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Glanders

Chapter 6

GLANDERS

BRIDGET CARR GREGORY, DVM, MPH * ; and DAVID M. WAAG, P h D †

INTRODUCTION

MILITARY RELEVANCE

HISTORY

INFECTIOUS AGENT

DISEASE

Epidemiology

Transmission

Pathogenesis

Clinical Disease in Animals

Clinical Disease in Humans

Diagnosis

Treatment

Prophylaxis

SUMMARY

* Lieutenant Colonel, US Air Force, Biomedical Sciences Corps; Public Health Flight Commander, 435 MDG/SGPM, Unit 3215, APO AE 09094;

formerly,Chief,EducationandTraining,DivisionofMedicine,USArmyMedicalResearchInstituteofInfectiousDiseases,1425PorterStreet,Fort

Detrick,Maryland21702

† Microbiologist,DivisionofBacteriology,USArmyMedicalResearchInstituteofInfectiousDiseases,1425PorterStreet,FortDetrick,Maryland21702

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MedicalAspectsofBiologicalWarfare

INTRODUCTION

Glanders, a highly contagious and often fatal zoo-

notic disease of solipeds, including horses, mules,

and donkeys, is caused by infection with the bacte-

rium Burkholderia mallei . Glanders is characterized

by ulcerating granulomatous lesions of the skin and

mucous membranes. Disease progression and pathol-

ogy in humans and horses are similar, although the

clinical presentation of any two cases in the same

species—even if related by direct transmission—may

vary significantly. 1-4 Generalized symptoms include

fever, myalgia, headache, fatigue, diarrhea, and weight

loss. After infection, the organism generally travels

through lymph channels, first to regional lymph nodes

often causing irritation (lymphangitis, lymphadeni-

tis) en route. Unchecked, organisms may enter the

bloodstream and travel throughout the body. Without

proper treatment, the disease course may range from

acute and rapidly fatal to slow and protracted with

alternating remissions and exacerbations.

Glanders, an old disease that was described toward

the beginning of recorded history, is less commonly

known by other names, including equinia, malleus,

droes, and farcy. Farcy is an ancient term for a par-

ticular cutaneous manifestation of glanders that before

1882 was believed to be a separate disease of horses.

With this cutaneous manifestation of glanders, nodular

abscesses (farcy buds) become ulcerated, and regional

cutaneous lymphatic pathways become thickened

and indurated (farcy pipes) and ooze a glanders-

typical yellow-green gelatinous pus (farcy oil). 5 Pure

farcy without ulceration of the mucous membranes

was rare—if not just a temporary stage of glanders

infection—as was vice versa. 3 Humans, goats, dogs,

cats, rabbits, and carnivorous predators living close

to infected equids or carcasses have been naturally

infected. 2,6 Camels have also been infected and are

associated with human disease. 6 Naturally occurring

glanders has been eradicated in most countries, but is

still found in parts of Africa, the Middle East, South

America, and Eastern Europe. B mallei has drawn

interest as a possible warfare agent in the biological

weapons programs of several countries.

MILITARY RELEVANCE

Bmallei was one of the first biological warfare agents

used in the 20th century. Germany launched an ambi-

tious biological sabotage campaign in several countries,

including the United States, Russia, Romania, France,

and Mesopotamia, on both the western and eastern

fronts during World War I. Additionally, cattle, horses,

mules, and other livestock shipped from the United

States to the Allies were inoculated with cultures of B

mallei . 7 In 1914 Anton Dilger, a member of the German

army and an American-educated surgeon, was sent

home to live with his parents in Virginia after a nervous

breakdown. He brought strains of anthrax and glanders

and, with his brother’s help, set up a laboratory to grow

the organisms in a private home in Chevy Chase, Mary-

land. Organisms were delivered to another contact from

Germany waiting in Baltimore, who then inoculated

horses awaiting shipment to the Allies in Europe.

Also, 4,500 mules in Mesopotamia were infected

with glanders by German agents; a German agent was

arrested in Russia with similar intentions in 1916; and

French cavalry horses were also targets for intentional

glanders infection. 8 Germany and its allies infected

many mules and horses on Russia’s eastern front, which

successfully impaired artillery movement and troop

and supply convoys. Concurrent with this increase in

animal cases during and after the war, human cases

increased in Russia. Attempts to contaminate animal

feeds in the United States were also made. A report by

the Monterey Institute of International Studies states

that between 1932 and 1945 Japan developed Bmallei

as a biowarfare agent, infecting horses, civilians, and

prisoners of war at the Ping Fan Institute, also known

as Unit 731, in occupied Manchuria. Two laboratory

workers accidentally exposed to Bmallei died at the

institute in 1937. 9 The former Soviet Union was alleged

to have used weaponized Bmallei against opposition

forces in Afghanistan between 1982 and 1984. 10

In response to perceived biological warfare threats

from Japan and Germany, the United States began

work on biological warfare agents at Camp Detrick,

Maryland (now Fort Detrick) in 1942. Glanders was

studied for potential use but was not weaponized.

Between November 1944 and September 1953, seven

laboratory-acquired human infections from Malleo-

mycesmallei (the taxonomic name of glanders at that

time) occurred in Camp Detrick employees. Howe and

Miller reported the first six of these infections in a case

series, which is the largest reported human case series

in US medical literature. 1 The seventh case has not

been previously published. All seven original case files

were thoroughly reviewed for this chapter. An eighth

laboratory-acquired infection occurred in March 2000

during US defensive research on Bmallei . 11

In 1972 the United States signed the Convention on

the Prohibition of the Development, Production and

Stockpiling of Bacteriological (Biological) and Toxin

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Glanders

Weapons and on Their Destruction, which banned de-

velopment, production, stockpiling, acquisition, and

retention of biological agents, toxins, and the weapons

to deliver them. 8 All offensive biological warfare work

at Fort Detrick had ceased by that time; any remaining

biological weapons were destroyed by 1973. Research

aimed at the biodefense of Bmallei warfare is currently

being conducted in the United States. There are no

known current attempts for acquisition and use by

terrorists. 12

Bmallei was considered a potential threat agent in

1947 because of its high infectivity, high degree of in-

capacitation among those infected, and agent availabil-

ity. 13 It poses a more significant threat if weaponized.

As exemplified by past clusters of laboratory-acquired

infections, Bmallei is infectious by the respiratory route,

but it is not contagious among humans. A determined

bioterrorist could likely gain access to the agent,

whether from an infected animal, laboratory culture,

or commercial culture. Because glanders is relatively

unknown in the West and its clinical symptoms are

protean and nonspecific, diagnosis and treatment

may be delayed postattack, even in regions with the

most advanced medical facilities. Delayed diagnosis

and treatment could lead to significant morbidity

and mortality. Treatment may be complicated by the

relative scarcity of knowledge and experience in

therapy. Because equids and some other animals are

susceptible, further spread from animals to humans

could occur long after an attack. Glanders is curable,

and postexposure prophylaxis may be an option after

an attack. As with other agents, genetic engineering

could produce unpredictable virulence and atypi-

cal antibiotic resistance. If glanders were cultivated,

concentrated, and delivered as a wet or dry bacterial

aerosol, significant casualties could result. 14

HISTORY

Aristotle first described glanders in horses in 330

bce , and named it malleus, meaning hammer or mallet.

Glanders was associated with various horse populations

around the globe, particularly army horses and mules.

The association of glanders with domesticated equids

was so familiar that ”horses and their glanders” com-

monly appeared together in early literature. Glanders

was not studied systematically until the 19th century.

In 1882 the causative agent now called Bmallei was iso-

lated from a glanderous horse’s liver and spleen. 2 The

first account of the disease in humans was published in

1821, 3 yet the medical community recognized it earlier as

a syndrome. The first veterinary school was established

in Lyon, France, in the mid-1700s to study rinderpest

and glanders. Many researchers at the school became

infected and died of glanders. 15

Horses and mules were the primary modes of

transportation in all developing economies until the

Industrial Revolution. Particularly in urban locations,

glanders passed from the infected to the uninfected

animals housed in crowded conditions. Horses and

mules were in high demand during the American Civil

War. Thousands of animals passed through remount

stations where glanders existed in epidemic propor-

tions. The problem was exacerbated after the war,

when glanders was spread to communities as infected

military stock was sold to civilians. Heavy losses of

horses and the infrequent but deadly transmission to

humans in the late 19th century led several countries

to consider glanders control and eradication programs.

Early programs in some countries involved destroy-

ing only clinically ill equids, with compensation, and

meticulously disinfecting the premises of such cases.

Despite these tactics, glanders would reemerge in

new or remaining animals in stables and barns that

once housed infected animals, and cases increased

countrywide. The notion of a carrier-state began to be

accepted. Despite epidemic disease in equine popu-

lations, no simultaneous epidemics occurred in the

human population.

Vaccines and therapeutic agents were developed but

were unsuccessful in reducing the glanders incidence.

By 1890 the mallein diagnostic skin test was developed.

Control and eradication programs soon incorporated

the testing of all contact equids, followed by quaran-

tine and a recommendation for slaughter of all skin-

test–positive animals. These programs failed in some

locales at first because of lax enforcement and lack of

incentive to owners for killing their nonclinically ill

animals. Some horse owners hid contact animals to

avoid testing, or they sold contact and asymptomatic

test-positive animals to unsuspecting individuals to

minimize their economic loss. 4 Inexpensive steam

transportation aided disease spread when glanders

carriers were shipped to other regions and countries.

The United States was blamed for the import of glan-

ders-infected horses to Cuba in 1872 3 and for the great

increase of glanders cases in Canada, where tens of

thousands of US horses were shipped annually, near

the turn of the 20th century. 3,4

Once control programs offered indemnity to test-

positive and contact animals and people accepted

the existence of a carrier-state, glanders eradication

progressed more rapidly. Eliminating glanders in

livestock effectively also eradicated the disease in hu-

mans in countries with such programs. Great Britain’s

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MedicalAspectsofBiologicalWarfare

Equine Glanders (and Farcy) in Great Britain: 1877 - 1928

3200

3000

2800

2600

Outbreaks

Cases

2400

2200

2000

1800

1600

1400

1200

1000

800

Eradicated in 1928

600

400

200

Year

Fig. 6-1. Glanders cases and outbreaks reported to the Department for Environment, Food, and Rural Affairs in Great Britain,

1877–1928. Glanders was eradicated in Great Britain in 1928.

Data source: Available at: http://www.defra.gov.uk/animalh/diseases/notifiable/glanders/index.htm.

experience with the rise and fall of glanders outbreaks in

equids 16 typifies many countries as shown in Figure 6-1.

Great Britain eradicated glanders by 1928, about 30 years

after eradication programs were initiated. The United

States eradicated glanders by 1942. 17 The last naturally

occurring human case was recorded in 1934.

Glanders is a zoonotic disease of concern interna-

tionally and is notifiable to the 164-member Office In-

ternational des Epizooties (OIE) in accordance with the

International Animal Health Code. 18 Several countries

still have eradication programs. In over 500,000 equids

tested in Turkey between 2000 and 2001, for example,

less than 2% tested positive and were destroyed. Only

one of these—a mule—showed clinical signs of infec-

tion. Between 1996 and 2003, glanders in livestock was

reported in Bolivia, Belarus, Brazil, Eritrea, Ethiopia,

Iran, Latvia, Mongolia, Myanmar, Pakistan, and

Turkey. During the same time frame, glanders in hu-

mans was reported in Cameroon, Curaçao, Sri Lanka,

Turkey, and the United States (laboratory-acquired). 17

Exhibit 6-1 depicts the year equine glanders was last

reported to the OIE among countries and territories

without glanders activity (by OIE report) since 1996.

Bioterrorism should be considered as a possible source

if confirmed glanders is found in the countries and

territories listed in Exhibit 6-1.

INFECTIOUS AGENT

Glanders is caused by B mallei , a gram-negative

bacillus that is a close relative to Bpseudomallei (caus-

ative agent for melioidosis). B mallei is an obligate

animal pathogen 19 and has not been found free-liv-

ing in the environment; however, Bpseudomallei can

be isolated from tropical soil. The lack of motility is

a primary means of differentiating B mallei from B

pseudomallei . Growth requirements are not complex;

Bmallei can be cultivated on basic nutrient medium,

and glycerol can be added to the medium to enhance

growth. When stained, the cells typically exhibit

bipolar staining.

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Glanders

EXHIBIT 6-1

YEAR EQUINE GLANDERS WAS LAST REPORTED TO OIE BEFORE 1996*

Country or Territory

Year

Country or Territory

Year

Australia

1891

Moldavia

1957

Austria

1952

Nambia

1925

Bulgaria

1954

Netherlands

1957

Canada

1938

Norway

1889

Croatia

1959

Poland

1957

Denmark

1928

Portugal

1952

Egypt

1928

Romania

1960

Estonia

1945

Serbia and Montenegro

1959

Finland

1943

Slovakia

1954

Yug Rep of Macedonia (former) 1957

South Africa

1945

France

1965

Spain

1956

Georgia

1960

Sudan

1989

Germany

1955

Sweden

1943

Greece

1965

Switzerland

1937

Hungary

1956

Taipei China

1950

India

1988

Great Britain

1928

Ireland

1920

Northern Ireland

1910

Israel

1951

United States of America 1942

Japan

1935

Zimbabwe

1911

* The most recent year evidence of equine glanders was reported to the OIE among countries and territories free of equine glanders

for at least 5 years between 1996 and 2003. (Data are available only for the listed countries and territories.)

OIE: Office International des Epizooties

Bmallei is well-traveled taxonomically. Since its

discovery, this microorganism has been placed in

several genera, including Bacillus , Corynebacterium ,

Mycobacterium , Loefflerella , Pfeifferella , Malleomyces ,

Actinobacillus, and Pseudomonas, 20 and was finally

assigned to the genus Burkholderia in 1992. 21 Not

particularly hardy in the environment, 20 Bmallei is

susceptible to drying, heat, and sunlight. In warm

and moist environments, the organism may survive

a few months and can survive in room temperature

water for 1 month. 2,16,22 Experimentally and under

the most favorable temperature and moisture con-

ditions, Loeffler extended the viability of B mallei

to 100 days. In nature, the organism’s viability is

unlikely after 90 days, and most infectivity is lost

within 3 weeks.

Particularly in culture B mallei is easily aerosolized,

as demonstrated by at least seven of the eight laboratory-

acquired infections in the United States since 1944. Be-

cause of its high infectivity by aerosol, laboratory studies

on this Category B pathogen 23 are performed at biosafety

level 3 (BSL-3). Varying degrees of virulence among

strains have been shown in the laboratory and in na-

ture. 1,4,6 The infectious dose is low, depending on the route

of infection, susceptibility, and strain virulence. One to 10

organisms of some strains by aerosol are lethal to ham-

sters. 1,24 Inhaling only a very few organisms may cause

disease in humans, equids, and other susceptible species.

DISEASE

Epidemiology

activity with B pseudomallei precludes the accurate

distribution and prevalence of B mallei by serologic

means alone. Although human outbreaks have been

reported in Austria and Turkey, no human epidemic

has been recorded. 25

In nature, the horse is the reservoir of Bmallei and

may also be the amplifying host. A disease primarily of

Naturally acquired cases of glanders in humans

or equids are sporadic and rare; most countries have

eradicated the disease. Glanders is still infrequently

reported in northern Africa, the Middle East, South

America, and Eastern Europe. 17 Serologic cross-re-

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