- Email: [email protected]
Cholera
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Seminar
Cholera José L Sánchez, David N Taylor The 1990s have witnessed the changing face of cholera— its reemergence in one continent, a new epidemic strain in another, and a tragic reminder of the impact of the disease in an already suffering population. In January, 1991, cholera was reintroduced into Latin America after an absence of more than 100 years.1 Within two years the disease had spread from Peru to Mexico,2 and in the past six years there have been 1·4 million reported cases of cholera causing more than 10 000 deaths in the Americas (figure). As a result of the Latin American outbreak, more cases of cholera have been reported to WHO every year in the 1990s than in any other year since surveillance began. October, 1992, saw another unprecedented epidemiological event; a new epidemic strain of Vibrio cholerae emerged in India and Bangladesh.3 This cholera toxin (CT)-producing strain was the first non-O1 strain of V cholerae capable of causing epidemics, and it has since been classified as V cholerae O139 Bengal.3 The lack of cross-immunity between the Bengal strain and other O1 cholera strains led to major epidemics of cholera (up to 200 000 cases) in India, Bangladesh, and five other countries of South-East Asia.4 Travel-associated (imported) cases were reported in the USA, Europe, and Japan.4,5 Finally, the massive outbreak of El Tor cholera among Rwandan refugees in Goma, Zaire, resulting in 70 000 cases and 12 000 deaths in July, 1994, showed that during times of crisis cholera can be catastrophic.6,7 The very high cholera death rate (15 per 1000), with a fatality ratio as high as 48% at one camp, were principally due to the rapid waterborne spread of cholera (as well as shigellosis), which quickly overwhelmed the existing medical services and the capacity for oral rehydration therapy (ORT) at diarrhoea treatment centres.7 The morbidity and mortality rates during the Rwandan refugee crisis contrast sharply with Latin America, where mortality rates were consistently below 1%.2,8 Access to health care is an important factor determining outcome. In Peru, for example, most cholera was reported in urban areas where hospitals and rehydration units were readily available but in rural areas mortality rates were 5% and continued to be high for years after the initial outbreak.2,8
Cholera and international travel The resurgence of cholera has led to an increase both in the awareness of cholera and in the number of cases detected in travellers and workers going from the developed world to endemic areas. The most important example occurred in February, 1992, when 75 of 336 Lancet 1997; 349: 1825–30 US Army Medical Research Unit-Brazil, American Consulate-Rio Unit 3501, APO AA 34030-3501 (J L Sánchez MD); and Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington, DC, USA, and US Naval Medical Research Institute Detachment, Lima, Peru (D N Taylor MD) Correspondence to: LTC José L Sánchez e-mail: ([email protected] or [email protected])
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Cholera incidence (per 1000) in the Americas, 1991–96 From Pan American Health Organization.
passengers from an airliner returning to Los Angeles from South America developed cholera.9 The flight originated in Argentina but the outbreak was traced to a seafood salad prepared by the caterer in Peru that was picked up en route to Los Angeles. Many of the passengers had severe diarrhoea and had to be admitted to hospital; five progressed to renal failure and one died. In surveys done from the 1960s to 1980s cholera was rare in travellers but this was because the disease was present in areas that few people visited; also microbiologybased surveillance was lacking.10 In Japan, where there is regular microbiological screening for cholera by culture in returning travellers with diarrhoea, the incidence of cholera for all destinations was 5 per 100 000; it was 13 per 100 000 in Japanese travellers returning from Bali (table 1).11 In the USA the 10-fold increase in cholera cases noted by Centers for Disease Control and Prevention investigators was due to the proximity of the Latin American outbreak and increased awareness.9 Routine surveillance of expatriates living in endemic areas suggests a substantial risk exists. In a study of US embassy personnel in Lima, Peru, during the height of the cholera outbreak and among those who presented with diarrhoea, 1825
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a stool sample was cultured on thiosulphate/citrate/bilesalts/sucrose agar (TCBS) for V cholerae. Five cases of cholera were detected among 317 US citizens. The estimated incidence of cholera in US citizens was 5·3 per 1000 per year or 44 per 100 000 per month of exposure.12 Clearly, cholera can present as a severe form of traveller’s diarrhoea and may be missed if stools are not cultured for V cholerae.
Microbiology of V cholerae V cholerae is a motile, curved, gram-negative bacillus, first described in 1854 in Italy by Filippo Pacini.13 In 1883, Robert Koch demonstrated that cholera was caused by this microorganism (Kommabazillen).13 It is a well defined species.14 Of the 139 serogroups, as determined by the composition of the major surface antigen of the cell wall (O), only two, O1 and O139, have been associated with epidemics; these two serogroups produce cholera toxin, which is responsible for the fluid secretion. Other serogroups have only been associated with sporadic cases and small clusters of non-cholera diarrhoea.14,15 Serogroup O1 can be further subdivided into three serotypes, named Ogawa, Inaba, and Hikojima, based on quantitative differences of factors A, B, and C of the O antigen. V cholerae O1 strains are also divided into two biotypes, classical and El Tor. Isolates from the third pandemic (1852–59) to the sixth (1899–1923) were caused by the classical biotype. El Tor gave rise to the seventh pandemic, which originated in Sulawesi, Indonesia, in 1961, and is still ongoing.1,4 El Tor is now the predominant biotype but classical is still common in Bangladesh. The Latin American outbreak was exclusively El Tor Inaba at first but was replaced by El Tor Ogawa after the first year. Cholera due to classical or O139 strains has not been detected in Latin America. V cholerae O139 is genetically related to the seventh pandemic O1 strains (see below) because it possesses all of the virulence determinants typical of O1 biotype El Tor, but there is a mutation in the genes producing the O antigen.16 O139 strains can produce a polysaccharide capsule and have an increased capacity both for cholera toxin production and for spread and proliferation within the environment.17
Epidemiology Epidemics of cholera arise after the introduction of V cholerae in non-endemic areas where most of the population is non-immune.18,19 Under these circumstances the attack rates can be as high as 10% and all age groups are affected. The morbidity and mortality can be considerable—for example, the introduction of cholera into West Africa in 1970 resulted in over 150 000 cases and more than 20 000 deaths in the first year,20 and in Peru there were over 420 000 cases and 3300 deaths within the first 15 months of the start of the epidemic.2 Epidemics are often unpredictable but they are usually seasonal: in Bangladesh the main peak is in the winter (September to November) with a summer peak in March to May), in coastal Pacific regions of South America cholera epidemics occur during the summer (January to May), and in the tropical jungle regions epidemics tend to coincide with the cool, dry season (June to September). Chronic carriers are rare and do not play a significant part in maintaining the microorganism between epidemics. Asymptomatic infection is often found at the time that symptomatic 1826
Population
Western travellers (1991) to10 Asia (India) South America (Ecuador)
Cholera rate/100 000 population 0·05 (3·7) 0·3 (2·6)
Comments
Based on passive reporting; TCBS not routinely used
Japanese travellers (1991) to11 All destinations Bali, Indonesia
5 13
All travellers with diarrhoea screened with TCBS
US Embassy employees in Peru12 All employees US citizens
30 44
Study still in progress; people seen and cultured on site, TCBS media routinely used
136
National sur veillance system based on clinical case definition
Peruvian citizens Lima 1991 by month
TCBS=culture medium specific for V cholerae (table adapted from ref 12).
Table 1: Estimates of incidence of cholera among travellers and expatriates in three studies
cholera is occurring, and is probably important in intrafamilial transmission. The transition from the epidemic to an endemic phase occurs after a large proportion of the population is immune or semi-immune. Previous immunity decreases illness in adults so higher attack rates are seen in children and in women of childbearing age, who are exposed to large inocula of V cholerae organisms while caring for the very young.21 Attack rates tend to be low in adults in this situation (<1% per year). Studies in Bangladesh, where both classical and El Tor biotypes are present, have indicated that infection with classical organisms provides more potent and long-lasting immunity than infection with El Tor. In Peru, where outbreaks were caused exclusively by V cholerae El Tor, numbers of cholera cases fell from 322 000 cases in 1991 to only 4500 cases in 1996 and this decrease was at least in part due to heightened immunity. During the endemic phase secondary transmission of cholera occurs, principally by intrafamilial spread of infection among family contacts in the range 4–22% and sometimes as high as 50%.21,22 Contamination of food, at home, shared social functions, in markets, and by street vendors, is common. V cholerae O1 can survive for 2–14 days in food and for many weeks in shellfish and molluscs.23 Widespread contamination of surface water sources also contributes to the transmission of cholera. The epidemiology and transmission patterns of O139 seem similar to those of O1 strains. High attack rates of severe cholera due to O139 seen among adults in areas long endemic for O1 indicate that infection by V cholerae O1 strains does not provide cross-protection.4 The secondary infection rate among family members is about 25% within 10 days of the index case. If outbreaks of cholera due to this new serogroup continue to occur in newly affected countries, they may represent the advent of the eighth cholera pandemic. Bengal strains survive well in environmental water.4,24 Household (tubewell) water has often been found to be the principal source of infection in Bangladesh. Thus, the predominant mode of transmission of V cholera O139 appears to be waterborne.
Ecology of V cholerae Non-O1 V cholerae have been identified as free-living bacterial flora in estuarine areas. By contrast, V cholerae O1 is very difficult to isolate unless there is cholera in the population. The persistence of V cholerae within the environment, for months and probably years, is facilitated by its ability to enter a viable, nonculturable, dormant state
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Indicator
Degree of dehydration Mild or none
Moderate
Severe
Mental status Thirst Radial pulse Respirations Skin-pinch sign Eyes Urine flow Serum specific gravity Fluid deficit (mL/kg body weight) Preferred method of rehydration
Alert Present Normal Normal Skin retracts immediately Normal Normal 聿1·027 20–50 ORT in 4–6 h
Lethargic, stuporous Marked Rapid and feeble or impalpable Tachypnoeic, deep, laboured Skin retracts ver y slowly (>2 s) Dramatically sunken Scant or absent >1·034 91–120 IVRT, 2 L in 30–60 min, remainder in 3–4 h
Preferred type of rehydration
WHO ORT (all ages), Rehydralyte (adults), Pedialyte (children), Infalyte (infants) ORT for as long as diarrhoea persists
Restless or lethargic Present Rapid Tachypnoeic Skin retracts slowly (1–2 s) Sunken Scant and dark 1·028–1·034 51–90 ORT and/or IVRT; depends on presence of vomiting and stool losses WHO ORT and/or IVRT Normal saline*† NA
Maintenance
Lactate Ringer‘s* NA
ORT=oral rehydration therapy, IVRT=intravenous rehydration therapy, NA=not applicable. *Dextrose-containing solutions (2–5%) are preferred due to risk of hypoglycaemia in cholera. Addition of potassium chloride (10 mmol/L) is recommended to reduce risk of hypokalaemia.
Table 2: Guidelines for clinical evaluation of dehydration and recommendations for rehydration and maintenance fluid therapy
where its requirements for nutrients and oxygen are much decreased.25 V cholerae can also bind to chitin, a component of crustacean shells, and it can colonise the surfaces of algae, phytoplankton, and copepods (zooplankton) and the roots of aquatic plants such as water hyacinths. Environmental factors such as an increase in water temperature, pH, and seawater nutrients and a decrease in salinity may trigger conversion of the organism from the viable, non-culturable to the culturable, and therefore, infectious phase. These same environmental factors may also lead to an increase in numbers of crustaceans, and thus to a rise in the population of freeliving V cholerae. The periodic introduction of such infectious environmental isolates into the human population, through ingestion of undercooked shellfish and seafood, is probably responsible for isolated foci of endemic disease in the US Gulf Coast and Australia and for the clusters that gave rise to the Latin American epidemic.23,25 V cholerae has recently been found to shift to a “rugose” form, associated with the production of an exopolysaccharide which promotes cell aggregation. This form resists disinfectants such as chlorine,26 a key intervention in controlling cholera.27 Rugose strains, if present in the potable water system, may thus contribute to the waterborne transmission of cholera.
Clinical features The incubation period of cholera ranges from several hours up to 5 days35 and is determined by the inoculum size18,28 and whether food was the vehicle of transmission (food protects vibrios from the action of stomach acid). Inoculum sizes as low as 100–1000 organisms may cause disease but doses of around 1 million are needed to reliably induce disease in volunteers.28,29 Few patients infected with V cholerae O1 develop severe cholera (cholera gravis). In Bangladesh only 11% of classical infections and 2% of El Tor result in severe cholera30 and in Peru only 25% of cholera illnesses among the local population were detected in hospital.31 The most striking feature of severe cholera is the voluminous water stool output, and the dehydration it causes (table 2). Stool output can reach 500–1000 mL per hour, leading rapidly to hypotension, tachycardia, and vascular collapse. The patient becomes lethargic or stuporous with sunken eyes and cheeks and dry mucous membranes. Decreased skin turgor (skin-pinch sign) is found in all such cases. Urine flow is decreased or absent and serum specific gravity is consistently raised. Clinical
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illness which goes untreated resolves in 4–6 days in most cases (unless circulatory collapse occurs).
Treatment The key to treatment is rapid rehydration, ORT for mildly dehydrated patients or with a combination of ORT and intravenous rehydration if the dehydration is moderate or severe32 (table 2). In Peru, nearly all patients ill enough to be taken to hospital required intravenous rehydration before they could be maintained on oral fluids. The approach in Peru was rapid intravenous replacement with normal saline, attempting to restore blood pressure and urine flow in 4 h. Patients in the large hospitals were monitored in cholera seats rather than cholera beds to make sure that hydration was maintained. Once the patient is alert and can tolerate oral fluids, ORT should be started. Stool losses, fluid intake, and serum specific gravity should continue to be monitored closely at the bedside at least hourly for the first 4–6 h. Serum specific gravity is the best objective indicator of the success of rehydration; it can be measured with a simple, inexpensive hand-held refractometer. Once ORT begins the patient should be encouraged to drink freely to at least equal 1·5 times the volume of stool losses. ORT should be continued for as long as the patient has diarrhoea. The most common complication seen in Peru was acute renal failure; this was seen in 1% of patients admitted to hospital and was significantly more common in those over 60 years of age.8 Oral antimicrobial therapy can halve the duration of illness and stool volume losses and also shorten the duration of excretion.32 Tetracycline or doxycycline are the recommended first-line drugs.8,32 For children less than 8 years of age and for pregnant women, erythromycin, furazolidone or co-trimoxazole are indicated. In areas where there is significant resistance, quinolones can be used.8 These drugs are effective as single-dose therapy and they rapidly shorten the excretion of V cholerae from stools.8,33,34 This rapid clearance of vibrios from stool may help to reduce secondary transmission of cholera, especially in hospitals, treatment centres, and refugee settings.33
Public health prevention and control of cholera Strategies for the prevention and control of cholera are:35,36 ● Early detection of epidemics through diarrhoeal disease surveillance and investigation of severe cases and clusters of illness. ● Education to promote good personal hygiene emphasising proper handwashing with soap and food 1827
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preparation techniques. Bathing in potentially contaminated open water should also be discouraged. ● Construction and maintenance of sewage disposal facilities. ● Provision and protection of safe and plentiful water and storage (eg, in homes and restaurants). Simple and inexpensive methods of domestic water disinfection and storage have been developed and they reduce the risk of cholera and diarrhoeal diseases.37 Point-of-use disinfection and the appropriate use of safe water storage containers is important in maintaining the water supply.
Recent advances in vaccine development Parenteral, whole-cell cholera vaccines have been in use since the late 19th century. Controlled trials in the 1960s in cholera-endemic areas demonstrated they were only 60% effective for the first 3 months, declining to 30% during months 4–6 after vaccination.38 Moreover, this vaccine has to be given in two doses at 7–28 days apart and is associated with significant local reactions in up to 30% of vaccinees. This vaccine does not reduce carriage of V cholera O1 and its protective efficacy is below 30% in children.39 This vaccine is no longer recommended. Beginning in the early 1980s inactivated oral cholera vaccine candidates have been developed. An oral vaccine, consisting of the B subunit of cholera toxin (1 mg) and 1011 cholera whole cells (WC/BS, Cholerix; SBL Vaccin AB, Stockholm, Sweden), was found to protect against diarrhoeal illness caused by V cholerae O1 and, to some extent, against enterotoxigenic Escherichia coli in Bangladesh.40 This vaccine provided 85% efficacy against cholera in the first 6 months and a cumulative efficacy of 50% over 3 years when two or three doses were given 6 weeks apart. Protection was also found to be better against classical than El Tor cholera, especially among young children less than 5 years of age. A cheaper, recombinant formulation (WC/rBS, SBL Vaccin AB), developed in the late 1980s, was also found to be safe and immunogenic in volunteers.41 Immunity is conferred 7–10 days after the second dose. This oral vaccine, given in two doses 1–2 weeks apart, provided 86% efficacy for 3 months against cholera among Peruvian military personnel immediately before an epidemic of El Tor with high attack rates (2–3%) in the summer of 1994.42 A similar inactivated oral cholera vaccine, manufactured in Vietnam, had a protective efficacy of 66% against El Tor cholera.43 Protection in the Vietnam study was found to be similar in young children (68%) and older people (66%). The main drawback of the oral, inactivated vaccines is the need for two or three doses, 1–2 weeks apart. If immunity could be obtained more rapidly, a vaccine could be considered as an option for immunisation in the military and/or for travellers and for the control of threatened cholera epidemics or epidemics already in progress. Live attenuated, oral cholera vaccines would be ideal for these needs (table 3). The best studied of these vaccines is CVD 103-HgR (Orochol Berna; Swiss Serum and Vaccine Institute, Berne, Switzerland). This vaccine confers an immune response (and protection in challenged volunteers) within 8 days.44 It is safe and produces after one dose, in the immunologically naive individual, a vibriocidal immune response that approximates natural infection. In the volunteer challenge model, CVD103-HgR 1828
WC/BS
CBD103-HgR
Type of vaccine
Inactivated
Bio/serotype Dosage
Four strains 1011 cells+1 mg BS
Storage Buffer required Route Number of doses Booster Booster efficacy Estimated shelf life Cold chain Safety Transmission Environmental concerns Serum vibriocidal GMT Vibriocidal antibody seroconversion rate† Anti-CT seroconversion rate Protection in field studies Protection in volunteers‡
Suspension Bicarbonate Oral Two 1 yr Yes 3–4 yr 5°C Yes No None 1:100 25–50%
Recombinant to live, attenuated Classical, Inaba 108 cells in travellers, 109 cells in LDC Lyophilised Bicarbonate Oral One 6 mo Unknown 3–4 yr 5°C Yes Yes, minimal <1% Possible 1:1000 75%
80–90% 50–85% vs El Tor 65%
Onset of protection
17–21 days
70% No data available 60% vs El Tor, 90% vs classical 7 days
GMT=geometric mean titre; CT=cholera toxin. *LDC=less developed countries. †4-fold increase. ‡=all degrees of illness.
Table 3: Characteristics of oral killed and oral live cholera vaccines
produces higher protection against the homologous classical strain than against El Tor.44 This vaccine is licensed in Switzerland and in parts of Latin America. A trial in north Jakarta, Indonesia, in 68 000 people given a single dose of CVD 103-HgR is being organised at the US Navy Medical Research Unit No 2. Other single-dose, live attenuated vaccines developed at Harvard Medical School (Mekalonos et al) and at the Center for Vaccine Development, Baltimore (Levine et al), are being tested in volunteers. Attenuation of El Tor was unsuccessful for many years but new methods of strain selection and attenuation have now led to several new candidate vaccines. For example, two El Tor based, live attenuated, oral vaccines developed from Peruvian strains (Peru-14 and Peru-15) show promise as safe, effective vaccines against El Tor cholera,45,46 and Peru-15 has proved to be safe and highly protective against El Tor cholera in human challenge studies. The rapid spread of V cholerae O139 among all age groups in areas where V cholerae O1 is endemic indicates that immunity to O1 type is not protective against O139.4 Epidemiological and laboratory studies suggest that natural immunity to O1 is not protective against O139,4 and this has been confirmed in challenge studies in rabbits and volunteers.4,47 The high rates of severe illness seen with this new strain and its potential to cause large epidemics among non-immune adults mean that attenuated V cholerae O139 type vaccines are needed urgently. Such vaccines are being developed and tested in animal models. Initial volunteer studies with live, attenuated O139 vaccine candidates seem promising, and protective efficacies as high as 83% have been recorded with one candidate vaccine, Bengal-15.48 The hope is that oral cholera vaccines, killed and live, will become readily available for use in immunisation programmes in developing countries,49 and for travellers, expatriates, and military personnel. Other possibly important, albeit controversial, applications are during emergencies (such as famines, typhoons, and floods) and for refugees in both primitive and well-established camps where the risk of cholera outbreaks is considered high.50
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References 1 2
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Lacey SW. Cholera: calamitous past, ominous future. Clin Infect Dis 1995; 20: 1409–19. Tauxe R, Seminario L, Tapia R, Libel M. The Latin American epidemic. In: Wachsmuth IK, Blake PA, Olsvik O, eds. Vibrio cholerae and cholera: molecular to global perspectives.Washington, DC: American Society for Microbiology, 1994: 321–44. Cholera Working Group, International Centre for Diarrhoeal Diseases Research, Bangladesh. Large epidemic of cholera-like disease in Bangladesh caused by Vibrio cholerae O139 synonym Bengal. Lancet 1993; 342: 387–90. Sack RB, Albert MJ, Siddique AK. Emergence of Vibrio cholerae O139. Curr Clin Topics Infect Dis 1996; 16: 172–93. Dalsgard A, Nielsen GL, Echeverria P, Larsen JL, Schonheider HC. Vibrio cholerae O139 in Denmark. Lancet 1995; 345: 1637–38. Centers for Disease Control and Prevention. Morbidity and mortality surveillance in Rwandan refugees—Burundi and Zaire, 1994. MMWR 1996; 45: 104–07. Siddique AK, Salam A, Islam MS, et al.Why treatment centres failed to prevent cholera deaths among Rwandan refugees in Goma, Zaire. Lancet 1995; 345: 359–61. Scas C, Gotuzzo E. Cholera: overview of epidemiologic, therapeutic, and preventive issues learned from recent epidemics. Int J Infect Dis 1996; 1: 37–46. Besser RE, Feikin DR, Eberhart-Phillips JE, Mascola L, Griffin PM. Diagnosis and treatment of cholera in the United States: are we prepared? JAMA 1994; 272: 1203–05. Weber JT, Levine WC, Hopkins DP, Tauxe RV. Cholera in the United States, 1965–1991: risks at home and abroad. Arch Intern Med 1994; 154: 551–56. Wittlinger F, Steffen R, Watanabe H, Handszuh H. Risk of cholera among Western and Japanese travelers. J Trav Med 1995; 2: 154–58. Taylor DN, Rizzo J, Meza R, Perez J,Watts D. Cholera among Americans living in Peru. Clin Infect Dis 1996; 22: 1108–09. Pollitzer R. Cholera (WHO Monogr no 43). Geneva:WHO, 1959. Kaper JB, Morris JG, Levine MM. Cholera. Clin Microbiol Rev 1995; 8: 48–86. Swerdlow DL, Rics AA. Vibrio cholerae non-O1: the eighth pandemic? Lancet 1993; 342: 382–83. Hall RH, Khambaty FM, Khotary M, Keasler SP. Non-O1 Vibrio cholerae. Lancet 1993; 342: 430. Morris JG and the Cholera Laboratory Task Force. Vibrio cholerae O139 Bengal. In:Wachsmuth IK, Blake PA, Olsvik O, eds. Vibrio cholerae and cholera: molecular to global perspectives.Washington, DC: American Society for Microbiology, 1994: 95–115. Glass RI, Black RE. The epidemiology of cholera. In: Barua D, Greenough III WB, eds. Cholera. New York: Plenum, 1992: 129–54. Shcars P. Cholera. Ann Trop Med Parasitol 1994; 88: 109–22. Goodgame RW, Greenough WB. Cholera in Africa: a message for the West. Ann Intern Med 1975; 82: 959–70. Glass RI, Becker S, Huq MI, et al. Endemic cholera in rural Bangladesh. Am J Epidemiol 1982; 116: 959–70. Feachem RG. Environmental aspects of cholera epidemiology III: transmission and control. Trop Dis Bull 1982; 79: 1–47. Kolvin JL, Roberts D. Studies on the growth of Vibrio cholerae biotype El Tor and biotype classical in foods. J Hyg Camb 1982; 89: 243–52. Islam MS, Hasan MK, Miah MA, et al. Isolation of Vibrio cholerae O139 Bengal from water in Bangladesh. Lancet 1993; 342: 430. Colwell RR, Huq A.Vibrios in the environment: viable but nonculturable Vibrio cholerae. In:Wachsmuth IK, Blake PA, Olsvik O, eds. Vibrio cholerae and cholera: molecular to global perspectives. Washington, DC: American Society for Microbiology, 1994: 117–33. Morris JG, Sztein MB, Rice EW, et al. Vibrio cholerae O1 can assume a chlorine-resistant rugose survival form that is virulent for humans. J Infect Dis 1996; 174: 1364–68. Deb BC, Sircar BK, Sengu pta PG, et al. Studies on interventions to prevent El Tor cholera transmission in urban slums. Bull World Health Organ 1986; 64: 127–31. Levine MM, Black RE, Clements ML, Nalin DR, Cisneros L, Finkelstein RA. Volunteer studies in development of vaccines against cholera and enterotoxigenic Escherichia coli: a review. In: Holme T, Holmgren J, Merson MH, Mollby R, eds. Acute enteric infections in children: new prospects for treatment and prevention. Amsterdam:
Further reading Resurgence of cholera and risk for international travellers (including V cholerae O139) . Alber t MJ, Siddique AK, Islam MS, et al. A large outbreak of clinical cholera due to Vibrio cholerae non-O1 in Bangladesh. Lancet 1993; 341: 704. CDC. Update: cholera—western hemisphere, 1992. MMWR 1993; 42: 89–91.
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Elsevier/North-Holland Biomedical Press, 1981: 443–59. 29 Cash RA, Music SI, Libonati JP, et al. Response of man to infection with Vibrio cholerae I. Clinical, serologic, and bacteriologic responses to known inoculum. J Infect Dis 1974; 129: 45–52. 30 Gangarosa EJ, Mosley WH. Epidemiology and surveillance of cholera. In: Barua D, Burrows W, eds. Cholera. Philadelphia: Saunders, 1974: 381–403. 31 Sanchez JL, Begue R, Gaillour A, et al. Feasibility of an efficacy trial of the whole cell plus recombinant B subunit (WC/rBS) oral cholera vaccine in Lima, Peru. Proceedings of the 43rd Annual American Society of Tropical Medicine and Hygiene meeting, Cincinnati, November, 1994 abstr 295. 32 Bennish ML. Cholera: pathophysiology, clinical features, and treatment. In: Wachsmuth IK, Blake PA, Olsvik O, eds.Vibrio cholerae and cholera: molecular to global perspectives.Washington, DC: American Society for Microbiology, 1994: 229–55. 33 Khan WA, Bennish ML, Seas C, et al. Randomised controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by Vibrio cholerae O1 or O139. Lancet 1996; 348: 296–300. 34 Gotuzzo E, Seas C, Echevarria J, Carrillo C, Mostorino R, Ruiz R. Ciprofloxacin for the treatment of cholera: a randomized, double-blind, controlled clinical trial of a single daily dose in Peruvian adults. Clin Infect Dis 1995; 20: 1485–90. 35 Benenson AS. Cholera. In: Benenson AS. Control of communicable diseases in man, 15th edn. Washington, DC: American Public Health Association, 1990: 89–94. 36 Barua D, Merson MH. Prevention and control of cholera. In: Barua D, Greenough III WB, eds. Cholera. New York: Plenum, 1992: 329–49. 37 Tauxe RV, Mintz ED, Quick RE. Epidemic cholera in the New World: translating field epidemiology into new prevention strategies. Emerg Infect Dis 1995; 1: 141–46. 38 Feeley JC, Gangarosa EJ. Field trials of cholera vaccine. In: cholera and related diarrheas. 43rd Nobel Symposium, Stockholm, Sweden, 1978. Basel: Karger, 1980: 204–10. 39 Joo I. Cholera vaccines. In: Barua D, Burrows W, eds. Cholera. Philadelphia: Saunders, 1974: 333–35. 40 Holmgren J, Osek J, Svennerholm AM. Protective oral cholera vaccine based on a combination of cholera toxin B subunit and inactivated cholera vibrios. In: Wachsmuth IK, Blake PA, Olsvik O, eds.Vibrio cholerae and cholera: molecular to global perspectives.Washington, DC: American Society for Microbiology, 1994: 415–24. 41 Sanchez JL, Trofa A, Taylor DN, et al. Safety and immunogenicity of the oral, inactivated, whole cell plus recombinant B subunit of cholera toxin (WC/rBS) cholera vaccine in North American volunteers. J Infect Dis 1993; 167: 1446–49. 42 Sanchez JL, Vasquez B, Begue RE, et al. Protective efficacy of oral whole-cell/recombinant-B-subunit cholera vaccine in Peruvian military recruits. Lancet 1994; 344: 1273–76. 43 Trach DD, Clemens JD, Ke NT, et al. Field trial of a locally produced, killed, oral cholera vaccine in Vietnam. Lancet 1997; 349: 231–35. 44 Levine MM, Tacket CO. Recombinant live cholera vaccines. In: Wachsmuth IK, Blake PA, Olsvik O, eds.Vibrio cholerae and cholera: molecular to global perspectives.Washington, DC: American Society for Microbiology, 1994: 395–413. 45 Taylor DN, Killeen KP, Hack DC, et al. Develpment of a live, oral, attenuated vaccine against El Tor cholera. J Infect Dis 1994; 170: 1518–23. 46 Kenner JR, Coster TS, Taylor DN, et al. Peru-15, an improved live attenuated oral vaccine candidate for Vibrio cholerae O1. J Infect Dis 1995; 172: 1126–29. 47 Morris JG, Losonsky Ge, Johnson JA, et al. Clinical and immunologic characteristics of Vibrio cholerae O139 Bengal infection in North American volunteers. J Infect Dis 1995; 171: 903–08. 48 Coster TS, Killeen KP,Waldor MK, et al. Safety, immunogenicity and efficacy of live attenuated Vibrio cholerae O139 vaccine prototype. Lancet 1995; 345: 949–52. 49 Levine MM. Oral vaccines against cholera: lessons from Vietnam and elsewhere. Lancet 1997; 349: 220–21. 50 World Health Organization. The potential role of new cholera vaccines in the prevention and control of cholera outbreaks during acute emergencies. Report of meeting, Feb 13–14, 1995, Geneva, Switzerland, document no CDR/GPV/95.1. Echeverria P, Hoge CW, Bodhidatta L, et al. Molecular characterization of Vibrio cholerae O139 isolates from Asia. Am J Trop Med Hyg 1995; 52: 124–27. Glass RI, Libel M, Brandling-Bennett AD. Epidemic cholera in the Americas. Science 1992; 256: 1524–25. Morger H, Steffen R, Schar M. Epidemiology of cholera in travellers, and conclusions for vaccination recommendations, BMJ 1983; 286: 184–86.
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Microbiology
V cholerae 0139: designation of the disease as cholera. J Infect 1993; 33: 560–62. Begue RE, Castellares G, Hayashi KE, et al. Diarrheal disease in Peru after the introduction of cholera. Am J Trop Med Hyg 1994; 51: 585–89. Dhar U, Bennish ML, Khan WA, et al. Clinical features, antimicrobial susceptibility and toxin production in Vibrio cholerae 0139 infection: comparison with V cholerae 01 infection. Trans R Soc Trop Med Hyg 1996; 90: 402–05. Editorial: water with sugar and salt. Lancet 1978; ii: 300–01. Maggi P, Carbonara S, Santantonio S, Pastore G, Angarano G. Ciprofloxacin for treating cholera. Lancet 1996; 348: 1446–47. Mahalanabis D, Faruque ASG, Albert MJ, Salam MA, Haque SS. An epidemic of cholera due to V cholerae 0139 in Dhaka, Bangladesh: clinical and epidemiological features. Epidemiol Infect 1993; 112: 463–71. Swerdlow DL, Ries AA. Cholera in the Americas: guidelines for the clinician. JAMA 1992; 267: 1495–99.
McLaughlin JC. Vibrio. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of clinical microbiology. Washington, DC: American Society for Microbiology, 1995: 465–76. Mhalu FS, Mmari PW, Ijumba J. Rapid emergence of El Tor Vibrio cholerae resistant to antimicrobial agents during the first six months of the four th cholera epidemic in Tanzania. Lancet 1979; 1: 345–47. Mitra R, Basu A, Dutta D, Nair GB, Takeda Y. Resurgence of Vibrio cholerae 0139 Bengal with altered antibiogram in Calcutta, India. Lancet 1996; 348: 1181. Sakazaki R, Tamura K. Somatic antigen variation in Vibrio cholerae. Japan J Med Sci Biol 1971; 24: 93–100. Waldor MK, Mekalanos JJ. ToxR regulates virulence gene expression in non-01 strains of Vibrio cholerae that cause epidemic cholera. Infect Immun 1994; 62: 72–78. Yamamoto T, Nair GB, Albert MJ, Parodi CC, Takeda Y. Sur vey of in vitro susceptibilities of Vibrio cholerae 01 and 0139 to antimicrobial agents. Antimicrob Agents Chemother 1995; 39: 241–44.
Brown V, Reilley B, Ferrir M-C, Gabaldon J, Manoncourt S. Cholera outbreak during massive influx of Rwandan returnees in November, 1996. Lancet 1997; 349: 212. Glass RI, Claeson M, Blake PA, Waldman RJ, Pierce NF. Cholera in Africa: lessons on transmission and control for Latin America. Lancet 1991; 338: 791–95. Goma Epidemiology Group. Public health impact of Rwandan refugee crisis: what happened in Goma, Z aire, in July, 1994? Lancet 1995; 345: 339–44.
Epidemiology and ecology
Recent advances in vaccine development
Clemens J, Sack D, Harris J, et al. ABO blood groups and cholera: new obser vations on specificity and modification of vaccine efficacy. J Infect Dis 1989; 159: 770–73. Dizon JJ, Fukumi H, Barua D, et al. Studies on cholera carriers. Bull World Health Organ 1967; 37: 737–43. Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group: possible evolutionary significance. Am J Epidemiol 1985; 121: 791–96. Glass RI, Svennerholm AM, Stoll BJ, Khan MR, Hossain KM, Huq MI, Holmgren J. Protection against cholera in breast-fed children by antibodies in breast milk. N Engl J Med 1983; 308: 1389–92. Swerdlow DL, Mintz ED, Rodriguez M, et al. Waterborne transmission of epidemic cholera in Trujillo, Peru: lessons for a continent at risk. Lancet 1992; 340: 28–32. van Loon FPL, Clemens JD, Shahrier M, et al. Low gastric acid as a risk factor for cholera: application of a new, non-invasive gastric acid field test. J Clin Epidemiol 1990; 43: 1361–67.
Clemens J, Sack D, Harris JR, et al. Field trial of oral cholera vaccines in Bangladesh: results from three-year follow-up. Lancet 1990; 335: 270–73. Tacket CO, Losonsky G, Nataro JP, et al. Onset and duration of protective immunity in challenged volunteers after vaccination with live oral cholera vaccine CVD 103-HgR. J Infect Dis 1992; 166: 837–41. Tacket CO, Morris JG, Losonsky GA, et al. Volunteer studies investigating the pathogenicity of Vibrio cholerae 0139 and the protective efficacy conferred by both primary infection and by vaccine strain CVD 112. In: Proceedings of the 30th Joint Conference on Cholera and Related Diarrheal Diseases. Fukuoka, Japan: US-Japan Cooperative Medical Science Program, 1994: 142–47. van Loon FPL, Clemens JD, Chakraborty J, et al. Field trial of inactivated oral cholera vaccines in Bangladesh: results from 5 years of follow-up. Vaccine 1996; 14: 162–66. Waldor MK, Coster TS, Killeen KP, et al. Vibrio cholerae 0139: genetic analysis, immunobiology, and volunteer studies of live attenuated vaccines. In: Proceedings of the 30th Joint Conference on Cholera and Related Diarhheal Diseases. Fukuoka, Japan: US-Japan Cooperative Medical Science Program, 1994: 148–52.
Clinical features and treatment Battachar ya SK, Battacharya MK, Nair GB, et al. Clinical profile of acute diarrhoea cases infected with the new epidemic strain of
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Prevention and control
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Seminar
Cholera José L Sánchez, David N Taylor The 1990s have witnessed the changing face of cholera— its reemergence in one continent, a new epidemic strain in another, and a tragic reminder of the impact of the disease in an already suffering population. In January, 1991, cholera was reintroduced into Latin America after an absence of more than 100 years.1 Within two years the disease had spread from Peru to Mexico,2 and in the past six years there have been 1·4 million reported cases of cholera causing more than 10 000 deaths in the Americas (figure). As a result of the Latin American outbreak, more cases of cholera have been reported to WHO every year in the 1990s than in any other year since surveillance began. October, 1992, saw another unprecedented epidemiological event; a new epidemic strain of Vibrio cholerae emerged in India and Bangladesh.3 This cholera toxin (CT)-producing strain was the first non-O1 strain of V cholerae capable of causing epidemics, and it has since been classified as V cholerae O139 Bengal.3 The lack of cross-immunity between the Bengal strain and other O1 cholera strains led to major epidemics of cholera (up to 200 000 cases) in India, Bangladesh, and five other countries of South-East Asia.4 Travel-associated (imported) cases were reported in the USA, Europe, and Japan.4,5 Finally, the massive outbreak of El Tor cholera among Rwandan refugees in Goma, Zaire, resulting in 70 000 cases and 12 000 deaths in July, 1994, showed that during times of crisis cholera can be catastrophic.6,7 The very high cholera death rate (15 per 1000), with a fatality ratio as high as 48% at one camp, were principally due to the rapid waterborne spread of cholera (as well as shigellosis), which quickly overwhelmed the existing medical services and the capacity for oral rehydration therapy (ORT) at diarrhoea treatment centres.7 The morbidity and mortality rates during the Rwandan refugee crisis contrast sharply with Latin America, where mortality rates were consistently below 1%.2,8 Access to health care is an important factor determining outcome. In Peru, for example, most cholera was reported in urban areas where hospitals and rehydration units were readily available but in rural areas mortality rates were 5% and continued to be high for years after the initial outbreak.2,8
Cholera and international travel The resurgence of cholera has led to an increase both in the awareness of cholera and in the number of cases detected in travellers and workers going from the developed world to endemic areas. The most important example occurred in February, 1992, when 75 of 336 Lancet 1997; 349: 1825–30 US Army Medical Research Unit-Brazil, American Consulate-Rio Unit 3501, APO AA 34030-3501 (J L Sánchez MD); and Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington, DC, USA, and US Naval Medical Research Institute Detachment, Lima, Peru (D N Taylor MD) Correspondence to: LTC José L Sánchez e-mail: ([email protected] or [email protected])
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Cholera incidence (per 1000) in the Americas, 1991–96 From Pan American Health Organization.
passengers from an airliner returning to Los Angeles from South America developed cholera.9 The flight originated in Argentina but the outbreak was traced to a seafood salad prepared by the caterer in Peru that was picked up en route to Los Angeles. Many of the passengers had severe diarrhoea and had to be admitted to hospital; five progressed to renal failure and one died. In surveys done from the 1960s to 1980s cholera was rare in travellers but this was because the disease was present in areas that few people visited; also microbiologybased surveillance was lacking.10 In Japan, where there is regular microbiological screening for cholera by culture in returning travellers with diarrhoea, the incidence of cholera for all destinations was 5 per 100 000; it was 13 per 100 000 in Japanese travellers returning from Bali (table 1).11 In the USA the 10-fold increase in cholera cases noted by Centers for Disease Control and Prevention investigators was due to the proximity of the Latin American outbreak and increased awareness.9 Routine surveillance of expatriates living in endemic areas suggests a substantial risk exists. In a study of US embassy personnel in Lima, Peru, during the height of the cholera outbreak and among those who presented with diarrhoea, 1825
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a stool sample was cultured on thiosulphate/citrate/bilesalts/sucrose agar (TCBS) for V cholerae. Five cases of cholera were detected among 317 US citizens. The estimated incidence of cholera in US citizens was 5·3 per 1000 per year or 44 per 100 000 per month of exposure.12 Clearly, cholera can present as a severe form of traveller’s diarrhoea and may be missed if stools are not cultured for V cholerae.
Microbiology of V cholerae V cholerae is a motile, curved, gram-negative bacillus, first described in 1854 in Italy by Filippo Pacini.13 In 1883, Robert Koch demonstrated that cholera was caused by this microorganism (Kommabazillen).13 It is a well defined species.14 Of the 139 serogroups, as determined by the composition of the major surface antigen of the cell wall (O), only two, O1 and O139, have been associated with epidemics; these two serogroups produce cholera toxin, which is responsible for the fluid secretion. Other serogroups have only been associated with sporadic cases and small clusters of non-cholera diarrhoea.14,15 Serogroup O1 can be further subdivided into three serotypes, named Ogawa, Inaba, and Hikojima, based on quantitative differences of factors A, B, and C of the O antigen. V cholerae O1 strains are also divided into two biotypes, classical and El Tor. Isolates from the third pandemic (1852–59) to the sixth (1899–1923) were caused by the classical biotype. El Tor gave rise to the seventh pandemic, which originated in Sulawesi, Indonesia, in 1961, and is still ongoing.1,4 El Tor is now the predominant biotype but classical is still common in Bangladesh. The Latin American outbreak was exclusively El Tor Inaba at first but was replaced by El Tor Ogawa after the first year. Cholera due to classical or O139 strains has not been detected in Latin America. V cholerae O139 is genetically related to the seventh pandemic O1 strains (see below) because it possesses all of the virulence determinants typical of O1 biotype El Tor, but there is a mutation in the genes producing the O antigen.16 O139 strains can produce a polysaccharide capsule and have an increased capacity both for cholera toxin production and for spread and proliferation within the environment.17
Epidemiology Epidemics of cholera arise after the introduction of V cholerae in non-endemic areas where most of the population is non-immune.18,19 Under these circumstances the attack rates can be as high as 10% and all age groups are affected. The morbidity and mortality can be considerable—for example, the introduction of cholera into West Africa in 1970 resulted in over 150 000 cases and more than 20 000 deaths in the first year,20 and in Peru there were over 420 000 cases and 3300 deaths within the first 15 months of the start of the epidemic.2 Epidemics are often unpredictable but they are usually seasonal: in Bangladesh the main peak is in the winter (September to November) with a summer peak in March to May), in coastal Pacific regions of South America cholera epidemics occur during the summer (January to May), and in the tropical jungle regions epidemics tend to coincide with the cool, dry season (June to September). Chronic carriers are rare and do not play a significant part in maintaining the microorganism between epidemics. Asymptomatic infection is often found at the time that symptomatic 1826
Population
Western travellers (1991) to10 Asia (India) South America (Ecuador)
Cholera rate/100 000 population 0·05 (3·7) 0·3 (2·6)
Comments
Based on passive reporting; TCBS not routinely used
Japanese travellers (1991) to11 All destinations Bali, Indonesia
5 13
All travellers with diarrhoea screened with TCBS
US Embassy employees in Peru12 All employees US citizens
30 44
Study still in progress; people seen and cultured on site, TCBS media routinely used
136
National sur veillance system based on clinical case definition
Peruvian citizens Lima 1991 by month
TCBS=culture medium specific for V cholerae (table adapted from ref 12).
Table 1: Estimates of incidence of cholera among travellers and expatriates in three studies
cholera is occurring, and is probably important in intrafamilial transmission. The transition from the epidemic to an endemic phase occurs after a large proportion of the population is immune or semi-immune. Previous immunity decreases illness in adults so higher attack rates are seen in children and in women of childbearing age, who are exposed to large inocula of V cholerae organisms while caring for the very young.21 Attack rates tend to be low in adults in this situation (<1% per year). Studies in Bangladesh, where both classical and El Tor biotypes are present, have indicated that infection with classical organisms provides more potent and long-lasting immunity than infection with El Tor. In Peru, where outbreaks were caused exclusively by V cholerae El Tor, numbers of cholera cases fell from 322 000 cases in 1991 to only 4500 cases in 1996 and this decrease was at least in part due to heightened immunity. During the endemic phase secondary transmission of cholera occurs, principally by intrafamilial spread of infection among family contacts in the range 4–22% and sometimes as high as 50%.21,22 Contamination of food, at home, shared social functions, in markets, and by street vendors, is common. V cholerae O1 can survive for 2–14 days in food and for many weeks in shellfish and molluscs.23 Widespread contamination of surface water sources also contributes to the transmission of cholera. The epidemiology and transmission patterns of O139 seem similar to those of O1 strains. High attack rates of severe cholera due to O139 seen among adults in areas long endemic for O1 indicate that infection by V cholerae O1 strains does not provide cross-protection.4 The secondary infection rate among family members is about 25% within 10 days of the index case. If outbreaks of cholera due to this new serogroup continue to occur in newly affected countries, they may represent the advent of the eighth cholera pandemic. Bengal strains survive well in environmental water.4,24 Household (tubewell) water has often been found to be the principal source of infection in Bangladesh. Thus, the predominant mode of transmission of V cholera O139 appears to be waterborne.
Ecology of V cholerae Non-O1 V cholerae have been identified as free-living bacterial flora in estuarine areas. By contrast, V cholerae O1 is very difficult to isolate unless there is cholera in the population. The persistence of V cholerae within the environment, for months and probably years, is facilitated by its ability to enter a viable, nonculturable, dormant state
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THE LANCET
Indicator
Degree of dehydration Mild or none
Moderate
Severe
Mental status Thirst Radial pulse Respirations Skin-pinch sign Eyes Urine flow Serum specific gravity Fluid deficit (mL/kg body weight) Preferred method of rehydration
Alert Present Normal Normal Skin retracts immediately Normal Normal 聿1·027 20–50 ORT in 4–6 h
Lethargic, stuporous Marked Rapid and feeble or impalpable Tachypnoeic, deep, laboured Skin retracts ver y slowly (>2 s) Dramatically sunken Scant or absent >1·034 91–120 IVRT, 2 L in 30–60 min, remainder in 3–4 h
Preferred type of rehydration
WHO ORT (all ages), Rehydralyte (adults), Pedialyte (children), Infalyte (infants) ORT for as long as diarrhoea persists
Restless or lethargic Present Rapid Tachypnoeic Skin retracts slowly (1–2 s) Sunken Scant and dark 1·028–1·034 51–90 ORT and/or IVRT; depends on presence of vomiting and stool losses WHO ORT and/or IVRT Normal saline*† NA
Maintenance
Lactate Ringer‘s* NA
ORT=oral rehydration therapy, IVRT=intravenous rehydration therapy, NA=not applicable. *Dextrose-containing solutions (2–5%) are preferred due to risk of hypoglycaemia in cholera. Addition of potassium chloride (10 mmol/L) is recommended to reduce risk of hypokalaemia.
Table 2: Guidelines for clinical evaluation of dehydration and recommendations for rehydration and maintenance fluid therapy
where its requirements for nutrients and oxygen are much decreased.25 V cholerae can also bind to chitin, a component of crustacean shells, and it can colonise the surfaces of algae, phytoplankton, and copepods (zooplankton) and the roots of aquatic plants such as water hyacinths. Environmental factors such as an increase in water temperature, pH, and seawater nutrients and a decrease in salinity may trigger conversion of the organism from the viable, non-culturable to the culturable, and therefore, infectious phase. These same environmental factors may also lead to an increase in numbers of crustaceans, and thus to a rise in the population of freeliving V cholerae. The periodic introduction of such infectious environmental isolates into the human population, through ingestion of undercooked shellfish and seafood, is probably responsible for isolated foci of endemic disease in the US Gulf Coast and Australia and for the clusters that gave rise to the Latin American epidemic.23,25 V cholerae has recently been found to shift to a “rugose” form, associated with the production of an exopolysaccharide which promotes cell aggregation. This form resists disinfectants such as chlorine,26 a key intervention in controlling cholera.27 Rugose strains, if present in the potable water system, may thus contribute to the waterborne transmission of cholera.
Clinical features The incubation period of cholera ranges from several hours up to 5 days35 and is determined by the inoculum size18,28 and whether food was the vehicle of transmission (food protects vibrios from the action of stomach acid). Inoculum sizes as low as 100–1000 organisms may cause disease but doses of around 1 million are needed to reliably induce disease in volunteers.28,29 Few patients infected with V cholerae O1 develop severe cholera (cholera gravis). In Bangladesh only 11% of classical infections and 2% of El Tor result in severe cholera30 and in Peru only 25% of cholera illnesses among the local population were detected in hospital.31 The most striking feature of severe cholera is the voluminous water stool output, and the dehydration it causes (table 2). Stool output can reach 500–1000 mL per hour, leading rapidly to hypotension, tachycardia, and vascular collapse. The patient becomes lethargic or stuporous with sunken eyes and cheeks and dry mucous membranes. Decreased skin turgor (skin-pinch sign) is found in all such cases. Urine flow is decreased or absent and serum specific gravity is consistently raised. Clinical
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illness which goes untreated resolves in 4–6 days in most cases (unless circulatory collapse occurs).
Treatment The key to treatment is rapid rehydration, ORT for mildly dehydrated patients or with a combination of ORT and intravenous rehydration if the dehydration is moderate or severe32 (table 2). In Peru, nearly all patients ill enough to be taken to hospital required intravenous rehydration before they could be maintained on oral fluids. The approach in Peru was rapid intravenous replacement with normal saline, attempting to restore blood pressure and urine flow in 4 h. Patients in the large hospitals were monitored in cholera seats rather than cholera beds to make sure that hydration was maintained. Once the patient is alert and can tolerate oral fluids, ORT should be started. Stool losses, fluid intake, and serum specific gravity should continue to be monitored closely at the bedside at least hourly for the first 4–6 h. Serum specific gravity is the best objective indicator of the success of rehydration; it can be measured with a simple, inexpensive hand-held refractometer. Once ORT begins the patient should be encouraged to drink freely to at least equal 1·5 times the volume of stool losses. ORT should be continued for as long as the patient has diarrhoea. The most common complication seen in Peru was acute renal failure; this was seen in 1% of patients admitted to hospital and was significantly more common in those over 60 years of age.8 Oral antimicrobial therapy can halve the duration of illness and stool volume losses and also shorten the duration of excretion.32 Tetracycline or doxycycline are the recommended first-line drugs.8,32 For children less than 8 years of age and for pregnant women, erythromycin, furazolidone or co-trimoxazole are indicated. In areas where there is significant resistance, quinolones can be used.8 These drugs are effective as single-dose therapy and they rapidly shorten the excretion of V cholerae from stools.8,33,34 This rapid clearance of vibrios from stool may help to reduce secondary transmission of cholera, especially in hospitals, treatment centres, and refugee settings.33
Public health prevention and control of cholera Strategies for the prevention and control of cholera are:35,36 ● Early detection of epidemics through diarrhoeal disease surveillance and investigation of severe cases and clusters of illness. ● Education to promote good personal hygiene emphasising proper handwashing with soap and food 1827
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preparation techniques. Bathing in potentially contaminated open water should also be discouraged. ● Construction and maintenance of sewage disposal facilities. ● Provision and protection of safe and plentiful water and storage (eg, in homes and restaurants). Simple and inexpensive methods of domestic water disinfection and storage have been developed and they reduce the risk of cholera and diarrhoeal diseases.37 Point-of-use disinfection and the appropriate use of safe water storage containers is important in maintaining the water supply.
Recent advances in vaccine development Parenteral, whole-cell cholera vaccines have been in use since the late 19th century. Controlled trials in the 1960s in cholera-endemic areas demonstrated they were only 60% effective for the first 3 months, declining to 30% during months 4–6 after vaccination.38 Moreover, this vaccine has to be given in two doses at 7–28 days apart and is associated with significant local reactions in up to 30% of vaccinees. This vaccine does not reduce carriage of V cholera O1 and its protective efficacy is below 30% in children.39 This vaccine is no longer recommended. Beginning in the early 1980s inactivated oral cholera vaccine candidates have been developed. An oral vaccine, consisting of the B subunit of cholera toxin (1 mg) and 1011 cholera whole cells (WC/BS, Cholerix; SBL Vaccin AB, Stockholm, Sweden), was found to protect against diarrhoeal illness caused by V cholerae O1 and, to some extent, against enterotoxigenic Escherichia coli in Bangladesh.40 This vaccine provided 85% efficacy against cholera in the first 6 months and a cumulative efficacy of 50% over 3 years when two or three doses were given 6 weeks apart. Protection was also found to be better against classical than El Tor cholera, especially among young children less than 5 years of age. A cheaper, recombinant formulation (WC/rBS, SBL Vaccin AB), developed in the late 1980s, was also found to be safe and immunogenic in volunteers.41 Immunity is conferred 7–10 days after the second dose. This oral vaccine, given in two doses 1–2 weeks apart, provided 86% efficacy for 3 months against cholera among Peruvian military personnel immediately before an epidemic of El Tor with high attack rates (2–3%) in the summer of 1994.42 A similar inactivated oral cholera vaccine, manufactured in Vietnam, had a protective efficacy of 66% against El Tor cholera.43 Protection in the Vietnam study was found to be similar in young children (68%) and older people (66%). The main drawback of the oral, inactivated vaccines is the need for two or three doses, 1–2 weeks apart. If immunity could be obtained more rapidly, a vaccine could be considered as an option for immunisation in the military and/or for travellers and for the control of threatened cholera epidemics or epidemics already in progress. Live attenuated, oral cholera vaccines would be ideal for these needs (table 3). The best studied of these vaccines is CVD 103-HgR (Orochol Berna; Swiss Serum and Vaccine Institute, Berne, Switzerland). This vaccine confers an immune response (and protection in challenged volunteers) within 8 days.44 It is safe and produces after one dose, in the immunologically naive individual, a vibriocidal immune response that approximates natural infection. In the volunteer challenge model, CVD103-HgR 1828
WC/BS
CBD103-HgR
Type of vaccine
Inactivated
Bio/serotype Dosage
Four strains 1011 cells+1 mg BS
Storage Buffer required Route Number of doses Booster Booster efficacy Estimated shelf life Cold chain Safety Transmission Environmental concerns Serum vibriocidal GMT Vibriocidal antibody seroconversion rate† Anti-CT seroconversion rate Protection in field studies Protection in volunteers‡
Suspension Bicarbonate Oral Two 1 yr Yes 3–4 yr 5°C Yes No None 1:100 25–50%
Recombinant to live, attenuated Classical, Inaba 108 cells in travellers, 109 cells in LDC Lyophilised Bicarbonate Oral One 6 mo Unknown 3–4 yr 5°C Yes Yes, minimal <1% Possible 1:1000 75%
80–90% 50–85% vs El Tor 65%
Onset of protection
17–21 days
70% No data available 60% vs El Tor, 90% vs classical 7 days
GMT=geometric mean titre; CT=cholera toxin. *LDC=less developed countries. †4-fold increase. ‡=all degrees of illness.
Table 3: Characteristics of oral killed and oral live cholera vaccines
produces higher protection against the homologous classical strain than against El Tor.44 This vaccine is licensed in Switzerland and in parts of Latin America. A trial in north Jakarta, Indonesia, in 68 000 people given a single dose of CVD 103-HgR is being organised at the US Navy Medical Research Unit No 2. Other single-dose, live attenuated vaccines developed at Harvard Medical School (Mekalonos et al) and at the Center for Vaccine Development, Baltimore (Levine et al), are being tested in volunteers. Attenuation of El Tor was unsuccessful for many years but new methods of strain selection and attenuation have now led to several new candidate vaccines. For example, two El Tor based, live attenuated, oral vaccines developed from Peruvian strains (Peru-14 and Peru-15) show promise as safe, effective vaccines against El Tor cholera,45,46 and Peru-15 has proved to be safe and highly protective against El Tor cholera in human challenge studies. The rapid spread of V cholerae O139 among all age groups in areas where V cholerae O1 is endemic indicates that immunity to O1 type is not protective against O139.4 Epidemiological and laboratory studies suggest that natural immunity to O1 is not protective against O139,4 and this has been confirmed in challenge studies in rabbits and volunteers.4,47 The high rates of severe illness seen with this new strain and its potential to cause large epidemics among non-immune adults mean that attenuated V cholerae O139 type vaccines are needed urgently. Such vaccines are being developed and tested in animal models. Initial volunteer studies with live, attenuated O139 vaccine candidates seem promising, and protective efficacies as high as 83% have been recorded with one candidate vaccine, Bengal-15.48 The hope is that oral cholera vaccines, killed and live, will become readily available for use in immunisation programmes in developing countries,49 and for travellers, expatriates, and military personnel. Other possibly important, albeit controversial, applications are during emergencies (such as famines, typhoons, and floods) and for refugees in both primitive and well-established camps where the risk of cholera outbreaks is considered high.50
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