- Email: [email protected]
Malnutrition, zinc deficiency, and malaria in Africa
Correspondence
We are writing to make known to the international medical community the shocking imprisonment of Binayak Sen on May 14, 2007, in the central Indian state of Chhattisgarh. A well known paediatrician and public-health specialist, Sen’s is a rare example of the cost of involvement in civil rights activism by physicians. He is being charged by the local police with illicit communication with Maoists in custody. After a distinguished academic career at Christian Medical College, Vellore, during his undergraduate and postgraduate training, Sen joined the faculty of the Centre for Social Medicine and Public Health at the Jawaharlal Nehru University, New Delhi (1976–78). For the past 30 years, Sen has been developing models of primary health in Madhya Pradesh and subsequently in the new state of Chhattisgarh. He is well known for setting up a self-funded cooperative hospital for mine workers, the Shaheed hospital, and he had a significant role in evolving the statewide “Mitanin” programme of training community health workers. In 2004, the Christian Medical College conferred on him the Paul Harrison Award—the highest recognition accorded to an alumnus for distinguished work in rural areas. Apart from these socially relevant health-care activities, what sets Sen apart has been his deep commitment to the defence of civil liberties, including fact-finding missions into human rights violations such as custodial deaths, extra-judicial killings by state police, and hunger deaths in remote and politically turbulent communities. In recent times, he has worked ceaselessly to focus national and international attention on largescale oppression and malgovernance within the Salwa Judoom (which www.thelancet.com Vol 369 June 30, 2007
has become a kind of non-state militia) in the Dantewara district of Chhattisgarh. He has given leadership to the nationwide People’s Union for Civil Liberties as General Secretary in Chhattisgarh and as Vice President at the national level. Sen is a man of impeccable integrity, self-denial, and peace who has worked steadfastly for the rights and wellbeing of ordinary people, particularly the tribals. We feel that the allegations of unlawful activities on his part are aimed at silencing an inconvenient voice in defence of the oppressed. The Chhattisgarh Special Public Security Act, 2005, under which he is imprisoned, permits arbitrary detention with no remedy of appeal or review for a maximum period of imprisonment of 7 years for any expression or act which the state may deem as disturbing public order. The repressive features of this law make us concerned about his safety and wellbeing. We urge the international medical community to raise their voice to demand the release of this distinguished doctor and civil rights activist. We are colleagues of Binayak Sen.
*Anand Zachariah, Sara Bhattacharji [email protected] Christian Medical College, Vellore, India
Malnutrition, zinc deficiency, and malaria in Africa Sunil Sazawal and colleagues (March 17, 2007 p 927)1 did a large randomised controlled trial of zinc supplementation in a malaria holoendemic area of east Africa, which showed no significant effect on mortality among children younger than 5 years. However, in subgroup analyses, Sazawal and colleagues showed a significant effect of the intervention on mortality in children older than 12 months, and this
effect was significant for boys (relative risk 0·71), but not for girls (0·95). We did a similar study2 on the effects of zinc supplementation in a malaria holoendemic area of west Africa. Here, zinc supplementation had no effect on malaria morbidity, but significantly reduced diarrhoea morbidity in children younger than 3 years. A subgroup analysis showed that this effect was also significant for boys (relative risk 0·67), but not for girls (1·03), a finding that needs further explanation.3 Finally, we showed a significant association between malnutrition and mortality, but not between malnutrition and malaria in this cohort.4 In areas of high malaria transmission intensity, the peak of malariaattributed death occurs typically in late infancy.5 Thus, Sazawal and colleagues’ finding of an effect of zinc supplementation on mortality in older children is most likely to be a result of the effects of the intervention on diarrhoea and respiratory infections— the two leading causes of death in this age-group. We agree that malnutrition and micronutrient deficiencies are important causes of the high childhood mortality in Africa, and that they need to be addressed by appropriate interventions. However, contrary to Sazawal and colleagues, we do not think that nutritional interventions are important in malaria control. Here, existing effective preventive and curative interventions, such as insecticide-treated mosquito nets and new malaria combination therapies, need to be applied on a large scale and without further delay. We declare that we have no conflict of interest. Science Photo Library-
Arrest of paediatrician and human rights activist Binayak Sen
*Olaf Müller, Michel Garenne, Heiko Becher, Ali Sie, Bocar Kouyaté [email protected] Ruprecht-Karls-University, Department of Tropical Hygiene and Public Health, INF 324, 69120 Heidelberg, Germany (OM, HB); Pasteur Institute, Paris, France (MG); Centre de Recherche en Santé, Nouna, Burkina Faso (AS); and Centre National de Recherche et de la Formation au Paludisme, Ouagadougou, Burkina Faso (BK)
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
2155
Correspondence
1
2
3
4
5
Sazawal S, Black RE, Chwaya HM, et al. Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial. Lancet 2007; 396: 927–34. Müller O, Becher H, Baltussen A, et al. Effect of zinc supplementation on malaria and other causes of morbidity in west African children: randomized double-blind placebo-controlled trial. BMJ 2001; 322: 1567–72. Garenne M, Müller O, Becher H, et al. Sex specific responses to zinc supplementation in Nouna, Burkina Faso. J Pediatr Gastroenterol Nutr 2007; 44: 619–28. Müller O, Garenne M, Kouyaté B, Becher H. The association between protein-energy malnutrition, malaria morbidity and all-cause mortality in west African children. Trop Med Int Health 2003; 8: 507–11. Hammer GP, Somé F, Müller O, Kynast-Wolf G, Kouyaté B, Becher H. Pattern of cause-specific childhood mortality in a malaria endemic area of Burkina Faso. Malaria J 2006; 5: 47.
Sunil Sazawal and colleagues,1 in their large trial in Pemba, Zanzibar, found that zinc supplementation led to a less-than-expected reduction of mortality (7%; 95% CI –6 to 19). The study was designed with a 90% probability to detect a 20% reduction in mortality. It is not helpful that Sazawal and colleagues take this power into consideration when interpreting the results. First, the results indicate that power calculations were based on assumptions that were not met during trial implementation. A study with an expected upper limit equal to a particular value will have only 50% probability of yielding an upper limit below that value.2 Thus, under the conditions prevailing in the Pemba trial, the probability of detecting a mortality reduction of 19% is only 50%. A second, more fundamental concern is that statistical power is exclusively a pretrial concept,3 referring to the probability of obtaining outcomes that indicate significance, given a specified true difference between two groups. There is no sense, however, in calculating the probability that something happens after it happens. As put into perspective by Richard Feynman:4 “I had the most remarkable experience this evening. While coming in here, I saw 2156
license plate ANZ912. Calculate for me, please, the odds that of all license plates in the state of Washington I should happen to see ANZ912.” Having seen that particular licence plate first, that probability is exactly 1. Interpretation of results should be based exclusively on confidence intervals. From the findings from the Pemba study, the possibility that zinc supplementation had no effect on child mortality cannot be excluded. Thus further research is required, and the use of placebo in randomised trials remains warranted. The findings bring the exciting prospect, however, that zinc interventions might become a much-needed tool to control malaria. I declare that I have no conflict of interest.
Hans Verhoef [email protected] Wageningen University, Cell Biology and Immunology Group, PO Box 338, 6700 AH Wageningen, Netherlands 1
2
3
4
Sazawal S, Black RE, Ramsan M, et al. Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial. Lancet 2007; 369: 927–34. Greenland S. On sample-size and power calculation for studies using confidence intervals. Am J Epidemiol 1988; 128: 231–37. Goodman SN, Berlin JA. The use of predicted confidence intervals when planning experiments and the misuse of power when interpreting results. Ann Intern Med 1994; 121: 200–06. Feynman R. The meaning of it all. London: Penguin Books, 1999.
Authors’ reply We agree with Olaf Müller that the sex differences in the effect of micronutrient supplementation now seen in two trials1,2 need to be further investigated in other available datasets and in future trials. Contrary to findings in Burkina Faso,3 in Pemba the malaria-attributable mortality, although increasing in late infancy, remains as high, if not higher, in the second and third years of life. Since the person-years contributed in the second and third years are more than in late infancy, the mortality burden does become substantial. In our study, malaria-
related mortality was 2·1% in children older than 12 months compared with 1% in infants in the control group.1 There is no evidence to suggest that mortality reduction in those older than 12 months was attributable to diarrhoea and respiratory infections only. The intent of our discussion was not to recommend the use of zinc interventions as a replacement for other malaria control measures, but to supplement such measures as nutritional interventions affect a wider variety of causes of death. Our data suggest that zinc supplementation might affect the malaria case-fatality rate in children admitted to hospital and given active treatment (overall relative risk 0·80, 95% CI 0·58–1·10, p=0·17; relative risk among boys 0·51, 0·31–0·85, p=0·01). This concept might well explain the association between malnutrition and mortality but not malnutrition and malaria seen by Müller and colleagues.4 We also agree with Hans Verhoef that power calculation for observed results has very little meaning and confidence intervals should be used instead. In view of this, although statistically the overall results are consistent with no effect of zinc supplementation (which was stated in the paper), the 7% reduction with a CI of –6 to 19, as recommended by Verhoef himself, does suggest a tilt towards benefit, which we agree needs to be confirmed. However, given the age interactions and significant mortality reduction in children older than 12 months, we are not sure that use of placebo in that age-group would be accepted by many ethics committees. Use of placebo in children younger than 12 months would still be an open issue. Pooling of data from various sources so far available might provide one approach to confirming these findings and to making decisions as to whether further supplementation trials with placebo control are warranted and justified. We declare that we have no conflict of interest.
www.thelancet.com Vol 369 June 30, 2007
We are writing to make known to the international medical community the shocking imprisonment of Binayak Sen on May 14, 2007, in the central Indian state of Chhattisgarh. A well known paediatrician and public-health specialist, Sen’s is a rare example of the cost of involvement in civil rights activism by physicians. He is being charged by the local police with illicit communication with Maoists in custody. After a distinguished academic career at Christian Medical College, Vellore, during his undergraduate and postgraduate training, Sen joined the faculty of the Centre for Social Medicine and Public Health at the Jawaharlal Nehru University, New Delhi (1976–78). For the past 30 years, Sen has been developing models of primary health in Madhya Pradesh and subsequently in the new state of Chhattisgarh. He is well known for setting up a self-funded cooperative hospital for mine workers, the Shaheed hospital, and he had a significant role in evolving the statewide “Mitanin” programme of training community health workers. In 2004, the Christian Medical College conferred on him the Paul Harrison Award—the highest recognition accorded to an alumnus for distinguished work in rural areas. Apart from these socially relevant health-care activities, what sets Sen apart has been his deep commitment to the defence of civil liberties, including fact-finding missions into human rights violations such as custodial deaths, extra-judicial killings by state police, and hunger deaths in remote and politically turbulent communities. In recent times, he has worked ceaselessly to focus national and international attention on largescale oppression and malgovernance within the Salwa Judoom (which www.thelancet.com Vol 369 June 30, 2007
has become a kind of non-state militia) in the Dantewara district of Chhattisgarh. He has given leadership to the nationwide People’s Union for Civil Liberties as General Secretary in Chhattisgarh and as Vice President at the national level. Sen is a man of impeccable integrity, self-denial, and peace who has worked steadfastly for the rights and wellbeing of ordinary people, particularly the tribals. We feel that the allegations of unlawful activities on his part are aimed at silencing an inconvenient voice in defence of the oppressed. The Chhattisgarh Special Public Security Act, 2005, under which he is imprisoned, permits arbitrary detention with no remedy of appeal or review for a maximum period of imprisonment of 7 years for any expression or act which the state may deem as disturbing public order. The repressive features of this law make us concerned about his safety and wellbeing. We urge the international medical community to raise their voice to demand the release of this distinguished doctor and civil rights activist. We are colleagues of Binayak Sen.
*Anand Zachariah, Sara Bhattacharji [email protected] Christian Medical College, Vellore, India
Malnutrition, zinc deficiency, and malaria in Africa Sunil Sazawal and colleagues (March 17, 2007 p 927)1 did a large randomised controlled trial of zinc supplementation in a malaria holoendemic area of east Africa, which showed no significant effect on mortality among children younger than 5 years. However, in subgroup analyses, Sazawal and colleagues showed a significant effect of the intervention on mortality in children older than 12 months, and this
effect was significant for boys (relative risk 0·71), but not for girls (0·95). We did a similar study2 on the effects of zinc supplementation in a malaria holoendemic area of west Africa. Here, zinc supplementation had no effect on malaria morbidity, but significantly reduced diarrhoea morbidity in children younger than 3 years. A subgroup analysis showed that this effect was also significant for boys (relative risk 0·67), but not for girls (1·03), a finding that needs further explanation.3 Finally, we showed a significant association between malnutrition and mortality, but not between malnutrition and malaria in this cohort.4 In areas of high malaria transmission intensity, the peak of malariaattributed death occurs typically in late infancy.5 Thus, Sazawal and colleagues’ finding of an effect of zinc supplementation on mortality in older children is most likely to be a result of the effects of the intervention on diarrhoea and respiratory infections— the two leading causes of death in this age-group. We agree that malnutrition and micronutrient deficiencies are important causes of the high childhood mortality in Africa, and that they need to be addressed by appropriate interventions. However, contrary to Sazawal and colleagues, we do not think that nutritional interventions are important in malaria control. Here, existing effective preventive and curative interventions, such as insecticide-treated mosquito nets and new malaria combination therapies, need to be applied on a large scale and without further delay. We declare that we have no conflict of interest. Science Photo Library-
Arrest of paediatrician and human rights activist Binayak Sen
*Olaf Müller, Michel Garenne, Heiko Becher, Ali Sie, Bocar Kouyaté [email protected] Ruprecht-Karls-University, Department of Tropical Hygiene and Public Health, INF 324, 69120 Heidelberg, Germany (OM, HB); Pasteur Institute, Paris, France (MG); Centre de Recherche en Santé, Nouna, Burkina Faso (AS); and Centre National de Recherche et de la Formation au Paludisme, Ouagadougou, Burkina Faso (BK)
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
2155
Correspondence
1
2
3
4
5
Sazawal S, Black RE, Chwaya HM, et al. Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial. Lancet 2007; 396: 927–34. Müller O, Becher H, Baltussen A, et al. Effect of zinc supplementation on malaria and other causes of morbidity in west African children: randomized double-blind placebo-controlled trial. BMJ 2001; 322: 1567–72. Garenne M, Müller O, Becher H, et al. Sex specific responses to zinc supplementation in Nouna, Burkina Faso. J Pediatr Gastroenterol Nutr 2007; 44: 619–28. Müller O, Garenne M, Kouyaté B, Becher H. The association between protein-energy malnutrition, malaria morbidity and all-cause mortality in west African children. Trop Med Int Health 2003; 8: 507–11. Hammer GP, Somé F, Müller O, Kynast-Wolf G, Kouyaté B, Becher H. Pattern of cause-specific childhood mortality in a malaria endemic area of Burkina Faso. Malaria J 2006; 5: 47.
Sunil Sazawal and colleagues,1 in their large trial in Pemba, Zanzibar, found that zinc supplementation led to a less-than-expected reduction of mortality (7%; 95% CI –6 to 19). The study was designed with a 90% probability to detect a 20% reduction in mortality. It is not helpful that Sazawal and colleagues take this power into consideration when interpreting the results. First, the results indicate that power calculations were based on assumptions that were not met during trial implementation. A study with an expected upper limit equal to a particular value will have only 50% probability of yielding an upper limit below that value.2 Thus, under the conditions prevailing in the Pemba trial, the probability of detecting a mortality reduction of 19% is only 50%. A second, more fundamental concern is that statistical power is exclusively a pretrial concept,3 referring to the probability of obtaining outcomes that indicate significance, given a specified true difference between two groups. There is no sense, however, in calculating the probability that something happens after it happens. As put into perspective by Richard Feynman:4 “I had the most remarkable experience this evening. While coming in here, I saw 2156
license plate ANZ912. Calculate for me, please, the odds that of all license plates in the state of Washington I should happen to see ANZ912.” Having seen that particular licence plate first, that probability is exactly 1. Interpretation of results should be based exclusively on confidence intervals. From the findings from the Pemba study, the possibility that zinc supplementation had no effect on child mortality cannot be excluded. Thus further research is required, and the use of placebo in randomised trials remains warranted. The findings bring the exciting prospect, however, that zinc interventions might become a much-needed tool to control malaria. I declare that I have no conflict of interest.
Hans Verhoef [email protected] Wageningen University, Cell Biology and Immunology Group, PO Box 338, 6700 AH Wageningen, Netherlands 1
2
3
4
Sazawal S, Black RE, Ramsan M, et al. Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial. Lancet 2007; 369: 927–34. Greenland S. On sample-size and power calculation for studies using confidence intervals. Am J Epidemiol 1988; 128: 231–37. Goodman SN, Berlin JA. The use of predicted confidence intervals when planning experiments and the misuse of power when interpreting results. Ann Intern Med 1994; 121: 200–06. Feynman R. The meaning of it all. London: Penguin Books, 1999.
Authors’ reply We agree with Olaf Müller that the sex differences in the effect of micronutrient supplementation now seen in two trials1,2 need to be further investigated in other available datasets and in future trials. Contrary to findings in Burkina Faso,3 in Pemba the malaria-attributable mortality, although increasing in late infancy, remains as high, if not higher, in the second and third years of life. Since the person-years contributed in the second and third years are more than in late infancy, the mortality burden does become substantial. In our study, malaria-
related mortality was 2·1% in children older than 12 months compared with 1% in infants in the control group.1 There is no evidence to suggest that mortality reduction in those older than 12 months was attributable to diarrhoea and respiratory infections only. The intent of our discussion was not to recommend the use of zinc interventions as a replacement for other malaria control measures, but to supplement such measures as nutritional interventions affect a wider variety of causes of death. Our data suggest that zinc supplementation might affect the malaria case-fatality rate in children admitted to hospital and given active treatment (overall relative risk 0·80, 95% CI 0·58–1·10, p=0·17; relative risk among boys 0·51, 0·31–0·85, p=0·01). This concept might well explain the association between malnutrition and mortality but not malnutrition and malaria seen by Müller and colleagues.4 We also agree with Hans Verhoef that power calculation for observed results has very little meaning and confidence intervals should be used instead. In view of this, although statistically the overall results are consistent with no effect of zinc supplementation (which was stated in the paper), the 7% reduction with a CI of –6 to 19, as recommended by Verhoef himself, does suggest a tilt towards benefit, which we agree needs to be confirmed. However, given the age interactions and significant mortality reduction in children older than 12 months, we are not sure that use of placebo in that age-group would be accepted by many ethics committees. Use of placebo in children younger than 12 months would still be an open issue. Pooling of data from various sources so far available might provide one approach to confirming these findings and to making decisions as to whether further supplementation trials with placebo control are warranted and justified. We declare that we have no conflict of interest.
www.thelancet.com Vol 369 June 30, 2007