Pediatric Plague

Plague, a zoonotic disease caused by the gram-negative bacterium Yersinia pestis, is transmitted to humans by the bites of infected fleas (eg, Xenopsylla cheopis), scratches from infected animals, inhalation of aerosols, or consumption of food contaminated with Y pestis.[1, 2] No disease has impacted civilization as deeply as the plague. As many as 200 million people have died from this disease.

The first pandemic, known as the Justinian plague (AD 541-544), began in Egypt and spread throughout the Middle East and Mediterranean areas. Eventually, the entire known world was affected. By the 8th century, plague receded into scattered endemic areas.

The second pandemic began in 1347, when traders from central Asia introduced plague into ports of Sicily. This became the first epidemic, known as the Black Death, which killed over one third of the population of Europe. Later, following the Great Plague of London (1665), the disease subsided.

The third pandemic began in Hong Kong in 1894 and continues to the present. Alexandre Yersin discovered the plague bacillus, Y pestis, and effective antibiotics were introduced in the early 1940s; however, plague remains endemic in much of the world.[3, 4]

Examples of findings are shown in the images below.

 

 

The classic mode of transmission to humans is a flea bite (see the image below).

Alternately, broken skin serves as a portal when tissue or blood of an infected animal is handled (skinning or evisceration of infected animals). Competency of the flea to serve as vector for transmission of plague to humans depends on its willingness to feed on a human host and its tendency to regurgitate intestinal contents during a blood meal. Fleas from sylvatic rodents feed on humans only reluctantly. However, the Oriental rat flea (Xenopsylla cheopis) is an effective vector because of its tendency to regurgitate and to feed on nonrodent hosts (see the image below).

When the flea takes a blood meal from an infected rodent, stomach enzymes cause a clot to form, blocking the flea's proventricularis. At its next attempt to feed, unable to swallow due to the blockage, the flea regurgitates plague bacilli into the bite wound.

The organisms invade the lymphatics and travel to regional lymph nodes, causing inflammation (see the image below).

Large, tender lymph nodes are termed buboes and give the bubonic form of plague its name. If the infection is not contained at this site, the organisms may be further spread via the bloodstream to organs such as lungs, spleen, liver, kidneys, and meninges. Bacteremia without the appearance of buboes is considered septicemic plague. Pneumonic plague occurs when pneumonia results from either hematogenous spread (secondary pneumonic plague) or inhalation (primary pneumonic plague) of organisms transmitted from animals or other humans.

Bacteriology

The causative bacterium (Y pestis) was discovered by Yersin in 1894. It is a nonmotile, pleomorphic, gram-negative coccobacillus that belongs to the family Enterobacteriaceae. Bipolar staining (giving the appearance of a closed safety pin) can be observed with Giemsa, Wayson, or Wright stains (see the image below).

It grows at a wide range of temperatures (4-40ºC) but demonstrates optimal growth at room temperature.

Both an endotoxin and an exotoxin are produced, adding to the organism's pathogenicity.

Transmission

Human infection is usually acquired through the bites of infected rodent fleas. X cheopis, the Oriental rat flea, is the classic vector, but many other species of flea are also capable of transmitting plague. Typically, this form of transmission is common in crowded urban areas.

Plague can also be contracted from handling infected animals, especially rodents, lagomorphs (eg, rabbits or hares), and domestic cats, or through close contact with patients with pneumonic plague.

A recent study suggests that lice might play a role in transmission of Y pestis and that preventing and controlling louse infestations might help limit the extension of plague epidemics in louse-infested populations.[5]

Another potential cause of plague transmission in humans is contact with an infected dog. In 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory isolated Y pestis in a blood specimen from a hospitalized man with pneumonia. Further investigation found that the man’s dog had recently died with hemoptysis and that 3 other persons who came into contact with the dog had respiratory symptoms and fever. Specimens from the dog and the other three persons showed evidence of acute Y pestis infection. One of the transmissions may have been human to human, which would be the first such reported US case since 1924. [6]

Person-to-person transmission is extremely rare. Person-to-person transmission occurs primarily through droplet exposure from a patient with the pneumonic form of the disease, although direct contact with body fluids can also be infectious.

United States data

Plague is considered endemic in all western and southwestern states.[7] Most human cases in the United States occur in two regions:

·       Northern New Mexico, northern Arizona, and southern Colorado

·       California, southern Oregon, and far western Nevada

Most cases of plague are acquired in rural areas. Native Americans who reside on reservations are at increased risk for acquisition of the disease. Ground squirrels and prairie dogs serve as major enzootic foci (see the image below).[8]

Dogs and cats are susceptible to plague. Domestic animals, cats in particular, have been responsible for human cases.

Between 1900 and 2012, 1006 confirmed or probable human plague cases occurred in the United States. Over 80% of United States plague cases have been the bubonic form. During 2001–2012, the annual number of human plague cases reported in the United States ranged from one to 17 (median = three cases).[9, 10]

However, plague activity increased during 2015. In a CDC report published on August 25, 2015, a total of 11 cases of human plague had been reported since April 1, 2015.[11] Affected patients were residents of six states: Arizona (two), California (one), Colorado (four), Georgia (one), New Mexico (two), and Oregon (one). The two cases in Georgia and California residents were linked to exposures at or near Yosemite National Park in the southern Sierra Nevada Mountains of California. It is unclear why the number of cases in 2015 is higher than usual.

International data

Plague reached a worldwide maximum of 5419 cases (274 fatal) in 1997, and the incidence has declined since that time.[12] In 2003, 9 countries reported 2118 cases (182 fatal) to the World Health Organization (WHO).[13] Algeria reported cases of human plague for the first time in 50 years. India and Indonesia also recently reported cases after a 30-year to 50-year quiescent period. Almost all of the cases reported in the last 20 years have occurred among people living in small towns and villages or agricultural areas rather than in larger towns and cities. Between 1,000 and 2,000 cases each year are reported to the World Health Organization (WHO), though the true number is likely much higher. Occurrence is thought to be underreported.[14, 15] Currently, about 95% of the world’s human plague cases now occur in the African region, including Madagascar.[16] World distribution of plague is shown below.

Sex- and age-related demographics

Plague occurs in both men and women. It is slightly more common among men.

Plague has occurred in people of all ages, although, 50% of cases occur in people aged 12-45 years. 

Mortality rate for untreated plague is 40-70%. Untreated pneumonic plague is nearly 100% fatal.

From 1947-1996, reported mortality rate in the United States was 15%.

Because plague is often a difficult disease to consider in the differential diagnosis, many patients who succumb to it have previously sought medical care.

Morbidity/mortality

Bubonic plague

Mortality is approximately 16%, which increases to 40-70% in untreated cases.[17]  Practitioners must maintain a high index of suspicion for plague, especially with patients exposed to animals or fleas in endemic areas. The most common complications are secondary septicemia, pneumonia, and meningitis. Polyarthritis, lung abscesses, and superinfection of lymph nodes also rarely occur.

Septicemic plague

Mortality ranges from 30-50% for patients with septicemic plague and increases to nearly 100% in untreated cases. This high mortality rate reflects the difficulty in diagnosis, given the disease's similarity to gram-negative bacterial sepsis. Diagnosis is often made postmortem.

Pneumonic plague

The fatality rate of untreated pneumonic plague approaches 100%. The last reported case of person-to-person transmission occurred during a plague epidemic in Los Angeles in 1924. Since then, cases of primary pneumonic plague have been acquired chiefly from infected cats.

Complications

Complications include the following:

• Polyarthritis

• Lung abscesses

• Suppuration or superinfection of buboes

• Meningitis

• Death

The incubation period of plague is 3-4 days (range, hours to 10 d). Sore throat may be the only complaint of patients with plague pharyngitis.

Bubonic plague

Bubonic plague, resulting from the bite of an infected flea, accounts for approximately 80%–85% of cases.

Patients complain of fever with abrupt onset and other constitutional symptoms. These symptoms usually manifest 3-6 days after contracting the organism but may appear in the first day or be delayed for longer than a week. Clinical manifestations of plague are the same for children and adults.

Fever with chills is virtually universal. Temperatures typically range from 38.5-40ºC.

Headache, malaise, and weakness are all very common.

An area of focal painful lymphadenopathy (bubo) develops and progresses during the first few days of illness (see the image below).

This bubo rapidly becomes very tender and can measure up to 10 cm. Over time, fluctuance develops, and the buboes often suppurate and drain. The most common site affected is the groin, followed by the axillary and cervical lymph nodes. Intra-abdominal buboes may present as an acute abdomen.

Nausea, vomiting, diarrhea, and abdominal pain are common. These, as well as the constitutional symptoms of headache and malaise, are thought to result from the gram-negative septicemia caused by Y pestis.

Patients with plague may complain of sleep disturbance, vertigo, and loss of memory. Weakness, delirium, stupor, ataxia, and speech disorders may also occur. These manifestations are due to the effects of endotoxin on the brain. Meningitis may develop. Children younger than 15 years appear to be more susceptible to meningitis.

Septicemic plague

Constitutional symptoms are similar to bubonic plague. Absence of palpable buboes differentiates the 2 forms.

Meningitis is 4 times more common in this form of the disease than with bubonic plaque. Additionally, pneumonic plaque occurs twice as often in septicemic plaque than in the bubonic form.

Patients with septicemia are often older than 60 years. They are usually less febrile, but mortality is higher.

Bacteremia may be so great that organisms can be visualized on peripheral smears.

Pneumonic plague

Primary pneumonic plague is a fulminant infection, occurring in approximately 3% of plague patients. It results from inhalation of infectious droplets. Secondary pneumonic plague results from the spread of Y. pestis to the lungs in patients with bubonic or septicemic infection.

Patients primarily manifest fever and respiratory symptoms, including cough, hemoptysis, and chest pain. Tachypnea and dyspnea are also common.

Thin, watery, blood-tinged sputum becomes frankly bloody and mucopurulent as the disease rapidly progresses.

Plague bacillus can be cultured from sputum, and disease transmission is thought to occur up to 2 meters from a patient who may be coughing.

Generally, patients with any form of plague are toxic in appearance. Apprehension and tachycardia are also common.

All patients are febrile with chills.

A large bubo is palpable in the groin, axilla, or neck of patients with bubonic plague. The mass is fixed, edematous, exquisitely tender, and often surrounded by an area of erythema.

Intra-abdominal buboes may be accompanied by tenderness, guarding, and other peritoneal signs. Hepatomegaly can be present.

Septicemic patients present with tachycardia, tachypnea, and hypotension. Systolic blood pressures are usually less than 100 mm Hg. Differentiation of patients with septicemic plague from patients with other types of gram-negative sepsis is often difficult due to the similarity of signs and symptoms.

Patients with pneumonic plague manifest cough productive of bloody sputum, tachypnea, and dyspnea.

Fever and meningismus accompany plague meningitis.

Patients with plague pharyngitis resemble those with any other form of bacterial pharyngitis or tonsillitis. Large anterior cervical adenopathy may be appreciated.

Laboratory diagnosis can be very slow in patients with plague. Any patient with suspected plague based on clinical or epidemiological reasons should be empirically treated with prompt appropriate antibiotic therapy after blood and tissue samples have been collected.

Culture of Y pestis from clinical samples is diagnostic.[18, 19] The organism can be isolated from blood, sputum, cerebrospinal fluid, and bubo aspirates, depending on the patient's presentation. Y pestis is slow growing, but it does not require any special growth media. When attempting to culture Y pestis from a suspected case, the microbiology laboratory should be alerted to minimize the possibility of accidental transmission to personnel.

Staining lymph node aspirates with Wright, Wayson, or Giemsa stain reveals the typical bipolar (safety pin) morphology. Blood of patients who are septicemic can also be stained to reveal organisms. A positive fluorescence antibody test on smears or cultures is presumptive evidence of infection (see the image below).

Serologic tests may be an adjunct to diagnosis. Acute and convalescent sera can be tested for fraction 1 (F1) envelope antigen and antibody by enzyme immunoassay or passive hemagglutination. A single positive hemagglutination assay or enzyme immunoassay in a patient who has not received plague vaccine nor has had previous plague is also presumptive of infection.

Polymerase chain reaction (PCR) is available.[20]

Associated laboratory findings include leukocytosis, elevated liver function enzymes, and evidence of disseminated intravascular coagulopathy.

Pneumonic plague does not exhibit specific chest radiography findings.

Bilateral patchy infiltrates may be seen, but unilateral consolidation is also common.

Pleural effusion and hilar lymphadenopathy can also be appreciated.

Plague is a treatable disease, but clinicians must have a high index of suspicion and initiate appropriate antibiotics at the earliest possible time.[21] Initial evaluation of patients with plague may begin on an emergent outpatient basis. However, hospitalization is generally required to initiate therapy. Isolation of hospitalized patients varies based on the type of disease. Standard precautions are indicated for cases of bubonic plague. Droplet precautions are indicated for patients with pneumonic plague and for all patients until pneumonia has been excluded and treatment initiated. In patients with pneumonic plague, isolation should be continued until 48 hours of appropriate antibiotic treatment has been administered. Aggressive supportive medical care as necessary to stabilize and maintain the patient's hemodynamic and respiratory status.

Currently recommended antibiotic treatment for plague is summarized in the tables below. Gentamicin and fluoroquinolones are typically first-line treatments in the United States. Duration of treatment is 10 to 14 days, or until 2 days after fever subsides. Oral therapy may be substituted once the patient improves.

 Recommended antibiotic treatment for plague in adults (Source: CDC, Atlanta, GA)[22]

Table. (Open Table in a new window)

 

Recommended antibiotic treatment for plague in Children* (Source: CDC, Atlanta, GA)[22]

Table. (Open Table in a new window)

* All recommended antibiotics for plague have relative contraindications for use in children and; however, use is justified in life-threatening situations.

In 2021, the CDC updated its Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response.[23] See Guidelines for a brief summary of the recommendations.

Additionally, updated guidelines on the diagnosis and treatment of bubonic plague have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[24]

Provide supportive medical care as necessary to stabilize and maintain the patient's hemodynamic and respiratory status.

Updated (2014) guidelines on the diagnosis and treatment of bubonic plague have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[24]

Incision and drainage of buboes may be indicated. Material drained from the buboes is infectious until patient is appropriately treated.

Consultations may include the following:

• Infectious disease specialist

• Intensive care specialist, if hemodynamic or respiratory instability is present

Diet

No special diet is required.

Activity

No specific activity restrictions are required.

Persons engaging in outdoor activities in areas where plague is endemic should wear long pants when possible and use insect repellent on clothing and skin. Persons also should avoid direct contact with ill or dead animals and never feed squirrels, chipmunks, or other rodents. In addition, pet owners should regularly use flea control products on their pets and consult a veterinarian if their pet is ill. Rodent habitat can be reduced around the home by removing brush, clutter, and potential rodent food sources such as garbage or pet food.

In 2021, the Centers for Disease Control and Prevention (CDC) published clinical practice guidelines on the treatment of plague.[23, 25] These are some of the highlights of the guidelines.

Plague is treatable with antimicrobials and supportive care. Early recognition and administration of effective antimicrobials are key to saving lives. Persons exposed to Yersinia pestis can avoid illness if given effective antimicrobial prophylaxis.

Aminoglycosides and fluoroquinolones are the mainstays of treatment for plague. Tetracyclines, chloramphenicol, and trimethoprim-sulfamethoxazole might also be suitable treatment, depending on the type of disease and the age and pregnancy status of the patient. Dual therapy with distinct classes of antimicrobials is recommended in the case of a bioterrorist attack with Y pestis engineered for resistance to treatment.

FDA-approved antimicrobials for plague include streptomycin, ciprofloxacin, levofloxacin, moxifloxacin, and doxycycline. Although not approved for plague, gentamicin, chloramphenicol, and trimethoprim-sulfamethoxazole are considered effective.

Bubonic and pharyngeal plague

Gentamicin or streptomycin is a first-line agent for bubonic plague; they must be given parenterally and are associated with nephrotoxicity and ototoxicity. Alternative first-line agents include high-dose ciprofloxacin, levofloxacin, moxifloxacin, and doxycycline, administered intravenously or orally. Consider dual therapy and drainage for patients with large buboes. Treatment is for 10-14 days.

Pneumonic and septicemic plague

For naturally occurring pneumonic plague, the CDC recommends levofloxacin or moxifloxacin. Because plague is life threatening, doxycycline is not considered contraindicated in children and has not been shown to cause tooth staining, unlike other tetracyclines, which should be avoided if possible. For children aged 3 mo to 17 yr, moxifloxacin is recommended as an alternative antimicrobial, rather than a first-line agent, because of lack of FDA approval for use in children and because of higher reported rates of prolonged QTc interval than seen with other fluoroquinolones.

Plazomicin is not recommended as an alternative antimicrobial for children 1 mo to 17 yr because there are no published data on use and dosage in pediatric patients.

Plague meningitis

Moxifloxacin and levofloxacin should be effective for plague meningitis because they have been shown to have robust activity against Y pestis and excellent CNS penetration. Quinolones, however, can cause seizures. When possible, dual therapy with chloramphenicol and moxifloxacin or levofloxacin should be used as initial treatment in patients with plague and signs of meningitis, such as nuchal rigidity. If chloramphenicol is not available, a non-fluoroquinolone first-line antimicrobial or an alternative antimicrobial for septicemic plague can be used.

For patients who develop secondary plague meningitis while already receiving antimicrobial therapy, chloramphenicol should be added to the existing antimicrobial treatment regimen for plague. Moxifloxacin or levofloxacin can be added to the treatment regimen instead of chloramphenicol if it is not available or if the clinician prefers not to use chloramphenicol in young children because of potential adverse effects. After chloramphenicol, moxifloxacin, or levofloxacin is added, the entire regimen of antimicrobials should be continued for an additional 10 days.

Treatment of plague in neonates

The CDC recommends that treatment should be started without delay for symptomatic neonates who have been infected with Y pestis. First-line antimicrobial options for neonates with pneumonic or septicemic plague are gentamicin, ciprofloxacin, levofloxacin, and streptomycin. For neonates with bubonic or pharyngeal plague, first-line options are gentamicin, ciprofloxacin, levofloxacin, streptomycin, and doxycycline. Administration via the intravenous route is recommended to ensure that the full dose is successfully given.

All neonates who are exposed postnatally to Y pestis should receive postexposure prophylaxis. Prophylaxis also should be considered for asymptomatic neonates whose mothers had untreated Y pestis infection during the last 7 days of pregnancy.

Infection control

Caretakers should wear a mask in addition to taking standard precautions, as well as wear eye protection and a face shield if splashing is likely.

Class Summary

Patients suspected to have plague should be promptly treated. Prompt treatment with antimicrobials such as aminoglycosides, fluoroquinolones, or doxycycline greatly improves outcome. Streptomycin or gentamicin are preferred. Doxycycline is an effective alternative. Levofloxacin has been approved by the FDA for adults and children aged 6 months or older. New multidrug-resistant strains of Y pestis have been reported in Madagascar.

Streptomycin

Aminoglycoside antibiotic is considered the drug of choice. Disadvantages include an intramuscular route of administration, resistant strains, and high toxicity.

Gentamicin (Garamycin)

Aminoglycoside used as an alternative to streptomycin and is equally effective.

Levofloxacin (Levaquin)

Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. It inhibits bacterial topoisomerase IV and DNA gyrase (topoisomerases type II), enzymes required for DNA replication, transcription, repair, and recombination. It is indicated for treatment and prophylaxis of plague, including pneumonic and septicemic plague, caused by Yersinia pestis in adults and pediatric patients, aged 6 months or older.

Tetracycline (Sumycin)

Frequently used for prophylaxis as well as treatment. Is usually substituted for streptomycin after a few days of therapy to minimize toxicity. Inhibits bacterial protein synthesis by binding with 30S and, possibly, 50S ribosomal subunits.

Doxycycline (Doxy, Vibramycin)

Used as an alternative for tetracycline. Inhibits protein synthesis and thus bacterial growth by binding to 30S and, possibly, 50S ribosomal subunits.

Chloramphenicol (Chloromycetin)

DOC for plague meningitis. The PO form is not available in the United States, but the IV formulation can be obtained. Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis.

Patient may be discharged on oral tetracycline or doxycycline after 48 hours if hemodynamically stable and symptoms are resolving.

Follow up closely for potential relapse.

Admit patients with plague for antibiotic therapy and isolation.

Antibiotics include streptomycin, tetracycline, doxycycline, and chloramphenicol. Y pestis is often susceptible in vitro to ampicillin, but this antibiotic is rarely effective in vivo. Gentamicin is equally as effective as streptomycin. Antipyretics are useful for patient comfort.

Transfer may be required for further hemodynamic and respiratory monitoring and isolation.

Plague continues to pose a threat to humans.[26] Identifying the source of infection is vital in preventing outbreaks. If an urban area is involved, rodent control should be undertaken. In rural plague-endemic areas, the public must be instructed to avoid handling sick or dead animals and to avoid places where wild animals live. Pets should be kept free of fleas.

Patients with plague pneumonia should be placed in airborne precautions.

Contacts of pneumonic plague victims should receive antibiotic prophylaxis. Ciprofloxacin or doxycycline is typically used. Trimethoprim-sulfamethoxazole has also been effective for prophylaxis. Contacts of those with bubonic or septicemic plague have no need for prophylaxis.

A number of vaccines are currently under development, including live-attenuated, DNA, and subunit vaccines. A recent review details the new approaches to live-attenuated plague vaccines through construction of attenuated Y pestis strains with specifically defined mutations.[27] Traditionally, live-attenuated plague vaccines have been developed by multiple passages of fully virulent Y pestis. These vaccines raise safety concerns and are not recommended for the general population in the United States.