BW-ch25.pdf

Emerging Infectious Diseases and Future Threats

Chapter 25

EmErging infECtious DisEasEs

anD futurE thrEats

CHRIS A. WHITEHOUSE, P h D * ; ALAN L. SCHMALJOHN, P h D † ; and ZYGMUNT F. DEMBEK, P h D, MS, MPH ‡

introDuCtion

EmErging BaCtEriaL DisEasEs

Waterborne Diseases

foodborne Diseases

tick-borne Diseases

Emerging antibiotic resistance

EmErging ViraL DisEasEs

avian influenza and the threat of Pandemic influenza

severe acute respiratory syndrome

Emerging Paramyxoviruses

Emerging arthropod-borne Viruses: Dengue and West nile Viruses

gEnEtiCaLLY EnginEErED thrEats

summarY

* Microbiologist, Diagnostic Systems Division, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Maryland

21702; formerly, Microbiologist, US Army Dugway Proving Ground, Dugway, Utah

† Branch Chief, Department of Viral Pathogenesis and Immunology, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort

Detrick, Maryland 21702

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

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

21702

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Medical Aspects of Biological Warfare

introDuCtion

Emerging infectious diseases, as defined in the

landmark 1992 report by the Institute of Medicine,

are diseases whose incidence has increased within the

past 20 years or whose incidence threatens to increase

in the near future. 1 Even though some “emerging”

diseases have now been recognized for over 20 years

(eg, acquired immunodeficiency syndrome [AIDS],

Lyme disease, Legionnaire’s disease), their impor-

tance has not diminished, and the factors associated

with their emergence are still relevant. Emerging

infections include diseases caused by new agents (or

newly described agents) and reemerging pathogens

(those whose incidence had previously declined but

now is increasing). This definition also includes or-

ganisms that are developing antimicrobial resistance

and established diseases with a recently discovered

infectious origin.

Many factors contribute to the emergence of new

diseases. In the United States, in particular, these

factors include increasing population density and

urbanization; immunosuppression (resulting from ag-

ing, malnutrition, cancer, or infections such as AIDS);

changes in land use (eg, deforestation and reforesta-

tion), climate, and weather; international travel and

commerce; and microbial or vector adaptation and

change (mutations which result in drug or pesticide

resistance). 1 Internationally, many of these factors also

hold true; however, many developing countries also

have to deal with war, political instability, inadequate

healthcare, and basic sanitation issues.

The numerous examples of “new” infections origi-

nating from animal species (ie, zoonoses) suggest that

the zoonotic pool is an important and potentially

rich source of emerging diseases. 2 Although classify-

ing AIDS as a zoonotic disease is controversial, 3 it is

now clear that both human immunodeficiency virus

[HIV]-1 and HIV-2 had zoonotic origins. 4-6 In addition,

as shown by the 2003 outbreak of monkeypox in the

United States, increasing trade in exotic animals for

pets has led to increased opportunities for pathogens

to “jump” from animal reservoirs to humans. The

use of exotic animals (eg, Himalayan palm civets) for

food in China and the close aggregation of numerous

animal species in public markets may have led to the

emergence of the severe acute respiratory syndrome

(SARS) coronavirus. 7

Many of the viruses or bacteria that may be poten-

tial bioweapons are considered emerging pathogens.

In particular, some of these agents have appeared in

new geographical locations where they have not previ-

ously been seen; for example, monkeypox suddenly

occurred in the US Midwest in 2003, and the largest

recorded outbreak of Marburg hemorrhagic fever oc-

curred in Angola in 2005. Sometimes the specific use

of a pathogen in an act of bioterrorism can cause the

pathogen to be classified as an emerging or reemerg-

ing disease agent, as what happened with Bacillus

anthracis during the 2001 anthrax attacks in the United

States. Through increasingly easy molecular biology

techniques, completely new organisms (or significantly

modified existing organisms) can now be made in the

laboratory. The use of these methods is mostly benefi-

cial and necessary for modern biomedical research to

proceed. However, the same methods and techniques

can be used for destructive purposes and, along with

naturally occurring emerging infections, represent

significant future threats to both military and civilian

populations.

EmErging BaCtEriaL DisEasEs

Waterborne Diseases

pathogens responsible for gastroenteritis outbreaks

associated with recreational water exposure included

E coli O157:H7 (four outbreaks) and Shigella sonnei (two

outbreaks). Twenty dermatitis outbreaks associated

with spa or pool use were attributed to Pseudomonas ,

primarily P aeruginosa . 9

Emerging waterborne diseases constitute a major

health hazard in both developing and developed coun-

tries. In 2001 and 2002, 31 disease outbreaks associated

with contaminated drinking water were reported in

the United States, resulting in 1,020 ill people and 7

deaths. 8 During this same time, over 2,500 cases of

illness and 8 deaths nationally were associated with

recreational waterborne diseases. 9 Bacterial pathogens

associated with drinking water disease outbreaks

included Legionella species, Escherichia coli O157:H7,

and Campylobacter jejuni (one outbreak each), and

one outbreak involving infection with two different

bacteria: C jejuni and Yersinia enterolitica . 8 Bacterial

Vibrio cholerae and Cholera

Accounts of cholera date to Hippocrates. 10 Seven

worldwide cholera pandemics have occurred. An 1892

cholera outbreak in Hamburg, Germany, affecting

17,000 people and causing 8,605 deaths was attributed

to the inadvertent contamination of the city’s water

supply by bacteriologists studying the pathogen. 11 This

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Emerging Infectious Diseases and Future Threats

event underscores the potential for cholera to cause

widespread illness where water is not disinfected with

a modern bacteriocide such as chlorine. 11

In 1991, after almost a century without cholera, out-

breaks in Latin America resulted in about 400,000 cases

of cholera and over 4,000 deaths. 12 Off the Peruvian

coast, a significant correlation between cholera inci-

dence and elevated sea surface temperature occurred

between 1997 and 2000, which included the 1997–1998

El Niño event. 13 Some people believe that the eighth

worldwide pandemic began in 1992 with the emer-

gence and spread of a new epidemic-causing strain (see

below). 14 During 2003, 45 countries reported a total of

about 112,000 cases and almost 1,900 deaths from chol-

era. 15 Paradoxically, cholera cases in the United States

have decreased to about 10 cases per year during 1995

through 2000. Most of these cases were associated with

either travel or consumption of undercooked seafood

harvested along the Gulf coast.

Cholera occurs through fecal-oral transmission

brought about by deterioration of sanitary conditions.

Epidemics are strongly linked to the consumption

of unsafe water, poor hygiene, poor sanitation, and

crowded living conditions (Figure 25-1). Water or food

contaminated by human waste is the major vehicle for

disease transmission. Cholera transmission is thought

to require 10 3 organisms to exert an effect in the gut,

with 10 11 organisms as the minimum infective dose

able to survive stomach acid. 16

Before 1992, all cholera pandemics were caused

by the V cholerae serogroup O1 (classical) or El Tor

biotypes. Large outbreaks in 1992 resulted from trans-

mission of a previously unknown serogroup, V cholerae

O139, which has since spread from India and Bangla-

desh to countries throughout Asia, including Pakistan,

Nepal, China, Thailand, Kazakhstan, Afghanistan, and

Malaysia. 17,18 Cholera vaccines have had mixed success.

Historically, live attenuated vaccines are more effective

than killed whole-cell vaccines. 19 No licensed cholera

vaccines are available in the United States.

Enterotoxin produced by V cholera O1 and O139 can

cause severe fluid loss from the gut. In severe cases,

profuse watery diarrhea, nausea, and vomiting can

lead to rapid dehydration, acidosis, circulatory col-

lapse, and renal failure. Successful treatment of cholera

patients depends on rapid fluid and electrolyte replace-

ment; antimicrobial therapy can also be useful.

from human clinical specimens and apparently are

pathogenic for humans. 20 Vibrio species are primarily

aquatic and are very common in marine and estuarine

environments and on the surface and in the intestinal

tracts of marine animals. V parahaemolyticus and V

vulnificus are halophilic vibrios commonly associated

with consumption of undercooked seafood. Diarrhea,

cramping, nausea, vomiting, fever, and headache are

commonly associated with V parahaemolyticus infec-

tions. V vulnificus , the most common source of vibrio

infections in the United States, results in gastrointes-

tinal symptoms similar to those of V parahaemolyticus

and may also lead to ulcerative skin infections if

open wounds are exposed to contaminated water.

Septicemia can also occur in infected persons who are

immunosuppressed or have liver disease or chronic

alcoholism, and septicemic patients can have a mortal-

ity rate of up to 50%. In most cases the disease begins

several days after the patient has eaten raw oysters.

Other human pathogenic species include V mimicus , V

Other Vibrios

fig. 25-1. Typical conditions that can lead to a cholera

epidemic. This photograph was taken in 1974 during a

cholera research and nutrition survey amidst floodwaters

in Bangladesh.

Photograph: Courtesy of Dr Jack Weissman, Centers for Dis-

ease Control and Prevention Public Health Image Library.

In recent years, some noncholera vibrios have

acquired increasing importance because of their asso-

ciation with human disease. Over 70 members are in

the family Vibrionaceae , 12 of which have been isolated

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Medical Aspects of Biological Warfare

metschnikovii , V cincinnatiensis , V hollisae , V damsela , V

fluvialis , V furnissii , V alginolyticus , and V harveyi; most

of these have been associated with sporadic diarrhea,

septicemia, and wound infections. 20

associated with nonproductive cough, abdominal pain,

and diarrhea. The disease may eventually progress to

respiratory failure and has a case-fatality rate as high

as 39% in hospitalized cases. Nonpneumonic legionel-

losis, or Pontiac fever, occurs after exposure to aerosols

of water colonized with Legionella species. 35-37 Attack

rates after exposure to an aerosol-generating source are

exceptionally high, often in the range of 50% to 80%.

After a typical asymptomatic interval of 12 to 48 hours

after exposure, patients note the abrupt onset of fever,

chills, headache, malaise, and myalgias. Pneumonia

is absent, and those who are affected recover in 2 to 7

days without receiving specific treatment. 38

Legionella is now recognized around the world as an

important cause of community-acquired and hospital-

acquired pneumonia, occurring both sporadically and

in outbreaks. Although 90% of Legionella infections

in humans are caused by L pneumophila , there are 48

named species of Legionella , with at least 20 known

to cause human infections. 39 Some unusual strains of

bacteria, which infect amoebae and have been termed

Legionella -like amoebal pathogens (LLAPs), appear to

be closely related to Legionella species on the basis of

16S ribosomal RNA gene sequencing. 40,41 Three LLAP

strains are now named Legionella species, 42 and one of

them, LLAP-3, was first isolated from the sputum of

a patient with pneumonia by coculture with amoebae

and is considered a human pathogen. 43

Legionella Species

Legionnaire’s disease was first recognized in 1976

after a large outbreak of severe pneumonia occurred

among attendees at a convention of war veterans in

Philadelphia. A total of 182 people, all members of

the Pennsylvania American Legion, developed an

acute respiratory illness, and 29 individuals died from

the disease. 21 The cause of the outbreak remained a

mystery for 6 months until the discovery by Joseph

McDade, a Centers for Disease Control and Prevention

microbiologist, of a few gram-negative bacilli, subse-

quently named Legionella pneumophila , 22 in a gram stain

of tissue from a guinea pig inoculated with lung tissue

of a patient who died from the disease. 23 Using the

indirect immunofluorescence assay, McDade showed

that the sera of patients from the convention mounted

an antibody response against the newly isolated bacte-

rium, 24 marking the discovery of a whole new family of

pathogenic bacteria. Retrospective analysis, however,

has shown that outbreaks of acute respiratory disease

from as far back as 1957 can be attributed to L pneu-

mophila . 24,25 The earliest recorded isolate of a Legionella

species was recovered by Hugh Tatlock in 1943 during

an outbreak of Fort Bragg fever. 26,27

Legionnaire’s disease is normally acquired by inha-

lation or aspiration of L pneumophila or other closely

related Legionella species. Water is the major reservoir

for legionellae, and the bacteria are found in freshwater

environments worldwide. Legionnaire’s disease has

been associated with various water sources where bac-

terial growth is permitted, including cooling towers, 28

whirlpool spas, 29 and grocery store mist machines. 29

The association between a potable shower and noso-

comial legionellosis was demonstrated 25 years ago. 30

The most common source of legionellosis in hospitals

is from the hot water system, 31 and sustained transmis-

sion of Legionnaire’s disease in the hospital can be dif-

ficult to control. 32 Community-acquired legionellosis

is thought to account for most infections. 33 A recent

Italian survey of household hot water systems found

bacterial contamination with Legionella species in 23%

of the homes and Pseudomonas species in 38%. One

Legionella species, L longbeachae , has been associated

with disease transmission from potting soil. 34

Legionnaire’s disease is an acute bacterial illness. Pa-

tients initially present with anorexia, malaise, myalgia,

and headache, with a rapidly rising fever and chills.

Temperatures commonly reach 102°F to 105°F and are

foodborne Diseases

More than 200 diseases are transmitted through

food, including illnesses resulting from viruses,

bacteria, parasites, toxins, metals, and prions. In the

United States the burden of foodborne illness is esti-

mated at approximately 76 million illnesses, 325,000

hospitalizations, and 5,000 deaths each year. 44 Among

the bacterial pathogens estimated to cause the greatest

number of US foodborne illnesses are Campylobacter ,

Salmonella , Shigella , Clostridium , and Staphylococcus spe-

cies. 44 Emerging bacterial illnesses include E coli O157:

H7 and other enterohemorrhagic and enterotoxigenic

E coli , as well as antibiotic-resistant bacteria. Many of

the pathogens of greatest concern today (eg, C jejuni ,

E coli O157:H7, Listeria monocytogenes , Cyclospora cay-

etanensis ) were not recognized as causes of foodborne

illness just 20 years ago, and some proportion of

gastrointestinal illness is caused by foodborne agents

that have not yet been identified. It is estimated that

62 million foodborne-related illnesses and 3,200 deaths

occur in the United States each year from unknown

pathogens. 44 Bacillus anthracis , although rarely seen

as a gastrointestinal illness in the United States, has

become a concern since cases occurred in 2000 (see

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Emerging Infectious Diseases and Future Threats

below). Even in areas of the world where gastrointes-

tinal anthrax is more common, the oropharyngeal form

is underreported because physicians are unfamiliar

with it. 45 Unreported foodborne disease, deaths from

unknown food agents, 46 and chronic sequelae 47 may be

a huge unrecognized burden of illness.

asymptomatic, infection with this pathogen has been

associated with development of Guillain-Barré syn-

drome and arthritis. 52,53 Infants are more susceptible

to C jejuni infections upon first exposure. 54 Persons

who recover from C jejuni infection develop immunity.

Poultry colonized with Campylobacter species is a ma-

jor source of infections for humans. 55-58 The reported

incidence of Campylobacter species on poultry carcasses

has varied but has been as high as 100%. 57

Several virulence properties, including motility,

adherence, invasion, and toxin production, have been

recognized in C jejuni . 59 Along with several other en-

teric bacteria, C jejuni produces a toxin called cytolethal

distending toxin that works by a completely novel

mechanism: mammalian cells exposed to the toxin

distend to almost 10 times their normal size from

a molecular blockage in their cell cycle. 60 Although

cytolethal distending toxin is the best-characterized

Campylobacter toxin, its role in the pathogenesis of

human campylobacteriosis is unclear. 61

Because illness from Campylobacter infection is gen-

erally self limited, no treatment other than rehydration

and electrolyte replacement is generally recommend-

ed. However, in more severe cases (ie, with high fever,

bloody diarrhea, or septicemia), antibiotic therapy

can be used to shorten the duration of symptoms if it

is given early in the illness. Because infection with C

jejuni in pregnant women may have deleterious effects

on the fetus, infected pregnant women should receive

antimicrobial treatment. Erythromycin, because it is

safe, lacks serious toxicity, and is easy to administer,

is the drug of choice for C jejuni infections. However,

most clinical trials performed in adults or children

Bacillus anthracis

B anthracis is the causative agent of anthrax, a

naturally occurring zoonotic disease. The greatest

bioweapon threat from anthrax is through aerosol

dispersion and subsequent inhalation of concentrated

spores (for more details see Chapter 4, Anthrax). Gas-

trointestinal anthrax, however, is contracted through

the ingestion of B anthracis spores in contaminated

food or water. This form of the disease occurs more

commonly than inhalational anthrax in the developing

world, but is rare in the United States and other de-

veloped nations. 45,48 In one large outbreak in Uganda,

155 villagers ate the meat of a zebu (bovine) that had

died of an unknown disease. Within 15 to 72 hours,

143 persons (92%) developed presumed anthrax. Of

these, 91% had gastrointestinal complaints and 9% had

oropharyngeal edema; 9 of the victims, all children,

died within 48 hours of illness onset. 48 Gastrointestinal

anthrax can occur naturally in the United States, and

anthrax-contaminated meat has been found to be as-

sociated with gastrointestinal illness in Minnesota as

recently as 2000. 49 Purposeful contamination of food

or water is possible but would require a high infective

dose. Misdiagnosis may lead to a higher mortality in

gastrointestinal anthrax than in other forms of the dis-

ease; thus, awareness of this disease remains important

in anthrax-endemic areas and in the setting of possible

bioterrorism.

Campylobacter jejuni

Campylobacter was first identified in 1909 (then

called Vibrio fetus ) from the placentas and aborted

fetuses of cattle. The organism was not isolated from

humans until nearly 40 years later, when it was found

in the blood of a pregnant woman who had an infec-

tious abortion in 1947. 50 Campylobacter jejuni (Figure

25-2), along with C coli , have been recognized as agents

of gastrointestinal infection since the late 1970s. C jejuni

is considered the most commonly reported foodborne

bacterial pathogen in the United States, affecting 2.4

million persons annually. 51 Campylobacteriosis is an

enteric illness of variable severity, including symptoms

of diarrhea (which may be bloody), abdominal pain,

malaise, fever, nausea, and vomiting, occurring 2 to

5 days after exposure. Although many infections are

fig. 25-2. Scanning electron microscope image of Campylo-

bacter jejuni illustrating its corkscrew appearance.

Photograph: Courtesy of Janice Carr, Centers for Disease

Control and Prevention Public Health Image Library.

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