Biannual azithromycin distribution and child mortality among malnourished children: A subgroup analysis of the MORDOR cluster-randomized trial in Niger


Autoři: Kieran S. O’Brien aff001;  Ahmed M. Arzika aff003;  Ramatou Maliki aff003;  Farouk Manzo aff003;  Alio K. Mamkara aff003;  Elodie Lebas aff001;  Catherine Cook aff001;  Robin L. Bailey aff004;  Sheila K. West aff005;  Catherine E. Oldenburg aff001;  Travis C. Porco aff001;  Benjamin Arnold aff001;  Jeremy D. Keenan aff001;  Thomas M. Lietman aff001
Působiště autorů: Francis I. Proctor Foundation, University of California, San Francisco, California, United States of America aff001;  Division of Epidemiology, School of Public Health, University of California, Berkeley, California, United States of America aff002;  The Carter Center, Niamey, Niger aff003;  Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom aff004;  Dana Center for Preventive Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States of America aff005;  Department of Ophthalmology, University of California, San Francisco, California, United States of America aff006;  Department of Epidemiology and Biostatistics, University of California, San Francisco, California, United States of America aff007;  Institute for Global Health Sciences, University of California, San Francisco, California, United States of America aff008
Vyšlo v časopise: Biannual azithromycin distribution and child mortality among malnourished children: A subgroup analysis of the MORDOR cluster-randomized trial in Niger. PLoS Med 17(9): e32767. doi:10.1371/journal.pmed.1003285
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003285

Souhrn

Background

Biannual azithromycin distribution has been shown to reduce child mortality as well as increase antimicrobial resistance. Targeting distributions to vulnerable subgroups such as malnourished children is one approach to reaching those at the highest risk of mortality while limiting selection for resistance. The objective of this analysis was to assess whether the effect of azithromycin on mortality differs by nutritional status.

Methods and findings

A large simple trial randomized communities in Niger to receive biannual distributions of azithromycin or placebo to children 1–59 months old over a 2-year timeframe. In exploratory subgroup analyses, the effect of azithromycin distribution on child mortality was assessed for underweight subgroups using weight-for-age Z-score (WAZ) thresholds of −2 and −3. Modification of the effect of azithromycin on mortality by underweight status was examined on the additive and multiplicative scale. Between December 2014 and August 2017, 27,222 children 1–11 months of age from 593 communities had weight measured at their first study visit. Overall, the average age among included children was 4.7 months (interquartile range [IQR] 3–6), 49.5% were female, 23% had a WAZ < −2, and 10% had a WAZ < −3. This analysis included 523 deaths in communities assigned to azithromycin and 661 deaths in communities assigned to placebo. The mortality rate was lower in communities assigned to azithromycin than placebo overall, with larger reductions among children with lower WAZ: −12.6 deaths per 1,000 person-years (95% CI −18.5 to −6.9, P < 0.001) overall, −17.0 (95% CI −28.0 to −7.0, P = 0.001) among children with WAZ < −2, and −25.6 (95% CI −42.6 to −9.6, P = 0.003) among children with WAZ < −3. No statistically significant evidence of effect modification was demonstrated by WAZ subgroup on either the additive or multiplicative scale (WAZ < −2, additive: 95% CI −6.4 to 16.8, P = 0.34; WAZ < −2, multiplicative: 95% CI 0.8 to 1.4, P = 0.50, WAZ < −3, additive: 95% CI −2.2 to 31.1, P = 0.14; WAZ < −3, multiplicative: 95% CI 0.9 to 1.7, P = 0.26). The estimated number of deaths averted with azithromycin was 388 (95% CI 214 to 574) overall, 116 (95% CI 48 to 192) among children with WAZ < −2, and 76 (95% CI 27 to 127) among children with WAZ < −3. Limitations include the availability of a single weight measurement on only the youngest children and the lack of power to detect small effect sizes with this rare outcome. Despite the trial’s large size, formal tests for effect modification did not reach statistical significance at the 95% confidence level.

Conclusions

Although mortality rates were higher in the underweight subgroups, this study was unable to demonstrate that nutritional status modified the effect of biannual azithromycin distribution on mortality. Even if the effect were greater among underweight children, a nontargeted intervention would result in the greatest absolute number of deaths averted.

Trial registration

The MORDOR trial is registered at clinicaltrials.gov NCT02047981.

Klíčová slova:

Antibiotics – Antimicrobial resistance – Census – Death rates – Child health – Malnutrition – Medical risk factors – Nutrition


Zdroje

1. Keenan JD, Bailey RL, West SK, Arzika AM, Hart J, Weaver J, et al. Azithromycin to reduce childhood mortality in sub-Saharan Africa. The New England journal of medicine. 2018;378(17):1583–92. Epub 2018/04/26. doi: 10.1056/NEJMoa1715474 29694816; PubMed Central PMCID: PMC5849140.

2. Keenan JD, Arzika AM, Maliki R, Boubacar N, Elh Adamou S, Moussa Ali M, et al. Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa. The New England journal of medicine. 2019;380(23):2207–14. Epub 2019/06/06. doi: 10.1056/NEJMoa1817213 31167050; PubMed Central PMCID: PMC6512890.

3. Doan T, Arzika AM, Hinterwirth A, Maliki R, Zhong L, Cummings S, et al. Macrolide Resistance in MORDOR I—A Cluster-Randomized Trial in Niger. The New England journal of medicine. 2019;380(23):2271–3. Epub 2019/06/06. doi: 10.1056/NEJMc1901535 31167060; PubMed Central PMCID: PMC6518950.

4. O'Brien KS, Emerson P, Hooper PJ, Reingold AL, Dennis EG, Keenan JD, et al. Antimicrobial resistance following mass azithromycin distribution for trachoma: a systematic review. The Lancet Infectious diseases. 2019;19(1):e14–e25. Epub 2018/10/08. doi: 10.1016/S1473-3099(18)30444-4 30292480.

5. Austin DJ, Kristinsson KG, Anderson RM. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc Natl Acad Sci U S A. 1999;96(3):1152–6. Epub 1999/02/03. doi: 10.1073/pnas.96.3.1152 9927709; PubMed Central PMCID: PMC15366.

6. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, et al. Maternal and child undernutrition and overweight in low-income and middle-income countries. The Lancet. 2013;382(9890):427–51. doi: 10.1016/S0140-6736(13)60937-X

7. Scrimshaw NS, SanGiovanni JP. Synergism of nutrition, infection, and immunity: an overview. The American journal of clinical nutrition. 1997;66(2):464S–77S. Epub 1997/08/01. doi: 10.1093/ajcn/66.2.464S 9250134.

8. Dewey KG, Mayers DR. Early child growth: how do nutrition and infection interact? Maternal & child nutrition. 2011;7 Suppl 3:129–42. Epub 2011/10/05. doi: 10.1111/j.1740-8709.2011.00357.x 21929641

9. Langtry HD, Balfour JA. Azithromycin. A review of its use in paediatric infectious diseases. Drugs. 1998;56(2):273–97. Epub 1998/08/26. doi: 10.2165/00003495-199856020-00014 9711451.

10. Humphrey JH. Child undernutrition, tropical enteropathy, toilets, and handwashing. Lancet (London, England). 2009;374(9694):1032–5. Epub 2009/09/22. doi: 10.1016/s0140-6736(09)60950-8 19766883.

11. Lunn PG. The impact of infection and nutrition on gut function and growth in childhood. Proceedings of the Nutrition Society. 2007;59(1):147–54. Epub 02/28. doi: 10.1017/S0029665100000173 10828184

12. Berkley JA, Ngari M, Thitiri J, Mwalekwa L, Timbwa M, Hamid F, et al. Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial. The Lancet Global health. 2016;4(7):e464–73. Epub 2016/06/07. doi: 10.1016/S2214-109X(16)30096-1 27265353.

13. Rafii F, Sutherland JB, Cerniglia CE. Effects of treatment with antimicrobial agents on the human colonic microflora. Therapeutics and clinical risk management. 2008;4(6):1343–58. Epub 2009/04/02. doi: 10.2147/tcrm.s4328 19337440; PubMed Central PMCID: PMC2643114.

14. Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological balance of human microflora. The Lancet Infectious diseases. 2001;1(2):101–14. Epub 2002/03/02. doi: 10.1016/S1473-3099(01)00066-4 11871461.

15. Trehan I, Goldbach HS, LaGrone LN, Meuli GJ, Wang RJ, Maleta KM, et al. Antibiotics as part of the management of severe acute malnutrition. The New England journal of medicine. 2013;368(5):425–35. Epub 2013/02/01. doi: 10.1056/NEJMoa1202851 23363496; PubMed Central PMCID: PMC3654668.

16. Isanaka S, Langendorf C, Berthe F, Gnegne S, Li N, Ousmane N, et al. Routine Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children. The New England journal of medicine. 2016;374(5):444–53. Epub 2016/02/04. doi: 10.1056/NEJMoa1507024 26840134.

17. Vray M, Hedible BG, Adam P, Tondeur L, Manirazika A, Randremanana R, et al. A multicenter, randomized controlled comparison of three renutrition strategies for the management of moderate acute malnutrition among children aged from 6 to 24 months (the MALINEA project). Trials. 2018;19(1):666. Epub 2018/12/06. doi: 10.1186/s13063-018-3027-3 30514364; PubMed Central PMCID: PMC6278112.

18. Oldenburg CE, Arzika AM, Maliki R, Kane MS, Lebas E, Ray KJ, et al. Safety of azithromycin in infants under six months of age in Niger: A community randomized trial. PLoS Negl Trop Dis. 2018;12(11):e0006950. Epub 2018/11/13. doi: 10.1371/journal.pntd.0006950 30419040; PubMed Central PMCID: PMC6258425.

19. WHO Multicentre Growth Reference Study Group. Assessment of differences in linear growth among populations in the WHO Multicentre Growth Reference Study. Acta paediatrica (Oslo, Norway: 1992) Supplement. 2006;450:56–65. Epub 2006/07/05. doi: 10.1111/j.1651-2227.2006.tb02376.x 16817679.

20. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass indexfor-age: Methods and development. Geneva: World Health Organization, 2006. [cited 2020 Aug 21]. https://www.who.int/childgrowth/standards/technical_report/en/

21. R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2003. http://www.R-project.org/.

22. VanderWeele TJ. Sample size and power calculations for additive interactions. Epidemiologic Methods. 2012;1:159–88. doi: 10.1515/2161-962X.1010 PubMed Central PMCID: PMC4249707. 25473594

23. VanderWeele TJ, Knol MJ. A tutorial on interaction. Epidemiologic Methods. 2014;3:33–72. [cited 2020 Aug 21]. https://cdn1.sph.harvard.edu/wp-content/uploads/sites/603/2018/04/InteractionTutorial_EM.pdf

24. Knol MJ, VanderWeele TJ, Groenwold RH, Klungel OH, Rovers MM, Grobbee DE. Estimating measures of interaction on an additive scale for preventive exposures. Eur J Epidemiol. 2011;26(6):433–8. Epub 2011/02/24. doi: 10.1007/s10654-011-9554-9 21344323; PubMed Central PMCID: PMC3115067.

25. Knol MJ, VanderWeele TJ. Recommendations for presenting analyses of effect modification and interaction. International journal of epidemiology. 2012;41(2):514–20. Epub 2012/01/19. doi: 10.1093/ije/dyr218 22253321; PubMed Central PMCID: PMC3324457.

26. Li R, Chambless L. Test for additive interaction in proportional hazards models. Ann Epidemiol. 2007;17(3):227–36. Epub 2007/02/27. doi: 10.1016/j.annepidem.2006.10.009 17320789.

27. Pelletier DL. The relationship between child anthropometry and mortality in developing countries: implications for policy, programs and future research. The Journal of nutrition. 1994;124(10 Suppl):2047s–81s. Epub 1994/10/01. doi: 10.1093/jn/124.suppl_10.2047S 7931716.

28. McDonald CM, Olofin I, Flaxman S, Fawzi WW, Spiegelman D, Caulfield LE, et al. The effect of multiple anthropometric deficits on child mortality: meta-analysis of individual data in 10 prospective studies from developing countries. The American journal of clinical nutrition. 2013;97(4):896–901. Epub 2013/02/22. doi: 10.3945/ajcn.112.047639 23426036.

29. Tam CC, Offeddu V, Lim JM, Voo TC. One drug to treat them all: ethical implications of the MORDOR trial of mass antibiotic administration to reduce child mortality. J Glob Health. 2019;9(1):010305. Epub 2019/01/16. doi: 10.7189/jogh.09.010305 30643634; PubMed Central PMCID: PMC6318831.

30. Brander RL, Weaver MR, Pavlinac PB, John-Stewart GC, Hawes SE, Walson JL. Projected impact and cost-effectiveness of community-based versus targeted azithromycin administration strategies for reducing child mortality in sub-Saharan Africa. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2020. Epub 2020/01/07. doi: 10.1093/cid/ciz1220 31905386.

31. Rose G. Sick individuals and sick populations. International journal of epidemiology. 1985;14(1):32–8. Epub 1985/03/01. doi: 10.1093/ije/14.1.32 3872850.

32. Chowkwanyun M, Bayer R, Galea S. “Precision” Public Health—Between Novelty and Hype. New England Journal of Medicine. 2018;379(15):1398–400. doi: 10.1056/NEJMp1806634 30184442.

33. Oldenburg CE, Arzika AM, Maliki R, Lin Y, O'Brien KS, Keenan JD, et al. Optimizing the Number of Child Deaths Averted with Mass Azithromycin Distribution. The American journal of tropical medicine and hygiene. 2020. Epub 2020/02/19. doi: 10.4269/ajtmh.19-0328 32067626.

34. Akombi BJ, Agho KE, Merom D, Renzaho AM, Hall JJ. Child malnutrition in sub-Saharan Africa: A meta-analysis of demographic and health surveys (2006–2016). PLoS ONE. 2017;12(5):e0177338. Epub 2017/05/12. doi: 10.1371/journal.pone.0177338 28494007; PubMed Central PMCID: PMC5426674.

35. O'Brien KS, Amza A, Kadri B, Nassirou B, Cotter SY, Stoller NE, et al. Comparison of anthropometric indicators to predict mortality in a population-based prospective study of children under 5 years in Niger. Public health nutrition. 2020;23(3):538–43. Epub 2019/09/10. doi: 10.1017/S1368980019002520 31496465; PubMed Central PMCID: PMC7024038.

36. Myatt M, Khara T, Dolan C, Garenne M, Briend A. Improving screening for malnourished children at high risk of death: a study of children aged 6–59 months in rural Senegal. Public health nutrition. 2019;22(5):862–71. Epub 2018/12/07. doi: 10.1017/S136898001800318X 30501655; PubMed Central PMCID: PMC6521791.

37. Myatt M, Khara T, Schoenbuchner S, Pietzsch S, Dolan C, Lelijveld N, et al. Children who are both wasted and stunted are also underweight and have a high risk of death: a descriptive epidemiology of multiple anthropometric deficits using data from 51 countries. Archives of public health = Archives belges de sante publique. 2018;76:28. Epub 2018/07/22. doi: 10.1186/s13690-018-0277-1 30026945; PubMed Central PMCID: PMC6047117.

38. Vaitla B, Devereux S, Swan SH. Seasonal hunger: a neglected problem with proven solutions. PLoS Med. 2009;6(6):e1000101. Epub 2009/07/01. doi: 10.1371/journal.pmed.1000101 19564900; PubMed Central PMCID: PMC2696035.

39. Porco TC, Hart J, Arzika AM, Weaver J, Kalua K, Mrango Z, et al. Mass Oral Azithromycin for Childhood Mortality: Timing of Death After Distribution in the MORDOR Trial. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2019;68(12):2114–6. Epub 2018/12/19. doi: 10.1093/cid/ciy973 30561577; PubMed Central PMCID: PMC6541729.

40. Perumal N, Bassani DG, Roth DE. Use and Misuse of Stunting as a Measure of Child Health. The Journal of nutrition. 2018;148(3):311–5. Epub 2018/03/17. doi: 10.1093/jn/nxx064 29546307.


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