When plague first arrived in Madagascar in November 1898, its appearance mirrored events in port cities around the world. Alexandria, Bombay, Buenos Aires, San Francisco, Saigon, and Sydney were all affected as part of the “third pandemic,” a global event that began in China but spread widely with the aid of long-distance steamships. Like the Justinian Plague of 542 c.e. and the Black Death of 1346 c.e., the third pandemic took millions of lives and disrupted societies. Although the disease eventually died out in some regions, enzootic foci established during the third pandemic persist in many areas, including the western United States and the central highlands of Madagascar.

Plague is caused by Yersinia pestis, a gram-negative bacillus that is believed to have evolved relatively recently from Y. pseudotuberculosis. The organism cycles in nature among rodents and their fleas, and it is generally susceptible to aminoglycosides, tetracyclines, and fluoroquinolones. Most human plague is of the bubonic form, characterized by fever and regional lymphadenitis, and results from percutaneous exposure through the bite of infected rodent fleas. Without treatment, infection can spread from regional lymph nodes to the lungs, causing a secondary pneumonia. Patients with secondary pneumonic plague can transmit the infection to others through respiratory droplets. Inhalation of these droplets produces a primary pneumonic infection. Primary pneumonic plague has a typical incubation period of 1 to 4 days, is rapidly progressive, and is nearly always fatal in the absence of prompt antimicrobial treatment.

Although many patients with pneumonic plague do not transmit the disease to anyone, one patient can — under the right circumstances — infect many people and thus initiate an outbreak. The current epidemic in Madagascar appears to have been triggered by such an event. In late August 2017, an ill 31-year-old man boarded a bush taxi in the central highlands, bound for the eastern city of Toamasina (also called Tamatave), by way of the capital city, Antananarivo. Details of his illness are not publicly available, but his symptoms worsened quickly, and he died in transit. Dozens of persons who had direct contact with the man or his contacts subsequently became ill.1

Since notice of this first cluster, cases of suspected plague have been reported from many areas of Madagascar. According to the World Health Organization (WHO), 2417 total cases had been identified between August 1 and November 26, including 1854 (77%) that were clinically identified as pneumonic plague. Among pneumonic cases, 390 (21%) have been classified as confirmed, 618 (33%) as probable, and the remaining 846 (46%) as suspect.1 In most instances, laboratory confirmation is based on detection of fraction 1 (F1) capsular antigen in specimens by a locally produced rapid diagnostic test, combined with detection of Y. pestis by polymerase chain reaction.2 Unfortunately, information on the sensitivity and specificity of these assays for testing sputum is limited.3 Cases in which samples test positive by only one of these two methods are considered probable, and those in which laboratory tests are negative or pending remain suspect. Many cases lack any apparent epidemiologic links to known cases. More than 80 health care workers have reportedly been infected, but none have died.1

National and international response to the outbreak has been substantial. The government of Madagascar has established a high-level workgroup, chaired by the prime minister, to provide strategic direction, while the Ministry of Public Health coordinates health activities in collaboration with various partner organizations. The WHO is providing direct technical and operational support through mobilization of the Global Outbreak Alert and Response Network, drawing on resources from the region and from member nations, including the United Kingdom, France, and the United States. The Institut Pasteur de Madagascar and the International Federation of the Red Cross, Madagascar, along with other nongovernmental organizations, have been assisting with laboratory testing, surveillance, and patient care activities. As of November 24, governments, international agencies, and businesses had contributed more than $4 million in direct or in-kind aid to the response. Collectively, these efforts have been directed toward active case finding and treatment, comprehensive identification and prophylaxis of contacts, rodent and flea control, safe and dignified burials, and departure screening and preparedness to prevent spread to other countries.1

Recent reports suggest that the outbreak is subsiding. This is encouraging news, but the epidemic will leave in its wake several important questions — first and foremost: How big was it really? Without diminishing the suffering of individual patients and their loved ones, it’s important to recognize that plague’s gruesome reputation can cloud short-term understanding of an outbreak.4 This tendency was amply demonstrated during the 1994 plague epidemic in India in which more than 6300 suspected cases were reported from 12 Indian states. When the dust finally settled, fewer than 300 clinically compatible cases were confirmed by laboratory testing, and even then only by methods of questionable specificity.4

Reports of plague can create a positive feedback loop. Health care providers fearful of missing a case may suspect plague in any ill patient, thereby generating more suspected cases and a spiraling case count. Though this problem can be mitigated by adherence to specific case definitions and use of reliable laboratory testing, such requirements can be difficult to enforce during a plague epidemic. Current reports of more than 2000 cases in Madagascar are clearly cause for concern, but our worry should be tempered by the knowledge that only 33 culture-confirmed cases have been identified to date.1 The true magnitude of the outbreak may take time to determine, but it probably lies somewhere between these extremes.

Malagasy Education Poster Showing Bubonic and Pneumonic Forms of the Plague. The poster instructs patients to seek immediate care at a health center if they have symptoms of bubonic or pneumonic plague, including fever, headache, fatigue, buboes, or cough and bloody sputum.

A second important issue will be identifying which components of the response actually helped and which did not. These assessments can be more difficult than one might imagine, especially since multiple measures were employed simultaneously. Acting through difficult-to-quantify mechanisms such as social distancing, simple public awareness may substantially reduce opportunities for person-to-person transmission and thus curtail an outbreak (see poster).5 On the other hand, tracing and prophylaxis of contacts of all persons with suspected cases can be costly and inefficient, especially if the criteria for a suspected case are lax. In the current response, thousands of contract tracers have been mobilized, yet few, if any, infected contacts have been identified. The situation can be aggravated by widespread use of point-of-care diagnostics for testing patients with a low prior probability of infection. In the absence of a highly specific test, such use can generate more false positive than true positive results.

Finally, it is worth considering how best to advance development and validation of better tests and treatments for plague. Fundamentally a disease of poverty, plague strikes communities with the least capacity to respond, and the unpredictable and episodic nature of the disease complicates efforts to conduct planned studies. The current standard for the treatment of plague in Madagascar is repeated intramuscular injections of streptomycin. The Food and Drug Administration has recently approved oral fluoroquinolones for the treatment of plague; however, this approval was based on animal models rather than on formal trials or extensive clinical experience. Advances in care will require sustained research in high-risk areas, or at least greater capacity to implement important studies promptly when outbreaks occur.

For much of the world, the public health importance of plague has waned substantially over the past century. Antibiotic treatment and prophylaxis have reduced morbidity and mortality, and improved living standards have reduced human contact with rodents and the fleas that transmit the disease. Barring a catastrophic global event, the likelihood of a plague pandemic comparable to the Black Death is extremely low.

Nevertheless, the disease continues to cycle quietly in discrete, enzootic foci in rural areas of Asia, Africa, and the Americas. Inevitable eruptions, like the current outbreak in Madagascar, pose a pernicious challenge to the world’s medical and public health community. They also, however, provide important opportunities to improve medical care for infected persons and to enhance detection and response capabilities. The responses to these events should be judged not only by how quickly cases diminish, but also by how they advance the prevention and control of future outbreaks.