1314 PART 5 Infectious Diseases

is ~10% in trial conditions but rises to >20% in many nontrial situations, possibly because doxycycline levels are reduced and clearance

rates increased by concomitant rifampin administration. Patients who

cannot tolerate or receive tetracyclines (children, pregnant women)

can be given high-dose TMP-SMX instead (two or three standardstrength tablets twice daily for adults, depending on weight).

Increasing evidence supports the use of an aminoglycoside such

as gentamicin (5–6 mg/kg per day for at least 2 weeks) instead of

streptomycin. Shorter courses have been associated with high failure

rates in adults. A 5- to 7-day course of therapy with gentamicin and

a 3-week course of TMP-SMX may be adequate for children with

uncomplicated disease, but prospective trials are still needed to support this recommendation. Early experience with fluoroquinolone

monotherapy was disappointing, although it was suggested that

ofloxacin or ciprofloxacin, given together with rifampin for 6 weeks,

might be an acceptable alternative to the other 6-week regimens

for adults. A substantial meta-analysis did not support the use of

fluoroquinolones in first-line treatment regimens, and these drugs

are not recommended by an expert consensus group (the Ioannina

Recommendations) except in the context of well-designed clinical

trials. However, a more recent meta-analysis is more supportive of

the efficacy of these drugs, and an adequately powered prospective

study will be needed to resolve their role in standard combination

therapy. A triple-drug regimen—doxycycline and rifampin combined with an initial course of an aminoglycoside—was superior to

double-drug regimens in a meta-analysis. The triple-drug regimen

should be considered for all patients with complicated disease and

for those for whom treatment adherence is likely to be a problem.

Focal neurologic disease due to Brucella species requires prolonged

treatment (i.e., for 3–6 months), usually with ceftriaxone supplementation of a standard regimen. Brucella endocarditis is treated with at

least three drugs (an aminoglycoside, a tetracycline, and rifampin),

and many experts add ceftriaxone and/or a fluoroquinolone to reduce

the need for valve replacement. Treatment is usually given for at least

4–6 months, and clinical endpoints for its discontinuation are often

difficult to define. Surgery is still required for the majority of cases of

infection of prosthetic heart valves and prosthetic joints.

There is no evidence base to guide prophylaxis after exposure to

Brucella organisms (e.g., in the laboratory), inadvertent immunization with live vaccine intended for use in animals, or exposure to

deliberately released brucellae. Most authorities have recommended

the administration of rifampin plus doxycycline for 3 weeks after a

low-risk exposure (e.g., an unspecified laboratory accident) and for

6 weeks after a major exposure to aerosol or injected material. However, such regimens are poorly tolerated, and doxycycline monotherapy of the same duration may be substituted. (Monotherapy is

the standard recommendation in the United Kingdom but not in

the United States.) Rifampin should be omitted after exposure to

vaccine strain RB51, which is resistant to rifampin, and replaced

by another agent such as TMP-SMX in combination with doxycycline. After significant brucellosis exposure, expert consultation is

advised for women who are (or may be) pregnant.

■ PROGNOSIS AND FOLLOW-UP

Relapse occurs in up to 30% of poorly compliant patients. Thus

patients should ideally be followed clinically for up to 2 years to detect

relapse, which responds to a prolonged course of the same therapy used

originally. The general well-being and the body weight of the patient

are more useful guides than serology to lack of relapse. IgG antibody

levels detected by the standard agglutination test and its variants can

remain in the diagnostic range for >2 years after successful treatment.

Complement fixation titers usually fall to normal within 1 year of cure.

Immunity is not solid; patients can be reinfected after repeated exposures. Fewer than 1% of patients die of brucellosis. When the outcome

is fatal, death is usually a consequence of cardiac involvement; more

rarely, it results from severe neurologic disease. Despite the low mortality rate, recovery from brucellosis is slow, and the illness can cause

prolonged inactivity, with domestic and economic consequences.

The existence of a prolonged chronic brucellosis state after successful treatment remains controversial. Evaluation of patients in whom

this state is considered (often those with work-related exposure to brucellae) includes careful exclusion of malingering, nonspecific chronic

fatigue syndromes, and other causes of excessive sweating, such as alcohol abuse and obesity. In the future, the availability of more sensitive

assays to detect Brucella antigen or DNA may help to identify patients

with ongoing infection.

■ PREVENTION

Vaccines based on live attenuated Brucella strains, such as B. abortus

strain 19BA or 104M, have been used in some countries to protect

high-risk populations but have displayed only short-term efficacy and

high reactogenicity. Subunit vaccines have been developed but are of

uncertain value and cannot be recommended at present. Research in

this area has been stimulated by interest in biodefense (Chap. S3) and

may eventually yield new products. The mainstay of veterinary prevention is a national commitment to testing and slaughter of infected

herds/flocks (with compensation for owners), control of animal

movement, and active immunization of animals. These measures are

usually sufficient to control human disease as well. In their absence,

pasteurization of all milk products before consumption is sufficient to

prevent nonoccupational animal-to-human transmission. All cases of

brucellosis in animals and humans should be reported to the appropriate public health authorities.

■ FURTHER READING

Ariza J et al: Perspectives for the treatment of brucellosis in the 21st

century: The Ioannina recommendations. PLoS Med 4:e317, 2007.

Beeching NJ et al: Brucellosis. BMJ Best Practice, 2019. https://

bestpractice.bmj.com/topics/en-us/911.

Centers for Disease Control and Prevention: Brucellosis.

https://www.cdc.gov/brucellosis/index.html.

Dean AS et al: Clinical manifestations of human brucellosis: a systematic review and metaanalysis. PLoS Negl Trop Dis 6:e1929, 2012.

Norman FF et al: Imported brucellosis: a case series and literature

review. Travel Med Infect Dis 14:182, 2016.

Yagupsky P et al: Laboratory diagnosis of human brucellosis. Clin

Microbiol Rev 33:e00073, 2019.

DEFINITION

Tularemia is a zoonosis caused by the gram-negative, facultative

intracellular bacterium Francisella tularensis. This microorganism

was isolated first in 1911 by McCoy and Chapin from rodents in

Tulare County, California, and then from humans in 1914 by Wherry

and Lamb. Because of taxonomic evolution, only two subspecies of

F. tularensis are currently associated with tularemia: F. tularensis subsp.

tularensis and F. tularensis subsp. holarctica are responsible for type A

and type B tularemia, respectively. These two subspecies are highly virulent human pathogens belonging to category A of potential biological

threat agents, as defined by the U.S. Centers for Disease Control and

Prevention.

FRANCISELLA SPECIES, SUBSPECIES,

AND CLADES

The Francisella genus currently comprises seven species. F. tularensis

is split into four subspecies: F. tularensis subsp. tularensis (type A);

F. tularensis subsp. holarctica (type B); F. tularensis subsp. mediasiatica,

restricted to central Asia and Russia, but never associated with human

170 Tularemia

Max Maurin, Didier Raoult

1315CHAPTER 170 Tularemia

■ RESERVOIRS AND MODES OF TRANSMISSION

F. tularensis can infect a wide range of mammals, birds, amphibians,

reptiles, and fish, causing many of these vertebrate species to develop

severe and often fatal infections. Because this organism can infect

so many animal species, the actual animal reservoir of F. tularensis remains unknown. However, small terrestrial and semi-aquatic

rodents (including mice, gerbils, beavers, lemmings, and voles) and

lagomorphs (hares and rabbits) are the predominant animal sources

for human tularemia cases.

Some arthropods are able to transmit F. tularensis between animal

species, including from animals to humans. Ixodidae ticks are the

primary vectors of tularemia and may also represent a reservoir due

to transstadial transmission of F. tularensis. Mosquitoes (especially

Aedes species) are vectors of this microorganism in Sweden and

Finland. Other blood-sucking arthropods (especially tabanids) may

also transmit tularemia in restricted areas. F. tularensis survives for

weeks or months in contaminated soil or water environments, which

possibly represent other natural reservoirs of this bacterium.

The modes of transmission of F. tularensis to humans are varied,

reflecting the ubiquitous nature of this microbe. A common mode

of infection is direct contact with infected animals or, less frequently,

through animal bites. Lagomorphs and other game animals as well

as small rodents are most frequently involved. Domestic animals,

especially cats and dogs, are occasionally involved in transmission to

humans or as recipients of the microbe from wild animals. Tularemia

can also be acquired through the consumption of contaminated food

products (especially those from game animals) or water (often nonpotable water from water wells or spring water). Arthropod-borne

tularemia cases mainly occur through tick bites except in Sweden and

Finland, where mosquitoes are the primary vectors. Human infections

also occur through contact with contaminated soil or water environments or inhalation of contaminated dust.

■ AT-RISK EXPOSURES AND POPULATIONS

In endemic areas, the people most at risk for tularemia are those

frequently exposed to wild animals, arthropod bites (mainly those of

ticks), or contaminated hydrotelluric environments.

Occupational Risk Tularemia is recognized as an occupational

disease in most endemic countries. The high-risk occupational groups

include breeders, farmers, veterinarians, game wardens, forest rangers,

Tularemia endemic countries

A1, A2, B4, B6, B12, B16:

main F. tularensis clades

A1, B4

B4, B6

A2 A1

A1 A1

B6

B6

B6

B4

B12

B12

B12

B12

B12

B12

B12, B16 B12 B16 B4, B16

Predominance of oropharyngeal

forms due to consumption of nonpotable water

Predominance of mosquitoborne tularemia cases

Possums as an unusual

tularemia reservoir

B16

FIGURE 170-1 Global distribution of reported (or strongly suspected) autochthonous human tularemia cases. The major clades detected in specific areas—A1, A2, B4,

B6, B12, and B16—are shown. In most countries, the actual endemic areas are poorly defined. The actual distribution of clades and subclades is complex and overlapping.

Lagomorphs, small rodents, and ticks are the primary sources of human tularemia cases except in the indicated specific situations.

diseases; and F. tularensis subsp. novicida, an aquatic bacterium and

rare opportunistic human pathogen. Molecular methods (especially

those based on whole genome sequencing) have now allowed the

characterization of a large number of F. tularensis genotypes, which are

divided into clades and subclades. The major clades are A1 (divided

into A1a and A1b) and A2 for type A strains, and B4, B6, B12, and

B16 for type B strains. These clades vary in geographic distribution,

virulence, and resistance to macrolides; clade B12 strains are naturally

highly resistant to erythromycin.

EPIDEMIOLOGY

■ GEOGRAPHIC DISTRIBUTION

Tularemia-endemic areas are mainly distributed in the Northern

Hemisphere (Fig. 170-1). Human tularemia cases are described

in North America (the United States, Canada, and part of Central

America), Asia (Japan, China, Mongolia, Russia, Pakistan, Turkey, Iran,

Kazakhstan, Georgia, Armenia, and Azerbaijan), and Europe (almost all

countries except Iceland, Ireland, the United Kingdom, Portugal, and

the southern Balkan countries). Type A strains are classically restricted

to North America, although a few strains (probably imported laboratory strains) have been detected from arthropods in Slovakia. Type B

strains are classically found in the whole Northern Hemisphere but have

also been detected in southern Australia. In the United States, human

tularemia cases predominate in southern and central states (especially,

in order of decreasing incidence, Arkansas, Oklahoma, South Dakota,

Kansas, Missouri, North Dakota, and Nebraska) and, to a lesser extent,

in eastern states (mainly Massachusetts and Martha’s Vineyard) and

western states (especially California, Oregon, and Montana).

There is a specific, complex, and overlapping geographic distribution of F. tularensis clades and subclades (Fig. 170-1). Clade A1

is found throughout North America, while clade A2 is restricted to

the U.S. western states. Clade B4 predominates in North America but

has also been detected in Scandinavia, Germany, and western China.

Clade B6 is spread throughout western Europe (with a predominance of subclade B44), but also in central Europe, Scandinavia, and

North America. Clade B12 has been found mainly in eastern Europe,

Scandinavia, and Asia (e.g., Russia and China). Finally, clade B16

is currently restricted to Japan, Turkey, Australia, and western

China.

1316 PART 5 Infectious Diseases

landscapers, trappers, tanners, slaughterhouse workers, renderers, zoological park employees, butchers who handle game meat, military personnel (especially during the navigation of military obstacle courses),

and laboratory personnel handling F. tularensis cultures.

Leisure-Associated Risk The leisure activities potentially associated with exposure to F. tularensis include hunting, trapping, gardening,

mowing the lawn, canyoneering, fishing or swimming in contaminated

fresh water, and walking or biking in forests and other areas infested

with ticks. Owning pets that may carry F. tularensis (especially unusual

animals such as prairie dogs) is also a risk factor.

At-Risk Populations and Seasonal Variations The most

at-risk population varies according to the geographic area and the predominant mode(s) of contamination. When infections occur through

contact with wildlife fauna and tick bites, middle-aged men living in

rural areas are most frequently involved. Game-related contamination

usually occurs during the hunting (autumn and winter) seasons, while

tick-borne tularemia cases are more frequent during the warm season.

Infections caused by the consumption of contaminated water occur

throughout the year and involve men, women, and children. Mosquitoborne tularemia cases predominate during the warm season in both

adults and children in Scandinavia.

■ NATURAL CYCLES OF F. TULARENSIS

The highly variable epidemiologic and clinical aspects of tularemia in

different geographic areas suggest several F. tularensis natural cycles.

These cycles probably vary with the predominant animal reservoirs,

arthropod vectors, climatic conditions, and F. tularensis species and

lineages. However, two cycles have been hypothesized to explain the

spatiotemporal maintenance of tularemia. In the terrestrial cycle,

lagomorphs, terrestrial rodents, and ticks are considered primarily

involved. Human infections occur mainly through contact with the

terrestrial wildlife fauna and tick bites. This cycle is characterized

by sporadic tularemia cases in the most exposed population (often

middle-aged men), with a predominance of ulceroglandular and

glandular forms. In the aquatic cycle, semi-aquatic rodents and the

aquatic environment play a significant role. In Turkey, most patients

are infected through the consumption of nonpotable water (especially

spring water). Water-borne tularemia outbreaks have occurred, involving both adults and children, with a predominance of oropharyngeal

forms. In Sweden and Finland, mosquito-borne tularemia cases predominate. These arthropods are likely infected during their larval cycle

in contaminated aquatic environments. Tularemia outbreaks can recur

and can involve both adults and children, who develop mainly ulceroglandular and glandular forms of disease.

PATHOGENESIS

F. tularensis inoculation can occur through the skin, the conjunctiva,

and the oral or respiratory route. After a short incubation period

(usually 3–5 days), patients experience a flulike illness with symptoms

localized to the site of initial tissue invasion. The organism mainly

survives intracellularly and can infect a broad spectrum of eukaryotic

cells, including phagocytes and epithelial cells. After phagocytosis by

macrophages, the F. tularensis pathogenicity island encoding a type VI

secretion system allows this bacterium to rapidly exit the phagocytic

vacuole and multiply within the cytoplasm. The oxidative response of

the infected phagocytic cell is attenuated and delayed, in part because of

the specific structure of F. tularensis lipopolysaccharide, which is stealth

to the innate Toll receptor immune system. Many other virulence factors have been partially characterized. Infected cells eventually undergo

apoptosis, which allows released bacteria to initiate new rounds of

infection. The organism spreads between cells through the bloodstream, and infected blood cells (e.g., monocytes) participate in the

spread of the bacteria in the body. A few bacteria are enough to induce

severe infection, resulting in the patient’s death within days for the most

virulent F. tularensis strains. Most frequently, however, the infection is

controlled both by the humoral and cellular immune responses.

The earliest infected organs—and thus the earliest clinical manifestations—depend on the route of infection. Infection through the

skin results in a local inoculation lesion and development of regional

lymphadenopathy within days. Conjunctival inoculation leads to

conjunctivitis with local lymphadenopathy. The oral route of infection

manifests as pharyngitis with cervical lymphadenopathy, but intestinal

involvement may occasionally lead to enteritis and other intraabdominal organ involvement. The inhalation of a contaminated aerosol can

result in acute, subacute, or chronic pneumonia. All these localized

infections can lead to F. tularensis bacteremia (hence the term tularemia) and secondary infection of almost all organs.

CLINICAL MANIFESTATIONS

Tularemia can be considered as two separate diseases: a severe, often

life-threatening disease observed in North America and caused by the

most virulent type A strains; and a disease of mild to moderate severity,

with protean clinical manifestations that often resemble those of other

infectious diseases; in fact, these other diseases typically are initially

suspected before the diagnosis of tularemia is made. The incubation

period of tularemia is typically short (3–5 days on average) but can last

up to 3 weeks.

■ SEVERE TYPE A TULAREMIA

The most virulent strains of F. tularensis subsp. tularensis (genotype

A1b) can cause severe systemic disease, usually of acute onset. These

infections justify the classification of F. tularensis as a Tier 1 select

agent in the United States and most other countries. For severe type A

tularemia cases, the most frequently reported mode of contamination

is the inhalation of an infected aerosol. This event results in the rapid

development of acute, life-threatening pneumonia or pleuropneumonia, which is the most severe presentation of the so-called pneumonic

form of tularemia. Systemic infections are acquired through other

modes of contamination, including ingestion of contaminated food or

water and arthropod bites. A severe typhoid-like disease (referred to

as the typhoidal form of tularemia) is consistent with a combination of

high fever, sepsis, and neurologic symptoms (ranging from confusion

to deep coma), but no localized infection (e.g., no skin inoculation

lesion and no lymphadenopathy). The acute pneumonic and typhoidal

forms of tularemia are usually associated with F. tularensis bacteremia,

although bloodstream infection may not be detected at hospital admission because of its intermittent and temporary nature.

Severe type A tularemia is not restricted to persons with compromised immunity or underlying disorders and can occur in young,

healthy adults. If untreated, the acute pneumonic form rapidly progresses to acute respiratory distress syndrome. Patients with severe type

A infections often develop severe sepsis, septic shock, and multipleorgan dysfunction syndrome. Altogether, these severe systemic infections are associated with mortality rates up to 40–60% without appropriate antibiotic therapy. Among patients who are admitted early to an

intensive care unit and receive appropriate antibiotics, the death rate is

reduced to 3–5%. However, rapid etiologic diagnosis of these nonspecific clinical presentations remains difficult, and a delay in initiating

appropriate antibiotic therapy is associated with poorer prognosis.

■ MORE COMMON PRESENTATIONS

OF TULAREMIA

Other than the acute and severe forms of type A infection, the majority of human cases of tularemia are characterized by subacute clinical

manifestations of progressive onset and of mild to moderate severity.

These less severe forms of disease are almost the only forms observed in

Europe and Asia and also are common in North America. Apart from

the six classical forms of tularemia (see below), a wide variety of other

clinical manifestations can be observed. The predominant clinical presentations vary from one geographic area to another according to the

primary sources and modes of transmission of F. tularensis to humans.

Prodromal Flulike Illness An unknown proportion of persons

infected with F. tularensis either do not develop clinical symptoms or

have a self-limited febrile illness and do not seek medical attention. In

symptomatic patients, early clinical manifestations usually correspond

to a flulike illness and may include fever, headache, chills, fatigue, malaise, arthralgia, and myalgia.

1317CHAPTER 170 Tularemia

Classical Forms of Tularemia Following the prodromal period,

tularemia usually evolves into one of six classical clinical forms, which

are occasionally combined.

ULCEROGLANDULAR FORM This form is the most common and typical presentation of tularemia worldwide. It occurs after F. tularensis

inoculation through the skin (e.g., during manipulation of an infected

animal or via an arthropod bite). A cutaneous inoculation lesion

develops that may be papular or vesicular but that often evolves to a

skin ulcer persisting for several weeks before healing. A few days after

infection, regional lymphadenopathy develops at locations that vary

with the inoculation site (e.g., axillary, epitrochlear, or inguinal). The

differential diagnosis of the combination of a skin lesion and regional

lymphadenopathy is difficult and includes cat-scratch disease caused

by Bartonella henselae (Chap. 172) as well as several rickettsioses

(Chap. 187). However, in patients with the above clinical presentation,

tularemia should be considered.

GLANDULAR FORM The glandular form is similar to the ulceroglandular form, but the skin lesion either has not developed or has healed

by the time the patient seeks medical attention. This form is a common

but clinically less typical presentation. Because many infectious agents

may cause regional lymphadenopathy, the diagnosis of tularemia is

often delayed.

OCULOGLANDULAR FORM Infection through the conjunctiva usually leads to painful granulomatous unilateral conjunctivitis. Bilateral

conjunctivitis due to contamination of both eyes rarely occurs. Within

a few days, swollen periauricular lymphadenopathy develops. Thus,

tularemia is a rare etiology of Parinaud oculoglandular syndrome.

B. henselae (the cause of cat-scratch disease) is the most common

etiology of this syndrome, but tularemia should be considered as an

alternative diagnosis.

OROPHARYNGEAL FORM The oral route of contamination (usually

via the hands or through consumption of contaminated water or food)

corresponds to painful pharyngitis and the development within days

of submandibular or cervical lymphadenopathy. The oropharyngeal

form resembles a group A streptococcal infection (Chap. 148), but

with swollen cervical lymphadenopathy in most patients and almost

no efficacy of β-lactam therapy. This form may also include digestive

symptoms of variable severity, including nausea and vomiting, abdominal pain, bloody diarrhea, and occasionally the involvement of other

intraabdominal organs.

PNEUMONIC FORM The inhalation of an F. tularensis–contaminated

aerosol may result in pneumonia or pleuropneumonia. However, the

most common presentations of this clinical form consist of subacute

lung involvement with low-grade fever and mild pulmonary symptoms

(dry cough, moderate dyspnea, and mild chest pain). Some patients

suffer from prolonged clinical symptoms, with intermittent fever,

fatigue, progressive weight loss, and deterioration in general condition.

The diagnosis is usually delayed for weeks or months until chest x-ray

or CT reveals hilar or mediastinal lymphadenopathy, often with no or

only minor pulmonary lesions. Tuberculosis and lymphoma are usually suspected first. The tularemia diagnosis is usually fortuitous and

obtained thanks to histologic and bacteriologic analysis of surgically

removed mediastinal or hilar lymph nodes.

TYPHOIDAL FORM In Europe and Asia, a diagnosis of typhoidal tularemia may be considered in patients presenting with sepsis and confusion

but without a localized infection (no skin lesion, lymphadenopathy,

pharyngitis, or conjunctivitis). However, the prognosis of this form of

illness is much better than that of type A infections in North America.

Many of these patients experience F. tularensis bacteremia. Fatal cases

are rare and most often occur in debilitated and elderly patients.

Skin Manifestations Apart from skin inoculation lesions, tularemia patients may present with various other types of skin involvement.

Reported manifestations include skin rash, Sweet syndrome, dermatitis, urticaria, acneiform eruption, vasculitis-like eruption, lymphangitis, cellulitis, subcutaneous abscesses, erythema nodosum, erythema

multiforme, and livedo reticularis.

Complications Up to 20–30% of symptomatic tularemia patients

with common clinical presentations require hospitalization, either in

the early stage of the disease—because of severe clinical symptoms—or

after several weeks or months of evolution—because of an unfavorable

course.

BACTEREMIA, SEPSIS, AND SEPTIC SHOCK These complications are

rare among patients with the above classical forms of tularemia and

have been reported more frequently in immunocompromised persons,

transplant recipients, persons with severe underlying disorders, and

the elderly.

LYMPH NODE SUPPURATION, SOFT TISSUE INFECTIONS, AND DEEP

ABSCESSES Because of delayed diagnosis, 30–40% of tularemia

patients with regional lymphadenopathy experience a progression to

lymph node suppuration, which can spontaneously drain through a

skin fistula. Soft tissue infections usually occur in the area adjacent to

suppurative lymphadenopathy and may consist of cellulitis or subcutaneous abscesses. Periauricular lymphadenopathy may lead to parotid

infection. Myositis and rhabdomyolysis have also been reported.

Deep abscesses of variable location may occur through the diffusion

of a lymph node suppuration into the surrounding tissues or through

hematogenous spread of bacteria.

OCULAR COMPLICATIONS Tularemia conjunctivitis rarely evolves to

more severe ocular infections. Rare cases of dacryocystitis, keratitis,

chorioretinitis, cyclitis, and optic neuritis have been reported.

OTITIS Otitis media is a rare complication likely occurring as a

complication of oropharyngeal tularemia or direct inoculation of

F. tularensis through a tympanic perforation.

MENINGITIS, MENINGOENCEPHALITIS, AND NEUROLOGIC DISEASE Meningitis and meningoencephalitis are hematogenous complications that, although uncommon, can occur as an inaugural and

unique clinical manifestation. Their clinical presentation is not specific, and a tularemia diagnosis is usually established by isolation of

F. tularensis from cerebrospinal fluid. Meningitis has been more commonly reported in the United States than in Europe and Asia. Other

rare neurologic complications include cerebral abscesses, polyneuritis

cranialis, ataxia, and Guillain-Barré syndrome.

CARDIOVASCULAR INFECTIONS Endocarditis (including prosthetic

valve endocarditis), myocarditis, pericarditis, and aortitis are rare

complications of tularemia. Therefore, diagnosis may be particularly

challenging unless blood cultures allow rapid isolation of F. tularensis.

ABDOMINAL INFECTIONS Rare abdominal complications include

granulomatous hepatitis, peritonitis, acute renal failure, and liver or

spleen abscesses or nodules.

OSTEOARTICULAR INFECTIONS Osteoarticular infections, including

osteomyelitis, arthritis, and prosthetic joint infections, are rare hematogenous complications of tularemia.

ADVERSE PREGNANCY OUTCOMES Tularemia is not considered a

disease responsible for complications during pregnancy or fetal abnormalities. A single tularemia case in the first trimester of pregnancy,

followed by intrauterine fetal death in the third trimester, has been

reported.

DIAGNOSIS

A tularemia diagnosis is often missed or delayed. This delay may be

related to inadequate knowledge of this disease by some clinicians,

lack of specific clinical symptoms, and a high frequency of mild disease

with spontaneous recovery. Once clinically suspected, a diagnosis of

tularemia usually is readily confirmed by specific laboratory tests.

■ NONSPECIFIC BIOLOGIC FINDINGS

Routine blood tests usually are not very informative in the diagnosis of tularemia. The leukocyte count can be normal or moderately

high, usually with a relative increase in mononuclear cells. Moderate

thrombocytopenia is more frequently observed. The erythrocyte sedimentation rate is usually elevated, and the C-reactive protein level may

1318 PART 5 Infectious Diseases

also be slightly elevated. Levels of liver enzymes, including alkaline

phosphatase, aspartate aminotransferase, alanine aminotransferase,

and gamma-glutamyl transpeptidase, can be moderately elevated.

High levels of creatine phosphokinase are found in patients with

rhabdomyolysis.

■ RADIOLOGIC FINDINGS

Radiologic examinations (e.g., CT, MRI, ultrasonography) may be

useful for detecting and specifying the extent of lymphadenopathy

and lung or other organ involvement. Although usually not specific to

tularemia, radiologic findings may include superficial or deep lymphadenopathies; soft tissue, lymph node, or other organ abscesses; brain

tissue involvement; cardiovascular disease; lung or pleural involvement; and osteoarticular lesions. The pneumonic form of tularemia

may be associated with variable radiologic findings, including unilateral or bilateral infiltrates, lung consolidation, lung abscess, cavitary

lesions, pleural effusion, and hilar or mediastinal enlargement due to

lymphadenopathy.

■ CLINICAL SAMPLES

Blood samples should be collected in blood culture bottles (aerobic

and anaerobic) when patients have febrile disease. On the basis of

clinical manifestations, biological samples can be obtained for culture

and polymerase chain reaction (PCR) testing, including samples of

cutaneous biopsies or exudates (especially from the inoculation lesion),

conjunctival or pharyngeal exudates, lymph node aspirates or biopsies,

various suppurations and abscesses, sputum and other lower respiratory tract secretions, pleural and other serous fluid, cerebrospinal fluid,

and organ biopsies.

■ SEROLOGIC DIAGNOSIS

A serum sample should be collected as early as possible and analyzed

for antibodies to F. tularensis. Ideally, a second serum sample should

be collected at least 2 weeks later. The serologic diagnosis of tularemia

is widely used and is sensitive. Antibodies are measured by different

techniques, depending on the laboratory. Assays include the microagglutination test, immunofluorescence assays (IFAs), enzyme-linked

immunosorbent assays (ELISAs), and Western blots. The IFA and

ELISA methods allow separate titration of IgM- and IgG-type antibodies. Significant antibody titers (i.e., titers above the cutoff of the technique used) are usually detected 2–3 weeks after disease onset, with

ELISAs allowing the earliest detection. Antibody titers peak 4–6 weeks

after disease onset and then decline progressively over the following

months. However, in many patients, residual IgG titers and, to a lesser

extent, IgM titers persist for several years.

False-negative results may be obtained in the early stage of tularemia or in the rare patients who do not mount a significant antibody

response. False-positive results classically arise as a result of antigenic

cross-reactions between F. tularensis and other bacterial species,

including Brucella spp. and Yersinia enterocolitica. The risk of falsepositive results linked to antigenic cross-reactions is high in patients

with antibody titers close to the cutoff thresholds. In addition, the

long-term persistence of anti–F. tularensis antibodies in patients with

past infection may also lead to false-positive results. Lack of kinetics

between antibody titers in early and (when available) late serum samples may allow the differentiation of recent from past infections.

■ CULTURE-BASED DIAGNOSIS

F. tularensis is a highly infectious and virulent bacterium. Cultures of

this pathogen should be handled in a biosafety level 3 laboratory to prevent the contamination of laboratory personnel. Blood-enriched media

(especially chocolate agar supplemented with vitamins) are needed to

isolate this fastidious-growth bacterium. Current blood culture systems

are adequate for F. tularensis isolation within 5 days of incubation.

F. tularensis may also be isolated from various other clinical samples.

F. tularensis can be presumptively identified by Gram’s staining

(small gram-negative coccobacilli), a few biochemical tests, agglutination, and matrix-assisted laser desorption/ionization–time of flight

(MALDI-TOF) mass spectrometry. Molecular tests are the gold

standard for determination of the involved species, subspecies, and

genotype (see below).

■ MOLECULAR DIAGNOSIS

F. tularensis DNA can be detected in blood or other clinical samples.

Available real-time PCR is both rapid and accurate. Whole genome

sequencing of a large number of F. tularensis strains has allowed the

development of molecular tests for the detection and identification

of this pathogen at the species, subspecies, or genotype level. The fact

that PCR tests usually remain positive despite 1–2 weeks of antibiotic

therapy may help establish the diagnosis of tularemia, whereas specific

cultures can be negative at that point.

Blood samples may be PCR-positive, especially when collected from

patients with F. tularensis bacteremia. However, PCR results are more

frequently positive for other clinical samples, especially samples of

lymph nodes, skin ulcers, and conjunctival and pharyngeal exudates.

It is interesting that lymph node tissue surgically removed because of

suppuration several weeks after disease onset are PCR-positive in >90%

of cases, whereas F. tularensis is rarely isolated from these samples.

■ OPTIMIZED DIAGNOSTIC STRATEGY

Molecular tests are the most useful diagnostic tools for rapid tularemia

diagnosis. In the acute phase of the disease, F. tularensis DNA can

be detected in various biologic samples collected in light of clinical

manifestations, including blood, skin inoculation lesions, conjunctival

or pharyngeal exudates, sputum or pleural fluid, and cerebrospinal

fluid. Real-time PCR can provide a rapid (within 2 h) and accurate

diagnosis of acute pneumonic tularemia, especially in the context of

bioterrorism. Molecular tests are also useful in patients with late clinical manifestations, especially those with lymph node suppuration. The

combination of several molecular tests allows a rapid search for several

pathogens responsible for similar clinical manifestations. For example,

in patients with a skin inoculation lesion and regional lymphadenopathy, PCR testing of a skin lesion biopsy allows rapid detection of B.

henselae, Rickettsia spp., and F. tularensis.

F. tularensis culture remains the most specific diagnostic technique,

providing definitive diagnostic confirmation whatever the site of its

isolation, although this pathogen is most frequently isolated from

blood samples. However, isolation of F. tularensis is challenging and

classically has <10% sensitivity.

Serologic methods remain useful in patients with common clinical

forms of tularemia when no clinical sample is available for culture or

PCR. Serologic findings must be interpreted according to the clinical and epidemiologic context. Only seroconversion or a fourfold or

greater rise in F. tularensis antibody titers between two serum samples

collected at least 2 weeks apart is considered a diagnostic confirmation

of tularemia. A single antibody titer higher than the cutoff should be

interpreted cautiously and may represent a false-positive result.

TREATMENT

Tularemia

ANTIBIOTIC THERAPY

Three antibiotic classes are commonly used for tularemia treatment: the aminoglycosides, the tetracyclines, and the fluoroquinolones. No acquired resistance to these antibiotics has been reported

in natural strains of F. tularensis. Chloramphenicol is now rarely

used because of bone marrow toxicity. The β-lactams are considered ineffective and the macrolides only poorly effective; however,

azithromycin is bacteriostatic in vitro against F. tularensis (except

for B12 genotypes). Table 170-1 summarizes current treatment

recommendations for patients in the United States and Europe.

The aminoglycosides streptomycin and gentamicin remain the

gold standard for the treatment of severe tularemia because of

their significant and rapid bactericidal activity against F. tularensis.

Doxycycline or a fluoroquinolone are usually prescribed for

treating common clinical forms of mild to moderate severity.

1319CHAPTER 170 Tularemia

The  fluoroquinolones are usually associated with lower rates of

treatment failure and relapse than doxycycline.

However, the efficacy of antibiotic treatment varies dramatically

with the type and duration of clinical manifestations and with

immune status. Antibiotic efficacy is usually poor in curing suppurated lymphadenopathies or other soft tissue or organ abscesses. No

standardized treatment has been defined for tularemia complications such as meningitis, endocarditis, and osteoarticular infections.

The same holds for infections occurring in immunocompromised

patients. The combination of an aminoglycoside with either doxycycline or a fluoroquinolone is often used in these specific situations, although the superiority of dual therapy over monotherapy

has not been demonstrated.

For pregnant women in the United States, gentamicin is advocated as first-line treatment and doxycycline or a fluoroquinolone

as second-line treatment. All these antibiotics have potential side

effects on the mother and the fetus and thus are classically avoided

before childbirth—most importantly, during the first trimester of

pregnancy. Azithromycin has been used successfully in a few pregnant women with mild disease in western Europe, where tularemia

cases are caused only by type B F. tularensis strains susceptible to

this antibiotic.

SURGICAL TREATMENT

Removal of suppurated lymph nodes in tularemia patients with

regional lymphadenopathy is the leading cause of surgical intervention. The combination of surgery and appropriate antibiotic

therapy is the most effective treatment of this complication. Several

surgeries are sometimes necessary for definite cure. Surgery may

also be needed in other clinical situations, including skin or subcutaneous abscesses, cellulitis, deep abscesses, endocarditis, osteoarticular infections, and ocular complications.

PROGNOSIS

The prognosis of patients with tularemia depends on the patient’s

immune status, the clinical form of disease, and the involved F. tularensis strain. Classically, spontaneous mortality rates range from 5 to 15%

for type A tularemia and are <1% for type B disease. With receipt

of appropriate antibiotic therapy, <2% of type A tularemia patients

die. The pneumonic and typhoidal forms have been associated with

mortality rates up to 30%. A more recent evaluation of mortality rates

in culture-confirmed tularemia cases in the United States highlighted

significant variations depending on the involved F. tularensis genotype:

24% for A1b, 4% for A1a, 7% for B, and 0% for A2 strains. Therefore,

an accurate prognostic evaluation of type A tularemia will require

genotyping of the causative F. tularensis strain.

PREVENTION

■ LACK OF HUMAN-TO-HUMAN TRANSMISSION

Human-to-human transmission of F. tularensis is considered unlikely.

In the literature, such transmission has been reported in only two

specific situations: the autopsy of a person who died of tularemia and

organ transplantation from a person who died of tularemia. Thus, no

isolation measures for tularemia patients are necessary during routine

medical care, even those with the pneumonic form of disease.

■ EXPOSURE PREVENTION

The most effective prophylactic measures against tularemia are those

reducing the risk of exposure to F. tularensis. Persons manipulating

potentially contaminated animals (especially lagomorphs and small

rodents) or their carcasses should wear appropriate protective equipment (gloves, glasses, a respiratory mask, and protective clothing).

Use of repellants against arthropods (especially ticks) is also essential

in tularemia-endemic areas. Water-borne and food-borne tularemia

cases can be prevented by consuming potable water and well-cooked

food. Hydrotelluric sources of contamination are more challenging to

identify and, therefore, to avoid. Finally, laboratory personnel handling

F. tularensis cultures should work in biosafety level 3 facilities with

appropriate safety equipment.

■ POSTEXPOSURE PROPHYLAXIS

The most at-risk situation is exposure to an F. tularensis aerosol. A

highly suspected F. tularensis aerosol inhalation requires postexposure

antibiotic prophylaxis. The need for such treatment is more easily identified for laboratory personnel handling F. tularensis cultures. Current

recommendations are to treat the exposed person with either doxycycline or a fluoroquinolone for 14 days (Table 170-1). Subsequent medical and possibly serologic monitoring is usually carried out. At least

1 month of surveillance after the end of treatment seems reasonable.

■ VACCINATION

The live vaccine strain (LVS), a virulence-attenuated type B strain of

F. tularensis, was widely used before and after World War II to vaccinate

highly exposed persons (especially laboratory staff). This vaccine has

been abandoned because of its limited efficacy against severe type A

pneumonia, unstable colony phenotype, and potentially severe side

effects at the inoculation site as well as fear of a potential reversion of

LVS to a virulent strain. In recent years, significant efforts have been

made to develop new and safer vaccines. F. tularensis mutants for

metabolic enzymes, virulence factors, or regulatory proteins have been

developed. However, no vaccine has currently been authorized by the

U.S. Food and Drug Administration or by health protection agencies

in other countries.

TABLE 170-1 Guidelines for Tularemia Treatment and

Postexposure Prophylaxis

REGION, PATIENT GROUP

United States, Nonpregnant Adultsa

First line Streptomycin, 1 g IM bid, 10 days; or

Gentamicin,b

 5 mg/kg IM or IV daily, 10 days

Second line Doxycycline, 100 mg IV bid, 14–21 days; or

Chloramphenicol,b

 15 mg/kg IV qid, 14–21 days; or

Ciprofloxacin,b

 400 mg IV bid, 10 days

Prophylaxis Doxycycline, 100 mg PO bid, 14 days; or

Ciprofloxacin,b

 500 mg PO bid, 14 days

United States, Pregnant Womena

First line Gentamicin,b

 5 mg/kg IM or IV daily, 10 days; or

Streptomycin, 1 g IM bid, 10 days

Second line Doxycycline, 100 mg IV bid, 14–21 days; or

Ciprofloxacin,b

 400 mg IV bid, 10 days

Prophylaxis Ciprofloxacin,b

 500 mg PO bid, 14 days; or

Doxycycline, 100 mg PO bid, 14 days

Europe, Nonpregnant Adults and Pregnant Women

First line Gentamicin, 5 mg/kg IM or IV daily or bid, 10 days; or

Streptomycin, 1 g IM bid, 10 days

Second linec Ciprofloxacin, 400 mg IV bid, then 500 mg PO bid, 14 days; or

Ofloxacin, 400 mg IV bid, then 400 mg PO bid, 14 days; or

Levofloxacin, 500 mg IV daily, then 500 mg PO daily, 14 days

Third linec Doxycycline, 100 mg IV bid, then 100 mg PO bid, 21 days

Prophylaxis Ciprofloxacin, 500 mg PO bid, 14 days; or

Ofloxacin, 400 mg PO bid, 14 days; or

Levofloxacin, 500 mg PO daily, 14 days; or

Doxycycline, 100 mg PO bid, 14 daysd

a

Persons beginning with IM or IV doxycycline, ciprofloxacin, or chloramphenicol

can switch to oral antibiotic administration when clinically indicated. b

Not a use

approved by the U.S. Food and Drug Administration. c

Persons beginning with IV

treatment can switch to oral antibiotic administration when clinically indicated.

d

Second line.

1320 PART 5 Infectious Diseases

■ FURTHER READING

Bossi P et al: Bichat guidelines for the clinical management of tularaemia and bioterrorism-related tularaemia. Euro Surveill 9:E9, 2004.

Centers for Disease Control and Prevention: Tularemia:

United States. Available at https://www.cdc.gov/tularemia/index.html.

Accessed October 3, 2020.

Dennis DT et al: Tularemia as a biological weapon: Medical and public

health management. JAMA 285:2763, 2001.

Maurin M, Gyuranecz M: Tularaemia: Clinical aspects in Europe.

Lancet Infect Dis 16:113, 2016.

World Health Organization: WHO Guidelines on Tularaemia.

Geneva, WHO Press, 2007.

PLAGUE

Plague is a systemic zoonosis caused by Yersinia pestis. It predominantly affects small rodents in rural areas of Africa, Asia, and the

Americas and is usually transmitted to humans by an arthropod

vector (the flea). Less often, infection follows contact with animal

tissues or respiratory droplets. Plague is an acute febrile illness that

is treatable with antimicrobial agents, but mortality rates among

untreated patients are high. Ancient DNA studies have confirmed

that both the fourteenth-century Black Death and the sixth-century

Plague of Justinian in Europe were due to Y. pestis infection. Patients

can present with the bubonic, septicemic, or pneumonic form of the

disease. Although there is concern about epidemic spread of plague

by the respiratory route, this is not the most common route of plague

transmission, and established infection-control measures for respiratory plague exist. However, the fatalities associated with plague and

the capacity for infection via the respiratory tract mean that Y. pestis

fits the profile of a potential agent of bioterrorism (Chap. S3). Consequently, measures have been taken to restrict access to the organism,

including legislation affecting diagnostic and research procedures in

some countries (e.g., the United States).

171 Plague and Other

Yersinia Infections

Michael B. Prentice

Countries reporting human plague cases, 1970−2005 Probable sylvatic foci

FIGURE 171-1 Approximate global distribution of Yersinia pestis. (Compiled from WHO, CDC, and country sources. From DT Dennis, GL Campbell: Plague and other Yersinia

infections, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al [eds]. New York, McGraw-Hill, Chap. 152, 2008.)

■ ETIOLOGY

The genus Yersinia comprises gram-negative bacteria of the order

Enterobacterales (class Gammaproteobacteria). Overwhelming taxonomic and paleogenomic evidence shows Y. pestis recently evolved

from Yersinia pseudotuberculosis, an enteric pathogen of mammals

spread by the fecal–oral route, and thus has a phenotype distinctly

different from that of Y. pestis. When grown in vivo or at 37°C, Y. pestis

forms an amorphous capsule made from a plasmid-specified fimbrial

protein, Caf or fraction 1 (F1) antigen, which is an immunodiagnostic

marker of infection.

■ EPIDEMIOLOGY

Human plague generally follows an outbreak in a host rodent population (epizootic). Mass deaths among the rodent primary hosts lead

to a search by fleas for new hosts, with consequent incidental infection of other mammals. The precipitating cause for an epizootic may

ultimately be related to climate or other environmental factors. The

reservoir for Y. pestis causing enzootic plague in natural endemic foci

between epizootics (i.e., when the organism may be difficult to detect

in rodents or fleas) is a topic of ongoing research and may not be the

same in all regions. The enzootic/epizootic pattern may be the result

of complex dynamic interactions of host rodents that have different

plague susceptibilities with different flea vectors; alternatively, an environmental reservoir may be important.

■ GLOBAL FEATURES

In general, the enzootic areas for plague are lightly populated regions

of Africa, Asia, and the Americas (Fig. 171-1). Between January 2013

and December 2018, 2886 cases of plague with a global case–fatality

rate of 17% were notified to the World Health Organization (WHO)

under the International Health Regulations. More than 97% of these

cases were in Africa. The majority of cases in each year were from the

island of Madagascar, which in 2017 experienced an urban outbreak of

over 2400 clinically suspected cases, with an unusually high proportion

of pneumonic plague (78%). A decline in reports from the Democratic

Republic of the Congo (DRC) may reflect ongoing conflict in that

country affecting surveillance rather than a true decrease. In the past

decade, outbreaks of pneumonic plague have been recorded in the

DRC, Uganda, Algeria, Madagascar, China, and Peru.

Plague was introduced into North America via the port of

San Francisco in 1900 as part of the Third Pandemic, which spread

around the world from Hong Kong. The disease is presently enzootic

on the western side of the continent from southwestern Canada to

Mexico. Most human cases in the United States occur in two regions:

1321CHAPTER 171 Plague and Other Yersinia Infections

1321CHAPTER 171

encoded by the ymt gene on the pFra (pMT1) plasmid, and biofilm

synthesis requires the chromosomal hms locus shared with Y. pseudotuberculosis. Three Y. pseudotuberculosis genes inhibiting biofilm formation or promoting its degradation are inactivated in Y. pestis,

together with urease (urease activity otherwise causes acute flea gastrointestinal toxicity). Blockage takes days or weeks to come about after

initial infection of the flea and is followed by the flea’s death. Many flea

vectors (including X. cheopis) are also able to transmit plague in an

early-phase unblocked state for up to a week after feeding, but 10 fleas

in this state are required to infect a mammalian host (mass

transmission).

Y. pestis disseminates from the site of inoculation in the mammalian

host in a process initially dependent on plasminogen activator Pla,

which is encoded by the small pPCP1 (pPst) plasmid. This surface

protease activates mammalian plasminogen, degrades complement,

and adheres to the extracellular matrix component laminin. Pla is

essential for the high-level virulence of Y. pestis in mice by subcutaneous or intradermal injection (laboratory proxies for fleabites) and for

the development of primary pneumonic plague. When actual fleabite

inoculation is used in mouse models, the fimbrial capsule-forming

protein (Ca1 or fraction 1; F1 antigen) encoded on pFra increases the

efficiency of transmission, and plasminogen activator is required for

the formation of buboes.

Paleogenomics (sequencing of DNA extracts from teeth of ancient

human remains) shows that Y. pestis was a common cause of death in

Eurasia in the Bronze age. Remarkably, the ymt gene is absent from the

pFra (pMT1) plasmid in Y. pestis sequences from remains more than

4000 years old, while pla is present. This suggests that plague was a common fatal human infection before flea-borne transmission was possible,

presumably spread by the pneumonic or gastrointestinal route.

Macrophages, neutrophils, and dendritic cells are all involved in

the innate immune response to flea-transmitted Y. pestis. The organism is taken up by macrophages but avoids being killed by autophagy

and can also survive and replicate in neutrophils. Rapid transport of

the bacteria to regional lymph nodes occurs. Y. pestis then undergoes

extracellular replication with full expression of its antiphagocytic systems: the type III secretion machines and their effectors encoded by

pYV as well as the F1 capsule. These factors prevent neutrophil uptake,

and the type III secretion effectors also block extrusion of microbicidal

DNA by neutrophils and trigger apoptotic cell death. Immune cell

targeting follows binding of the N-formylpeptide receptor (FPR1) on

phagocytic cells by LcrV, the needle cap protein of the type III secretion system. Overproduction of LcrV also exerts an anti-inflammatory

effect, reducing host immune responses. Likewise, Y. pestis lipopolysaccharide is modified to minimize stimulation of host Toll-like receptor

4, thereby reducing protective host inflammatory responses during

peripheral infection and prolonging host survival with high-grade

bacteremia—an effect that probably enhances the pathogen’s subsequent transmission by fleabite.

Replication of Y. pestis in a regional lymph node results in the local

swelling of the lymph node and periglandular region known as a bubo.

On histology, the node is found to be hemorrhagic or necrotic, with

thrombosed blood vessels, and the lymphoid cells and normal architecture are replaced by large numbers of bacteria and fibrin. Periglandular

tissues are inflamed and also contain large numbers of bacteria in a

serosanguineous, gelatinous exudate.

Continued spread through the lymphatic vessels to contiguous

lymph nodes produces second-order primary buboes. Infection is

initially contained in the infected regional lymph nodes, although

transient bacteremia can be detected. As infection progresses, spread

via efferent lymphatics to the thoracic duct produces high-grade bacteremia. Hematogenous spread to the spleen, liver, and secondary buboes

follows, with subsequent uncontrolled septicemia leading to death.

In some patients, this septicemic phase occurs without obvious prior

bubo development or lung disease (septicemic plague). Hematogenous

spread to the lungs results in secondary plague pneumonia, with bacteria initially more prominent in the interstitium than in the air spaces

(the reverse being the case in primary plague pneumonia). Hematogenous spread to other organs, including the meninges, can occur.

“Four Corners” (the junction point of New Mexico, Arizona, Colorado,

and Utah), especially northern New Mexico, northern Arizona, and

southern Colorado; and further west in California, southern Oregon, and western Nevada (www.cdc.gov/plague/maps/). From 1970 to

2017, 482 cases of plague were reported in the United States; in recent

decades incidence has fallen to an average of 7 cases per year. Most

cases occur from May to October—the time of year when people are

outdoors and rodents and their fleas are most plentiful. Prior animal

contact occurs in at least 50% of cases, and about 60% of these include

domestic animals (usually dogs or cats) that brought wild animals or

plague-infected fleas home. Infected cats or dogs may transmit plague

directly to humans by the respiratory route. A slightly lower percentage

of prior animal contacts involve direct handling of living or dead wild

small mammals (e.g., rabbits, hares, prairie dogs) or wild carnivores

(e.g., wildcats, coyotes, mountain lions). In 2014, an outbreak of nonfatal pneumonic plague in Colorado affected four people exposed to an

infected dog, with possible interhuman transmission in one case. Prior

to this report, the most recent case of person-to-person transmission

in the United States occurred in the Los Angeles pneumonic plague

outbreak of 1924.

Plague most often develops in areas with poor sanitary conditions

and infestations of rats—in particular, the widely distributed roof rat

Rattus rattus and the brown rat Rattus norvegicus (which serves as a

laboratory model of plague). Rat control in warehouses and shipping

facilities has been recognized as important in preventing the spread

of plague since the early twentieth century and features in the current

WHO International Health Regulations. Urban rodents acquire infection from wild rodents, and the proximity of the former to humans

increases the risk of transmission. The oriental rat flea Xenopsylla

cheopis is the most efficient vector for transmission of plague among

rats and onward to humans in Asia, Africa, and South America.

Worldwide, bubonic plague is the predominant form reported

(80–95% of suspected cases), with mortality rates of 10–20%. The mortality rate is higher (22%) in the small proportion of patients (10–20%)

with primary septicemic plague (i.e., systemic Y. pestis sepsis with no

bubo; see “Clinical Manifestations,” below) and is highest with primary

pulmonary plague. The latter is generally the least common of the main

plague presentations, but, as in the 2017 Madagascar outbreak, it is

occasionally predominant. Mortality rates of 50% or more for primary

pulmonary plague are reported with delayed antimicrobial treatment

in small case series from the older literature. Rare outbreaks of pharyngeal plague following consumption of raw or undercooked camel or

goat meat have been reported.

A total of 744 (82%) of the 913 plague cases with clinically documented features (out of 1006 cases reported in total) in the United

States from 1900 to 2012 were bubonic disease, 87 (10%) were septicemic disease, and 74 (8%) were pneumonic disease; 6 cases (1%) were

pharyngeal. Sixteen percent of cases were fatal in the postantibiotic era

from 1942 onward compared with 66% in the period 1900–1941.

■ PATHOGENESIS

As mentioned earlier, genetic evidence shows Y. pestis is a clone

derived from the enteric pathogen Y. pseudotuberculosis in the

recent evolutionary past (7000–50,000 years ago). The change

from infection by the fecal–oral route to a two-stage life cycle, with

alternate parasitization of arthropod and mammalian hosts, occurred

as a result of two plasmid gene acquisitions (pla on pPCP1/pPst and

ymt on pFra/pMT1), and the inactivation of a handful of Y. pseudotuberculosis genes, in conjunction with preexisting properties of the Y.

pseudotuberculosis ancestor, including the presence of a virulence plasmid, pYV, and the capacity to cause septicemia. In the arthropodparasitizing portion of its life cycle, Y. pestis multiplies and forms biofilm-embedded aggregates in the flea midgut after ingestion of a blood

meal containing bacteria. In some fleas, biofilm-embedded bacteria

eventually fill the proventriculus (a valve connecting the esophagus to

the midgut) and block normal blood feeding. Both “blocked” fleas and

those containing masses of biofilm-embedded Y. pestis without complete blockage inoculate Y. pestis into each bite site. The ability of Y.

pestis to colonize and multiply in the flea requires phospholipase D