1322 PART 5 Infectious Diseases

FIGURE 171-2 Plague patient in the southwestern United States with a left axillary

bubo and an unusual plague ulcer and eschar at the site of the infective flea bite.

(Reproduced with permission from AS Fauci et al: Harrison’s Principles of Internal

Medicine, 17th ed. New York: McGraw-Hill; 2008.)

■ CLINICAL MANIFESTATIONS

Bubonic Plague After an incubation period of 2–6 days, the onset

of bubonic plague is sudden and is characterized by fever (>38°C),

malaise, myalgia, dizziness, and increasing pain due to progressive

lymphadenitis in the regional lymph nodes near the fleabite or other

inoculation site. Lymphadenitis manifests as a tense, tender swelling

(bubo) that, when palpated, has a boggy consistency with an underlying hard core. Generally, there is one painful and erythematous bubo

with surrounding periganglionic edema. The bubo is most commonly

inguinal but can also be crural, axillary (Fig. 171-2), cervical, or submaxillary, depending on the site of the bite. Abdominal pain from

intraabdominal node involvement can occur without other visible signs.

Children are most likely to present with cervical or axillary buboes.

The differential diagnosis includes acute focal lymphadenopathy

of other etiologies, such as streptococcal or staphylococcal infection,

tularemia, cat-scratch disease, tick typhus, infectious mononucleosis,

or lymphatic filariasis. These infections do not progress as rapidly, are

not as painful, and are associated with visible cellulitis or ascending

lymphangitis—both of which are absent in plague.

Without treatment, Y. pestis dissemination occurs and causes

serious illness, including pneumonia (secondary pneumonic plague)

and meningitis. Secondary pneumonic plague can be the source of

person-to-person transmission of respiratory infection by productive

cough (droplet infection), with the consequent development of primary plague pneumonia. Appropriate treatment of bubonic plague

results in fever resolution within 2–5 days, but buboes may remain

enlarged for >1 week after initial treatment and can become fluctuant.

Primary Septicemic Plague A minority (10–25%) of infections

with Y. pestis present as gram-negative septicemia (hypotension, shock)

without preceding lymphadenopathy. Septicemic plague occurs in all

age groups, but persons >40 years of age are at elevated risk. Some

chronic conditions may predispose to septicemic plague: in 2009 in

the United States, a fatal laboratory-acquired infection with an attenuated Y. pestis strain manifested as septicemic plague in a 60-year-old

researcher with diabetes mellitus and undiagnosed hemochromatosis.

These conditions also carry an increased risk of septicemia with other

pathogenic Yersinia species. The term septicemic plague can be confusing since most patients with buboes have detectable bacteremia

at some stage, with or without systemic signs of sepsis. In laboratory

experiments, however, septicemic disease without histologic changes in

lymph nodes is seen in a minority of mice infected via fleabites.

Pneumonic Plague Primary pneumonic plague results from inhalation of infectious bacteria in droplets expelled from another person

or an animal with primary or secondary plague pneumonia. This

syndrome has a short incubation period, averaging from a few hours

to 2–3 days (range, 1–7 days), and is characterized by a sudden onset

of fever, headache, myalgia, weakness, nausea, vomiting, and dizziness. Respiratory signs—cough, dyspnea, chest pain, and sputum

production with hemoptysis—typically arise after 24 h. Progression of

initial segmental pneumonitis to lobar pneumonia and then to bilateral lung involvement may occur (Fig. 171-3). The possible release

of aerosolized Y. pestis bacteria in a bioterrorist attack, manifesting as

an outbreak of primary pneumonic plague in nonendemic regions or

in an urban setting where plague is rarely seen, has been a source of

public health concern. Secondary pneumonic plague is a consequence

of bacteremia occurring in ~10–15% of patients with bubonic plague.

Bilateral alveolar infiltrates are seen on chest x-ray, and diffuse interstitial pneumonitis with scanty sputum production is typical.

Meningitis Meningeal plague is uncommon, occurring in ≤6% of

plague cases reported in the United States. Presentation with headache

and fever typically occurs >1 week after the onset of bubonic or septicemic plague and may be associated with suboptimal antimicrobial

therapy (delayed therapy, penicillin administration, or low-dose tetracycline treatment) and cervical or axillary buboes.

Pharyngitis Symptomatic plague pharyngitis can follow the consumption of contaminated meat from an animal dying of plague or

contact with persons or animals with pneumonic plague. This condition can resemble tonsillitis, with peritonsillar abscess and cervical

lymphadenopathy. Asymptomatic pharyngeal carriage of Y. pestis can

also occur in close contacts of patients with pneumonic plague.

■ LABORATORY DIAGNOSIS

Because of the scarcity of laboratory facilities in regions where human

Y. pestis infection is most common, and because of the potential significance of Y. pestis isolation in a nonendemic area or an area from which

human plague has been absent for many years, the WHO recommends an

initial presumptive diagnosis followed by reference laboratory confirmation (Table 171-1). In the United States, comprehensive national diagnostic facilities for plague have been in place since 1999 (Laboratory Response

Network for Biological Threats; emergency.cdc.gov/lrn/) to detect possible

use of biological terrorism agents, including Y. pestis. Routine diagnostic

clinical microbiology laboratories that are included in this network as

sentinel-level laboratories use joint protocols from the Centers for Disease

Control and Prevention (CDC) and the American Society for Microbiology (https://asm.org/Articles/Policy/Laboratory-Response-NetworkLRN-Sentinel-Level-C) to identify suspected Y. pestis isolates and to refer

these specimens to LRN reference laboratories for confirmatory tests. Y.

pestis is designated a “Tier 1 select agent” under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 and subsequent executive orders; the provisions of this act, the Patriot Act of 2001,

and related executive orders apply to all U.S. laboratories and individuals

working with Y. pestis. Details of the applicable regulations are available

from the CDC (www.selectagents.gov).

Yersinia species are gram-negative coccobacilli (short rods with

rounded ends) 1–3 μm in length and 0.5–0.8 μm in diameter. Y. pestis

in particular appears bipolar (with a “closed safety pin” appearance)

and pleomorphic when stained with a polychromatic stain (Wayson or

Wright-Giemsa; Fig. 171-4). Its lack of motility distinguishes Y. pestis

from other Yersinia species, which are motile at 25°C and nonmotile

at 37°C. Transport medium (e.g., Cary-Blair medium) preserves the

viability of Y. pestis if transport is delayed.

The appropriate specimens for diagnosis of bubonic, pneumonic,

and septicemic plague are bubo aspirate, bronchoalveolar lavage fluid

or sputum, and blood, respectively. Culture of postmortem organ

biopsy samples also can be diagnostic. A bubo aspirate is obtained

1323CHAPTER 171 Plague and Other Yersinia Infections

1323CHAPTER 171

by injection of 1 mL of sterile normal saline into a bubo under local

anesthetic and aspiration of a small amount of (usually blood-stained)

fluid. The WHO has provided interim guidance on how to aspirate

buboes and collect sputum from patients with suspected pneumonic

plague (www.who.int/csr/disease/plague/collecting-sputum-samples.

PDF). Gram’s staining of these specimens may reveal gram-negative

rods, which are shown by Wayson or Wright-Giemsa staining to be

bipolar. These bacteria may even be visible in direct blood smears in

septicemic plague (Fig. 171-4); this finding indicates very high numbers of circulating bacteria and a poor prognosis.

Y. pestis grows on nutrient agar and other standard laboratory

media but forms smaller colonies than do other Enterobacteriaceae.

FIGURE 171-3 Sequential chest radiographs of a patient with fatal primary plague pneumonia. Left: Upright posteroanterior film taken at admission to hospital emergency

department on third day of illness, showing segmental consolidation of right upper lobe. Center: Portable anteroposterior film taken 8 h after admission, showing extension

of pneumonia to right middle and right lower lobes. Right: Portable anteroposterior film taken 13 h after admission (when patient had clinical acute respiratory distress

syndrome), showing diffuse infiltration throughout right lung and patchy infiltration of left lower lung. A cavity later developed at the site of initial right-upper-lobe

consolidation. (Reproduced with permission from AS Fauci et al: Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill; 2008.)

Specimens should be inoculated onto nutrient-rich media such as

sheep blood agar (SBA), into nutrient-rich broth such as brain-heart

infusion broth, and onto selective agar such as MacConkey or eosin

methylene blue (EMB) agar. Yersinia-specific CIN (cefsulodin, triclosan [Irgasan], novobiocin) agar can be useful for culture of contaminated specimens, such as sputum. Blood should be cultured in

a standard blood culture system. The optimal growth temperature is

<37°C (25–29°C), with pinpoint colonies only on SBA at 24 h. Slower

growth occurs at 37°C. Y. pestis is oxidase-negative, catalase-positive,

urease-negative, indole-negative, and lactose-negative. Automated biochemical or mass spectrometry identification systems can misidentify

Y. pestis as Y. pseudotuberculosis or other bacterial species.

Reference laboratory tests for definitive identification of isolates

include direct immunofluorescence for F1 antigen; specific polymerase

chain reaction (PCR) for targets such as F1 antigen, the pesticin gene,

and the plasminogen activator gene; and specific bacteriophage lysis.

PCR can also be applied to diagnostic specimens, as can direct immunofluorescence for F1 antigen (produced in large amounts by Y. pestis)

by slide microscopy. An immunochromatographic test strip for F1

antigen detection by monoclonal antibodies in clinical specimens has

been devised in Madagascar. This method is effective for both laboratory and near-patient use and is now widely used in endemic countries.

A similar test strip for Pla antigen has been developed and could be

used to detect wild-type or engineered F1-negative virulent strains. In

TABLE 171-1 World Health Organization Case Definitions of Plague

Suspected Case

Compatible clinical presentation

And

Consistent epidemiologic features, such as exposure to infected animals or

humans and/or evidence of fleabites and/or residence in or travel to a known

endemic focus within the previous 10 days

Presumptive Case

Meeting the definition of a suspected case

Plus

Putative new or reemerging focus: ≥2 of the following tests positive

•  Microscopy: gram-negative coccobacilli in material from bubo, blood, or

sputum; bipolar appearance of Wayson or Wright-Giemsa staining

• F1 antigen detected in bubo aspirate, blood, or sputum

•  A single anti-F1 serology without evidence of previous Yersinia pestis infection

or immunization

•  PCR detection of Y. pestis in bubo aspirate, blood, or sputum

Known endemic focus: ≥1 of the above tests positive

Confirmed Case

Meeting the definition of a suspected case

Plus

•  Identification of an isolate from a clinical sample as Y. pestis (colonial

morphology and 2 of the following 4 tests positive: phage lysis of cultures at

20–25°C and 37°C; F1 antigen detection; PCR; Y. pestis biochemical profile)

Or

•  A fourfold rise in anti-F1 titer in paired serum samples

Or

•  In endemic areas when no other confirmatory test can be performed, a

positive rapid diagnostic test with immunochromatography to detect F1 antigen

Abbreviation: PCR, polymerase chain reaction.

Source: Reproduced with permission from Interregional meeting on prevention and

control of plague, World Health Organization, 2006.

FIGURE 171-4 Peripheral-blood smear from a patient with fatal plague septicemia

and shock, showing characteristic bipolar-staining Yersinia pestis bacilli (Wright’s

stain, oil immersion). (Reproduced with permission from AS Fauci et al: Harrison’s

Principles of Internal Medicine, 17th ed. New York: McGraw-Hill; 2008.)

1324 PART 5 Infectious Diseases

the 2017 Madagascar outbreak, diagnosis by F1-antigen strip or molecular diagnosis from sputum proved more challenging than from bubo

aspirates because of the normal respiratory microbiota. Twenty-three

percent of pneumonic plague cases had a positive culture, strip, or

molecular diagnostic test compared to 45% of bubonic cases. This

suggests assays involving multiple real-time PCR targets are required to

augment conventional culture with sputum. Yersinia pestis is included

in the FDA-authorized Biofire® FilmArray® Next Generation Diagnostic System (NGDS) Warrior Panel for use with the FilmArray®

2.0 system (Biomérieux) as a medical diagnostic device suitable for

whole blood (EDTA), blood cultures and sputum specimens by U.S.

Department of Defense laboratories, and laboratories designated by the

Department of Defense. Detailed phylogeographic DNA sequence data

based on culture collections have been accumulated to trace plague

evolution, and this approach could be adapted in the future to real-time

clinical plague epidemiology.

In the absence of other positive laboratory diagnostic tests, a retrospective serologic diagnosis may be made on the basis of rising titers

of hemagglutinating antibody to F1 antigen. Enzyme-linked immunosorbent assays (ELISAs) for IgG and IgM antibodies to F1 antigen are

also available.

The white blood cell (WBC) count is generally raised (to 10,000–

20,000/μL) in plague, with neutrophilic leukocytosis and a left shift

(numerous immature neutrophils); in some cases, however, the WBC

count is normal or leukopenia develops. WBC counts are occasionally

very high, especially in children (>100,000/μL). Levels of fibrinogen

degradation products are elevated in a majority of patients, but platelet counts are usually normal or low-normal. However, disseminated

intravascular coagulation, with low platelet counts, prolonged prothrombin times, reduced fibrinogen, and elevated fibrinogen degradation

product levels, occurs in a significant minority of patients.

TREATMENT

Plague

Guidelines for the treatment of plague are given in Table 171-2. A

10- to 14-day course of antimicrobial therapy (or a course continued

until 2 days after fever subsides) is recommended. Streptomycin has

historically been the parenteral treatment of choice for plague and is

approved for this indication by the FDA. Although not yet approved

by the FDA for plague, gentamicin has proved safe and effective

in clinical trials in Tanzania and Madagascar and in retrospective

reviewed cases in the United States. In view of streptomycin’s

adverse-reaction profile and limited availability, some experts now

recommend gentamicin over streptomycin. The FDA has approved

levofloxacin, moxifloxacin, and ciprofloxacin for prophylaxis and

treatment of plague (including septicemic and pneumonic plague)

under a regulatory approach based on animal studies alone, known

as the Animal Rule. Levofloxacin has more efficacy than ciprofloxacin in postexposure prophylaxis of inhalational anthrax in animal

models and has also received FDA approval for this indication

(Chap. S3); thus it is a suitable agent for prophylaxis against two

diseases in possible bioterrorism exposures.

While systemic chloramphenicol therapy is available in the

resource-poor countries primarily affected by plague, it is less

likely to be available or used in high-income countries because of

its adverse-effect profile. Tetracyclines are also effective and can be

given by mouth but are not generally recommended for children

age <7 years because of tooth discoloration. Doxycycline is the

tetracycline of choice; at an oral dosage of 100 mg twice daily, this

drug was as effective as intramuscular gentamicin (2.5 mg/kg twice

daily) in a trial in Tanzania. There is recent evidence that doxycycline does not cause dental staining in children because it binds

calcium less readily than other tetracyclines. Because of reduced

efficacy in some non-human primate models of pneumonic plague,

CDC recommends doxycycline as a first line agent for bubonic

plague and an alternative agent for septicemic and pneumonic

plague.

Although Y. pestis is sensitive to β-lactam drugs in vitro and

these drugs have been efficacious against plague in some animal

models, the response to penicillins has been poor in some clinical

cases; thus β-lactams and macrolides are not generally recommended as first-line therapy. Chloramphenicol, alone or in combination, is recommended for some focal complications of plague

(e.g., meningitis, endophthalmitis, myocarditis) because of its tissue

penetration properties. Fluoroquinolones, effective in vitro and

in animal models, are recommended in guidelines for possible

bioterrorism-associated pneumonic plague and are increasingly

used in plague therapy.

■ PREVENTION

In endemic areas, the control of plague in humans is based on reduction of the likelihood of being bitten by infected fleas or exposed to

TABLE 171-2 Guidelines for the Treatment of Plague

DRUG DAILY DOSE

DOSING

INTERVAL, h ROUTE

Gentamicin

Adult  5 mg/kga 24 IM/IV

Child 4.5-7.5 mg/kga 24 IM/IV

Streptomycin

Adult 2 g 12 IM

Child 30 mg/kg (maximum 1 g

per dose)

12 IM

Levofloxacin

Adult (child >50 kg) 750 (500-750) mg 24 PO/IV

Child <50 kg and

≥6 months of age

16 mg/kg (maximum,

250 mg/dose)

12 PO/IV

Ciprofloxacin

Adult 1500 mg 12 PO

1200 mg 8 IV

Child 30-45 mg/kg (maximum,

500 mg/dose)

8-12 PO

20-30 mg/kg (maximum,

400 mg/dose)

8-12 IV

Moxifloxacin

Adult 400 mg (no loading dose) 24 PO/IV

Doxycycline

Adult and child ≥45 kg 200 mg (200 mg loading dose) 12 PO/IV

Child <45 kg 4.4 mg/kg (maximum, 100 mg/

dose), 4.4 mg/kg loading dose

12 PO/IV

Tetracycline

Adult 2 g 6 PO/IV

Child >8 yr 40–50 mg/kg 6 PO/IV

Chloramphenicol

Adult 50-100 mg/kg 6 PO/IV

Child >2 yr 50-100 mg/kg (maximum, 4 g) 6 PO/IV

a

Aminoglycoside dose is adjusted with impaired renal function. No trial data have

been published for once-daily gentamicin therapy for plague in adults or children,

but this regimen is efficacious in gram-negative sepsis of other etiologies and

has been successful in a recent outbreak of pneumonic plague in the Democratic

Republic of the Congo. Neonates (up to 1 week of age) should receive gentamicin at

4 mg/kg IV once daily.

Source: TV Inglesby et al: Plague as a biological weapon: Medical and public

health management. Working Group on Civilian Biodefense. JAMA 283:2281, 2000;

and https://www.cdc.gov/plague/healthcare/clinicians.html. For detailed guidelines

on recommended regimens for pneumonic vs bubonic plague, plague meningitis,

treatment during pregnancy and lactation, and neonatal infection see CA Nelson

et al: Antimicrobial treatment and prophylaxis of plague: Recommendations for

naturally acquired infections and bioterrorism response. MMWR Recomm Rep

70(No. RR-3):1, 2021.

1325CHAPTER 171 Plague and Other Yersinia Infections

1325CHAPTER 171

infected droplets from either humans or animals with plague pneumonia. In the United States, residence and outdoor activity or contact with

wild or pet animals in rural areas of western states where epizootics

occur are the main risk factors for infection. To assess potential risks

to humans in specific areas, surveillance for Y. pestis infection among

animal plague hosts and vectors is carried out regularly as well as in

response to observed animal die-offs. Personal protective measures

include avoidance of areas where a plague epizootic has been identified

and publicized (e.g., by warning signs or closure of campsites). Sick or

dead animals should not be handled by the general public. Hunters,

zoologists and pet-owners should wear gloves if handling wild-animal

carcasses in endemic areas. General measures to avoid rodent fleabite

during outdoor activity are appropriate and include the use of insect

repellent, insecticide, and protective clothing. General measures to

reduce peridomestic and occupational human contact with rodents

are advised and include rodent-proofing of buildings and food-waste

stores and removal of potential rodent habitats (e.g., woodpiles and

junk heaps). Flea control by insecticide treatment of wild rodents is an

effective means of minimizing human contact with plague if an epizootic is identified in an area close to human habitation. Any attempt to

reduce rodent numbers must be preceded by flea suppression to reduce

the migration of infected fleas to human hosts. An oral F1-V subunit

vaccine using raccoon poxvirus (RCN) as a vector (sylvatic plague

vaccine) is partially protective against plague when administered to

wild prairie dogs in field trials and may in the future provide a means

of reducing the risk of human exposure to Y. pestis.

Patients in whom pneumonic plague is suspected should be managed in isolation (with negative pressure, if available), with droplet

precautions observed until pneumonia is excluded or effective antimicrobial therapy has been given for 48 h. Review of the literature published before the advent of antimicrobial agents suggests that the main

infective risk is posed by patients in the final stages of disease who are

coughing up sputum with plentiful visible blood and/or pus. Cotton

and gauze masks were protective in these circumstances. Current surgical masks capable of barrier protection against droplets, including

large respiratory particles, are probably protective, but the differential

diagnosis of fever and hemoptysis in plague-endemic areas includes

aerosol-transmitted infections such as tuberculosis. In addition, WHO

guidance recommends that personal protective equipment for potential aerosol-generating procedures (e.g., collection of respiratory samples from patients with suspected or confirmed plague) should include

a fit-tested N95 face mask, a gown, gloves, and a face shield or goggles.

Antimicrobial Prophylaxis Postexposure antimicrobial prophylaxis lasting 7 days is recommended following household, hospital, or

other close contact with persons with untreated pneumonic plague.

(Close contact is defined as contact with a patient at <2 m.) In animal

aerosol-infection studies, levofloxacin and ciprofloxacin are associated

with higher survival rates than doxycycline (Table 171-3).

Immunization Studies with candidate plague vaccines in animal

models show that neutralizing antibody provides protection against

exposure but that cell-mediated immunity is critical for protection

and clearance of Y. pestis from the host. A killed whole-cell vaccine

used in humans required multiple doses, caused significant local and

systemic reactions, and was not protective against pneumonic plague;

this vaccine is not currently available. A live attenuated vaccine based

on strain EV76 is still used in countries of the former Soviet Union

and China but has significant side effects. Different subunit vaccines

devised by governmental agencies in the United States, UK, and China

all comprising recombinant F1 (rF1) and various recombinant V (rV)

proteins produced in Escherichia coli, combined either as a fusion protein or as a mixture, purified, and adsorbed to aluminum hydroxide

for injection are close to licensing. This combination protects mice

and various nonhuman primates in laboratory models of bubonic and

pneumonic plague and has been evaluated in phase 2 clinical trials.

Prelicensing field-efficacy studies (phase 3 trials) are difficult to devise

because of plague epidemiology. In the United States, the FDA will

assess plague vaccines for human use under the Animal Rule, using

efficacy data from animal studies and antibodies and other correlates of

immunity from human vaccinees (www.fda.gov/emergencypreparedness/

counterterrorism/medicalcountermeasures/mcmregulatoryscience/

ucm391604.htm), and the rF1-V subunit vaccine has orphan drug

status. The World Health Organization has produced a target product

profile (TPP) for phase 3 trial design and prioritization of the 17 known

vaccine candidates. These include protein subunit vaccines, live-attenuated

vaccines, and bacterial, viral, and bacteriophage vectors, or outer membrane vesicles, carrying Y. pestis antigens. Antigens other than F1 and

V are being investigated because of the recovery of F1-negative Y. pestis

strains from natural sources and the observation that F1 antigen is not

required for virulence in primate models of pneumonic plague.

YERSINIOSIS

Yersiniosis is a zoonotic infection with an enteropathogenic Yersinia species, usually Y. enterocolitica or Y. pseudotuberculosis. The usual hosts for

these organisms are pigs and other wild and domestic animals; humans

are usually infected by the oral route, and outbreaks from contaminated

food occur. Yersiniosis is most common in childhood and in colder

climates. Patients present with abdominal pain and sometimes with

diarrhea (which may not occur in up to 50% of cases). Y. enterocolitica

is more closely associated with terminal ileitis and Y. pseudotuberculosis

with mesenteric adenitis, but both organisms may cause mesenteric

adenitis and symptoms of abdominal pain and tenderness that result

in pseudoappendicitis, with the surgical removal of a normal appendix.

Diagnosis was historically based on culture of the organism or convalescent serology, but proprietary multiplex PCR systems for gastrointestinal

infection diagnosis now include Y. enterocolitica. Y. pseudotuberculosis

and some rarer strains of Y. enterocolitica (serogroup O:8) are especially

likely to cause systemic infection, which is also more likely in patients

with diabetes or iron overload. Systemic sepsis is treatable with antimicrobial agents, but postinfective arthropathy responds poorly to such

therapy. Sixteen other Yersinia species lacking the virulence plasmid

pYV common to Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica are

now recognized. These are, at most, opportunistic pathogens of humans

(Y. aldovae, Y. aleksiciae, Y. bercovieri, Y. entomophaga, Y. frederiksenii,

Y. hibernica, Y. intermedia, Y. kristensenii, Y. massiliensis, Y. mollaretii,

Y. nurmii, Y. pekkanenii, Y. rohdei, Y. similis, Y. ruckeri, and Y. wautersii).

Whole genome sequencing has recently detected several more probable

novel Yersinia species. Molecular phylogeny shows that Y. enterocolitica

is more distantly related to Y. pseudotuberculosis than these other

TABLE 171-3 Guidelines for Plague Prophylaxis

DRUG DAILY DOSE

DOSING

INTERVAL, h ROUTE

Doxycycline

Adult 200 mg 12 or 24 PO

Child ≥8 y ≥45 kg: adult dose 12 PO

≤45 kg: 2.2 mg/kg bid

(maximum, 200 mg)

12 PO

Tetracycline

Adult 2 g 6 or 12 PO

Child ≥8 y 40 mg/kg (maximum

500 mg/dose)

6 or 12 PO

Levofloxacin

Adult and child >50 kg 500-750 mg 24 PO

Child <50 kg and

≥6 months of age

16 mg/kg (maximum,

250 mg/dose)

12 PO

Ciprofloxacin

Adult 1-1.5 g 12 PO

Child 30 mg/kg (maximum

750 mg dose)

12 PO

Source: TV Inglesby et al: Plague as a biological weapon: Medical and public health

management. Working Group on Civilian Biodefense. JAMA 283:2281, 2000; https://

www.cdc.gov/plague/healthcare/clinicians.html; CA Nelson et al: Antimicrobial

treatment and prophylaxis of plague: Recommendations for naturally acquired

infections and bioterrorism response. MMWR Recomm Rep 70(No. RR-3):1, 2021.

1326 PART 5 Infectious Diseases

Yersinia species, and the similar virulence plasmid they share has probably been acquired independently by at least one of the two since the

species diverged.

■ EPIDEMIOLOGY

Y. enterocolitica Y. enterocolitica is found worldwide and has been isolated from a wide variety of wild and domestic animals and environmental samples, including samples of food and water. In vitro, Y. enterocolitica

is resistant to predation by the protozoon Acanthamoeba castellani and

can survive inside it, suggesting a possible mode of environmental persistence. Strains are differentiated by combined biochemical reactions

(biovar) and serogroup, and increasingly by whole genome sequence.

Most clinical infections are associated with serogroups O:3, O:9, and

O:5,27, with a declining number of O:8 infections in North America.

Some O:8 infections, previously confined to North America, have been

reported from Europe and Japan in recent years, and O:8 infections

caused a high percentage of yersiniosis cases in Poland in 2008–2011,

with a subsequent decline. Yersiniosis, >99% due to Y. enterocolitica,

remains the third commonest bacterial food-borne zoonosis reported

in Europe, especially prevalent in Germany and Scandinavia. The incidence is highest among children; children <4 years of age are more likely

to present with diarrhea than are older children. Abdominal pain with

mesenteric adenitis and terminal ileitis is more prominent among older

children and adults. Septicemia is more likely in patients with preexisting conditions such as diabetes mellitus, liver disease, any condition

involving iron overload (including thalassemia and hemochromatosis),

advanced age, malignancy, or HIV/AIDS. As in enteritis of other bacterial etiologies, postinfective complications such as reactive arthritis occur

mainly in individuals who are HLA-B27 positive. Erythema nodosum

(Fig. A1-39) following Yersinia infection is not associated with HLA-B27

and is more common among women than among men.

Consumption or preparation of raw pork products (such as chitterlings) and some processed pork products is strongly linked with

infection because a high percentage of pigs carry pathogenic Y.

enterocolitica strains. Outbreaks of Y. enterocolitica infection have been

associated with consumption of milk (pasteurized, unpasteurized,

and chocolate-flavored) and various foods contaminated with spring

water. Person-to-person transmission is suspected in a few cases (e.g.,

in nosocomial and familial outbreaks) but is much less likely with

Y. enterocolitica than with other causes of gastrointestinal infection,

such as Salmonella. A multivariate analysis indicates that contact with

companion animals is a risk factor for Y. enterocolitica infection among

children in Sweden, and low-level colonization of dogs and cats with

Y. enterocolitica has been reported. Transfusion-associated septicemia

due to Y. enterocolitica, while recognized as a very rare but frequently

fatal event for >30 years, has been difficult to eradicate.

Y. pseudotuberculosis Y. pseudotuberculosis is much less frequently

reported as a cause of human disease than Y. enterocolitica, and infection

with Y. pseudotuberculosis is more likely to present as fever and abdominal pain due to mesenteric lymphadenitis and to be identified from a

blood culture isolate. This organism is associated with wild mammals

(rodents, rabbits, and deer), birds, and domestic pigs. Although outbreaks are generally rare, several have recently occurred in Finland in

association with consumption of lettuce, raw carrots, or unpasteurized

milk. Strains have historically been differentiated by combined biochemical reactions (biovar) and serogroup. Multilocus sequence typing shows

that some strains previously assigned to Y. pseudotuberculosis belong

to the closely related but distinct species now called Yersinia wautersii

(opportunistic pathogenic) and Yersinia similis (nonpathogenic).

■ PATHOGENESIS

The usual route of infection is oral. Studies with both Y. enterocolitica

and Y. pseudotuberculosis in animal models suggest that initial replication in the small intestine is followed by invasion of Peyer’s patches of

the distal ileum via M cells, with onward spread to mesenteric lymph

nodes. The liver and spleen also can be involved after oral infection.

The characteristic histologic appearance of enteropathogenic Yersinia

after invasion of host tissues is as extracellular microabscesses surrounded by an epithelioid granulomatous lesion.

Experiments involving oral infection of mice with tagged Y. enterocolitica show that only a very small proportion of bacteria in the gut

invade tissues. Individual bacterial clones from an orally inoculated

pool give rise to each microabscess in a Peyer’s patch, and the host

restricts the invasion of previously infected Peyer’s patches. A prior

model positing progressive bacterial spread from Peyer’s patches and

mesenteric lymph nodes to the liver and spleen appears to be inaccurate: spread of Y. pseudotuberculosis and Y. enterocolitica to the liver and

spleen of mice occurs independently of regional lymph node colonization and in mice lacking Peyer’s patches.

Invasion requires the expression of several nonfimbrial adhesins, such as invasin (Inv) and—in Y. pseudotuberculosis—

Yersinia adhesin A (YadA). Inv interacts directly with β1

integrins, which are expressed on the apical surfaces of M cells but

not enterocytes. YadA of Y. pseudotuberculosis interacts with extracellular matrix proteins such as collagen and fibronectin to facilitate

host cell integrin association and invasion. YadA of Y. enterocolitica lacks

a crucial N-terminal region and binds collagen and laminin but not

fibronectin and does not cause invasion. Inv is chromosomally

encoded, whereas YadA is encoded on the virulence plasmid pYV.

YadA also helps to confer serum resistance in Y. enterocolitica by

binding host complement regulators such as factor H and C4-binding

protein. Another chromosomal gene, ail (attachment and invasion

locus), encodes the extracellular protein Ail, which is the main factor

conferring serum resistance in Y. pseudotuberculosis by binding these

complement regulators.

By binding to host cell surfaces, YadA allows targeting of immune

effector cells by the pYV plasmid–encoded type III secretion system

(injectisome). As a consequence, the host’s innate immune response is

altered; toxins (Yersinia outer proteins, or Yops) are injected into host

macrophages, neutrophils, and dendritic cells, affecting signal transduction pathways, resulting in reduced phagocytosis and inhibited

production of reactive oxygen species by neutrophils, and triggering

apoptosis of macrophages. Other factors functional in invasive disease

include yersiniabactin (Ybt), a siderophore produced by some strains of

Y. pseudotuberculosis and Y. enterocolitica as well as other Enterobacterales.

Ybt allows bacteria to access iron from saturated lactoferrin during infection and reduces production of reactive oxygen species by innate immune

effector cells, thereby decreasing bacterial killing. Y.  pseudotuberculosis

and Y. pestis make other siderophores apart from Ybt.

■ CLINICAL MANIFESTATIONS

Self-limiting diarrhea is the most common reported presentation in

infection with pathogenic Y. enterocolitica, especially in children <4 years

of age, who form the single largest group in most case series. Blood may

be detected in diarrheal stool. Older children and adults are more likely

than younger children to present with abdominal pain, which can be

localized to the right iliac fossa—a situation that often leads to laparotomy for presumed appendicitis (pseudoappendicitis). Appendectomy

is not indicated for Yersinia infection causing pseudoappendicitis.

Thickening of the terminal ileum and cecum is seen on endoscopy

and ultrasound, with elevated round or oval lesions that may overlie

Peyer’s patches. Mesenteric lymph nodes are enlarged. Ulcerations of

the mucosa are noted on endoscopy. Gastrointestinal complications

include granulomatous appendicitis, a chronic inflammatory condition

affecting the appendix that is responsible for ≤2% of cases of appendicitis; Yersinia is involved in a minority of cases. Y. enterocolitica infection

can present as acute pharyngitis with or without other gastrointestinal symptoms. Fatal Y. enterocolitica pharyngitis has been recorded.

Mycotic aneurysm can follow Y. enterocolitica bacteremia, as can focal

infection (abscess) in many other sites and body compartments (liver,

spleen, kidney, bone, meninges, endocardium).

Y. pseudotuberculosis infection is more likely to present as abdominal pain and fever than as diarrhea. A superantigenic toxin—Y. pseudotuberculosis mitogen (YPM)—is produced by strains seen in eastern

Russia in association with Far Eastern scarlet-like fever, a childhood

illness with desquamating rash, arthralgia, and toxic shock. A similar

illness is recognized in Japan (Izumi fever) and Korea. Similarities have

been noted with Kawasaki disease, the idiopathic acute systematic vasculitis of childhood. There is an epidemiologic link between exposure

1327CHAPTER 171 Plague and Other Yersinia Infections

1327CHAPTER 171

of populations to superantigen-positive Y. pseudotuberculosis and an

elevated incidence of Kawasaki disease.

Y. enterocolitica or Y. pseudotuberculosis septicemia presents as a

severe illness with fever and leukocytosis, often without localizing features, and is significantly associated with predisposing conditions such

as diabetes mellitus, liver disease, and iron overload. Hemochromatosis

combines several of these risk factors. Administration of iron chelators

like deferoxamine, which provide iron accessible to Yersinia (and have

an inhibitory effect on neutrophil function), may result in Yersinia

septicemia in patients with iron overload who presumably have an otherwise mild gastrointestinal infection. HIV/AIDS has been associated

with Y.  pseudotuberculosis septicemia. The unusual phenomenon of

transfusion-associated septicemia is linked to the ability of Y. enterocolitica to multiply at refrigerator temperature (psychrotrophy). Typically,

the transfused unit has been stored for >20 days, and it is believed that

small numbers of yersiniae from an apparently healthy donor with

subclinical bacteremia are amplified to very high numbers by growth

inside the bag at ≤4°C, with consequent septic shock after transfusion.

Complete prevention of this very rare event (1 case in several million

transfused units in countries such as the United States and France)

without unacceptable restriction in the blood supply has not yet been

devised.

■ POSTINFECTIVE PHENOMENA

As in other invasive intestinal infections (salmonellosis, shigellosis),

reactive arthritis (articular arthritis of multiple joints developing

within 2–4 weeks of a preceding infection) occurs as a result of autoimmune activity initiated by the deposition of bacterial components (not

viable bacteria) in joints in combination with the immune response

to invading bacteria. The majority of individuals affected by reactive

arthritis due to Yersinia are HLA-B27 positive. Myocarditis with electrocardiographic ST-segment abnormalities may occur with Yersiniaassociated reactive arthritis. Most Yersinia-associated cases follow Y.

enterocolitica infection (presumably because it is more common than

infection with other species), but Y. pseudotuberculosis–associated

reactive arthritis is also well documented in Finland, where sporadic

and outbreak infections with Y. pseudotuberculosis are more common

than in other countries. Of infected individuals identified in a recent

Y. pseudotuberculosis serotype O:3 outbreak in Finland, 12% developed

reactive arthritis affecting the small joints of the hands and feet, knees,

ankles, and shoulders and lasting >6 months in most cases. Erythema

nodosum (Fig. A1-39) occurs after Yersinia infection (more commonly

in women) with no evidence of HLA-B27 linkage.

There is a long-standing association between antithyroid and antiYersinia antibodies. Antibody evidence of prior Y. enterocolitica infection in Graves’ disease and increased levels of antithyroid antibody in

patients with Y. enterocolitica antibodies were first noted in the 1970s.

Y. enterocolitica contains a thyroid-stimulating hormone (TSH)–binding

site that is recognized by antibodies to TSH from Graves’ disease

patients. Raised titers of antibodies to Y. enterocolitica whole cells and

Yops have been found in some series of Graves’ disease patients but not

in others. It remains unclear whether this cross-reactivity is significant

in the etiology of Graves’ disease.

■ LABORATORY DIAGNOSIS

Standard laboratory culture methods can be used to isolate enteropathogenic Yersinia species from sterile samples, including blood

and cerebrospinal fluid. Culture on specific selective media (CIN

agar), with or without pre-enrichment in broth or phosphate-buffered

saline at either 4°C or 16°C, is the basis of most schema for isolation of yersiniae from stool or other nonsterile samples. Outside

known high-incidence areas, specific culture may only be carried out

by laboratories on request, or if a multiplex PCR screen detects Y.

enterocolitica–specific DNA in feces. Several CE-marked, FDAapproved kits for enteric pathogens now offer Y. enterocolitica detection

(the precise assay targets are not disclosed), and their use has increased

detection of Y. enterocolitica. A standard for PCR detection of pathogenic Y. enterocolitica and Y. pseudotuberculosis in food samples is

available from the International Organization for Standardization.

Matrix-assisted laser desorption ionization time of flight (MALDITOF) mass spectrometry systems can speciate isolates of Y. enterocolitica and Y. pseudotuberculosis (but cannot separate Y. similis or Y. pestis

from Y. pseudotuberculosis). Virulence plasmid–negative strains of Y.

enterocolitica can be isolated from cultures of stool from asymptomatic

individuals, especially after cold enrichment. These strains usually differ in biotype (typically biovar 1a) from virulence plasmid–possessing

strains; although some display apparent pathogenicity in a mouse

model and all are pathogenic in an insect model, virulence plasmid–

negative strains are not commonly accepted as human pathogens.

Because of the frequency with which the virulence plasmid is lost on

laboratory subculture, combined biochemical identification (with biotyping according to a standard schema) and serologic identification are

usually required to interpret the significance of an isolate of Y. enterocolitica from a nonsterile site. Most pathogenic Y. enterocolitica strains

currently isolated from humans are of serogroup O:3/biovar 4 or serogroup O:9/biovar 2; this pattern holds even in the United States, where

serogroup O:8/biovar 1B strains were previously predominant. Whole

genome DNA sequencing applying a Yersinia genus-wide seven-gene

MLST scheme can speciate Y. enterocolitica, Y. pestis, and Y. pseudotuberculosis and differentiate Y. enterocolitica biotypes. A core-genome

MLST scheme has recently been developed, providing an even more

detailed population structure and revealing novel as yet phenotypically

undefined Yersinia species.

Agglutinating or ELISA antibody titers to specific O-antigen types

are used in the retrospective diagnosis of both Y. enterocolitica and

Y. pseudotuberculosis infections. IgA and IgG antibodies persist in

patients with reactive arthritis. Serologic cross-reactions between Y.

enterocolitica serogroup O:9 and Brucella are due to the similarity of

their lipopolysaccharide structures. Multiple assays are required to

cover even the predominant serogroups (Y. enterocolitica O:3, O5,27,

and O:9; Y. pseudotuberculosis O:1a, O:1b, and O:3), and these assays

are generally available only in reference laboratories. ELISA and

Western blot tests for antibodies to Yops, which are expressed by all

pathogenic strains of Y. enterocolitica and Y. pseudotuberculosis, also

are available; most of the positivity in these assays probably relates to

previous infection with Y. enterocolitica.

TREATMENT

Yersiniosis

Most cases of diarrhea caused by enteropathogenic Yersinia are

self-limiting. Data from clinical trials do not support antimicrobial

treatment for adults or children with Y. enterocolitica diarrhea.

Systemic infections with bacteremia or focal infections outside

the gastrointestinal tract generally require antimicrobial therapy.

Infants <3 months of age with documented Y. enterocolitica infection may require antimicrobial treatment because of the increased

likelihood of bacteremia in this age group. Y. enterocolitica strains

nearly always express β-lactamases. Because of the relative rarity of

systemic Y. enterocolitica infection, there are no clinical trial data

to guide antimicrobial choice or to suggest the optimal dose and

duration of therapy. On the basis of retrospective case series and in

vitro sensitivity data, fluoroquinolone therapy is effective for bacteremia in adults; for example, ciprofloxacin is given at a typical dose

of 500 mg twice daily by mouth or 400 mg twice daily IV for at least

2 weeks (longer if positive blood cultures persist). A third-generation

cephalosporin is an alternative—e.g., cefotaxime (typical dose,

6–8  g/d in 3 or 4 divided doses) or ceftriaxone. In children,

third-generation cephalosporins are effective; for example, cefotaxime is given to children ≥1 month of age at a typical dose of

75–100 mg/kg per day in 3 or 4 divided doses, with an increase

to 150–200 mg/kg per day in severe cases (maximal daily dose,

8–10 g). Amoxicillin and amoxicillin/clavulanate have shown poor

efficacy in case series. Trimethoprim-sulfamethoxazole, gentamicin, and imipenem are all active in vitro. Y. pseudotuberculosis

strains do not express β-lactamase but are intrinsically resistant to

polymyxin. Because human infection with Y. pseudotuberculosis is

less common than that with Y. enterocolitica, less case information is