Plague

Clinical Features

Plague appears in three predominant forms in humans: bubonic, septicemic, and pneumonic. The vast majority of the 1 to 40 human cases reported annually in the United States are from the desert Southwest, where plague is endemic in rural rodent populations. Most naturally occurring human cases in the U.S. are bubonic (85%), with less primary septicemic (13%) or primary pneumonic (1-2%) disease.

Bubonic Plague. The bubonic form may occur after an infected flea bites a human host. The disease begins after a typical incubation period of 2-8 days, with acute and fulminant onset of nonspecific symptoms, including high fever up to 40*C), severe malaise, headache, myalgias, and sometimes nausea and vomiting (25-50%). Up to half of patients will have abdominal pain. Simultaneous with or shortly after the onset of these nonspecific symptoms, the characteristic bubo develops - a swollen, extremely painful, infected lymph node. Buboes are typically 1-10 cm in diameter with erythema of the overlying skin and variable degrees of surrounding edema. They rarely become fluctuant or suppurate, and lymphangitis is uncommon. Buboes are most commonly seen in the femoral or inguinal lymph nodes as the legs are the most commonly flea-bitten part of the adult human body. But any lymph nodes can be involved, to include intra-abdominal nodes (presumably through hematogenous extension) which can present as a febrile, acute abdomen. The liver and spleen are often tender and palpable. One quarter of patients will have various types of skin lesions: a pustule, vesicle, eschar or papule (containing leukocytes and bacteria) in the lymphatic drainage of the bubo, and presumably representing the site of the inoculating flea bite. Secondary septicemia is common, as greater than 80 percent of blood cultures are positive for the organism in patients with bubonic plague. However, only about a quarter of bubonic plague patients progress to clinical septicemia, typically within 2-6 days of symptom onset in untreated patients. In humans, the mortality of untreated bubonic plague is approximately 60 percent, but this is reduced to less than 5 percent with prompt, effective therapy.

Septicemic Plague. In those that do progress to secondary septicemia, as well as those presenting septicemic but without lymphadenopathy (primary septicemia), the symptoms and signs are similar to other gram-negative septicemias: high fever, chills, malaise, hypotension, tachycardia, tachypnea, nausea, vomiting, and diarrhea. All age groups can be affected, but the elderly seem at increased risk. Plague septicemia can produce thromboses in the acral vessels (presumably assisted by a low-temperature-activated coagulase protein produced by the organism), possibly leading to necrosis and gangrene, and disseminated intravascular coagulation; thus, black necrotic appendages may be accompanied by more proximal, purpuric lesions due to endotoxemia in advanced disease. Organisms can spread via the bloodstream to the lungs and, less commonly, to the central nervous system and elsewhere. Untreated septicemic plague is virtually 100% fatal, while treated disease has 30-50% mortality.

Pneumonic Plague. Pneumonic plague is an infection of the lungs due to either inhalation of the organisms (primary pneumonic plague), or spread to the lungs from septicemia (secondary pneumonic plague). Secondary pneumonic plague has been a complication in 12% of bubonic cases in the U.S. over the past 50 years. 28% of human plague cases resulting from exposure to plague-infected domestic cats in the US in recent decades presented as primary pneumonic plague; 25% of these human cases were in veterinarians or their assistants. Person-to-person spread of pneumonic plague has not occurred in the US since 1925. After an incubation period varying from 1 to 6 days for primary pneumonic plague (usually 2-4 days, and presumably dose-dependent), onset is acute and often fulminant. The first signs of illness include high fever, chills, headache, malaise, and myalgias, followed within 24 hours by tachypnea and cough, eventually productive of bloody sputum. Although bloody sputum is characteristic, it can sometimes be watery or, less commonly, purulent. Gastrointestinal symptoms, including nausea, vomiting, diarrhea, and abdominal pain, may be present. Rarely, a cervical bubo might result from an inhalational exposure. The chest X-ray findings are variable, but most commonly reveal bilateral infiltrates, which may be patchy or consolidated. The pneumonia progresses rapidly, resulting in dyspnea, stridor, and cyanosis. The disease terminates with respiratory failure, and circulatory collapse. The mortality rate for untreated pneumonic plague is nearly 100 percent. In the U.S. in the past 50 years, four of the seven pneumonic plague patients (57 percent) died. Recent data from the ongoing Madagascar epidemic, which began in 1989, corroborate that figure; the mortality associated with respiratory involvement was 57 percent, while that for bubonic plague was 15 percent.

Pneumonic plague is the only form of plague disease which readily spreads from person to person. From the sparse historical data available on past pneumonic plague epidemics, the average secondary infection rate is 1.3 cases per primary case (range 0 to 6). Transmission has been greatest under crowded, cold, and humid conditions. The majority of secondary cases have been in caregivers at home (80%) or medical professionals (14%) after close contact (within 6ft) with the primary cases.

Plague Meningitis. Meningitis is a rare complication of plague (up to 6 % of patients with septicemia, more common in children), most often occurring in bubonic or septicemic plague patients a week or more into illness. Typically these patients have been receiving sub-therapeutic doses of antibiotics or bacteriostatic antibiotics which do not cross the blood brain barrier well (e.g. tetracyclines). Signs and symptoms are consistent with subacute bacterial meningitis, and CSF demonstrates a leukocytosis with neutrophil predominance and perhaps gram negative coccobacilli.

Nonspecific laboratory findings in all forms of plague disease include a leukocytosis, with a total white blood count up to 20,000 cells per ml or more with increased band forms, and greater than 80 percent polymorphonuclear cells. Platelet counts can be normal or low. One also often finds increased fibrin split products and elevated partial thromboplastin time indicating a low-grade disseminated intravascular coagulation. The blood urea nitrogen, creatinine, transaminases, and bilirubin may also be elevated, consistent with multiorgan failure.

Clinical Syndromes

Overview

Y pestis infection can cause the following clinical syndromes:

  • Bubonic plague
  • Primary septicemic plague
  • Primary pneumonic plague
  • Plague meningitis
  • Plague pharyngitis
  • Pestis minor
  • Subclinical infection

The classic forms of plague are bubonic plague, septicemic plague, and pneumonic plague; these are outlined in the tables below. Septicemic plague can be either primary or secondary to bubonic plague. Similarly, pneumonic plague can be either primary or secondary to septicemic plague or bubonic plague (ie, following hematogenous spread).

Brief information about other syndromes caused by Y pestis infection follows:

  • Plague meningitis occurs as a complication of bacteremia and may be the presenting clinical syndrome for some cases. Symptoms are typical of meningitis from other causes and include fever, headache, meningismus, and mental status changes. If meningitis occurs as a complication of bubonic plague, some data suggest that a bubo in the axillary region is a predisposing factor (see References: Butler 1976). The cerebrospinal fluid demonstrates PMNs; characteristic gram-negative organisms usually can be seen on Gram stain (see References: Butler 1991).
  • Plague pharyngitis occurs as a result of inhaling or ingesting Y pestis organisms. The clinical illness is similar to severe pharyngitis or acute tonsillitis from other causes (eg, streptococcal infection); inflamed cervical nodes usually are present (and usually have the features of a characteristic bubo or buboes). As with bubonic plague, septicemia can occur. Asymptomatic pharyngeal colonization with Y pestis has been noted among healthy contacts of pneumonic plague cases (see References: Dennis 2010).
  • Pestis minor is a milder form of bubonic plague. Patients usually have a febrile illness with localized lymphadenopathy. The nodes drain and patients recover without therapy. Patients with this form of plague are more likely to have some preexisting immunity to Y pestis (see References: Legters 1970).
  • Subclinical infections can occur as evidenced by cross-sectional surveys of serum antibody titers in populations living in endemic areas (see References: Ratsitorahina 2000).

Clinical Features of Bubonic Plague

Feature

Characteristics

Incubation period

1-7 days

Presenting features

—Sudden onset of fever, chills, weakness
—Usually within 1 day, painful swollen lymph node or group of nodes (bubo) occurs in groin, axilla, or cervical region:
    ~1-10 cm, smooth, uniform, unfixed, egg-shaped mass or irregular
    cluster of several nodes
    ~Extremely tender
    ~Region may be erythematous, with surrounding edema
    ~Buboes usually occur in only one location, but multiple buboes may be seen
    ~Rarely, buboes may suppurate and rupture
—Skin lesions may occur at site of flea bite (ie, papules, vesicles, pustules) but are present in <10% of cases
—Associated lymphangitis uncommonly occurs
—Presenting symptoms for case series of 40 Vietnamese patients with bubonic plaguea:
    ~Fever (100%) (mean temperature for 32 patients: 102.9°F [39.4°C])
    ~Chills (40%)
    ~Bubo (100%) (groin, 88%; axilla, 15%; cervical, 5%; epitrochlear, 3%)
    ~Headache (85%)
    ~Prostration (75%)
    ~Altered mental status (38%) (lethargy, confusion, delirium, seizures)
    ~Anorexia (33%)
    ~Vomiting (25%)
    ~Abdominal pain (18%)
    ~Cough (25%)
    ~Chest pain (13%)
    ~Rash (23%) (petechiae, purpura, papular eruptions)

Laboratory features

—Laboratory features for case series of 40 Vietnamese patientsa:
    ~Mean WBC count: 21,500/mm3 (range, 6,000/mm3-100,000/mm3)
     (most patients had left shifts, and 3 had leukemoid reactions)
    ~PMNs showed cytoplasmic vacuolation in 24 patients, Dohle bodies
    in 20 patients, toxic granules in 8 patients
    ~Mean platelet count: 210,000/mm3 (range, 72,000/mm3-496,000/mm3)
    (18 patients had platelet counts <150,000/mm3)
    ~SGOT elevated in 13 patients (20-92 U/L)
    ~LDH elevated in 7 patients (308-900 units)
    ~Alkaline phosphatase elevated in 9 patients (33-116 units)
    ~PTT >10 seconds over control in 6 patients

Complications

—Secondary septicemia (can lead to DIC, shock, multisystem involvement)
—Secondary pneumonic plague (5%-15% of patients)b
—Meningitis (may occur in patients with bubonic plague that was not adequately treated)b
—Buboes may become infected with other bacterial pathogensa

Case-fatality rate

—Over 50% without antibiotic therapyc
—With appropriate antibiotic therapy, <5%d

Abbreviations: WBC, white blood cell; PMNs, polymorphonuclear neutrophils; SGOT, serum glutamic oxaloacetic transaminase; LDH, lactic dehydrogenase; PTT, partial thromboplastin time; DIC, disseminated intravascular coagulation.

aSee References: Butler 1972.
bSee References: McGovern 1997.
cSee References: Dennis 1997.
dSee References: Butler 1991.


Clinical Features of Primary Septicemic Plague

Feature

Characteristics

Incubation period

1-4 days

Presenting featuresa,b

—10%-25% of US plague cases present with primary septicemic plagueb
—Presenting symptoms for 18 cases of primary septicemic plague in New Mexicoa:
    ~Fever (100%)
    ~Chills (61%)
    ~Malaise (44%)
    ~Headache (44%)
    ~Nausea (44%)
    ~Vomiting (50%)
    ~Diarrhea (39%)
    ~Abdominal pain (39%)
    ~Any gastrointestinal symptom (72%)
—Presenting signs for 18 cases of primary septicemic plague in New Mexicoa:
    ~Mean temperature: 38.5°C (range, 35.4°C-40.4°C)
    ~Mean pulse: 109 (range, 72-160)
    ~Mean respiratory rate: 31 (range, 16-60)
    ~Mean systolic BP: 104 (range, 80-130)
    ~Mean diastolic BP: 66 (range, 36-80)
—Mental status changes commonly occur (delirium, obtundation, coma)

Laboratory features

—Laboratory features consistent with severe bacterial infection and sepsis syndrome (as often seen with bubonic plague and secondary septicemia)
—Leukocytosis, leukopenia, or normal WBC count may be seen
—If plague pneumonia present, CXR shows patchy alveolar infiltrates (usually bilateral), often with consolidation
—Findings noted for 18 patients with septicemic plaguea:
    ~Mean WBC count: 18,950/mm3 (range, 3,000/mm3-68,700/mm3);
    all had marked left shifts
    ~Bacteria seen on peripheral blood smear (17.6%)

Complicationsa,c,d

—Illness rapidly progresses to sepsis syndrome, often with DIC, shock, and multisystem involvement
—Skin lesions reflect DIC (may be similar to meningococcemia)c:
    ~Purpura
    ~Petechiae
    ~Ecchymoses
    ~Gangrene of acral regions (caused by small artery thromboses)
    ~Ecthyma gangrenosum (rare)
—Meningitisd
—Secondary plague pneumonia (about 25% of patients)a

Case-fatality rated

—Overall 30%-50%b
—High CFR related to delay in appropriate diagnosis and antibiotic therapy
—Without antibiotic therapy, CFR approaches 100%

Abbreviations: BP, blood pressure; WBC, white blood cell; CXR, chest x-ray; DIC, disseminated intravascular coagulation; CFR, case-fatality rate.

aSee References: Hull 1987.
bSee References: Perry 1997.
cSee References: McGovern 1999.
dSee References: Dennis 1997.


Clinical Features of Primary Pneumonic Plaguea

Feature

Characteristics

Incubation period

1-4 days

Presenting features

—Symptoms of primary plague pneumoniab:
    ~Fever
    ~Chest pain
    ~Dyspnea
    ~Productive cough (sputum may be purulent or watery, frothy, blood-tinged)
    ~Hemoptysis
    ~Tachypnea (particularly in young children)
    ~Cyanosis
    ~Bubo not present (rarely, cervical bubo may be noted)
—Gastrointestinal symptoms common (nausea, vomiting, abdominal pain, diarrhea)

Laboratory features

—Findings consistent with severe bacterial infection and sepsis syndrome (as often seen with bubonic and primary septicemic plague)
—CXR findings in series of 9 cases of secondary pneumonic plaguec:
    ~Alveolar infiltrates (100%)
    ~Pleural effusion (55%)
    ~One patient developed cavitary lesion 3 weeks after illness onset
—Consolidation common on CXR; massive mediastinal adenopathy occurs rarely
—Organisms usually seen on sputum Gram stain

Complications

—Septicemia with sepsis syndrome
—Meningitis

Case-fatality rate

—Close to 100% without appropriate antibiotic therapy (generally, fatality rates are high if antibiotic therapy is not instituted soon after symptom onset [ie, within 24 hr]; however, patients may survive even if appropriate therapy is instituted beyond 24 hr)d
—Death often occurs 2-5 days after illness onsete

Abbreviations: CXR, chest x-ray.

aNote: Few detailed clinical descriptions of primary plague pneumonia are readily available since the condition is relatively rare.
bSee References: Dennis 1997.
cSee References: Alsofrom 1981.
dSee References: Begier 2006, Butler 1991, Gage 2000.
eSee References: Inglesby 2000.

 

A review of the medical literature on pneumonic plague was undertaken to characterize its early clinical course and presentation (see References: Babin 2010). Gastrointestinal symptoms (ie, nausea, vomiting, abdominal pain, and diarrhea) dominate in the early stages of pneumonic plague and are presumed to be due to central nervous system effects rather than direct gastrointestinal inflammation. Initially, minimal, if any, respiratory symptoms are present; a dry cough and increased respiration rate may occur. When respiratory symptoms do develop, they typically are much worse than the pulmonary signs would indicate, but the disease then progresses rapidly. These findings reveal that early diagnosis of pneumonic plague resulting from either natural or bioterrorist origins, as well as detection of this disease in syndromic surveillance systems, requires recognition of specific gastrointestinal symptoms followed by particular respiratory symptoms and signs.

Pediatric Considerations

The clinical presentation of plague in children is similar to that in adults. Several studies have made the following observations about pediatric plague:

  • Children with bubonic plague may have a slightly increased risk for development of secondary pneumonic plague or meningitis. In one study of 38 pediatric patients with plague, 16% developed pneumonia and 11% developed meningitis (see References: Mann 1982). In two other case series, most of the meningitis cases occurred among children (see References: Crook 1992, Reed 1970).
  • Vomiting may be more common in children at the time of presentation of illness than in adults (about 50% and 30%, respectively) (see References: Burkle 1973, Mann 1982).
  • In cases of bubonic plague, node pain is more common in children than lymph node swelling or a bubo; this may manifest as limb immobility (such as from painful axillary nodes).
  • Retroperitoneal adenopathy may be responsible for vomiting and/or abdominal pain.
  • Children may be more likely to have seizures as part of the presenting symptom complex (see References: Butler 1991). Most often these are febrile seizures, although they may be caused by plague meningitis, which may be more common in children.
  • The diagnosis often is not considered at time of initial presentation for pediatric cases, even in a plague-endemic area (see References: Mann 1982).

Presenting symptoms for 38 pediatric patients with bubonic or septicemic plague diagnosed in New Mexico between 1970 and 1980 are shown in the table below. The overall case-fatality rate was 15.8%.

Presenting Symptoms for 38 Pediatric Patients with Bubonic or Septicemic Plague

Symptom

Patients With Bubonic Plague (N=31)

Patients With Septicemic Plague (N=7)

Fever

30 (97%)

6 (86%)

Chills

11 (35%)

1 (14%)

Vomiting

16 (52%)

3 (43%)

Headache

11 (35%)

0

Abdominal distress or nausea

8 (26%)

2 (29%)

Diarrhea

3 (10%)

0

Lethargy, malaise, anorexia

12 (39%)

3 (43%)

Adapted from Mann 1982 (see References).

In the pre-antibiotic era, pregnant women with plague usually either died or had an adverse outcome of pregnancy (eg, spontaneous abortion, stillbirth). However, more recent reports have demonstrated successful outcomes with antibiotic therapy, including normal gestational periods and delivery of healthy infants (see References: Mann 1977, Welty 1985).

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