1. Why is child mortality so different across countries and regions with similar income levels ? Peter Boone May 2005

2. Questions: Why is child mortality so different across countries and regions with similar income levels ? Is it possible to replicate the low levels observed in some countries quickly in a RCT ? (at low cost ?)

4. Child mortality and income Ln PPP GDP per capita Child Mortality Rate

5. Case Study: Kerala State created in 1956 Communist government elected 1957 1993 and 1998/9 FHS provide large database Literature reports improvements in almost every area of health as reason for Kerala’s relative success

6. Child mortality in Indian States

7. Focus on ARI and Diarrhoea Source: Black et. Al. 2005 33% 32% 13% Cause of non-neonatal child death by major disease/syndrome

8. Pathogens causing diarrhoea PresentationOrganism Acute watery diarrhoea Salmonella, Staphylococci, B. cereus, C. perfringens, V. parahaemolyticus, Ecoli, Rotavirus + other enterovirsues, Cryptosporidium, V. cholerae Acute bloody diarrhoea Shigella sp., C. jejuni Chronic diarrhoea G. intestinalis Chronic diarrhoea with blood E. Histolytica, B. coli, S. mansoni Source: Webber (2005)

9. Pathogens causing ALRI PresentationOrganism PneumoniaStreptococcus pneumoniae, Haemophilius influenzae, Influenza A or B, RSV, Adenoviruses, Morbillivirus, Metapneumorvirus, and many more….. MeningitisNeisseria meningitis, Haemophilius influenzae, Streptococcus pneumoniae, Mycobacterium tuberculosis, Staphlycocci, Escherichia coli, Group B streptococci, Mumps virus, Rubella virus, and many more…. Source: Webber (2005)

10. Steps to child mortality and possible interventions Clinical Manifestation Exposure Treatment Outcome Raise immune response: Better nutrition and vaccines Improve sanitation, water, hygiene Improve health seeking decisions: education, proximity of services, cost of services Raise healthcare worker training and incentives, medical supplies, new treatments

11. Which stage is best targeted ? No consistent answer in the literature –Low CMR countries intervened in all areas Cuba, Sri Lanka, Kerala, Former communist block, Costa Rica –Consensus that vaccines (Measles, DPT, BCG) have been highly successful but Diarrhoea and ALRI not easy targets –Controlled trials demonstrate potential large impact of interventions at every stage –Cost effectiveness work (e.g. World Bank 1993) helps allocate resources across interventions but can’t capture synergies, social and institutional issues that could lead to a different package.

12. Two alternative hypotheses For groups with similar income levels: A.Healthier populations have reduced exposure to disease, and hence less morbidity and less mortality. B.Healthier populations have similar morbidity but lower case fatality rates.

13. Exposures & Morbidity DHS surveys compare disease incidence across low income countries. Sanitation, water and hygiene are the main interventions aimed to reduce pathogen exposures. International data is available.

14. ARI and Diarrhoea Incidence (31 low income countries) Diarrhoea: average cases per year per child ARI: average cases per year per child

15. Mortality and Disease Incidence Ln (Child Mortality Rate) Coef SE Ln (PPP GDP per capita) -3.073 ** 1.906 Ln (PPP GDP per capita) 2 0.184** 0.127 Diarrhoea (under age 5 cases per yr) 0.057 0.050 ARI (under age 5 cases per yr) 0.017 0.041 Measles vaccine (proportion popn) -1.005 ++ 0.488 Doctors per 100,000 -0.279 ++ 0.133 R2R2 0.732 N 31 ** : Jointly significant at 5% level ++: Significant at 5% level

16. Mortality and Sanitation/Water Ln (Child Mortality Rate) Coef SE Ln (PPP GDP per capita) 1.057** 0.546 Ln (PPP GDP per capita) 2 -0.103** 0.032 Improved Sanitation (proportion popn) -0.163 0.218 Improved Water (proportion popn) -0.160 0.311 Measles vaccine (proportion popn) -0.103** 0.646 DPT Vaccine (proportion popn) -1.051** 0.577 Doctors per 100,000 -0.202 ++ 0.044 R2R2 0.869 N 103 **: Jointly significant at 1% level (vaccines; income measures grouped separately) ++: Significant at 1% level

17. Mortality and Latrine Access (103 countries)

18. India: ARI and Diarrhoea Incidence (26 States, children aged <4)

19. India: Mortality and Disease Incidence (26 states) Ln (Child Mortality Rate) Coef SE Ln (SDP per capita) -0.0379 0.2011 Diarrhoea (under age 5 cases per yr) 0.0357 0.0344 ARI (under age 5 cases per yr) -0.0482 0.0482 All rec’d vaccines (proportion popn aged<4) -1.4000 ++ 0.3412 R2R2 0.54 N 26 ** : Jointly significant at 5% level ++: Significant at 5% level

20. India: Household access to latrines

21. India: Access to improved water supply

22. Latrines and Diarrhoea Incidence

23. Diarrhea and Water/Sanitation: Trial results Source: Val Curtis

24. Implication: Disease incidence and mortality Disease incidence is weakly correlated with mortality Sanitation and water improvements are weakly correlated with mortality No evidence from survey data that Kerala’s success is due to lower morbidity

25. B. Treatment regimes Treatments in theory should be able to stop most mortality –Treatment trials wr to ARI and Diarrhea at healthcare centers typically have miniscule case fatality rates –Population-based RCT with frequent participant monitoring have low mortality rates Regressions across countries and within India suggest treatment variables (vaccines, physicians) are more important than incidence measures

26. Treatment Protocol (WHO) PresentationTreatmentCase fatality if treated early and cost Suspected ALRI: Cough and rapid breathing Antibiotics at home, at hospital if severe 0.0% $0.50-$2.00 per course at home Diarrhea -Watery -Bloody - ORT - Antibiotics 0.0%, 10 cents per packet 0.0%, $0.50-$2.00 per course at home Suspected Malaria - Fever, parasites in blood (if measured) - Antimalarial chemoprophylaxis Near 0%, $0.25-$5.00 per course Source: Work in progress

27. Surprising longevity of control study participants (if you visit them)…. StudyLocationParticipants (intervention, control) Baseline mortality Study mortality rate (intervention; control) Luby et. al, 2005 Pakistan3,163 ; 1,528CMR 140 90 non- neonatal 24 ; 38 Schellenber g et. al. 2003 Tanzania350 ; 351IMR 100 60 non- neonatal 20 ; 23 The studies were not powered to measure mortality change

28. Treatment proxies and mortality (31 countries) Ln (Child Mortality Rate) Coef SE Ln (PPP GDP per capita) -3.073 ** 1.906 Ln (PPP GDP per capita) 2 0.184** 0.127 Diarrhoea (under age 5 cases per yr) 0.057 0.050 ARI (under age 5 cases per yr) 0.017 0.041 Measles vaccine (proportion popn) -1.005 ++ 0.488 Doctors per 100,000 -0.279 ++ 0.133 R2R2 0.732 N 31 ** : Jointly significant at 5% level ++: Significant at 5% level

29. India: Treatment proxies and Mortality (26 states) Ln (Child Mortality Rate) Coef SE Ln (SDP per capita) -0.0379 0.2011 Diarrhoea (under age 5 cases per yr) 0.0357 0.0344 ARI (under age 5 cases per yr) -0.0482 0.0482 All rec’d vaccines (proportion popn aged<=3) -1.4000 ++ 0.3412 R2R2 0.54 N 26 ** : Jointly significant at 5% level ++: Significant at 5% level

30. India: Vaccine coverage (children <4 yrs)

31. India: Proximity to health care and spending on healthcare

32. Why differences in treatment ? Poverty/Price ? –How do household’s value treatment without knowing its potential benefit ? Coordination and regulation failure ? –In Kerala, 2/3 of treatments are done by the private sector Knowledge (both within the health system and within the family) ? –Essential to make health decisions….

33. Two sorts of “health knowledge” Selected behavior in species Acquired knowledge

34. Disgust: Selected mechanism to control disease With child mortality rates at 40% over a long history, small deviations in behavior due to genetic factors that raised odds of survival would eventually dominate the population Our sense of disgust and beauty is probably intrinsically related to the fight against microscopic enemines

35. Two fluids x= 1.6 x= 3.9x= 1.6 x= 2.6 Source: Val Curtis

36. 3.6 vs. 4.6

37. Knowledge of AIDS and ORT

38. Should you reduce fluids when a child has diarrhoea ?

39. Uganda: Perceived causes of Malaria What causes Malaria ? %Comment: Mosquitoes 95.3 Most believed transmitted by drinking eggs or larvae Bad air 30.8 Contagious from others 51.5 Drinking water 67.0 Witchcraft 9.8 Convulsions cannot be cured by modern medicine: 51.0 Source: Nuwaha (2002)

40. What causes a common cold ? (Massachusetts, 197 families) Virus 93% Germs 88% Bacteria 66% Changes in the weather 60% Not enough clothes 56% Wet hair in cold weather 41% Cold weather 38% Teething 28% Walking barefoot 26% Source: Lee et. al. (2005)

41. Tanzanian RCT healthcare quality Assessment Indicators IMCI (%) Non-IMCI (%) P-Value Pneumonia correctly treated 75 40 <0.01 Malaria correctly treated 88 25 <0.001 Child needing antibiotic /antimalarial prescribed correctly 73 35 <0.001 Child not needing an antibiotic leaves with an antibiotic 14 43 <0.001 Child needing vaccinations gets all needed 12 0 >0.10 Caretaker of sick child advised to give extra liquids and continue feeding 90 4 <0.00`

42. Conclusion Clinical Manifestation Exposure Treatment Outcome Treatment variations probably explain the differences in mortality at similar income levels across regions and countries. An underlying factor leading to differerences in treatment outcomes may be variations in the perceived (and actual) value of existing available treatments.

43. Next steps Conduct one or more RCT with the goal being to reduce mortality sharply in a high mortality region through changes in the treatment regime –Preliminary research to understand treatment seeking, quality of healthcare in selected region –Outreach program in RCT - Intervention arm: provide information to mothers on disease recognition and treatment monitor child’s health frequently to ensure treatment regime has changed free provision of treatment and vaccination coverage Antenatal and neonatal program –Follow-up studies to measure duration of impact and changes in treatment seeking behavior once free assistance is ended

44. SOAP Trial Africa Objectives: –Determine the impact of an outreach program, including treatment for children that develop disease, on child mortality –Determine the impact of hand-washing behavior on incidence of acute lower respiratory infections and diarrhoea, and on the need for treatment

45. SOAP Trial Africa Neighborhoods: High mortality region (randomized to intervention arms or control) Households within intervention neighborhoods randomized to intervention arms Arm 1: Handwashing & treatment 800 children Arm 2: Treatment 800 children Arm 3: Mortality tracked 2800 children Note: Suggested structure

46. SOAP Trial: Endpoints Comparison of incidence of ALRI and Diarrhoea in Arm 1 vs Arm 2 –Powered at 80% to capture a 25% reduction in ALRI in Arm 1 Comparison of mortality in Arm 1 + Arm 2 versus Arm 3 –Powered at 80% to capture a 60% reduction in child mortality (assuming control 100 CMR) Comparison of the cost of treatment in Arm 1 versus Arm 2

47. SOAP Trial: Other components Surveys to understand (before and/or after the study): –Baseline disease incidence, mortality, and household characteristics –Hygiene behavior and beliefs –Treatment seeking behavior and beliefs –Quality of care in existing healthcare centers

48. SOAP Trial: Timeline Agreement on study design and structure –Within one month Location, local partner, detailed protocol –End 2005 Randomization –1Q 2006

49. Cause of neonatal deaths 24% 29%24% 7% 16% Source: Black et. al., 2005

50. Naandi Neonatal deaths trial Objectives –To determine the impact on neonatal mortality of a targeted outreach and education program

51. Neonatal Mortality Trial Villages: (randomized to intervention arms or control) Intervention Arm: Monthly education and healthcare visits Screening for high risk families Targeted outreach program (2000 births) Control Arm Delayed introduction (2000 births) Note: Suggested structure

52. Naandi Trial: Timeline Decision whether in principle we wish to proceed (within 3 months) Study team selected to work out detailed timeline and program (6 months) Start surveys and trial in 2006