An acute bacterial zoonosis of rodents, caused by Yersinia pestis. Plague is typically transmitted by fleas or through direct contact with infected animals, although human cases are occasionally acquired through inhalation of infectious respiratory droplets or other materials. Initial signs and symptoms may be nonspecific, with fever, chills, malaise, myalgia, nausea, prostration, sore throat and headache. Lymphadenitis often develops in those lymph nodes that drain the site of inoculation. This is bubonic plague, and the location of buboes can vary depending on the circumstances of exposure, with flea bites on the legs typically resulting in the appearance of buboes in the inguinal area. Axillary buboes can be associated with flea bites as well as with handling of infected animals. Cervical buboes are rare in the USA and certain other countries, but are relatively common in many developing countries, where people sleep on the dirt floors of flea-infested huts. Regardless of the location, the involved nodes become swollen, inflamed and tender, and may suppurate. The septicemic form of plague can occur subsequent to bubonic plague (secondary septicemic plague) or without prior lymphadenopathy (primary septicemic plague), and involves bloodstream dissemination to diverse parts of the body, including, in some instances, the meninges. Septicemic cases also can experience endotoxic shock and disseminated intravascular coagulation (DIC), in some instances without localizing signs of infection. Secondary involvement of the lungs results in pneumonia; mediastinitis or pleural effusion may develop. Secondary pneumonic plague is of special significance, since respiratory droplets may serve as the source of person-to-person transfer with resultant primary pneumonic or pharyngeal plague; this can lead to localized outbreaks or devastating epidemics. Though naturally acquired plague usually presents as bubonic plague, purposeful aerosol dissemination as a result of deliberate use would be manifest primarily as pneumonic plague.
Untreated bubonic plague has a case-fatality rate of about 50%–60%. Untreated primary septicemic plague and pneumonic plague are almost invariably fatal. Modern therapy markedly reduces fatalities from bubonic plague; pneumonic and septicemic plague also responds if recognized and treated early (within about 2 days). Plague is a medical and a public health emergency.
Yersinia pestis, the plague bacillus.
The main laboratory approaches to diagnosing plague are as follows. Visualization of characteristic bipolar staining, “safety pin” ovoid, gram-negative organisms in direct microscopic examination of material aspirated from a bubo, sputum or CSF is suggestive, but not conclusive, evidence of plague infection. Examination by FA test, antigen capture by ELISA or dipstick formats, or PCR are more specific and particularly useful in some instances. In the USA, cases are considered confirmed following isolation of Yersinia pestis by culture of bubo aspirates, blood, CSF or sputum samples, or demonstration of a 4-fold or greater rise or fall in antibody titer. Recently, the World Health Organization has proposed the use of dipstick assays designed to detect Y. pestis antigen as a means for case confirmation. Slow growth of the organism at normal incubation temperatures may lead to misidentification by automated systems. The passive hemagglutination test (PHA) using Yersinia pestis Fraction-1 antigen is most frequently used for serodiagnosis. Rapid diagnostic tests for detecting F1 antigen have been developed, produced and evaluated. They are used routinely in endemic African countries. Medical personnel should be aware of areas where the disease is endemic, and should entertain the diagnosis of plague early on; unfortunately, plague is often misdiagnosed, especially in travelers who develop illness after returning from an endemic area.
Two main patterns of transmission for naturally acquired human plague can be distinguished:
Human cases have been linked to domestic pets, particularly house cats and dogs, carrying plague-infected wild rodent fleas into homes. Cats may occasionally transmit infection through bites or respiratory droplets; cats develop plague abscesses that have been a source of infection to veterinary personnel.
On a worldwide basis the most frequent source of exposure for human cases are the bites of infectious infected rat fleas, especially the oriental rat flea (Xenopsylla cheopis). In some countries, wild rodent fleas can also be an important source of infection. The primary vector in North America is the ground squirrel flea Oropsylla montana.
Other important sources of human infection include the handling of infected animals, especially rodents and rabbits, but also wild carnivores and domestic cats; rarely, airborne droplets from human patients or household cats with plague pharyngitis or pneumonia; and careless manipulation of laboratory cultures. Human cases acquired by inhalation (primary pneumonic plague) have been reported in the past couple of decades in developing countries, such as India. Person-to-person transmission by Pulex irritans fleas (the “human” flea) is presumed to be important in the Andean region of South America and in other places where plague occurs and this flea is abundant in homes or on domestic animals. Poor rodent sanitation practices and certain activities, including hunting, trapping, cat ownership and rural residence, carry increased risk of exposure. In the case of deliberate use plague bacilli would possibly be transmitted as an aerosol. For more information on the deliberate use of infectious agents to cause harm, see the section on Deliberate use.
From 1 to 7 days; may be a few days longer in immunized persons who develop illness. For primary plague pneumonia, incubation period can be less than one day, up to four days, and is usually short.
Fleas may remain infective for months under suitable conditions of temperature and humidity. Bubonic plague is not usually transmitted directly unless there is contact with pus from suppurating buboes. Pneumonic plague may be highly communicable under appropriate climatic conditions; overcrowding and cool temperatures facilitate transmission.
Wild rodents are the natural vertebrate hosts of plague, and play a key role in maintaining natural plague cycles by serving as sources of infection (amplifying hosts) for the flea vectors of the disease, some species of which can survive for weeks to months in the burrows of their hosts and appear to represent a significant reservoir of infection. In North America, the most important rodents include species of ground squirrels, prairie dogs, chipmunks, wood rats, deer mice and voles. Certain other mammals, including lagomorphs (rabbits and hares), wild carnivores and domestic cats may also become infected, and act as sources of infection to people. In many developing countries, commensal rats play epidemiologically important roles by moving infected fleas into human dwellings from wild lands or agricultural fields.
Susceptibility among humans is general. Immunity after recovery is relative; it may not protect against a future large inoculum.
Plague continues to be a threat because of vast areas of persistent wild rodent infection; contact of wild rodents with domestic rats occurs frequently in some enzootic areas. Wild rodent plague exists in the Americas, with foci in northeastern Brazil, the Andean region near the border of Ecuador and Peru, and the western half of the USA, causing sporadic cases and occasional outbreaks, including an outbreak of pneumonic plague in Ecuador in 1998; scattered locations in east-central and southern Africa, as well as the interior of Algeria and perhaps other African countries bordering the Mediterranean Sea; central, southwestern and southeastern Asia; and extreme southeastern Europe, near the Caspian Sea. While urban plague has been controlled in most of the world, since 1990 the disease has occurred in several African countries, including Botswana, the Democratic Republic of Congo (DRC), Kenya, Madagascar, Malawi, Mozambique, the United Republic of Tanzania, Uganda, Zambia and Zimbabwe and Algeria. Plague is endemic in China, India, Lao People's Democratic Republic, Mongolia, Myanmar, Viet Nam and Indonesia. Outbreaks occasionally appear in areas that have been free of the disease for many decades, as was demonstrated in Algeria in 2003. Since the beginning of the 90s, there has been an increase in the annual incidence of human cases of plague; moreover, the disease has reappeared in countries where it had not been reported for decades. Today the distribution of plague coincides with the geographical distribution of its natural foci. In 2007, 7 countries reported 2 021 cases with 156 deaths. Among these, 99.6% of cases were reported from Africa. DRC has the most active foci of plague worldwide, with more than 1 000 suspected cases a year; following the eruption of several severe outbreaks of pneumonic plague in DRC, the diagnosis is now systematically evoked when a deadly outbreak with hemorrhagic signs is reported in Central Africa.
Human plague in the western USA is sporadic (typically 5–15 cases per year since 1970), with only single cases or small common source clusters in an area, usually following exposure to wild rodents or their fleas—although cases have also been acquired by persons handling infected rabbits, wild carnivores or domestic cats. No person-to-person transmission has occurred in the USA since 1924, although secondary plague pneumonia occurred in about 20% of bubonic cases in one reported series. Five instances of primary plague pneumonia through cat-to-human transmission have been recorded.
The basic objective is to reduce the likelihood of people being bitten by infectious fleas, having direct contact with infective tissues and exudates, or of being exposed to patients with pneumonic plague.
a) Educate the public in enzootic areas on the modes of human and domestic animal exposure; on rat-proofing buildings and preventing access to food and shelter by peri-domestic or wild rodents through appropriate storage and disposal of food, garbage and refuse; and on the importance of avoiding flea bites by use of insecticides and repellents. In sylvatic or rural plague areas, the public should be advised to use insect repellents when walking or working in suspect areas, and be warned not to camp near rodent burrows and to avoid handling of rodents—but to report dead or sick animals to health authorities or other appropriate persons. Dogs and cats in such areas should be protected periodically with appropriate insecticides to reduce the risk that infectious fleas will be transported into human environs, and should not be allowed to roam freely in plague-affect areas. Any animal carcasses brought home by these animals should be disposed of safely.
b) Survey rodent populations periodically to determine whether epizootics are in progress or conditions indicate that one is likely. The effectiveness of rodent sanitation measures in homes and public areas also should be evaluated. Although flea control is the primary means for controlling plague, rat suppression by poisoning may be necessary to augment basic environmental sanitation measures; rat control should always be preceded by measures to control fleas. Areas of plague activity can be identified by surveillance of natural foci by testing fleas collected from rodents and their burrows or nests; bacteriologic testing of sick or dead wild rodents; and serological analyses of samples from wild carnivores and outdoor ranging dogs and cats. Regular testing should take place to ensure the effectiveness of insecticides on target flea populations.
c) Control rats on ships and docks and in warehouses by rat-proofing or periodic fumigation, combined when necessary with destruction of rats and their fleas in vessels and in cargoes, especially containerized cargoes, before shipment and on arrival from locations endemic for plague.
d) Wear gloves when hunting and handling wildlife. Veterinarians and their staff should wear gloves and masks when examining sick cats.
e) Plague vaccine should not be relied upon as the sole preventive measure, and immunized persons should take other appropriate prevention precautions as indicated elsewhere in this section. Live attenuated vaccines are used in some countries, but can produce adverse reactions, and their efficacy has not been proven. Different vaccination strategies have been used in the past involving both a killed and a live attenuated vaccine, but these strategies have only conferred protection against bubonic plague and not against primary pneumonic plague. Currently, the next generation of plague vaccines is being researched—and, in some cases, vaccines are in clinical trials. Both new, live attenuated vaccines and recombinant F1-V vaccines are being examined.
a) Report to local health authority any suspected case. Case reports of suspected and confirmed cases from plague-endemic areas are no longer required by the International Health Regulations, but cases that occur outside plague-endemic areas or are likely to pose a threat for spread of the disease to other areas are still reportable. In the USA, because of the rarity of naturally acquired primary plague pneumonia, even a single case should initiate prompt investigation, and in the unlikely circumstance that a natural source of infection cannot be identified, public health and law enforcement authorities might be reasonably suspicious of deliberate use.
b) Isolation: Rid patients living in rat- and flea-infested dwellings of fleas and treat their clothing and baggage with an appropriate insecticide; hospitalize if practical. Strict isolation is only required for patients with pneumonic plague, for whom precautions against airborne spread are required until 48 hours of appropriate antibiotherapy have been completed and there has been a favorable clinical response. For patients with bubonic plague (if there is no cough and the chest X-ray is negative), drainage and secretion precautions are indicated for 48 hours after start of effective treatment.
c) Concurrent disinfection: Disinfect articles and surfaces contaminated with potentially infectious sputum and purulent discharges. Human cadavers and animal carcasses should be handled with strict aseptic precautions.
d) Quarantine: Quarantine measures have been shown to be ineffective in controlling plague outbreaks, and can trigger panic in the population. Those who have been in household or face-to-face contact with patients with pneumonic plague should be provided chemoprophylaxis and placed under surveillance for 7 days; those who refuse chemoprophylaxis should be maintained in strict isolation with careful surveillance for 7 days.
e) Protection of contacts: In epidemic situations where human dwellings are invaded by flea-infested rats or harbor human fleas (Pulex irritans) that also might act as vectors, consideration should be given to dis-insecting family members and other close contacts with an appropriate insecticide. All close contacts should be evaluated for chemoprophylaxis. Close contacts of confirmed or suspected plague pneumonia cases (including medical personnel) should be provided with chemoprophylaxis for a period of 7 days using tetracycline (2 g/day in two or four equal doses for adults; 25–50 mg/kg/day in two or four equal doses for children over eight years of age), doxycyline (100 mg twice daily for persons >45 kg; 2.2 mg/kg for those over eight years of age <45 kg) or chloramphenicol (30 mg/kg daily in 4 divided doses). Tetracycline and doxycyline cannot be used in children less than eight years of age. Contacts also should be advised about appropriate measures they can take to protect themselves and their families from plague, and should be placed under surveillance.
f) Investigation of contacts and source of infection: Search for sick or dead rodents and their fleas and, if possible, submit these for laboratory analysis. Identify household members and others likely to have had potential similar plague exposures to the cases under investigation. If pneumonic plague is involved, identify household members and others who are likely to have had face-to-face contact with pneumonic plague patients. Determine whether case contacts show evidence of plague and provide medical care, treatment and chemoprophylaxis as needed.
g) Specific treatment: Rapid diagnosis and treatment are essential to reduce complications and fatality. The laboratory confirmation is of first importance but must not delay the set up of the treatment. Although streptomycin (adults—2 g/day in two equal doses; children—30 mg/kg/day in two equal doses) is the drug of choice, gentamicin (adults—3 mg/kg/day in 3 equal doses; children—6.0–7.5 mg/kg/day in 3 equal doses) can be used when the former is not readily available; tetracyclines (adults—2 g/day in 4 equal doses; children over eight years of age—25–50 mg/day in 4 equal doses) and chloramphenicol (50 mg/kg/day in 4 equal doses for children and adults) are alternative choices. Chloramphenicol is required for treatment of plague meningitis. All are highly effective if used early. After a satisfactory response to drug treatment, reappearance of fever may result from a secondary infection or a suppurative bubo that may require incision and drainage.
a) Investigate all suspected plague deaths with autopsy and laboratory examinations when indicated. Develop and carry out case-finding. Establish the best possible facilities for diagnosis and treatment. Alert existing medical facilities to report cases immediately, and to use full diagnostic and therapeutic services.
b) Attempt to prevent or mitigate public hysteria by appropriate informational and educational releases through the press and news media.
c) Institute intensive flea control in affected areas and during epidemics. Apply flea control measures in expanding circles from known outbreak sites. Flea control should precede anti-rodent measures, and the latter should not be executed until the efficacy of the flea control measures has been demonstrated. To control fleas, apply insecticidal dusts to rodent runs, harborages, nests and burrows in and around known or suspected plague areas. All insecticides used for such control should be safe for human residents, labeled for flea control, and known to be effective against local fleas. If non-burrowing rodents are involved, insecticide bait stations can be used. If urban rats are involved, dis-insect houses and other structures with insecticidal dusts; dust the bodies and clothing of all residents in the immediate vicinity. After appropriate flea control measures have been taken, rat populations can be suppressed by environmental modifications intended to reduce rodent food and harborage, and applications of appropriate rodent poisons can be considered.
d) Implement tracing of contacts and medical surveillance/chemoprophylaxis.
e) Protect field workers against fleas; dust clothing with insecticide powder and use insect repellents daily. Antibiotic prophylaxis should be provided for those with documented close exposure.
Plague could become a significant problem in or near endemic areas when there are social upheavals, crowding and unhygienic conditions. See preceding and following paragraphs for appropriate actions.
a) According to the new International Health Regulations (June 2007), any event of potential international concern is subject to a notification to WHO. Plague cases will be notified only if the assessment done by the country shows that the public health impact can be considered as serious with at least one of the following characteristics: unusual or unexpected event; risk of international spread; significant risk of international travel; or trade restriction. Thus, the occurrence of a pneumonic plague case in a well-known focus should not be systematically notified. Conversely, the appearance of a bubonic case in a non-endemic region is typically an event to be notified.
b) Measures applicable to ships, aircraft and land transport arriving from plague areas are specified in International Health Regulations.
c) All ships should be free of rodents or periodically de-ratted.
d) Rat-proof buildings at seaports and airports; apply appropriate insecticides; eliminate rats with effective rodenticides.
e) WHO Collaborating Centres provide support as required. More information can be found at: http://www.who.int/collaboratingcentres/database/en/.
Y. pestis is distributed worldwide; techniques for mass production and aerosol dissemination are thought to exist. The fatality rate of primary pneumonic plague is high, and there is a real potential for secondary spread, particularly in those circumstances where cases are treated in home environments without modern medical care. For these reasons, the risk of a biological attack with plague is considered to be of serious public health concern. In some countries, a few sporadic cases may be missed or not attributed to a deliberate act, particularly in those with natural foci listed. Any suspect case of pneumonic plague should be reported immediately to the local health department. The sudden appearance of many patients presenting with fever, cough, a fulminant course and high case-fatality rate should provide a suspect alert for plague; if cough is primarily accompanied by hemoptysis, this presentation favors the tentative diagnosis of pneumonic plague. Depending on the extent of dissemination, mass prophylaxis of potentially exposed populations may be considered.
Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.