Plague. Richard W Titball and Sophie E C Leary

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1 Richard W Titball and Sophie E C Leary Defence Evaluation and Research Agency, CBD Porton Down, Salisbury, UK Correspondence to- Dr Richard W Titball, Defence Evaluation and Research Agency, CBD Porton Down, Salisbury, Wilts SP4 OJQ, UK Yersinia pestis, the aetiological agent of plague, has in the past caused social devastation on a scale unmatched by other infectious diseases. There is still a public health problem from plague, with at least 2000 cases reported annually. Most of these cases are of the bubonic form. Occasionally bubonic plague develops into pneumonic plague, and this form of the disease can spread rapidly between susceptible individuals. The recent outbreak of plague in India highlighted the potential for plague to explosively re-appear, and modern mass transport systems mean that there is the potential for the rapid spread of disease. Against this background, there is a need to ensure that vaccines and antibiotics are available to prevent and treat the disease. Progress has been made in devising a sub-unit vaccine, effective against bubonic and pneumonic plague. Antibiotics must be given in the early stages of disease to effect a cure. The aetiological agent of plague is the Gram-negative bacterium Yersinia pestts. Nowadays, most cases of the disease in man are of the bubonic form, which arises following a bite from an infective flea which has previously fed on an infected rodent 1. From the initial focus of infection, the bacterium becomes disseminated into the lymph nodes (often the inguinal or femoral lymph nodes) which drain the site of infection. These lymph nodes become swollen and tender and the classical feature of bubonic plague is the bubo which may reach the size of a hen's egg. Often the patient develops a bacteraemia with blood culture counts in the range < 10 to 4 x 10 7 cfu/rnl 2. A second form of the disease, septicaemic plague, occurs when there is a bacteraemia without the development of buboes. This form of the disease is characterised by an elevated temperature, chills, headache, malaise and gastrointestinal disturbances 1. Due to the absence of buboes, a diagnosis of plague is often delayed and, even with medical intervention, 50% of patients die, probably as a result of the induction of the systemic inflammatory response syndrome 2. The most feared form of plague arises when there is colonisation of the alveolar spaces leading to a suppurative pneumonia 1. Pneumonic plague results in the production of a highly infectious, watery, and bloody sputum which contains viable bacteria. Coughing results in the production of airborne droplets containing British Medical Bulletin 1998,54 (No 3) CThe Bntsh Council 1998

2 Resurgent/emergent infectious diseases bacteria, which can be inhaled by susceptible individuals 13. The pneumonic form of the disease is feared because of the rapidity with which the disease develops (1-3 days), the high mortality rate in infected individuals (approaching 100%) and the rapid spread of disease from man to man 1. Incidence of disease Past epidemics of plague Current incidence of plague During the last 2000 years, Y. pestis has caused social and economic devastation on a scale unmatched by other infectious diseases or by armed conflicts. It is generally considered that there have been three world pandemics of plague and credible estimates indicate that together these resulted in 200 million deaths 2. During these pandemics, the disease occurred in both the bubonic and pneumonic forms. The first of these, the Justinian plague, occurred during the period AD 542 to AD 750. This pandemic is thought to have originated in Central Africa and then spread throughout the Mediterranean basin 2. The second pandemic started on the Eurasian border in the mid-14th century. It is this pandemic which resulted in 25 million deaths in Europe and which is often referred to as the 'black death' 2. This pandemic lasted for several centuries, culminating in the Great Plague of London in The third pandemic started in China in the mid-19th century, spread East and West, and caused 12.5 million deaths in India alone between 1889 and World Health Organization (WHO) figures 5 indicate that there is still a public health problem from plague, especially in Africa, Asia and South America 5 and plague, cholera and yellow fever are the only internationally quarantinable infectious disease. As a class 1 notifiable disease, all suspected cases must be reported to, and investigated by, public health authorities and confirmed cases must be reported to the WHO in Geneva, Switzerland 6. During the period , the average worldwide incidence of plague was 1,666 cases 2. Although the incidence trend was downwards until 1981, there has been an apparent increase in the incidence of disease over the last decade 2 " 5, possibly because of more efficient diagnosis and reporting of cases (Fig. 1). Even today, many cases of plague are not diagnosed and it is likely that the true incidence of disease is several times the WHO figures. 626 British Medical Bulletin 1998,54 (No 3)

3 2500 Fig. 1 WHO figures for the incidence of plague worldwide during the period The solid line indicates the total number of cases of plague whilst the number of deaths due to plague are indicated by the dashed line The Indian outbreak of plague in Despite the high incidence of plague in India during the first half of this century, the number of cases had declined since 1950, and the last recorded case occurred in However, between August and October 1994 two outbreaks of suspected plague occurred, one of bubonic plague in the Beed District of Maharashtra State, and the other of pneumonic plague in the city of Surat in Gujarat State (Fig. 2). The Surat epidemic caused panic throughout India, resulting in a mass exodus of up to half a million people from the city, and attracted international media attention. At the peak of the epidemic, over 6300 suspected cases were recorded 8. However, official figures released later indicated that only 876 presumptive cases of plague were identified (by serological testing for antibodies to Fl antigen of Y. pestts) and there were 54 fatalities 8 (Fig. 2). The cases were confined to six states m central and western India; none of the suspected cases in other states, such as Bihar, Punjab, Rajasthan and West Bengal, had positive serological markers for presumptive plague. During the outbreaks, one of the major problems was the failure to collect systematically clinical samples for analysis. Routine tests to confirm a diagnosis of plague were not carried out and pure isolates of Y pestis were not cultured from blood, sputum or autopsy samples. As a result, the exact nature of the outbreaks in Maharashtra and Surat has provoked controversy and alternative causative agents have been proposed 9. To address concerns, a team of experts from the WHO visited India in October Although the WHO team was unable to isolate Y pestis from clinical samples, it established that there was clinical, epidemiological and serological evidence of an outbreak of plague 8. In response to the crisis, the Indian government constituted a Technical Advisory Committee (TAC) on 9 October, 'to elucidate the factors responsible for the current outbreak of plague and its spread'. In clinical and environmental studies co-ordinated by the TAC, pure Y pestis was British Medical Bulletin 1998,54 (No 3) 627

4 Resurgent/emergent infectious diseases Fig. 2 Map of India and its States, where relevant the numbers of presumptive cases of plague and fatalities (in brackets) are shown for the States isolated from the sputum of 11 pneumonic plague cases in Surat, and the tissues of 6 rodents trapped in Beed and 1 rodent trapped in Surat 9. The biochemical, genetic and immunological similarity of the Surat and Beed isolates suggested that they arose from the same Y. pestis strain and, for the first time, provided evidence that the outbreaks were linked 9. The TAC also conducted studies to identify the events leading up to the epidemics. In the Beed District of the Maharashtra State, the seeds of the outbreak were laid in October 1993 when the residents of Mamla village abandoned their homes in fear of tremors associated with a major earthquake in the neighboring districts of Latur and Osmanabad. Large quantities of grain remained in the homes, which provided a source of food for domestic rats leading to a population explosion and a rodent epizootic of plague 9. The initial source of human infection was the wild rodent population located in habitats surrounding the village. During August 1994, a heavy flea nuisance and 'rat fall' was reported in the village and, shortly afterwards, the first cases of bubonic plague occurred Bntish Medical Bulletin 1998,54 (No 3)

5 The origin of the pneumonic plague outbreak in Surat is less well understood. Monsoon flooding occurred in the city in the first week of September 1994 causing people to leave their homes. Although such disruptions to the local ecological balance are known to contribute to plague outbreaks, there is no evidence that this occurred in Surat. The index case locality of the pneumonic plague outbreak was traced to Laxminagar colony in the north of the city and, although the origin of the disease remains obscure, the most likely scenario is that an individual with pneumonic plague who travelled from the Beed district to Surat was the source of the epidemic 7 * 9. Animal reservoirs of plague Y. pestts is an obligate pathogen which is unable to replicate outside of an animal host. In parts of the world where plague is endemic, the bacterium persists in 'foci' of infected rodents 1 ' 2 ' 10. The observation that distinct foci of infection occur at sites throughout the world indicates that the bacterium can persist for long periods in some relatively resistant (enzootic) animal hosts and their fleas 1 * 2 ' 10. For this reason it would be very difficult, if not impossible, to eradicate Y pestts completely. The bacterium is transferred between animals by fleas and it is thought that the bacterium persists in the environment as the result of a stable rodent-flea infection cycle. Mice, voles and gerbils have all been suggested as enzootic hosts 2. The rapid spread of disease occurs when epizootic hosts such as the rat, prairie dog, squirrels or mice become infected. In the US, prairie dogs or ground squirrels are often the rodent reservoir 1>2 and a local increase in the number of infected animals is considered to be an indication of an increased risk of an outbreak of plague 2. In this situation the likelihood of direct infection of man is low, but domestic pets, which come into contact with prairie dogs, can become infected and then transmit the disease to man either via infective fleas even or via the pneumonic route. In the US, there has been an increase in the number of human cases of primary pneumonic plague, especially in veterinarians, following exposure to infected cats 2. Changes in the incidence and pattern of disease Changes in the patterns of contact with animal reservoirs Where man and rodents are in close proximity, or when the rodent population is reduced, as a result of the disease or as a consequence of British Medial Bulletin 1998,54 (No 3) 629

6 Resurgent/emergent infectious diseases rodent control measures, humans and other warm blooded mammals serve as alternative hosts for the infective fleas. The increase in plague in Vietnam during the Vietnam war has been attributed to deforestation which resulted in the movement of animal hosts into areas inhabited by man 1. In the US, a new trend in plague epidemiology appears to be related to the residential encroachment on former rural areas which contain enzootic foci of plague 2. This can lead to infection of humans as a result of bites by infected fleas or to infection as the result of close contact with domestic cats which have become infected 2. In summary, any change which results in man encroaching on areas of plague foci or which leads to the movement of infective animals hosts into populated areas brings with it the risk of an outbreak of plague. Potential for spread by mass transport systems The spread of plague during the great epidemics can be associated with the movement of man or infected animal hosts along trading routes. The spread of plague into South Africa and into San Francisco during the period 1899 to 1902 is thought to have occurred as a result of the entry of infected rats on ships from the Far East 10. The potential for the rapid spread of plague by mass transport systems (especially air transport) was also of concern during the Indian outbreak of plague. This concern is related especially to the pneumonic form of the disease because individuals with little evidence of serious disease when boarding a longhaul flight could become infectious during the flight. The spread of disease by air transport was controlled by two measures. Firstly, crews on flights which originated from or continued through India were instructed to pay special attention to passengers with a fever, cough or chills and to notify the destination airport of such passengers 11. In many countries, investigations also took place when the flight landed and passengers who displayed symptoms which might indicate pneumonic plague were placed under the surveillance of the local health department 11. If there was no rise in temperature or the development of further symptoms in the following 7 days, the individual was considered to be free from plague 11. If plague could not be excluded as a cause of disease, then the individual might have been placed in an isolation hospital. There was also concern that an infected individual might have transmitted the disease to other travellers. However, the air flow on passenger aircraft is downwards and only individuals within 2 m of the patient were considered to be at risk of inhaling an infectious dose of the bacteria 11. The possible impact of rapid mass transport systems on the spread of infectious disease was amply demonstrated during the Indian outbreak of plague and served to heighten our awareness that suitable 630 British Medical Bulletin 1998,54 (No 3)

7 systems and facilities for the diagnosis and surveillance of individuals infected with dangerous pathogens must be maintained. Advances in the prevention and treatment of disease Current vaccines Improved vaccines Two types of plague vaccine have been used in man. One of these, the killed whole cells vaccine was first produced in 1946 and, over the past decade, there have been several commercial suppliers of this type of vaccine 6. It is generally considered that antibody against the Fl capsular antigen is the key protective response induced by these vaccines 6. The V antigen is also known to induce a protective response against Y pestis but the level of V antigen is low or undetectable in killed whole cells vaccines 12. There is good epidemiological evidence that the killed whole cell vaccine was at least partially effective against bubonic plague. During the period , many thousands of Vietnamese civilians developed plague but the incidence of disease in immunised US troops based in Vietnam was low during this period 6. Furthermore, serological studies indicated that some immunised individuals were exposed to Y pestis and some developed sub-clinical infections 6. Evidence from studies in a murine model of disease indicates that the vaccine is less effective against pneumonic than bubonic plague and cases of pneumonic plague have been reported in vaccinated individuals 6 ' 13. The reason for the lower efficacy of the vaccine against pneumonic plague is not known, but the rapidity with which this form of the disease develops may overwhelm the primed host defence mechanisms. Over the past few years, a wide variety of antigens from Y pestis have been evaluated as potential components of a sub-unit vaccine 14. The Fl and V antigens show the greatest potential as components of an improved vaccine 14. Immunisation of mice with a mixture of the Fl and V antigens induced protection against 10 9 cfu of Y pestis given by the subcutaneous route and also protected mice against at least 100 LD J0 doses of Y pestis given by the inhalation route 15. Protection appears to be mainly antibody-mediated. When cultured at 37 C, the bacterium produces large amounts of the Fl capsule which surrounds bacteria 2 and antibody against the Fl antigen is thought to opsonise these bacteria. The V antigen has been shown to affect the ability of host phagocytic cells to produce TNFoc and EFN-y in response to infection 2. Antibody British Medical Bulletin 1998,54 (No 3) 631

8 Resurgent/emergent infectious diseases Antibiotic therapy against the V antigen would allow the host to mount a normal inflammatory response which would enable the host phagocytes to clear bacteria opsonised by antibody against Fl antigen. The Fl+V antigen subunit vaccine shows good promise for development as a replacement for the killed whole cell vaccines and this vaccine is currently being developed for use in man. A variety of antibiotics are effective against bubonic plague and antibiotic resistant strains have been reported infrequently 2. One notable exception involves the recent isolation, from a case of bubonic plague in Madagascar, of Y. pestts which was resistant to ampicillin, chloramphenicol, kanamycin, streptomycin, sulfonamide and tetracycline 16. Even without the complication of antibiotic resistance, the treatment of septicaemic and pneumonic plague is difficult; in the former case because diagnosis is often not made at a sufficiently early stage and in the latter case because the disease develops so rapidly that many patients are already close to death when treatment commences. Streptomycin is the drug of choice 2 but should be used with care since the ensuing bacteriolysis can result in the release of large amounts of endotoxin. Tetracycline is often used prophylactically and chloramphenicol used to treat plague meningitis 2. Key points for clinical practice Plague is a disease which most medical practitioners will not encounter during their working lifetime. However, plague does occur in many countries throughout the world and the incidence of disease does not appear to be declining. The epidemic potential of the disease is well recognised and any suspect case of plague must be reported to the public health authorities and confirmed cases of plague must be reported to the WHO. Outbreaks of the disease can occur explosively, especially when natural disaster strikes an area of the world where endemic plague foci already exist. Rapid mass transport systems provide the means for the spread of disease to other countries. Pneumonic plague is especially feared in this context, since the disease develops rapidly and is readily transmissible from man to man. Vaccines might well play a role in the control of disease in areas of the world where the disease is endemic but antibiotics will continue to play a key role in the control of disease in infected individuals arriving in the UK. Such a case of plague will 632 British Medical Bulletin 1998,54 (No 3)

9 certainly require hospitalisation in an isolation ward and measures will need to be taken to identify contacts who might have become infected. References 1 Poland JD, Barnes AM. Plague. In: Steele JH, Stoenner H, Kaplan W, Torten M. (eds) CRC Handbook Series in Zoonoses Boca Raton: CRC Press, 1979, Perry RD, Fetherston JD. Yersima pcstis etiologic agent of plague Chn Microbiol Rev 1997; 10: Meyer KF Pneumonic plague. Bactenol Rev 1961, Dennis D. Plague m India. BMJ 1994; 309: World Health Organization. Human plague m Wkly Epidemiol Rec 1996; 71: Centers for Disease Control and Prevention. Prevention of plague: recommendations of the advisory committee on immunisation practices (ACIP). MMWR 1996; 45: Ranga S, Gulati I, Pandey J et al. Plague - a review Indian J Pathol Microbiol 1995, 38: World Health Organization. Plague. Wkly Epidemiol Rec 1995, 5: 35 9 Special section. The plague epidemic of 1994 Curr Set 1996, Christie AB, Corbel MJ. Plague and other yersinial diseases In- Smith GR, Easmon CSF. (eds) Topley and Wilson's Principles of Bacteriology, Virology and Immunity, vol 3 London: Edward Arnold, 1990; Fritz CL, Dennis DT, Tipple MA et al. Surveillance for pneumonic plague m the United States during an international emergency: a model for control of imported emerging diseases. Emerg Infect Dis 1996; Russell P, Eley SM, Hibbs SE et al. A comparison of plague vaccme, USP and EV76 vaccine induced protection against Yersima pestis in a munne model. Vaccine 1995, 13: Cohen RJ, Stockard JL Pneumonic plague m an untreated plague-vaccinated individual JAMA 1967; 202: Williamson ED, Eley SM, Gnffin K et al A new unproved sub-unit vaccine for plague the basis of protection. FEMS Immunol Microbiol 1995, 12: Williamson ED, Eley SM, Stagg AJ et al. A sub-unit vaccine elicits IgG in serum, spleen cell cultures and bronchial washings and protects immunised animals against pneumonic plague. Vaccine 1996, 15: Galimand M, Guiyoule A, Gerbaud G et al. Multi-drug resistance m Yerstnta pestis mediated by a transferable plasmid New Engl J Med 1997; 337: British Medical Bulletin 1998,54 (No 3) 633