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Cholera
I'I~~:v~'JTI\'E
SIEDICINE
$456-460
(1974)
Cholera CHARLES Uniz;ersity
C. J. CARPENTER
Hospituls,
Cleveland,
Ohio 44106
Cholera, an acute infectious disease characterized by massive gastrointestinal loss of isotonic fluid, is prevalent throughout large parts of the world today. Although this disease can be effectively treated under ideal conditions, the mortality rate in most cholera-affected areas remains quite high. The only certain protection against this disease is provided by adequate water supply and sewage disposal facilities. In the absence of such facilities, careful personal hygiene can provide a very high level of protection. Chemoprophylaxis is potentially effective only for small, relatively isolated population groups. Currently available commercial cholera vaccines provide only limited protection for a relatively short period of time. Although experimental data suggest that a new toxoid vaccine, currently being tested in the field, may provide a higher degree of protection, the duration of immunity provided by this vaccine will probably also be of relatively short duration.
Definition. Cholera is an acute illness caused by an enterotoxin elaborated by Vibrio cholerae which have colonized the small bowel. It is characterized in the most severe cases by hypovolemic shock and metabolic acidosis, resulting from the rapid gastrointestinal loss of massive quantities of fluid and electrolytes. Although the mortality rate may be extremely high in untreated cases, excellent therapeutic results can be obtained by prompt replacement of lost water and electrolytes by either the intravenous or the oral route (3,6,7). Distribution. Throughout the first six decades of the twentieth century, cholera was largely confined to Asia, with a major endemic focus in the common delta of the Ganges and Brahmaputra rivers. However, the three major North American epidemics of 1832,1948, and 1867, had shown that the potential distribution of cholera was worldwide. The period 1961 to 1974 has witnessed a seventh major pandemic spread of cholera from Indonesia throughout South and Central Asia to Western Europe and the entire African continent. Serious outbreaks of cholera occurred in Spain in the summers of 1972 and 1974, and in Italy in the summer of 1973, and isolated cases have been identified in travelers returning from these areas to most of the other nations of Western Europe. The ultimate limits of the recent pandemic have not yet been delineated. Etiology: Vibrio cholerue (V. comma) Neisser is a short, curved, motile gram-negative rod, possessing a single polar flagellum. This microorganism grows aerobically on ordinary media with a pH of 7.0-7.9. Differentiation between the two major serotypes and the two major biotypes is based in simple laboratory procedures (1). Epidemiology. Man is the only documented natural host and victim of Vihrio cholerae. Most major outbreaks of this disease have been water borne, 456 Copyright 0 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.
FORUM:
CONTROL
OF
INFECTIOUS
DISEASES
457
and water plays a major role in transmission of Vibrio cholerae in endemic rural areas. Persons with mild or asymptomatic infections (contact carriers) may play an important role in the dissemination of epidemic disease. Convalescent carriers are unusual, and their role in the transmission of disease is not yet clarified. In the endemic areas of Bangladesh and West Bengal, cholera is predominantly a disease of children, with attack rates 10 times greater in the l- to 5-yr age group than in individuals above 20 yr of age. However, when the disease spreads to previously uninvolved areas, the attack rates are initially at least as high in adults as in children (4). Pathogen&s and Pathology. All symptoms, signs, and metabolic derangements in cholera result from the rapid loss of fluid and electrolytes from the gut. The increased electrolyte secretion is caused by a protein enterotoxin, which is elaborated by all pathogenic strains of Vibrio cholerae. The interaction of the enterotoxin with the gut mucosal cells leads to secretion of isotonic fluid by all segments of the small bowel. Disease caused by all known strains of Vibrio cholerae result in the same stool electrolyte pattern, with sodium and chloride concentrations slightly less than that of plasma, a bicarbonate concentration of approximately twice that of plasma, and a potassium concentration three to five times that of plasma. There is no evidence that the cholera vibrio invades any tissue, nor has enterotoxin been shown in the naturally occurring disease to have any direct effect on any organ other than the small intestine. Clinical Characteristics. All signs and symptoms of cholera result directly from the gastrointestinal fluid and electrolyte losses. The initial symptom is that of painless, watery diarrhea, which may be abrupt in onset. The stool volume varies greatly, and in the more severe cases the initial loss may be in excess of 1500 ml. At varying intervals after the onset of diarrhea effortless vomiting ensues. In fulminant cases, severe muscle cramps almost invariably develop. Prostration occurs at varying intervals after the onset of symptoms in direct relation to the magnitude of the fluid loss. The typical severe cholera patient presents with a characteristic appearance, with cyanosis, no palpable peripheral pulses, and extremely poor skin turgor. Laboratory abnormalities are those indicative of massive loss of isotonic fluid, and include elevated hematocrit, increased plasma specific gravity, decreased plasma bicarbonate, and low arterial pH. The illness may last from 12 hr to 7 days, and later clinical manifestations depend on the adequacy of therapy. With adequate fluid and electrolyte repletion, recovery is uniformly rapid. Without treatment the mortality in severe cholera cases exceeds 50%. During an epidemic of cholera, a wide variety of clinical types may be encountered varying from ambulatory cases with only mild diarrhea to fulminating disease in which death occurs, in the absence of appropriate treatment, within 2-3 hr after onset of diarrhea. Diagnosis. Although cultural techniques are simple (l), in endemic or epidemic areas the diagnosis should be made on the basis of the clinical picture and therapy instituted immediately. Although a cholera-like illness may be caused by organisms other than V. cholerae, the resulting metabolic abnor-
458
CHARLES
C. J. CARPENTER
malities are essentially the same, so that the same therapeutic approach should be used in all such cases, Treatment. Successful therapy demands only prompt replacement of the gastrointestinal losses of fluid and electrolytes (3,6,7). The treatment has been clearly delineated in a number of recent publications and will not be discussed in this publication (2,3,6,7). It is important, however, to point out that if intravenous fluids are in short supply, oral replacement of water and electrolytes is effective both in adults and in those children who are alert and able to retain orally administered solutions. Since the limiting factor in the treatment of cholera in both epidemic and endemic situations has often been the lack of adequate quantities of intravenous fluids, the availability of an oral treatment regimen has greatly reduced mortality from cholera during the recent pandemic spread of this disease. Although adequate fluid and electrolyte therapy alone results in rapid recovery in cholera patients, adjunctive therapy with antibiotics dramatically reduces the duration and volume of diarrhea and results in early eradication of vibrios from the feces. Tetracycline is the drug of choice for this disease. Prevention. Despite the excellent response of cholera patients to prompt and adequate fluid replacement, the mortality rate of this disease in recent outbreaks has remained *high, reflecting mainly the logistic problems in cholera-affected areas, including the lack of adequate quantities of pyrogenfree intravenous fluids, the difficulties of initiating treatment promptly when large numbers of cases are occurring in poverty-stricken populations, and the compromises which have to be made in an emergency situation. This emphasizes the overriding need for greater efforts toward preventive measures. There are four potential approaches to the prevention of this disease, none of which is universally applicable but each of which may play a major role in certain cholera affected areas. The ideal approach to the prevention of the disease is through improvement of sanitation. The fact that there have been no secondary cases after importation of at least a dozen cases of cholera into Japan during the past decade and no secondary spread from the single case of cholera identified in Texas in 1973 testifies to the effectiveness of high levels of hygiene in preventing the spread of this disease. However, the socioeconomic conditions which prevail among a large proportion of the world’s population clearly indicate that an eradication of cholera through improvement in water supply and sewage disposal is not an obtainable goal over the next few decades. Even in cholera-endemic areas, however, good individual hygienic practices, including boiling of drinking water and careful washing of hands before eating, are nearly uniformly effective in preventing this disease. It is exceedingly rare, even in major cholera epidemics in areas in which community sanitation is extremely poor, for any medical personnel to contract this disease. The explanation for the effectiveness of individual hygienic practice is a simple one, relating to the fact that a very large number of cholera organisms must be ingested in order to produce disease. Volunteer studies have indicated that, after alkalization of the stomach with sodium bicarbonate, a
FORUM:
CONTROL
OF
INFECTIOUS
DISEASES
459
million organisms must be ingested to produce even mild disease in 50% of individuals, and that even a dose of one billion organisms does not produce disease in individuals with normal gastric acid secretion (5). Because of the large dose of organisms required to produce disease, simple personal hygienic practices are exceedingly effective in prevention of disease even among those personnel who are dealing with large numbers of cases under extremely poor sanitary conditions. (Because of the extreme sensitivity of V. cholerue to a low pH, the gastric acid provides one of the most effective defenses against this disease. Individuals with achlorhydria or gastric resection are, therefore, abnormally susceptible to this disease, as has clearly been demonstrated both in India and in Israel. Even in such individuals, however, careful personal hygiene provides almost certain protection against cholera.) The third approach to the prevention of this disease is that of chemoprophylaxis. Although a number of factors, including difficulties in appropriate timing, expense, and potential side effects of most effective antibiotics, preclude massive chemoprophylaxis, this approach is a reasonable one when cholera strikes a relatively small and clearly defined population group such as a military barracks or a boarding school. In such cases, tetracycline may be administered in therapeutic dosage, 30-40 mg per kg of body weight per day, given in divided doses every 6 hr for 5 days. Although not uniformly effective, such chemoprophylaxis appears to have merit for small, clearly defined, highrisk population groups. The final approach to prevention is that of immunization. Unfortunately, immunization with standard commercial cholera vaccine (two doses at a 1 mo interval, each dose containing 10 billion killed organisms per ml) provides only 60-80% protection for 3-6 mo in individuals in cholera-endemic areas. The efficacy of this vaccine in individuals in nonendemic areas who have presumably had no previous exposure to cholera antigens is not known. Immunization with toxoid prepared from the cholera enterotoxin provides highly significant protection in experimental animals, but again the protection is relatively shortlived. Field trials with a commercially prepared toxoid, containing glutaraldehyde as an adjuvant, are currently being carried out in Bangladesh. The information obtained from studies in laboratory animals would suggest that, although the trial toxoid may provide a higher percentage of protection, it is not likely to provide the long-lasting protection which is desirable. Current information suggests that the most effective vaccine will ultimately be one which combines toxoid with vibrio cell-wall antigens. Although it is reasonable to expect that such a vaccine may provide a very high level of transient immunity, there is again no basis for expecting such a vaccine to provide long-lasting protection. An intensive study of the effect of a variety of adjuvants on the prolongation of protection is currently underway. REFERENCES
1. BARUA, D. Laboratory
diagnosis of cholera, in “Cholera” (D. Baroa and W. Burrows, Eds.), 1974. 2. CARPENTER, C. C. J. AND HIRSCHHORN, N. Pediatric cholera: current concepts. /. Pediet. 80, 874-882 (1972). Saunders,
Philadelphia,
460
CHARLES
C. J. CARPENTER
3. CARPEXTEH, C. C. J., MONDAL, A., SACK, R. B.,MITHA, P. P., DANS, P.E., WELLS, S. A., HIIYMBN, E. J., AND CHANDHURI, R. N. Clinical studies in Asiatic cholera. II. Bull. Johns Hopkins Hosp. 118, 174-196 (1966). 4. GANGAROSA, E. J., AND MOSLEY, W. H. Epidemiology and surveillance of cholera, in “Cholera” (D. Barua and W. Burrows, Eds.), Saunders, Philadelphia, 1974. 5. NORNICK, R. B., MUSIC, S. I., WENZEL, R., CASH, R., LIBONATI, J. P., SNYDER, M. J., AND WOODWARD, J. E. The Broad Street pump revisited: Response of volunteers to ingested cholera vibrios. Bull. N.Y. Acad. Med. 47, 1181-1191 (1971). 6. PIERCE,N. F., SACK, R. B., MITRA, R. C.,BANWELL, J. G., BRIGHAM, K. L., FEDSON, D. S., AND MONDAL, A. Replacement of water and electrolyte losses in cholera by an oral glucoseelectrolyte solution. Ann. Intern. Med. 70, 1173-1181 (1969). 7. WATTEN,R. H.,MoRGAN,F.M.,SONGKHLA,Y. N.,VA~\‘IKIATI,B.,AND PHILLIPS,R. A. Water and electrolyte studies in cholera. J. Ckn. Inuest. 38, 1879-1889 (1959).
SIEDICINE
$456-460
(1974)
Cholera CHARLES Uniz;ersity
C. J. CARPENTER
Hospituls,
Cleveland,
Ohio 44106
Cholera, an acute infectious disease characterized by massive gastrointestinal loss of isotonic fluid, is prevalent throughout large parts of the world today. Although this disease can be effectively treated under ideal conditions, the mortality rate in most cholera-affected areas remains quite high. The only certain protection against this disease is provided by adequate water supply and sewage disposal facilities. In the absence of such facilities, careful personal hygiene can provide a very high level of protection. Chemoprophylaxis is potentially effective only for small, relatively isolated population groups. Currently available commercial cholera vaccines provide only limited protection for a relatively short period of time. Although experimental data suggest that a new toxoid vaccine, currently being tested in the field, may provide a higher degree of protection, the duration of immunity provided by this vaccine will probably also be of relatively short duration.
Definition. Cholera is an acute illness caused by an enterotoxin elaborated by Vibrio cholerae which have colonized the small bowel. It is characterized in the most severe cases by hypovolemic shock and metabolic acidosis, resulting from the rapid gastrointestinal loss of massive quantities of fluid and electrolytes. Although the mortality rate may be extremely high in untreated cases, excellent therapeutic results can be obtained by prompt replacement of lost water and electrolytes by either the intravenous or the oral route (3,6,7). Distribution. Throughout the first six decades of the twentieth century, cholera was largely confined to Asia, with a major endemic focus in the common delta of the Ganges and Brahmaputra rivers. However, the three major North American epidemics of 1832,1948, and 1867, had shown that the potential distribution of cholera was worldwide. The period 1961 to 1974 has witnessed a seventh major pandemic spread of cholera from Indonesia throughout South and Central Asia to Western Europe and the entire African continent. Serious outbreaks of cholera occurred in Spain in the summers of 1972 and 1974, and in Italy in the summer of 1973, and isolated cases have been identified in travelers returning from these areas to most of the other nations of Western Europe. The ultimate limits of the recent pandemic have not yet been delineated. Etiology: Vibrio cholerue (V. comma) Neisser is a short, curved, motile gram-negative rod, possessing a single polar flagellum. This microorganism grows aerobically on ordinary media with a pH of 7.0-7.9. Differentiation between the two major serotypes and the two major biotypes is based in simple laboratory procedures (1). Epidemiology. Man is the only documented natural host and victim of Vihrio cholerae. Most major outbreaks of this disease have been water borne, 456 Copyright 0 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.
FORUM:
CONTROL
OF
INFECTIOUS
DISEASES
457
and water plays a major role in transmission of Vibrio cholerae in endemic rural areas. Persons with mild or asymptomatic infections (contact carriers) may play an important role in the dissemination of epidemic disease. Convalescent carriers are unusual, and their role in the transmission of disease is not yet clarified. In the endemic areas of Bangladesh and West Bengal, cholera is predominantly a disease of children, with attack rates 10 times greater in the l- to 5-yr age group than in individuals above 20 yr of age. However, when the disease spreads to previously uninvolved areas, the attack rates are initially at least as high in adults as in children (4). Pathogen&s and Pathology. All symptoms, signs, and metabolic derangements in cholera result from the rapid loss of fluid and electrolytes from the gut. The increased electrolyte secretion is caused by a protein enterotoxin, which is elaborated by all pathogenic strains of Vibrio cholerae. The interaction of the enterotoxin with the gut mucosal cells leads to secretion of isotonic fluid by all segments of the small bowel. Disease caused by all known strains of Vibrio cholerae result in the same stool electrolyte pattern, with sodium and chloride concentrations slightly less than that of plasma, a bicarbonate concentration of approximately twice that of plasma, and a potassium concentration three to five times that of plasma. There is no evidence that the cholera vibrio invades any tissue, nor has enterotoxin been shown in the naturally occurring disease to have any direct effect on any organ other than the small intestine. Clinical Characteristics. All signs and symptoms of cholera result directly from the gastrointestinal fluid and electrolyte losses. The initial symptom is that of painless, watery diarrhea, which may be abrupt in onset. The stool volume varies greatly, and in the more severe cases the initial loss may be in excess of 1500 ml. At varying intervals after the onset of diarrhea effortless vomiting ensues. In fulminant cases, severe muscle cramps almost invariably develop. Prostration occurs at varying intervals after the onset of symptoms in direct relation to the magnitude of the fluid loss. The typical severe cholera patient presents with a characteristic appearance, with cyanosis, no palpable peripheral pulses, and extremely poor skin turgor. Laboratory abnormalities are those indicative of massive loss of isotonic fluid, and include elevated hematocrit, increased plasma specific gravity, decreased plasma bicarbonate, and low arterial pH. The illness may last from 12 hr to 7 days, and later clinical manifestations depend on the adequacy of therapy. With adequate fluid and electrolyte repletion, recovery is uniformly rapid. Without treatment the mortality in severe cholera cases exceeds 50%. During an epidemic of cholera, a wide variety of clinical types may be encountered varying from ambulatory cases with only mild diarrhea to fulminating disease in which death occurs, in the absence of appropriate treatment, within 2-3 hr after onset of diarrhea. Diagnosis. Although cultural techniques are simple (l), in endemic or epidemic areas the diagnosis should be made on the basis of the clinical picture and therapy instituted immediately. Although a cholera-like illness may be caused by organisms other than V. cholerae, the resulting metabolic abnor-
458
CHARLES
C. J. CARPENTER
malities are essentially the same, so that the same therapeutic approach should be used in all such cases, Treatment. Successful therapy demands only prompt replacement of the gastrointestinal losses of fluid and electrolytes (3,6,7). The treatment has been clearly delineated in a number of recent publications and will not be discussed in this publication (2,3,6,7). It is important, however, to point out that if intravenous fluids are in short supply, oral replacement of water and electrolytes is effective both in adults and in those children who are alert and able to retain orally administered solutions. Since the limiting factor in the treatment of cholera in both epidemic and endemic situations has often been the lack of adequate quantities of intravenous fluids, the availability of an oral treatment regimen has greatly reduced mortality from cholera during the recent pandemic spread of this disease. Although adequate fluid and electrolyte therapy alone results in rapid recovery in cholera patients, adjunctive therapy with antibiotics dramatically reduces the duration and volume of diarrhea and results in early eradication of vibrios from the feces. Tetracycline is the drug of choice for this disease. Prevention. Despite the excellent response of cholera patients to prompt and adequate fluid replacement, the mortality rate of this disease in recent outbreaks has remained *high, reflecting mainly the logistic problems in cholera-affected areas, including the lack of adequate quantities of pyrogenfree intravenous fluids, the difficulties of initiating treatment promptly when large numbers of cases are occurring in poverty-stricken populations, and the compromises which have to be made in an emergency situation. This emphasizes the overriding need for greater efforts toward preventive measures. There are four potential approaches to the prevention of this disease, none of which is universally applicable but each of which may play a major role in certain cholera affected areas. The ideal approach to the prevention of the disease is through improvement of sanitation. The fact that there have been no secondary cases after importation of at least a dozen cases of cholera into Japan during the past decade and no secondary spread from the single case of cholera identified in Texas in 1973 testifies to the effectiveness of high levels of hygiene in preventing the spread of this disease. However, the socioeconomic conditions which prevail among a large proportion of the world’s population clearly indicate that an eradication of cholera through improvement in water supply and sewage disposal is not an obtainable goal over the next few decades. Even in cholera-endemic areas, however, good individual hygienic practices, including boiling of drinking water and careful washing of hands before eating, are nearly uniformly effective in preventing this disease. It is exceedingly rare, even in major cholera epidemics in areas in which community sanitation is extremely poor, for any medical personnel to contract this disease. The explanation for the effectiveness of individual hygienic practice is a simple one, relating to the fact that a very large number of cholera organisms must be ingested in order to produce disease. Volunteer studies have indicated that, after alkalization of the stomach with sodium bicarbonate, a
FORUM:
CONTROL
OF
INFECTIOUS
DISEASES
459
million organisms must be ingested to produce even mild disease in 50% of individuals, and that even a dose of one billion organisms does not produce disease in individuals with normal gastric acid secretion (5). Because of the large dose of organisms required to produce disease, simple personal hygienic practices are exceedingly effective in prevention of disease even among those personnel who are dealing with large numbers of cases under extremely poor sanitary conditions. (Because of the extreme sensitivity of V. cholerue to a low pH, the gastric acid provides one of the most effective defenses against this disease. Individuals with achlorhydria or gastric resection are, therefore, abnormally susceptible to this disease, as has clearly been demonstrated both in India and in Israel. Even in such individuals, however, careful personal hygiene provides almost certain protection against cholera.) The third approach to the prevention of this disease is that of chemoprophylaxis. Although a number of factors, including difficulties in appropriate timing, expense, and potential side effects of most effective antibiotics, preclude massive chemoprophylaxis, this approach is a reasonable one when cholera strikes a relatively small and clearly defined population group such as a military barracks or a boarding school. In such cases, tetracycline may be administered in therapeutic dosage, 30-40 mg per kg of body weight per day, given in divided doses every 6 hr for 5 days. Although not uniformly effective, such chemoprophylaxis appears to have merit for small, clearly defined, highrisk population groups. The final approach to prevention is that of immunization. Unfortunately, immunization with standard commercial cholera vaccine (two doses at a 1 mo interval, each dose containing 10 billion killed organisms per ml) provides only 60-80% protection for 3-6 mo in individuals in cholera-endemic areas. The efficacy of this vaccine in individuals in nonendemic areas who have presumably had no previous exposure to cholera antigens is not known. Immunization with toxoid prepared from the cholera enterotoxin provides highly significant protection in experimental animals, but again the protection is relatively shortlived. Field trials with a commercially prepared toxoid, containing glutaraldehyde as an adjuvant, are currently being carried out in Bangladesh. The information obtained from studies in laboratory animals would suggest that, although the trial toxoid may provide a higher percentage of protection, it is not likely to provide the long-lasting protection which is desirable. Current information suggests that the most effective vaccine will ultimately be one which combines toxoid with vibrio cell-wall antigens. Although it is reasonable to expect that such a vaccine may provide a very high level of transient immunity, there is again no basis for expecting such a vaccine to provide long-lasting protection. An intensive study of the effect of a variety of adjuvants on the prolongation of protection is currently underway. REFERENCES
1. BARUA, D. Laboratory
diagnosis of cholera, in “Cholera” (D. Baroa and W. Burrows, Eds.), 1974. 2. CARPENTER, C. C. J. AND HIRSCHHORN, N. Pediatric cholera: current concepts. /. Pediet. 80, 874-882 (1972). Saunders,
Philadelphia,
460
CHARLES
C. J. CARPENTER
3. CARPEXTEH, C. C. J., MONDAL, A., SACK, R. B.,MITHA, P. P., DANS, P.E., WELLS, S. A., HIIYMBN, E. J., AND CHANDHURI, R. N. Clinical studies in Asiatic cholera. II. Bull. Johns Hopkins Hosp. 118, 174-196 (1966). 4. GANGAROSA, E. J., AND MOSLEY, W. H. Epidemiology and surveillance of cholera, in “Cholera” (D. Barua and W. Burrows, Eds.), Saunders, Philadelphia, 1974. 5. NORNICK, R. B., MUSIC, S. I., WENZEL, R., CASH, R., LIBONATI, J. P., SNYDER, M. J., AND WOODWARD, J. E. The Broad Street pump revisited: Response of volunteers to ingested cholera vibrios. Bull. N.Y. Acad. Med. 47, 1181-1191 (1971). 6. PIERCE,N. F., SACK, R. B., MITRA, R. C.,BANWELL, J. G., BRIGHAM, K. L., FEDSON, D. S., AND MONDAL, A. Replacement of water and electrolyte losses in cholera by an oral glucoseelectrolyte solution. Ann. Intern. Med. 70, 1173-1181 (1969). 7. WATTEN,R. H.,MoRGAN,F.M.,SONGKHLA,Y. N.,VA~\‘IKIATI,B.,AND PHILLIPS,R. A. Water and electrolyte studies in cholera. J. Ckn. Inuest. 38, 1879-1889 (1959).