiol Infect . 2007;135:353-371.

Medical Aspects of Biological Warfare

INTRODUCTION

Preparing for and responding to biowarfare (BW)

or bioterrorism (BT) falls squarely in the realm of

public health and in the purview of public health

professionals. Basic epidemiology is needed for

management before, during, and after an event

to identify populations at risk, target preventive

measures such as vaccinations, recognize an out-

break, track and limit disease spread, and provide

postexposure treatment or prophylaxis. Many dis-

ease-specific management needs such as vaccination

and prophylaxis are discussed elsewhere and are

not considered here. Also, agricultural terrorism is

discussed in chapter 2. This chapter will focus on

detection and epidemiological investigation includ-

ing distinguishing between natural and intentional

events. Brief case studies will be presented to dem-

onstrate important indicators and lessons learned

from historical outbreaks. Finally, traditional meth-

ods of surveillance and ways to improve surveillance

for BW/BT will be discussed.

THE EPIDEMIOLOGY OF EPIDEMICS

Definition

herd immunity. However, if the environment is modi-

fied, spread may be limited; for example, cleaning up

garbage around a home limits rat food and harborage,

and thus reduces the likelihood of bringing fleas closer

to potential human hosts, limiting a potential bubonic

plague outbreak. 3

The word epidemic comes from the Greek “epi” and

“demos,” meaning “upon a mass of people assembled

in a public place.” 1 An epidemic is defined as the occur-

rence in a community or region of an unusually large or

unexpected number of disease cases for the given place

and time. 2 Therefore, baseline rates of disease are needed

to determine whether an epidemic occurs. This infor-

mation is obtained at the hospital or community level,

or at the state, national, or global level. As an example,

thousands of influenza cases in January in the United

States may not be unusual; however, thousands of cases

in mid-July may be cause for concern. Also, even a single

case of a rare disease can be considered an epidemic.

With the absence of woolen mill industry in the United

States, any inhalational anthrax case should be highly

suspect. Many of the diseases considered as classic BW

agents, such as smallpox, viral hemorrhagic fevers, and

plague (especially pneumonic), are rare, and a single

case should be investigated. Determining whether an

outbreak occurs depends, therefore, on the disease, the

at-risk population, the location, and the time of year.

For an outbreak to occur, three points of the classic

epidemiological triangle must be present (Figure 3-1).

There must be a pathogen or agent, typically a virus,

bacterium, rickettsia, fungus, or toxin, and a host (in

this case, a human) who is susceptible to that patho-

gen or agent. The two need to be brought together in

the right environment to allow infection of the host

directly, by a vector, or through another vehicle, such

as food, water, or contact with fomites (inanimate

objects). The environment must also permit potential

transmission to other susceptible hosts. Disruption of

any of these three points of the triangle can limit or

disrupt the outbreak; therefore, it is important to know

the characteristics of the three to control an epidemic.

In one scenario, if potential hosts are vaccinated, dis-

ease spread would be significantly limited because of

Recognition

Immediate effects are evident when an explosion

occurs or a chemical weapon is released. However,

casualties produced after a BW/BT release may be

dispersed in time and space to primary care clinics and

hospital emergency departments because of the inher-

ent incubation periods of the pathogens. Therefore, the

success in managing a biological event hinges directly

on whether and when the event is recognized.

An example of the ramifications of delayed disease

outbreak recognition occurred in 1972 in the former

Yugoslavia. A single unidentified smallpox case led to

11 secondary cases, also unrecognized. Within a few

weeks there was an outbreak of 175 smallpox cases and

Host

Agent

Environment

Fig. 3-1. The epidemiological triangle

Epidemiology of Biowarfare and Bioterrorism

35 deaths that led to a massive vaccination effort and

border closure. 4 Early disease recognition may have

significantly modified the outcome. One modeling

study of a BT-caused smallpox outbreak showed that

the more rapidly a postrelease intervention occurred,

including quarantine and vaccination, the greater the

chances that intervention would halt the spread of dis-

ease. 5 When medical professionals identify a new case, it

is unlikely that a BW/BT event would be the first cause

suspected, especially if the disease presents similar to

other diseases that might occur simultaneously, such as

influenza. Physicians are frequently taught to consider

common illnesses first and might instead consider the

source to be an endemic disease, a new or emerging

disease, or a laboratory accident before considering

BW/BT. 6 Therefore, care providers should be familiar

with the diseases of BW/BT and a maintain a healthy

“index of suspicion” to recognize an event early enough

to significantly modify the outcome. 7

Astute clinicians, hospital infection control person-

nel, school or healthcare facility nursing staff, laboratory

personnel, and other public health workers notify public

health authorities about disease outbreaks. State and lo-

cal public health officials regularly examine and review

disease surveillance information to detect outbreaks in a

timely manner and provide information to policymakers

on disease prevention programs. Time constraints are

inherent in obtaining case report information because of

the elapsed time from patient presentation, lab specimen

collection and submission, and laboratory testing time,

to final disease or organism identification reporting.

Furthermore, the initial BW/BT disease recognition

may not come from a traditional reporting partner or

surveillance method. Instead, pharmacists and clinical

laboratory staff who receive requests or samples from

numerous healthcare providers, may be the first to

note an increase in purchases or prescriptions of certain

medications (eg, doxycycline or ciprofloxacin) or orders

for certain laboratory tests (sputum or stool cultures),

respectively. Also, because many of the category A

high-threat diseases are zoonoses (primarily infecting

animals), with humans serving as accidental hosts, vet-

erinarians may be the first to recognize the disease in

animals prior to the ensuing human disease. Media and

law enforcement personnel and other nontraditional

reporters of outbreaks may also provide information

on a BT event or potential cases.

how a biological agent may be dispersed, whether

through the air, in contaminated food or water, or by

direct inoculation. In a biological attack, the number of

casualties may be small and therefore unrecognized as

intentionally infected, especially if the agent is a com-

mon cause of disease in the community. In addition,

given the agent’s incubation period, individuals may

seek care from different care providers or travel to dif-

ferent parts of the country before they become ill and

seek medical care. Despite the potential for these situ-

ations to occur, it is useful for healthcare providers to

be aware of potential clues that may be tip-offs or “red

flags” of something unusual. Although these clues may

occur with natural outbreaks and do not necessarily

signal a BW/BT attack, they should at least heighten

suspicion that an unnatural event has occurred. The

following compilation is an illustrative list; however,

additional clues may be found elsewhere. 8,9

Clue 1: A highly unusual event with large num-

bers of casualties. Although the mention of BW or BT

may elicit images of massive casualties, this may not

actually occur with a real BW/BT event. Numerous

examples of naturally spread illness have caused mas-

sive casualties. Nevertheless, the type of large outbreak

that should receive particular attention is one in which

no plausible natural explanation for the cause of the

infection exists.

Clue 2: Higher morbidity or mortality than is

expected. If clinicians are seeing illnesses that are

causing a higher morbidity or mortality than what is

typically seen or reported for a specific disease, this

may indicate an unusual event. A perpetrator may

have modified an agent to make it more virulent. If

the illness is normally sensitive to certain antibiotics

but displays resistance, then resistance may have been

purposefully engineered. Individuals could also be ex-

posed to a higher inoculum than they would normally

receive with natural spread of the agent, thus causing

higher morbidity or mortality.

Clue 3: Uncommon disease. Many infectious dis-

eases have predictable population and infectivity distri-

butions based on environment, host, and vector factors;

yet unnatural spread may occur if a disease outbreak

is uncommon for a certain geographical area. Concern

should be heightened if the naturally occurring disease

requires a vector for spread and the competent vector is

missing. If a case of a disease such as yellow fever, which

is endemic to parts of South and Central America and

sub-Saharan Africa, occurred in the United States with-

out any known travel, it would be a concern. Natural

outbreaks have occurred in new geographical locations

including the West Nile virus (WNV) in New York City

in 1999. 10 It is important to consider whether the occur-

rence of these uncommon diseases is natural.

Potential Epidemiological Clues to an Unnatural

Event

It is not possible to determine the objectives of a

bioterrorism perpetrator in advance, whether the

intent is to kill, incapacitate, or obtain visibility; or

Medical Aspects of Biological Warfare

Clue 4: Point source outbreak. For any outbreak,

it is useful to develop an outbreak curve demonstrat-

ing the timeline of dates when patients developed

illness. These timelines can have different morpholo-

gies depending on whether individuals are exposed

at the same time from a single source or over time,

and whether the illness propagates by person-to-per-

son spread. It is thought that with an intentional BT

event, a point source outbreak curve would be seen 11

in which individuals would be exposed at a similar

point in time. The typical point source outbreak curve

has a relatively quick rise in cases, a brief plateau, and

then an acute drop, as seen in Figure 3-2. The epidemic

curve might be slightly compressed because infected

individuals were exposed more closely in time (ie,

within seconds to minutes of each other) from an

aerosol release, compared with individuals becoming

ill after eating a common food over a period of minutes

to hours. The inoculum may also be greater than what

is typically seen with natural spread, thus yielding a

shorter incubation than expected.

Clue 5: Multiple epidemics. If a perpetrator can

obtain and release a single agent, why could multiple

perpetrators not do so with a single agent at different

locations? If simultaneous epidemics occur at the same

or different locations with the same or multiple organ-

isms, an unnatural source must be considered. It must

also be considered that a mixture of biological organ-

isms with different disease incubation periods could

be combined, and would thus cause serial outbreaks

of different diseases in the same population.

Clue 6: Lower attack rates in protected individuals.

This clue is especially important to military personnel.

If certain military units wore military-oriented protec-

tive posture (MOPP) gear or respiratory protection

(such as high-efficiency particulate air [HEPA]-filtered

masks), or stayed in a HEPA-filtered tent, and had

lower rates of illness than nearby groups that were

unprotected, this may indicate that a biological agent

has been released via aerosol.

Clue 7: Dead animals. Historically, animals have

been used as sentinels of human disease. The storied

use of canaries in coal mines to detect the presence of

noxious gases is one example. Because many biological

agents that could be used for BW/BT are zoonoses, a

local animal die-off may indicate a biological agent

release that might also infect humans. This phenom-

enon was observed during the WNV outbreak in New

York City in 1999, when many of the local crows, along

with the exotic birds at the Bronx Zoo, developed fatal

disease. 12,13

Clue 8: Reverse or simultaneous spread. Zoonotic

illnesses exhibit a typical pattern: an epizootic first oc-

curs among a susceptible animal population, followed

by cases of human illness. When Sin Nombre virus

initially appeared in the desert southwest of the United

States, 14 environmental factors increased food sources

and caused the field mouse ( Peromyscus maniculatus )

population to surge. The proliferating field mice en-

croached upon human habitats. The virus spread among

the mice, causing a persistent infection and subsequent

excretion in their urine. 15 Humans close to the mice

became infected. If human disease precedes animal

disease or human and animal disease is simultaneous,

then unnatural spread should be considered.

Clue 9: Unusual disease manifestation. Over

95% of worldwide anthrax cases are cutaneous ill-

ness. Therefore, a single case of inhalational anthrax

may likely be an unnatural event. This logic may be

applied to case reports of a disease such as plague,

where the majority of naturally occurring cases are

the bubonic, and not the pneumonic form. Any in-

halational anthrax case may be caused by BW/BT

unless proven otherwise. Perhaps the only exception

would be an inhalational anthrax case in a woolen

mill worker.

Clue 10: Downwind plume pattern. The geographic

locations where cases occur can be charted on a geo-

graphic grid or map. If the reported cases are found to

be clustered in a downwind pattern, an aerosol release

may have occurred. During the investigation into the

anthrax outbreak in Sverdlovsk in 1979, as examined

later in this chapter, mapping out case locations helped

to determine that the anthrax cases were caused by

an aerosol release rather than by a contaminated food

source. 16

Clue 11: Direct evidence. The final clue may be the

most obvious and the most useful. Determining the

intentional cause of illnesses is easier if a perpetrator

1 2 3 4 5 6 7 8 9

Onset by Day of Month

Fig. 3-2. Typical point source outbreak epidemic curve

Epidemiology of Biowarfare and Bioterrorism

leaves a signature. The signature could be a letter

filled with anthrax spores, 17 a spray device, or another

vehicle for agent spread. It would then be useful to

compare samples from such a device with the clinical

samples obtained from victims to verify that they are

the same organism.

EXHIBIT 3-2

TEN STEPS IN AN OUTBREAK

INVESTIGATION

Outbreak Investigation

1. Prepare for fieldwork.

2. Verify the diagnosis. Determine an outbreak

exists.

3. Define the outbreak and seek a diagnosis.

4. Develop a case definition and identify and

count cases.

5. Develop exposure data with respect of per-

son, place, and time.

6. Implement control measures and continually

evaluate them.

7. Develop the hypothesis.

8. Test and evaluate the hypothesis with ana-

lytical studies and refine the hypothesis.

9. Formulate conclusions.

10. Communicate findings.

It is important to understand the basic goals of

an outbreak investigation, as seen in Exhibit 3-1.

Any outbreak should be investigated quickly to find

the source of the disease. If an outbreak is ongoing,

the source of infection needs to be identified and

eliminated quickly. Even if the exposure source has

dissipated, all cases should be identified quickly,

so that ameliorative care can be offered and case

interviews can be conducted. Case identification can

assist in preventing additional cases, especially with

a transmissible infectious disease.

With notification of any outbreak, whether natural

or human-caused, there are standard steps to follow in

an outbreak investigation (Exhibit 3-2), although these

steps may not always occur in order. 18 The first step

is preparation, which involves having the necessary

response elements (personnel, equipment, laboratory

capabilities) ready, and establishing communications

in advance with partners in the investigation. Once

an event is ongoing, the second step is to investigate,

verify the diagnosis, and decide whether an outbreak

exists. Early in an outbreak, its significance and scope

are often not known. Therefore, existing surveillance

information and heightened targeted surveillance ef-

forts are used to determine whether reported items are

cause for concern.

The third step is to define the outbreak and seek a

definitive diagnosis based on historical, clinical, epide-

miological, and laboratory information. A differential

diagnosis can then be established.

The fourth step is to establish a case definition that

includes the clinical and laboratory features that the ill

individuals have in common. It is preferable to use a

broad case definition at first and avoid excluding any

potential cases too early. However, a definition should

use clinical features that are objectively measured

whenever possible, such as temperature exceeding

101.5ºF, rash, bloody vomitus, or diarrhea. The case

definition enables the investigator to count cases and

compare exposures between cases and noncases. To

obtain symptom information, it may not be sufficient

to look at healthcare facilities only, but it will likely

also be necessary to interview the ill persons and their

family members, as well as coworkers, classmates,

or others with whom they have social contact. It

is important to maintain a roster of potential cases

while obtaining this information. Commonly dur-

ing an investigation, there is a risk of double or even

triple-counting cases because they may be reported

more than once through different means. Key infor-

mation needed from each ill person includes date of

illness onset; signs and symptoms; recent travel; ill

contacts at work, home, or school; animal exposures;

and treatments received. With this information, an

epidemic curve can be constructed (see Figure 3-2)

that may provide information as to when a release

may have occurred, especially if the disease is known,

and an expected exposure date based on the typical

incubation period, known ill contacts, or geographic

risk factors.

Different modes of disease spread may have typical

features that comprise an epidemic curve. If the agent

is spread person-to-person, successive waves of illness

may be seen as one group of individuals infects a fol-

low-on group, which in turn infects another, and so on

EXHIBIT 3-1

GOALS OF AN OUTBREAK INVESTIGATION

• Find the source of disease

• Rapidly identify cases

• Prevent additional cases

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