Aetiology;

Vibrio cholerae.

V cholerae is a saltwater organism, and its primary habitat is the marine ecosystem where it lives in association with plankton.

Cholera has 2 main reservoirs, humans and water. V cholerae is rarely isolated from animals, and animals do not play a role in transmission of disease.

The hallmark of the disease is profuse secretory diarrhea which manifests as;

·         Effortless, painless, watery diarrhea usually voluminous.

Mode of Transmission;

Cholera is transmitted by the fecal-oral route by ingestion of contaminated food, water or contact with formites.,

NOTE;

Definitive diagnosis is not a prerequisite for the treatment of patients with cholera. The priority in management of any watery diarrhea is replacing the lost fluid and electrolytes and providing an antimicrobial agent when indicated.

A new strain of cholera, V cholerae serogroup O139 (Bengal) emerged in the fall of 1992 and caused outbreaks in Bangladesh and India in 1993. Disease from this strain has become endemic in at least 11 countries.

Cholera has been rare in industrialized nations for the past century; however, the disease is still common in other parts of the world, including the Indian subcontinent and sub-Saharan Africa. Epidemics occur after war, civil unrest, or natural disasters when water and food supplies become contaminated with V cholerae in areas with crowded living conditions and poor sanitation.

Pathophysiology;

The pathogen;

V cholerae is a comma-shaped, gram-negative aerobic or facultatively anaerobic bacillus that varies in size from 1-3 µm in length by 0.5-0.8 µm in diameter (see the image below).

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. Although more than 200 serogroups of V cholerae have been identified, V cholerae O1 and V cholerae O139 are the principal ones associated with epidemic cholera.

Currently, the El Tor biotype of V cholerae O1 is the predominant cholera pathogen.

Organisms in both the classical and the El Tor biotypes are subdivided into serotypes according to the structure of the O antigen, as follows:

1.     Serotype Inaba - O antigens A and C

2.    Serotype Ogawa - O antigens A and B

3.    Serotype Hikojima - O antigens A, B, and C

The clinical and epidemiologic features of disease caused by V cholerae O139 are indistinguishable from those of disease caused by O1 strains. Both serogroups cause clinical disease by producing an enterotoxin that promotes the secretion of fluid and electrolytes into the lumen of the small intestine.

Pathology;

To reach the small intestine, however, the organism has to negotiate the normal defense mechanisms of the GI tract. Because the organism is not acid-resistant, it depends on its large inoculum size to withstand gastric acidity.

The infectious dose of V cholerae required to cause clinical disease varies by the mode of administration. If V cholerae is ingested with water, the infectious dose is 103 -106 organisms. When ingested with food, fewer organisms (102 -104) are required to produce disease.

The use of antacids, histamine receptor blockers, and proton pump inhibitors increases the risk of cholera infection and predisposes patients to more severe disease as a result of reduced gastric acidity. The same applies to patients with chronic gastritis secondary to Helicobacter pylori infection or those who have undergone a gastrectomy.

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.

Cause of secretory diarrhea;

The A1 subunit of cholera toxin activates adenylate cyclase to cause a net increase in cyclic adenosine monophosphate (cAMP). The increased cAMP then carries on the downstream effects. 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.

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. Unless the lost fluid and electrolytes are replaced adequately, the infected person may develop shock from profound dehydration and acidosis from loss of bicarbonate.

The enterotoxin acts locally and does not invade the intestinal wall. As a result, few neutrophils are found in the stool.

 

History of Presenting illness;

After a 24- to 48-hour incubation period, symptoms begin with;

1.     The sudden onset of painless, effortless watery diarrhea that may quickly become voluminous and is often followed by

2.    Vomiting.

3.    Accompanying abdominal cramps, probably from distention of loops of small bowel as a result of the large volume of intestinal secretions.

Fever is typically absent.

An estimated 5% of infected patients will develop cholera gravis, ie, severe watery diarrhea, vomiting, and dehydration with hypovolaemic shock.

Diarrhea;

Profuse watery diarrhea is a hallmark of cholera. Cholera should be suspected when a patient older than 5 years develops severe dehydration from acute, severe, watery diarrhea (usually without vomiting) or in any patient older than 2 years who has acute watery diarrhea and is in an area where an outbreak of cholera has occurred.

Stool volume during cholera is more than that of any other infectious diarrhea. Patients with severe disease may have a stool volume of more than 250 mL/kg body weight in a 24-hour period. Because of the large volume of diarrhea, patients with cholera have frequent and often uncontrolled bowel movements.

The stool may contain fecal material early in the course of clinical illness. The characteristic cholera stool is an opaque white liquid that is not malodorous and often is described as having a “rice water” appearance (ie, in color and consistency, it resembles water that has been used to wash or cook rice).

Vomiting;

Vomiting, although a prominent manifestation, may not always be present. Early in the course of the disease, vomiting is caused by decreased gastric and intestinal motility; later in the course of the disease it is more likely to result from acidemia.

Dehydration;

If untreated, the diarrhea and vomiting lead to isotonic dehydration, which can lead to acute tubular necrosis and renal failure.

In patients with severe disease, vascular collapse, shock, and death may ensue. Dehydration can develop with remarkable rapidity, within hours after the onset of symptoms. This contrasts with disease produced by infection from any other enteropathogen. Because the dehydration is isotonic, water loss is proportional between 3 body compartments, intracellular, intravascular, and interstitial

Physical Examination in Cholera;

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:

1)    3-5% loss of normal body weight - Excessive thirst

2)   5-8% loss of normal body weight - Postural hypotension, tachycardia, weakness, fatigue, dry mucous membranes or dry mouth.

3)   >10% loss of normal body weight - Oliguria; glassy or sunken eyes; sunken fontanelles in infants; weak, thready, or absent pulse; wrinkled "washerwoman" skin; somnolence; coma

Assessment for Dehydration in Cholera;

The World Health Organization has classified dehydration in patients with diarrhea into the following 3 categories, to facilitate treatment

1.     Severe

2.    Some (previously termed moderate, in the WHO criteria)

3.    None (previously termed mild, in the WHO criteria)

Children without clinically significant dehydration (< 5% loss of body weight) may have increased thirst without other signs of dehydration. In children with some (ie, moderate) dehydration, cardiac output and vascular resistance are normal, and changes in interstitial and intracellular volume are the primary manifestations of illness. Skin turgor is decreased, as manifested by prolonged skin tenting in response to a skin pinch (the most reliable sign of isotonic dehydration), and a normal pulse.

For the skin pinch, it is important to pinch longitudinally (Skin contours)  rather than horizontally and to maintain the pinch for a few seconds before releasing the skin. The skin pinch may be less useful in patients with marasmus (severe wasting), kwashiorkor (severe malnutrition with edema), or obesity.

In adults and children older than 5 years, other signs of severe dehydration include tachycardia, absent or barely palpable peripheral pulses, and hypotension.

Tachypnea and hypercapnia also are part of the clinical picture and are attributable to the metabolic acidosis that invariably is present in patients with cholera who are dehydrated.

Atypical presentation in Pediatric patients;

In pediatric patients, the primary signs are similar to those in adults. However, children with severe cholera may present with signs that are rarely seen in adults. A child with cholera is usually very drowsy, and coma is not uncommon. In addition, pediatric patients may have convulsions that appear to be related, in part, to hypoglycemia because patients exhibit some response to intravenous dextrose. Another significant difference from the adult presentation is that children are often febrile.

CHOLERA SICCA

Cholera sicca is an old term describing a rare, severe form of cholera that occurs in epidemic cholera. This form of cholera manifests as ileus/Paralytic ileus and abdominal distention from massive outpouring of fluid and electrolytes into dilated intestinal loops.

Mortality is high, with death resulting from toxemia before the onset of diarrhea and vomiting. The mortality in this condition is high. Because of the unusual presentation, failure to recognize the condition as a form of cholera is common.

Differential Diagnoses of Cholera;

1.     Escherichia coli (E coli) Infections

2.    Pediatric Gastroenteritis

3.    Rotavirus

4.    Food poisoning/contamination.

Diagnosis of Cholera;

Definitive diagnosis is not a prerequisite for the treatment of patients with cholera. The priority in management of any watery diarrhea is replacing the lost fluid and electrolytes and providing an antimicrobial agent when indicated. Usually Doxycycline.

Case definition of Cholera;

According to World Health Organization (WHO) standard case definition, a case of cholera is suspected when the following conditions are met:

1)    In an area where the disease is not known to be present, a patient aged 5 years or older develops severe dehydration or dies from acute watery diarrhea

2)   In an area with a noted cholera epidemic, a patient aged 5 years or older develops acute watery diarrhea, with or without vomiting

In endemic areas, biochemical confirmation and characterization of the isolate are usually unnecessary. However, these tasks may be worthwhile in areas where Vibrio cholerae is an uncommon isolate.

1.    Stool analysis;/Also rectal swab is used in epidemics.

1)   Direct microscopy/ Dark field microscopy;

If identification of the organism is required, direct microscopic examination of stool (including dark-field examination- dark field microscopy) is indicated, along with Gram stain, culture, and serotype and biotype identification.

Polymerase chain reaction (PCR) tests for identifying V cholerae have been developed. These have a high degree of sensitivity and specificity. At present, however, such tests are used for screening of food samples.

Vibrio cholerae is a gram-negative curved bacillus that is motile by means of a single flagellum. Laboratory diagnosis is required not only for identification but also for epidemiological purposes.

Although observed as a gram-negative organism, the characteristic motility of Vibrio species cannot be identified on a Gram stain, but it is easily seen on direct dark-field examination of the stool.

2)   Stool Culture;

V cholerae is not fastidious in nutritional requirements for growth. However, it does need an adequate buffering system if fermentable carbohydrate is present because viability is severely compromised if the pH is less than 6, often resulting in autosterilization of the culture. Many of the selective media used to differentiate enteric pathogens do not support the growth of V cholerae.

a.    Routine differential media

Colonies are lactose-negative, like all other intestinal pathogens, but sucrose-positive. When plated onto triple-sugar iron agar to screen for Salmonella and Shigella species, the organism gives the nonpathogenic pattern of an acid (yellow) slant and acid butt because of fermentation of the sucrose contained in triple-sugar iron agar.

Unlike other Enterobacteriaceae, V cholerae is oxidase-positive; hence, in countries where selective media are not available and cholera is not endemic, V cholerae should be suspected if any motile, oxidase-positive, gram-negative rod isolated on routine differential media from the stool of a patient with diarrhea produces an acid reaction on triple sugar iron agar.

b.    Alkaline enrichment media

As Vibrio has the ability to grow at a high pH or in bile salts, which inhibit many other Enterobacteriaceae, peptone water (pH 8.5-9) or selective media containing bile salts (eg, thiosulfate-citrate-bile-sucrose-agar [pH 8.6]) are recommended to facilitate isolation and lab diagnosis. On thiosulfate-citrate-bile-sucrose-agar, the sucrose-fermenting V cholera grow as large, smooth, round yellow colonies that stand out against the blue-green agar.

3)   Serotyping and Biotyping

Specific antisera can be used in immobilization tests. A positive immobilization test result (ie, cessation of motility of the organism) is produced only if the antiserum is specific for the Vibrio type present; the second antiserum serves as a negative control. Vibrio antisera may be unavailable in countries where cholera is not endemic. In endemic regions, this is an excellent quick method of identification, even in small laboratories.

Classic and El Tor biotypes also can be identified using the same method. This is useful for epidemiologic studies.

4)   Hematologic Tests;

The major hematologic derangements in patients with cholera derive from the alterations in intravascular volume and electrolyte concentrations.

i.             Acute phase reactants;

Hematocrit, serum-specific gravity, and serum protein are elevated in dehydrated patients because of resulting hemoconcentration. When patients are first observed, they generally have a leukocytosis without a left shift. There is overally elevated acute phase reactants.

ii.            Metabolic Panel

a.    Serum sodium is usually 130-135 mmol/L, reflecting the substantial loss of sodium in the stool.

b.    Serum potassium usually is normal in the acute phase of the illness, reflecting the exchange of intracellular potassium for extracellular hydrogen ion in an effort to correct the acidosis.

c.     Hyperglycemia may be present, secondary to systemic release of epinephrine, glucagon, and cortisol due to hypovolemia.

d.    Patients have elevated blood urea nitrogen and creatinine levels consistent with prerenal azotemia. The extent of elevation depends on the degree and duration of dehydration.

e.    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.

Management of Cholera;

Rehydration is the first priority in the treatment of cholera. Rehydration is accomplished in 2 phases: rehydration and maintenance.

The goal of the rehydration phase is to restore normal hydration status, which should take no more than 4 hours. Set the rate of intravenous infusion in severely dehydrated patients at 50-100 mL/kg/hr.

Lactated Ringer solution is preferred over isotonic sodium chloride solution because saline does not correct metabolic acidosis.

The goal 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/hr is recommended.

WHO Treatment Guidelines for Cholera;

The World Health Organization (WHO) guidelines for the management of cholera are practical, easily understood, and readily applied in clinical practice. These guidelines can be used for the treatment of any patient with diarrhea and dehydration. Diagnosis of cholera is not required to initiate hydration therapy.

1.    Rehydration

The WHO has provided recommendations for fluid replacement in patients with dehydration. The recommendations include recommendations for fluid replacement for severe hydration, some dehydration, and no dehydration.

1)    SEVERE DEHYDRATION

Administer intravenous (IV) fluid immediately to replace fluid deficit. Use lactated Ringer solution or, if that is not available, isotonic sodium chloride solution. If the patient can drink, begin giving oral rehydration salt solution (ORS) by mouth while the drip is being set up; ORS can provide the potassium, bicarbonate, and glucose that saline solution lacks.

NOTE; Coconut fluid has been used in epidemics especially is shortage of IV fluid.

·         For patients older than 1 year, give 100 mL/kg IV in 3 hours—30 mL/kg as rapidly as possible (within 30 min) then 70 mL/kg in the next 2 hours.

·         For patients younger than 1 year, administer 100 mL/kg IV in 6 hours—30 mL/kg in the first hour then 70 mL/kg in the next 5 hours.

Monitor the patient frequently. After the initial 30 mL/kg has been administered, the radial pulse should be strong and blood pressure should be normal. If the pulse is not yet strong, continue to give IV fluid rapidly. Administer ORS solution (about 5 mL/kg/h) as soon as the patient can drink, in addition to IV fluid.

Reassess the hydration status after 3 hours (infants after 6 h). In the rare case that the patient still exhibits signs of severe dehydration, repeat the IV therapy already given. If signs of some dehydration are present, continue as indicated below for some dehydration. If no signs of dehydration exist, maintain hydration by replacing ongoing fluid losses.

Routes for parenteral rehydration in cholera;

Accessing a peripheral vein is relatively easy, despite the severe dehydration. If a peripheral vein is not readily accessible, scalp veins have been used for initial rehydration. As the vascular volume is reestablished, a larger needle or catheter can be introduced in a peripheral vein.

Intraosseous routes have been used successfully in young children when veins cannot be accessed. The intraperitoneal route has been tried, but is not recommended.

ORS solution can be administered via nasogastric tube if the patient has some signs of dehydration and cannot drink or if the patient has severe dehydration and IV therapy is not possible at the treatment facility.

Overhydration;

A risk of overhydration exists with intravenous fluids; it usually first manifests as puffiness around the eyes. Continued excessive administration of intravenous fluids can lead to pulmonary edema and has been observed even in children with normal cardiovascular reserve.

Thus, it is important to monitor patients who are receiving intravenous rehydration hourly. Serum-specific gravity is an additional measure of the adequacy of rehydration.

2)   SOME DEHYDRATION.

Administer ORS solution . WHO ORS contains the following

Sodium – 75 mmol/L

Chloride – 65 mmol/L

Potassium – 20 mmol/L

Bicarbonate – 30 mmol/L

Glucose – 111 mmol/L

A Satchet for reconstituting 500ml solution contains the following;

i.             Glucose anhydrous BP- 6.7 g.

ii.            Sodium Chloride BP- 1.3 g.

iii.           Sodium Citrate BP- 1.45 g.

iv.           Pottasium Chloride BP- 0.75g.

A homemade equivalent is 6 teaspoons of sugar and one half teaspoon of salt in a liter of water; a half cup of orange juice or some mashed banana can provide potassium.

Use the patient's age only when weight is unknown. The approximate amount of ORS required (in mL) also can be calculated by multiplying the patient's weight (in kg) times 75.

If the patient passes watery stools or wants more ORS solution than shown, give more. Monitor the patient frequently to ensure that the ORS solution is taken satisfactorily and to identify patients with profuse ongoing diarrhea who require closer monitoring.

Reassess the patient after 4 hours. In the rare case where signs of severe dehydration have appeared, rehydrate for severe dehydration, as above. If some dehydration is still present, repeat the procedures for some dehydration and start to offer food and other fluids. If no signs of dehydration are present, maintain hydration by replacing ongoing fluid losses.

Most patients absorb enough ORS solution to achieve rehydration, even when they are vomiting. Vomiting usually subsides within 2-3 hours, as rehydration is achieved.

Urine output decreases as dehydration develops and may cease. It usually resumes within 6-8 hours after starting rehydration. Regular urinary output (i e, every 3-4 h) is a good sign that enough fluid is being given.

3)   NO SIGNS OF DEHYDRATION

Patients who have no signs of dehydration when first observed can be treated at home. Give these patients ORS packets to take home, enough for 2 days. Demonstrate how to prepare and give the solution.

Instruct the patient or the caretaker to return if any of the following signs develop:

1.     Increased number of watery stools

2.    Eating or drinking poorly

3.    Marked thirst

4.    Repeated vomiting

5.    Any signs indicating other problems (eg, fever, blood in stool)

Maintenance of Hydration;

Maintain hydration of patients presenting with severe or some dehydration. Replace ongoing fluid losses until diarrhea stops.

When a patient who has been rehydrated with IV fluid or ORS solution is reassessed and has no signs of dehydration, continue to administer ORS solution to maintain normal hydration. The aim is to replace stool losses as they occur with an equivalent amount of ORS solution.

The amount of ORS solution required to maintain hydration varies greatly among patients, depending on the volume of stool passed. It is highest in the first 24 hours of treatment and is especially large in patients who present with severe dehydration. In the first 24 hours, the average requirement of ORS solution in such patients is 200 mL/kg, but some patients may need as much as 350 mL/kg.

Continue to reassess the patient for signs of dehydration at least every 4 hours to ensure that enough ORS solution is being taken. Patients with profuse ongoing diarrhea require more frequent monitoring. If signs of some dehydration are detected, the patient should be rehydrated as described earlier, before continuing with treatment to maintain hydration.

A few patients, whose ongoing stool output is very large, may have difficulty in drinking the volume of ORS needed to maintain hydration. If these patients become tired, vomit frequently, or develop abdominal distension, ORS solution should be stopped and hydration should be maintained intravenously with lactated Ringer solution or isotonic sodium chloride solution, administering 50 mL/kg in 3 hours. After this is done, resuming treatment with ORS solution is usually possible.

Keep the patient under observation, if possible, until diarrhea stops or is infrequent and of small volume. This is especially important for any patient presenting with severe dehydration. If a patient must be discharged from the hospital before diarrhea has stopped, show the caretaker how to prepare and give ORS solution, and instruct the caretaker to continue to give ORS solution, as above. Also instruct the caretaker to return the patient to the hospital if any signs of danger appear.

Antibiotic Treatment in Cholera;

An effective antibiotic can reduce the volume of diarrhea in patients with severe cholera and shorten the period during which V cholerae O1 is excreted.

In addition, it usually stops the diarrhea within 48 hours, thus shortening the period of hospitalization. Whenever possible, antibiotic therapy should be guided by susceptibility reports.

Antibiotic treatment is indicated for severely dehydrated patients who are older than 2 years. Begin antibiotic therapy after the patient has been rehydrated (usually in 4-6 h) and vomiting has stopped. No advantage exists to using injectable antibiotics, which are expensive. No other drugs should be used in the treatment of cholera. Antimicrobial agents typically are administered for 3-5 days.

However, single-dose therapy with tetracycline, doxycycline, furazolidone, or ciprofloxacin has been shown effective in reducing the duration and volume of diarrhea. Because single dose doxycycline has been shown to be as effective as multiple doses of tetracycline, this has become the preferred regimen.

1.     Doxycycline†

7 mg/kg; not to exceed 300 mg/dose

2 mg/kg bid on day 1; then 2 mg/kg qd on days 2 and 3; not to exceed 100 mg/dose

2.    Tetracycline

25 mg/kg; not to exceed 1 g/dose‡

40 mg/kg/d divided qid for 3 d; not to exceed 2 g/d

3.    Trimethoprim and sulfamethoxazole

< 2 months of age: CTX is Contraindicated

≥2 months: 5-10 mg/kg/d (based on trimethoprim component) divided bid for 3 d; not to exceed 320 mg/d trimethoprim and 1.6 g/d of sulfamethoxazole

4.    Ciprofloxacin

30 mg/kg; not to exceed 1 g/dose

30 mg/kg/d divided q12h for 3 d; not to exceed 2 g/d

5.    Ampicillin

50 mg/kg/d divided qid for 3 d; not to exceed 2 g/d

6.    Erythromycin

40 mg/kg/d erythromycin base divided tid for 3 d; not to exceed 1 g/d.

Antimicrobial therapy is an adjunct to fluid therapy of cholera and is not an essential component. However, it reduces diarrhea volume and duration by approximately 50%. The choice of antibiotics is determined by the susceptibility patterns of the local strains of V cholerae O1 or O139.

Diet in Cholera;

Resume feeding with a normal diet when vomiting has stopped. Continue breastfeeding infants and young children.

Malnutrition after infection is not a major problem, as it is after infection with Shigella species or rotavirus diarrhea. The catabolic cost of the infection is relatively low, anorexia is neither profound nor persistent, and intestinal enzyme activity remains intact after infection; hence, intestinal absorption of nutrients is near normal.

There is no reason to withhold food from cholera patients.

Prevention of Cholera;

1.     Food and water sanitation.

2.    Screening of food handlers.

3.    In outbreaks a single dose of Doxycycline 300mgs provides adequate prophylaxis to those exposed or at risk with no clinical disease.