Plague

The plague is a disease of bacterial origin, which is widespread in almost all parts of the world and has marked many moments in human history.

CAUSES

Yersinia pestis is a Gram-negative bacterium belonging to the Enterobacteriaceae family. It is a relatively recent enterobacterium, probably an evolution of Yersinia pseudotuberculosis that occurred between 9,000 and 40,000 years ago. During its evolution it must have acquired genes that would explain its greater virulence than its ancestor.

This bacterium has no natural resistance to antibiotics active against Gram-negative bacilli. However, three strains that show acquired plasma resistance to many antibiotics have recently been described. These strains all originate from Madagascar and contain several resistance plasmids that confer resistance to streptomycin alone, to doxycycline alone or to many antibiotics (amoxicillin, aminoglycosides, sulfonamides, and cyclins).

TRANSMISSION

The plague transmission cycle involves three carriers: rodents, fleas and humans.

Rodents are the reservoir of the disease and can be infected or healthy carriers. Some develop the disease and die, while others are resistant. In Madagascar, it appears that the black rat (Rattus rattus) has developed resistance to the plague and acts as the main reservoir.

Fleas, particularly Xenopsylla cheopis, become infected when they bite infected rodents, and at that point Y. pestis multiplies in the flea's digestive tract. The flea then proceeds to bite the human being, transmitting the bacteria.

Other modes of transmission in humans have been described:

• Bites or scratches from infected pets;
• Handling of tissues from infected animals;
• Inhalation of droplets from infected animals;
• Inhalation of droplets from patients with pneumonic plague;
• Laboratory infection as a result of handling the bacillus.

GEOGRAPHICAL DISTRIBUTION

The epidemiological characteristics of the disease, as well as the risk of transmission to humans, are conditioned by the nature of the main animal reservoir, which varies according to world regions and local socioeconomic conditions.

Between 1 January 2010 and 31 December 2015, 3,248 cases of human plague and 584 deaths were recorded worldwide. The increase in the number of cases since the 2000s makes the plague a re-emerging disease.

In Africa and South America it is a disease of poverty where transmission occurs through promiscuity with commensal rodents. In other endemic regions, the disease is rather sporadic and related to work or leisure activities in the countryside. Madagascar remains the most affected in the world with 2,404 cases (mostly bubonic) from 2010-2015, including 476 deaths.

On the American continent, cases of plague are very regularly reported in Peru in four departments in the Northwest Territory. These are mainly sporadic cases of bubonic plague related to agricultural activity in rural areas. In the western United States, plague circulates among wild rodents once again in rural and semi-rural areas, degenerating into bubonic plague in some cases each year. Human contamination regularly occurs through pets, cats or dogs.

Central Asia is considered the birthplace of the plague and remains the largest natural hotbed. The population at risk is limited to breeders and hunters in contact mainly with gerbils in the steppes and with marmots in mountainous areas. Transmission to humans is therefore very limited, and the bubonic form is quite sporadic in China, Mongolia, Kyrgyzstan and the Russian Federation.

As described above, the plague is an endemic disease in Madagascar. Each year it has a seasonal surge between September and April that mainly affects the central highlands at an altitude above 800 metres.

In 2017, a large-scale epidemic hit the country. Between 1 August 2017 and 22 November 2017, a total of 2,348 cases of plague (confirmed, probable and suspected) were notified to the Madagascar Central Plague Laboratory, including 1,791 (76%) cases of pneumonic plague, 341 (15%) cases of bubonic plague and 1 case of septicemic plague. The mortality rate stood at 8.6% (202 deaths).

Several factors could explain the greater extent of this epidemic: for example, the large proportion of pulmonary forms that facilitate human-to-human transmission, or the presence of cases of plague outside known outbreaks, particularly in the Antananarivo and Toamasima areas.

However, the real reasons affecting the continuing epidemics are still poorly understood.

SYMPTOMS

The plague affects people of all ages and genders and presents in three typical forms, which can sometimes overlap:

• bubonic plague;
• pneumonic plague;
• septicemic plague.

The bubonic plague

Incubation lasts from 1 to 7 days. The onset of symptoms is sudden, usually with a high fever (39°C - 40°C), general malaise, chills, headache, and severe pain in the area where the bubo develops, appearing after 24-48 hours.

It is a severe bacterial, usually single, inflammatory adenitis (inflammation of a gland) that gradually increases in size. Gradually the bubo softens and becomes more collected, from which time it can be incised. The natural course is ulceration, which releases pus in which many bacilli are present.

Evolution can sometimes develop into local dissemination (secondary buboes) then general dissemination of infection with potential secondary localizations. These may include meningeal or pulmonary damage (secondary pulmonary plague). Lethality is in the range of 50% in the absence of treatment.

If the outcome is favorable, wound healing is slow and can last for several weeks.

Pneumonic plague

Pneumonic plague is a rare form, which can be primary (human-to-human airborne infection or inhalation of dust from contaminated soil) or secondary (dissemination by blood or lymphatics from a bubo or septicemic plague). Due to increased human contact and air travel, it may pose a threat of rapid spread from an epidemic outbreak.

Primary pneumonic plague has a short incubation period, which can last from a few hours to 3 days.

This is a picture of sudden onset febrile pneumonia with cough, chest pain, sputum, and sometimes haemoptysis and dyspnea. The course of the disease progresses towards a picture of acute respiratory distress with which other symptoms may also be associated, including diarrhoea, agitation, prostration, or headaches.

Spontaneous development is usually fatal within 24-72 hours in more than 90% of cases.

Secondary pneumonic plague has an incubation period of 5-7 days in a patient whose respiratory involvement is usually secondary. The course of secondary pulmonary forms is usually less severe than that of primary pulmonary plague.

Septicemic plague

This clinical form is under discussion. It accounts for about 10-25% of cases and is defined by the isolation of the bacillus from blood cultures without finding a bubo. It is associated with a severe clinical picture (arterial hypotension, septic shock) and sudden haemorrhagic, cardiovascular, neurological, and renal complications with severe worsening of general conditions. It corresponds to the forms historically described as fast-moving. The lethality of this form is more than 90%.

However, for some authors, it is simply bubonic plague with hidden buboes, the blood passage of the bacillus being frequent.

DIAGNOSIS

Detection of Yersin's bacillus can be performed by direct examination of blood samples, respiratory samples or pus (bubo puncture). However, definitive diagnosis is based on culture of the bacillus growing on usual or enriched soils. These simple and rapid techniques make early and appropriate treatment possible in endemic areas or during epidemic periods.

Sudden onset with fever and buboes, a rapid and intense inflammatory reaction in the bubo, usual absence of visible lesions on the overlying skin and ascending lymphangitis, and the rapid progression, which can lead to death in 2 to 3 days, make the picture of the plague characteristic, which should, however, be differentiated from other infections causing acute lymphadenitis.

TREATMENT

The key to successful treatment of the plague is early recognition and timely administration of effective antibiotics. Even a delay of just 24 hours in administering effective antibiotics and shock therapies is usually fatal for patients.

If untreated, it has a mortality rate of 50-90% of cases for bubonic forms and almost total mortality for other clinical forms. Early diagnosis and appropriate antibiotic therapy reduce this mortality to 5-15%.

Y. pestis is sensitive in vitro to many antibiotics including aminoglycosides. Of these, streptomycin has been historically used and proven effective since the 1940s.

Currently, the good efficacy of fluoroquinolones in vitro and in animal models, as well as the practical methods of using these products, have made it possible to offer this class of drugs as a first-line treatment in French, American and other recommendations.

Most Y. pestis isolates worldwide are sensitive to streptomycin; however, a multidrug-resistant (MDR) strain was isolated from Madagascar. Fortunately, it has never again emerged naturally in this region or elsewhere in the world.

Streptomycin and gentamicin are recommended for adult patients, including immunocompromised patients and pregnant women.

In a large-scale plague outbreak or a bioterrorism attack, oral doxycycline and ciprofloxacin are recommended for adult patients and children.

Alternatively, chloramphenicol could also be chosen to treat adult patients; however, for children, a combination of chloramphenicol and ciprofloxacin should be used.

PREVENTION

The main aim of plague control is to reduce the likelihood of people being bitten by infected fleas, coming into direct contact with infected tissues and/or exudates, or being exposed to contact with humans or animals with the disease.

The plague remains strongly linked to poverty with rural areas being the most affected.

Surveillance and control of the animal reservoir is important in regions where plague is endemic. Some of the following specific measures may be proposed.

The measures for animals are:

• Collecting and analysing fleas from wild rodents;
• Combatting fleas by applying insecticides in the outbreak area;
• suppression of rats by poison may be necessary
• Increasing basic sanitation measures.

However, rat control should always be preceded by flea control measures, as it is possible to suppress the normal food supply of fleas by poisoning their hosts.

A key element remains raising awareness among the general population in urban enzootic areas (habitual presence of the disease in rodents) about:

• The exposure patterns of humans and pets;
• Protection of buildings against mice by preventing rodents from accessing food and shelter through proper storage and disposal of food, waste and rubbish;
• The use of insecticides and repellents to prevent flea bites;
• The risk involved in camping near burrows or handling rodents;
• Reporting dead or sick animals to health authorities.

For suspected bubonic cases, measures to prevent contact should be used while for suspected pulmonary cases, additional precautions should be added (wearing a surgical mask when entering the patient's room).

Patients with bubonic plague without secondary pneumonic and septicemic plague have a very low risk of spreading plague to close contacts.

Vaccine prevention was abandoned because early serums (live attenuated) caused many side effects, sometimes serious. Other forms of vaccine (inactivated whole) were later developed that were not effective enough in pulmonary forms and provided only short-lived immunity.

Recent concerns about the use of the plague agent for bioterrorism have revived research on the topic.

Two virulence factors of Y. pestis, capsular antigen F1 and LcrV (low-calcium response antigen), are currently the most promising avenues for developing new forms of the vaccine. Indeed, a subunit vaccine combining F1 and LcrV has shown promising results in animal models, although its efficacy in humans has yet to be evaluated.

This vaccine could be available in a few years for populations in endemic areas. However, because the immune response to the latter depends mainly on humoral immunity, a booster dose may be necessary.