Current epidemiology of human plague in Madagascar.

From 1996 to 1998, 5,965 patients with suspected plague were identified in 38 districts of Madagascar (40% of the total population are exposed). Using standard bacteriology, 917 of them were confirmed or presumptive (C + P) cases. However, more than 2,000 plague cases could be estimated using F1 antigen assay. Two out of the 711 Yersinia pestis isolates tested were resistant to chloramphenicol and to ampicillin (both isolates found in the harbour of Mahajanga). Urban plague (Mahajanga harbour and Antananarivo city) accounted for 37.4% of the C + P cases. Bubonic plague represented 97.2% of the cases, and the lethality rate was still high (20%). In comparing the exposed population, plague was more prevalent in males (M:F sex ratio 1.3:1) and patients under 20 years (2.7% babies under two years). Buboes were mainly localised in the inguinal/femoral regions (55.8%). The epidemiological risk factors are discussed.

[Update on plague in Madagascar]. / Actualités sur la peste à Madagascar.

After a thirty year period of successful control, bubonic plague showed the first signs of return in Madagascar where a fatal outbreak occurred in Antananarivo in 1978. A second outbreak was observed in Mahajanga in 1991 after more than a half century. In 1997, 459 confirmed or presumptive cases were reported, as compared to 150 to 250 cases during the last years. However the actual extent of this recrudescence must be placed in the perspective of a more efficient control program that has led to better reporting of suspected cases and availability of more accurate diagnostic techniques. Recent research has led to the development of highly effective immunological diagnostic tools (detection of antibodies and F1 antigen) allowing not only better surveillance of the disease in man and animals but also renewed study of the epidemiological cycle in the current environment. In this regard the capacity of several endemic fleas as vectors and the role of the rat Rattus norvegicus and the musk shrew Suncus murinus are currently under investigation. Genetic study of strains collected from 1936 to 1996 has demonstrated the appearance of 3 new ribotypes of Yersinia pestis since 1982 in the zones of strongest plague activity in Madagascar. A strain showing multiresistance to standard therapeutic antibiotic agents was isolated in 1995. Bubonic plaque is a priority health problem in Madagascar but remains a major concern for the rest of the world.

Plague, a reemerging disease in Madagascar.

Human cases of plague, which had virtually disappeared in Madagascar after the 1930s, reappeared in 1990 with more than 200 confirmed or presumptive cases reported each year since. In the port of Mahajanga, plague has been reintroduced, and epidemics occur every year. In Antananarivo, the capital, the number of new cases has increased, and many rodents are infected with Yersinia pestis. Despite surveillance for the sensitivity of Y. pestis and fleas to drugs and insecticides and control measures to prevent the spread of sporadic cases, the elimination of plague has been difficult because the host and reservoir of the bacillus, Rattus rattus, is both a domestic and a sylvatic rat.

Intérêts et difficultés de la microscopie pour le diagnostic de présomption de la peste

Le diagnostic bactériologique de la peste est basé sur la microscopie et l'isolement de Yersinia pestis à partir de prélèvements suspects. Lorsque la culture et l'inoculation à la souris sont négatives, l'examen direct du frottis permet de poser un diagnostic de présomption de peste. Examen simple à réaliser a priori, la microscopie pose cependant de réelles difficultés de lecture et de reproductibilité entre deux laboratoires. Cette étude compare les résultats obtenus au Centre Hospitalier Universitaire (CHU) de Mahajanga et au Laboratoire Central de la Peste (LCP), lors des deux épidémies successives de peste en 1995 et 1996.En prenant la culture comme référence, la microscopie réalisée à Mahajanga est plus sensible mais moins spécifique que celle réalisée au LCP. Entre l'année 1995 (350 patients) et 1996 (245 patients), la concordance entre les 2 laboratoires s'est améliorée, passant de 55% à 75%. Malgré une sensibilité et une spécificité assez faibles par rapport à la culture (elle-même peu sensible aussi en raison des conditions de transport des prélèvements), la microscopie conserve toute sa valeur pour le diagnostic de présomption de la peste lorsqu'elle est faite par un personnel entraîné. La solution idéale à terme sera un test immunodiagnostique simple et rapide, réalisable par des agents de santé non biologistes

La peste : maladie réémergente à Madagascar

La peste est aujourd'hui considérée par l'OMS comme une maladie résurgente dans le monde. A Madagascar, on assiste à sa recrudescence : 150 à 250 cas par an sont notifiés confirmés ou probables. La peste sévit surtout sur les Hauts-Plateaux où 32 Services de Santé de District sont concernés. Parmi eux, le district d'Antananarivo-ville où 23 cas contrôlés ont été recensés en 1996. Sur les côtes, la maladie a réapparu en 1991, dans la ville portuaire de Mahajanga après 63 années de silence apparent; entre 1991 et 1997, 3 épidémies sont survenues : 180 cas ont été confirmés ou probables de peste. A Antananarivo, la surveillance de la population murine a montré une circulation intense du bacille pesteux. Fait préoccupant, les puces vectrices, Xenopsylla cheopis, récoltées des rats capturés ont montré une résistance aux principales familles d'insecticides dont les pyréthrinoïdes. Cette situation alarmante exige un système d'alerte et de riposte. La mise à disposition d'un test de diagnostic simple, très rapide et sûr aux services sanitaires périphériques devrait améliorer les mesures de riposte devant un cas confirmé de peste

Recent emergence of new variants of Yersinia pestis in Madagascar.

Yersinia pestis, the causative agent of plague, has been responsible for at least three pandemics. During the last pandemic, which started in Hong Kong in 1894, the microorganism colonized new, previously unscathed geographical areas where it has become well established. The aim of this longitudinal study was to investigate the genetic stability of Y. pestis strains introduced into a new environment just under a century ago and to follow the epidemiology of any new genetic variant detected. In the present study, 187 strains of Y. pestis isolated between 1939 and 1996 from different regions of Madagascar and responsible mainly for human cases of bubonic and pneumonic plague were studied. Our principal genotyping method was rRNA gene profiling (ribotyping), which has previously been shown to be an effective scheme for typing Y. pestis strains of different geographical origins. We report that all studied Y. pestis strains isolated in Madagascar before 1982 were of classical ribotype B, the ribotype attributed to the Y. pestis clone that spread around the world during the third pandemic. In 1982, 1983, and 1994, strains with new ribotypes, designated R, Q, and T, respectively, were isolated on the high-plateau region of the island. Analysis of other genotypic traits such as the NotI genomic restriction profiles and the EcoRV plasmid restriction profiles revealed that the new variants could also be distinguished by specific genomic and/or plasmid profiles. A follow-up of these new variants indicated that strains of ribotypes Q and R have become well established in their ecosystem and have a tendency to spread to new geographical areas and supplant the original classical strain.

Field evaluation of an immunoglobulin G anti-F1 enzyme-linked immunosorbent assay for serodiagnosis of human plague in Madagascar.

Bacteriological isolation of Yersinia pestis is the reference test for confirming plague infection, but recovery of the pathogen from human samples is usually very poor. When the etiology of the disease cannot be bacteriologically confirmed, it may be useful to possess alternative tests such as detection of specific circulating antibodies to help guide the diagnosis. In the present study, the immunoglobulin G (IgG) anti-F1 enzyme-linked immunosorbent assay (ELISA) has been applied to various human sera to evaluate its large-scale applicability in the high-endemicity plague foci of Madagascar. The sensitivity of the test was found to be 91.4%, and its specificity was 98.5%. The positive and negative predictive values were 96 and 96.6%, respectively. Seroconversion was observed on day 7 after onset of the disease. Patients with a positive ELISA result could be separated into high (82%) and low (18%) IgG anti-F1 responders. Cross-reactions with eight other infectious diseases prevalent in Madagascar were scarce and were found in 1 of 27 Mycobacterium tuberculosis-, 3 of 34 Schistosoma haematobium-, and 1 of 41 Salmonella-infected patients. Finally, the efficiency of the IgG anti-F1 ELISA was evaluated during the Mahajanga, Madagascar, plague outbreak of 1995. When the number of ELISA-positive patients was added to the number of bacteriologically confirmed and probable cases, the number of positive patients was increased by 35%. In conclusion, although it does not replace bacteriology, IgG anti-F1 ELISA is a useful and powerful tool for retrospective diagnosis and epidemiological surveillance of plague outbreaks.

Urban epidemic of bubonic plague in Majunga, Madagascar: epidemiological aspects.

After an absence of 62 years, an epidemic of plague occurred in the harbour city of Majunga (Madagascar) from July 1995 to March 1996, following sporadic cases in March and May 1995. By 15 March 1996, 617 clinically suspected cases of bubonic plague had been notified. Laboratory testing was carried out for 394 individuals: 60 (15.2%) were confirmed to have bubonic plague and 48 (12.2%) were considered as presumptive cases. The incidence was significantly higher in males in all age groups and in both sexes in the 5-19 age group. Twenty-four deaths were related to plague, but early treatment with streptomycin has confirmed its effectiveness insofar as the case-farality ratio was only 8.7% among confirmed and presumptive cases admitted to hospital. The difficulty of clinically diagnosing bubonic plague was affirmed. The disease met favourable conditions through the poverty and low level of hygiene prevalent in most parts of Majunga.

[The plague in Madagascar: epidemiologic data from 1989 to 1995 and the national control program]. / La peste à Madagascar: données épidémiologiques de 1989 à 1995 et programme national de lutte.

After briefly reviewing the history and epidemiological cycle of the plague in Madagascar, we report a detailed analysis of 5,927 suspected cases of plague observed from 1989 to 1995 (average of 846 cases per year). Of those, 1,337 individuals (average of 191 cases per year) were confirmed (by isolation of Yersinia pestis) or indicated to be probable for plague (by positive smears). Since 1994, we observed an increasing number of confirmed and probable cases (252 cases in 1995). Most of the cases occurred between October and April in the central highlands, inside a geographical triangle limited by Alaotra lake, Itasy lake and the city of Fianarantsoa. Two exceptional epidemics occurred in the harbor of Majunga in 1991 and 1995. The bubonic plague was the most frequent clinical from (91.3%), with primarily an inguinal localization (67.8%). The mean case fatality rate was 19% of the confirmed or probable cases (14.8% for the bubonic form and 57.1% for the pneumonic form). The bubonic plague was significantly more frequent between the ages of 5 and 14 years, as compared to the general population, while the pneumonic plague was more frequent over 15 years of age. Males were more effected by the bubonic form, as the sex ratio (m:f) was 1.3. The national control program for plague is being strengthened to improve 1) the patient's early diagnosis and care system; 2) the measures for the prevention of epidemics; 3) the epidemiological surveillance; and 4) the studies on the biology of the plague vectors, rodents and fleas, and the agent, bacilli, in Madagascar.

[The plague: disease and vaccine?]. / La peste: maladie et vaccin?

Plague has existed in Madagascar since 1896, with epidemic control achieved by GIRARD with an EV vaccine in 1937. Plague persists in Madagascar, however, due to the large animal reservoir. With a predilection for nodal tissues, Yersinia pestis is a virulent bacteria that is potent inducer of antibody synthesis. Immunity mechanisms stimulated by infection were studied: 1. In human by immunoenzymatic methods 2. In mice by seroprotection and vaccinating tests. Induced immunity for people in endemic and endemic-epidemic areas, is significant, affecting approximately 70% of these populations. In non endemic areas, immunity is found in only 33% of the population, perhaps this explains the persistence of epidemic? In all cases, this immunity is a quick onset (6 days), is persistent (> 2 years), and has demonstrable serious recognition of YOP (Yersinia Outer Proteins) by Western Blot method. Human antibodies were shown to be protective for mice. Animals vaccinated by YOP were protected equally well, when compared to animals infected with Yersinia pestis and subsequently treated with antibiotics. Finally, YOP aerosols were also shown to induce antibodies. In conclusion, plague is a vaccinatable bacterial disease and YOP can be used as an animal vaccine to permit plague control in the rat reservoir.

[Seroepidemiologic survey on plague in an endemic zone: cumulative results: 1987-1990]. / Enquête séro-épidemiologique peste en zone d'endémie: résultats cumulés: 1987-1990.

Plague is a bacterial disease, induced by Yersinia pestis growth in rodents, with human transmission by fleas. In numerous cases, lymph node reaction is important. This survey (329 patients and contacts) is the most extensive ever realised, associating plasmidic virulence and immunity studies. From the results, we can retain that: All the strains were 47 Plasmid+. The immunity was precocious, specific, of high titer and persistent. In conclusion, in plaque endemic zone, high bacillus circulation induced a high and perhaps (to prove) protective immunity.

[Sensitivity of Yersinia pestis to antibiotics: 277 strains isolated in Madagascar between 1926 and 1989]. / Sensibilité de Yersinia pestis aux antibiotiques: 277 souches isolées à Madagascar entre 1926 et 1989.

The antimicrobial susceptibility of 277 strains of Yersinia pestis was studied using broth microdilution panel. In recent strains, trimethoprim, cotrimoxazole and ampicillin were the most active of the antibiotics tested (MICs less than 2 mg/l). All strains were inhibited by 16 mg/l of kanamycin and sulfamethoxazole, 32 mg/l of sulphadiazine and sulfanilamide, and 64 mg/l of sulfamethoxypyridazine. Doxycycline, minocycline, chloramphenicol, demeclocycline, tetracycline, oxytetracycline and chlortetracycline were equally active but some of strains were resistant (13% for tetracycline; 32.5% for oxytetracycline; 84.5% for chlortetracycline). Analysis of MICs in relation with time (comparison of the two period: 1926-1948 and 1948-1989) evidenced a trend towards a decrease in susceptibility to cyclines prime generation. Sulphonamides and streptomycin preserve the some efficacity on Y. pestis but we have to notice the possible existence of resistant strain on high level with streptomycin.