Zinc supplements for severe cholera

Abstract

Are simple, well tolerated, and could save money as well as lives

In the accompanying paper, Roy and colleagues report that zinc supplementation has an additional benefit over antimicrobial treatments in reducing the duration and severity of cholera in children.¹ The study was carried out in Bangladesh, where cholera is endemic.

Cholera is a common disease in many countries of the world. About 230 000 cases in more than 50 countries are reported globally, but the World Health Organization estimates that official notifications make up only 5-10% of the real burden of cholera.² This means that as many as three million cases and more than 100 000 deaths occur each year.^{2 3}

Cholera may be undetected for various reasons. About 80-90% of episodes are of mild to moderate severity. Therefore, without performing routine culture for Vibrio cholerae, the infection is difficult to distinguish clinically from other causes of acute diarrhoea, including traveller’s diarrhoea. Also, until recently economic repercussions such as restrictions to food exports and losses to tourism have acted as strong disincentives for reporting.^{2 3}

Several major outbreaks have occurred since 2005, and reported cases have doubled in the past three years, with a threefold increase in the absolute number of deaths. Almost all deaths occurred in Africa. Case fatality varies from about 1% to 4%, but in some regions—such as Angola’s provinces, mortality reached 30% in 2006. Children and women of childbearing age are the most susceptible to contracting and dying from the disease. People who are malnourished are, as always, more vulnerable.^{2 3}

The treatment of cholera has changed little in recent decades. The mild form can be treated with oral rehydration. Rice based solutions decrease stool output more than those based on glucose.^{3 4} Solutions with reduced osmolarity produce similar clinical outcomes to standard solutions.⁵ About 15-20% of patients have severe life threatening dehydration and need intravenous fluids. Most patients will recover even without antibiotics if hydration is maintained. Nevertheless, antibiotics (ciprofloxacin or azithromycin as a single dose or 12 doses of erythromycin) reduce the duration and severity of disease, and they can minimise the use of services and resources.^{2 3} However, resistant strains are common and treatment protocols should be adjusted accordingly.^{2 3} Antisecretives—drugs that reduce gut secretions of ions and water, such as racecadotril—have no effect.

What does zinc add to the current treatment of cholera in children? In Roy and colleagues’ study, significantly more children receiving zinc supplements than controls recovered on the second day (40 (49%) v 26 (32%), P=0.03) and on the third day (66 (81%) v 56 (68%), P=0.03).¹ On average, diarrhoea lasted for eight hours less in children taking zinc and their stool production was reduced by 200 mg a day. No excess vomiting was reported in this study, which is not the case when zinc syrup is not flavoured to mask its metallic taste.

Is this effect clinically relevant? At first glance this small benefit seems negligible. But imagine the potential effect at the International Centre for Diarrhoeal Disease Research, Bangladesh, where about 34 100 patients had cholera in 2005. During the epidemic season, the treatment ward is extended with tents to accommodate more than 500 patients each day. Under these circumstances, a 10-15% reduction in children being admitted to hospital would save lives.³ The cost of zinc treatment for three days is around $0.14 (£0.07; €0.1).¹ The average cost of full treatment for one patient with severe cholera is estimated at $15.³ Therefore, reducing hospital stay might even save money.

Why would zinc help treat cholera? Zinc is a catalytic or structural component of more than 200 human enzymes. It is involved in immune competence, resistance of skin and mucosa to infection, and development of the nervous system. Nutritional zinc deficiency is a common problem in developing countries, and giving zinc to children improves growth and the treatment and prevention of acute respiratory infections.^{6 7}

The beneficial effects of zinc on diarrhoea and cholera have a biologically plausible explanation. Zinc restores the integrity of the mucosal barrier and the activity of the enzymes in the brush border of enterocytes.⁸ It directly affects ion channels—it blocks potassium channels in the basolateral membrane and thus inhibits chloride secretion induced by cyclic AMP.⁹ Animals deficient in zinc show high fluid losses in response to cholera toxin,¹⁰ while zinc supplementation in humans reduces cyclic AMP concentrations in enterocytes, promotes ion absorption, and substantially reduces ion secretion induced by cholera toxin.¹¹ Finally, zinc also enhances the production of antibodies against intestinal pathogens, including cholera, and increases the numbers of circulating T cells in children.^{8 12}

In conclusion, the results of the study by Roy are consistent with previous studies in diarrhoea.¹ WHO and Unicef already recommend 10-20 mg of zinc a day for all children with diarrhoea. The current trial adds to our knowledge that zinc has a beneficial effect even in severe cholera, in children in hospital with high purging rates (both high frequency and volume of diarrhoea). The benefit of zinc in cholera may be small, but it is far from negligible in countries where the disease is endemic. Treatment is simple, has no serious adverse effects, and may even save money.