Cholera Sorokhan MD, PhD Bukovinian State Medical University Department of the infection diseases and epidemiology
Definition <ul><li>Cholera is an infection of the small intestine caused by the bacterium Vibrio cholerae . The main symptoms are profuse watery diarrhea , vomiting and abdominal pain. Transmission is primarily through contaminated drinking water or food. The severity of the diarrhea and vomiting can lead to rapid dehydration and electrolyte imbalance. </li></ul>
Etiology <ul><li>V . cholerae is a comma-shaped, gram-negative aerobic bacillus . Its antigenic structure consists of a flagellar H antigen and a somatic O antigen. The differentiation of the latter allows for separation into pathogenic and nonpathogenic strains. V . cholerae O1 and V . cholerae O139 are associated with epidemic cholera. </li></ul>Scanning electron microscope image of Vibrio cholerae bacteria, which infect the digestive system.
Etiology <ul><li>V . cholerae O1 is classified into 2 major biotypes: classic and El Tor. Organisms in both biotypes are subdivided into serotypes according to the structure of the O antigen, as follows: </li></ul><ul><ul><li>Serotype Inaba - O antigens A and C </li></ul></ul><ul><ul><li>Serotype Ogawa - O antigens A and B </li></ul></ul><ul><ul><li>Serotype Hikojima - O antigens A, B, and C </li></ul></ul>This scanning electron micrograph (SEM) depicts a number of Vibrio cholerae bacteria of the serogroup 01; magnified 22371x. Image courtesy of CDC/Janice Haney Carr.
Epidemiology <ul><li>Cholera is transmitted through ingestion of water contaminated with the cholera bacterium ( fecal-oral route ) , usually from feces . The source of the contamination is typically other cholera patients when their untreated diarrhea discharge is allowed to get into waterways or into groundwater or drinking water supplies. </li></ul>Vibrio cholerae is the causal agent of the diarrheal disease cholera. Cholera is a major epidemic disease that has killed millions of people, and continues to be a major health problem worldwide. Provider CDC .
Epidemiology <ul><li>Any infected water and any foods washed in the water, as well as shellfish living in the affected waterway , can cause an infection. Cholera is rarely spread directly from person to person. If ingested with water, the infectious dose is 10 0000 organisms. </li></ul>Ingestion of V. cholera contaminated water is a typical mode of pathogen transmission. Provider CDC
Pathophysiology <ul><li>V. cholerae O1 and V. cholerae O139 cause clinical disease by producing an enterotoxin that promotes the secretion of fluid and electrolytes into the lumen of the small intestine. The enterotoxin is a protein molecule composed of 5 B subunits and 2 A subunits. The B subunits are responsible for binding to a ganglioside (monosialosyl ganglioside, GM1) receptor located on the surface of the cells that line the intestinal mucosa. </li></ul>Vibrio cholerae is transmitted to humans through the ingestion of contaminated food or water, and produces a cholera toxin, which acts on the intestinal mucosa, and causes severe diarrhea. Provider CDC
Pathophysiology <ul><li>The activation of the A1 subunit by adenylate cyclase is responsible for the net increase in cyclic adenosine monophosphate (cAMP). cAMP blocks the absorption of sodium and chloride by the microvilli and promotes the secretion of chloride and water by the crypt cells. The result is watery diarrhea with electrolyte concentrations isotonic to those of plasma. </li></ul>
Pathophysiology <ul><li>Fluid loss originates in the duodenum and upper jejunum; the ileum is less affected. The colon is usually in a state of absorption because it is relatively insensitive to the toxin. However, the large volume of fluid produced in the upper intestine overwhelms the absorptive capacity of the lower bowel, resulting in severe diarrhea. </li></ul><ul><li>The enterotoxin acts locally and does not invade the intestinal wall. As a result, few neutrophils are found in the stool. </li></ul>
Mortality/Morbidity <ul><li>If untreated, the disease rapidly results in dehydration and can result in death in more than 50% of infected individuals. The mortality rate is increased in pregnant women and children. </li></ul>
History <ul><li>Incubation period is from some hours till 5 days (in average 48 hours). Profuse watery diarrhea is a hallmark of cholera. Stool volume during cholera is more than that of any other infectious diarrhea. The characteristic cholera stool is an opaque white liquid that is not malodorous and often is described as having a rice water. </li></ul>
History <ul><li>Vomiting is a prominent manifestation of illness. It occurs early in the course of the disease when the vomiting is caused by decreased gastric and intestinal motility and later in the course of the disease when acidemia is more likely. </li></ul>
Physical <ul><li>Clinical signs of cholera parallel the level of volume contraction. The amount of fluid loss and the corresponding clinical signs of cholera are as follows: </li></ul><ul><ul><li>With 3-5% loss of normal body weight - Excessive thirst </li></ul></ul><ul><ul><li>With 5-8% loss of normal body weight - Postural hypotension, tachycardia, weakness, fatigue, and dry mucous membranes or dry mouth </li></ul></ul>
Physical <ul><ul><li>With greater than 10% loss of normal body weight - Oliguria; glassy or sunken eyes; weak, thready, or absent pulse; wrinkled "washerwoman" skin; somnolence; and coma. </li></ul></ul>Due to severe dehydration, cholera manifests itself in decreased skin turgor, which produces the so-called "Washer Woman's Hand" sign. Provider CDC
Differential diagnoses <ul><li>Although other differential diagnosis of gastroenteritis may be considered, the clinical picture of cholera is unlikely to be confused with any other disease. This is especially true in adults in whom no other infectious disease causes such profound dehydration so quickly. </li></ul>
Workup Laboratory Studies <ul><li>An elevated hematocrit value due to hemoconcentration may be found in nonanemic patients. Neutrophil leukocytosis may be found, especially in severe cases. </li></ul><ul><li>Patients have elevated blood urea nitrogen and creatinine levels consistent with prerenal azotemia. A reduced bicarbonate level (<15 mmol/L) and an elevated anion gap occur as a result of increases in serum lactate, protein, and phosphate levels. The arterial pH is usually low (approximately 7.2). Calcium and magnesium levels are usually high as a result of hemoconcentration, and potassium levels are either normal or low. Hypovolemia may cause hyperglycemia secondary to systemic release of epinephrine, glucagon, and cortisol. </li></ul>
Workup Laboratory Studies <ul><li>In endemic areas, biochemical confirmation and characterization of the isolate are usually unnecessary. </li></ul><ul><li>Diagnosis may be confirmed via identification of V. cholerae in the stool. The organism may be detected directly with dark-field microscopy examination of a wet mount of fresh stool; chaotic motility is observed. Laboratory isolation requires a selective medium. </li></ul><ul><li>More recently, polymerase chain reaction (PCR) has been used with a high degree of sensitivity and specificity. </li></ul>
Treatment <ul><li>The primary goal of therapy is to replenish fluid losses caused by diarrhea and vomiting. Reserve the intravenous route of rehydration for patients who purge more than 10-20 mL/kg/h and for patients with severe dehydration. </li></ul><ul><li>Rehydration is accomplished in 2 phases, rehydration and maintenance. </li></ul><ul><li>The goal of the rehydration phase is to restore normal hydration status, which should take no more than 4 hours. Set the rate of infusion in severely dehydrated patients at 50-100 mL/kg/h. Lactated Ringer solution is preferred over isotonic sodium chloride solution because saline does not correct metabolic acidosis. </li></ul><ul><li>The objective of the maintenance phase is to maintain normal hydration status by replacing ongoing losses. The oral route is preferred, and the use of oral rehydration solution (ORS) at a rate of 500-1000 mL/h is recommended. </li></ul>
Treatment This patient with cholera is drinking oral rehydration solution (ORS) in order to counteract the cholera-induced dehydration. Image courtesy of the CDC.
Treatment <ul><li>Practical guidelines for the treatment of cholera are as follows: </li></ul><ul><li>Evaluate the degree of dehydration upon arrival. </li></ul><ul><li>Rehydrate the patient in 2 phases. These include rehydration (for 2-4 h) and maintenance (until diarrhea abates). </li></ul><ul><li>Register output and intake volumes on predesigned charts and periodically review these data. </li></ul><ul><li>Only use the intravenous route (1) during the rehydration phase for severely dehydrated patients for whom an infusion rate of 50-100 mL/kg/h is advised, (2) for moderately dehydrated patients who do not tolerate the oral route, and (3) during the maintenance phase in patients considered high stool purgers (ie, >10 mL/kg/h). </li></ul><ul><li>During the maintenance phase, use ORS at a rate of 800-1000 mL/h. Match ongoing losses with ORS administration. </li></ul><ul><li>Discharge patients to the treatment center if oral tolerance is greater than or equal to 1000 mL/h, urine volume is greater than or equal to 40 mL/h, and stool volume is less than or equal to 400 mL/h. </li></ul>
Antibiotics <ul><li>Azithromycin (Zithromax) - adult dose: 1 g PO once . </li></ul><ul><li>Tetracycline (Sumycin) - adult dose: 2 g PO once . </li></ul><ul><li>Doxycycline - adult dose: 300 mg PO once . </li></ul><ul><li>Ciprofloxacin (Cipro) - adult dose: 250 mg PO qd for 3 d or 1 g once; alternatively, 30 mg/kg PO once or 15 mg/kg PO bid for 3 d (not to exceed 1 g/dose). </li></ul><ul><li>Erythromycin - adult dose: 40 mg/kg PO divided tid for 3 d. </li></ul><ul><li>Trimethoprim and sulfamethoxazole - adult dose: 160 mg TMP/800 mg SMZ PO bid for 3 d. </li></ul><ul><li>Norfloxacin - adult dose: 400 mg PO bid for 3 d; not to exceed 800 mg/d. </li></ul><ul><li>Furazolidone (Furoxone) - adult dose: 100 mg PO qid for 3 d. </li></ul>
Prevention <ul><li>T he transmission of cholera was significantly reduced when uncontaminated water was provided to the population. Water can be made safer to drink by boiling or adding chlorine, although both methods are expensive and difficult to implement during epidemics. </li></ul>
Prevention <ul><li>The vaccines currently available are described as follows: </li></ul><ul><ul><li>The cholera vaccine developed by Wyeth-Ayerst Laboratories is a parenteral, whole-cell, inactivated vaccine directed only at V cholerae O1. It is considered ineffective and obsolete, but it may be useful in certain (rare) high-risk populations in whom no other vaccine is available, who have minimal access to medical care, and who can receive booster shots. The vaccine should not be used to treat contacts of persons with imported cases or to control the spread of infection. Repeated vaccination is occasionally required or advised for laboratory workers and for airline and ship crews. However, such groups are unlikely to acquire or transmit cholera. Because information on the long-term safety of repeated vaccination is limited, such practices should be discontinued for airline and ship crews except when resolutely demanded by some countries for international travel. This vaccine is not recommended for infants younger than 6 months. </li></ul></ul>
Prevention <ul><ul><li>CVD 103-HgR is a cholera vaccine developed by the Swiss Serum and Vaccine Institute in Berne, Switzerland. This vaccine is available in Europe, Latin America, and, since 1997, Canada. The vaccine is composed of attenuated V. cholerae O1 prepared by recombinant DNA. It has been tested in industrialized countries and in developing countries that have endemic, epidemic, and little or no cholera. The vaccine is highly protective against moderate and severe cholera, and it is very well tolerated and extremely immunogenic. Also, the rate and extent of vaccine excretion is minimal. </li></ul></ul><ul><ul><li>The WC/rBS cholera vaccine is currently available in Sweden and Latin America and, in 2006, was approved for use in the United States. This vaccine is composed of killed, whole-cell V. cholerae O1 in combination with the purified recombinant B subunit of the cholera toxin (WC/rBS). The vaccine stimulates both antibacterial and antitoxic antibodies and attempts to stimulate the intestinal mucosal immune response similar to that induced by natural infection. </li></ul></ul>
Complications <ul><li>If a patient is adequately treated with fluid and electrolytes, complications are averted and the self-limited process resolves in a few days. </li></ul><ul><li>Potential complications include dehydration and volume loss that lead to acute tubular necrosis and renal failure. Hypovolemic shock and death ensue. </li></ul>