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Appendix C
The Burden of Disease Resulting from Diarrhea

Various publications contain (or provide information for developing) estimates of the total burden of illness (deaths and episodes) that results from all diarrheal disease. Few publications, if any, however, provide the data necessary for estimating the global morbidity and mortality burdens that arise from specific pathogens. To arrive at such estimates in the form required for comparing diseases and vaccine benefits, the committee adopted the approach described below.

On the basis of published data and field experience, a group of persons familiar with diarrheal diseases in developing countries estimated the number of diarrheal episodes per individual in various age groups for the four major regions where developing countries predominate. These estimates are shown in Table C.1.

Applying these incidence rates to the relevant population estimates (Table C.2, from Chapter 4) yields, for the various regions, the estimated number of diarrheal episodes in the age groups shown in Table C.3.

The estimated distribution of diarrheal episodes by severity within age groups is shown in Table C.4.

Combining the estimates in Tables C.3 and C.4 yields the estimates of the burden of diarrheal disease distributed by age and severity shown in Table C.5.

An estimated 10.4 million infant deaths (under 1 year of age) and 4.4 million child deaths (1 to 4 years of age) occur annually in the developing world (United Nations Children’s Fund, 1983). Of deaths in the 1 to 4 years age group, one-third probably occur in the second year of life. Hence, the total number of deaths in children under 2 years of age is probably about 11.9 million, and in the 2 to 4 years age group—2.9 million. Since about 25 percent of infant and child deaths in developing countries are due to diarrhea, this means there are 2.97 million diarrheal deaths in children under 2 years of age and 0.7 million in the 2 to 4 years age group (i.e., a total of about 3.7

The committee gratefully acknowledges the advice and assistance of R.E.Black, R.Glass, M.M.Levine, R.B.Sack, B.Stoll, and R.G. Wyatt. The committee assumes full responsibility for all judgments and assumptions.



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix C The Burden of Disease Resulting from Diarrhea Various publications contain (or provide information for developing) estimates of the total burden of illness (deaths and episodes) that results from all diarrheal disease. Few publications, if any, however, provide the data necessary for estimating the global morbidity and mortality burdens that arise from specific pathogens. To arrive at such estimates in the form required for comparing diseases and vaccine benefits, the committee adopted the approach described below. On the basis of published data and field experience, a group of persons familiar with diarrheal diseases in developing countries estimated the number of diarrheal episodes per individual in various age groups for the four major regions where developing countries predominate. These estimates are shown in Table C.1. Applying these incidence rates to the relevant population estimates (Table C.2, from Chapter 4) yields, for the various regions, the estimated number of diarrheal episodes in the age groups shown in Table C.3. The estimated distribution of diarrheal episodes by severity within age groups is shown in Table C.4. Combining the estimates in Tables C.3 and C.4 yields the estimates of the burden of diarrheal disease distributed by age and severity shown in Table C.5. An estimated 10.4 million infant deaths (under 1 year of age) and 4.4 million child deaths (1 to 4 years of age) occur annually in the developing world (United Nations Children’s Fund, 1983). Of deaths in the 1 to 4 years age group, one-third probably occur in the second year of life. Hence, the total number of deaths in children under 2 years of age is probably about 11.9 million, and in the 2 to 4 years age group—2.9 million. Since about 25 percent of infant and child deaths in developing countries are due to diarrhea, this means there are 2.97 million diarrheal deaths in children under 2 years of age and 0.7 million in the 2 to 4 years age group (i.e., a total of about 3.7 The committee gratefully acknowledges the advice and assistance of R.E.Black, R.Glass, M.M.Levine, R.B.Sack, B.Stoll, and R.G. Wyatt. The committee assumes full responsibility for all judgments and assumptions.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE C.1 Annual Incidence of Diarrheal Diseasea (episodes per individual per year)   Age Group (years) Region Under 2b 2–4b Under 5 5–14 15–59 60 and Over Africa 7.0 3.0 5 1 0.3 0.3 Asia 5.25 1.5 3 0.5 0.2 0.2 Latin America 6.0 2.0 4 1 0.25 0.25 Oceania 3.5 1.0 2 0.5 0.2 0.2 More developed countries 1–2 0.5 0.5 0.1 0.1 0.1 aModified from Programme for Control of Diarrhoeal Diseases (1984). bUnder 5 years episodes are estimated to be distributed 0.7:0.3 between under 2 years and 2 to 4 years age groups. TABLE C.2 Estimated 1984 Population for Regions Where Developing Countries Predominatea (thousands)   Age Group (years)   Region Under 5 5–14 15–59 60 and Over Total Africa 96,802 141,459 265,451 27,288 531,000 Asia 343,700 666,402 1,472,242 179,656 2,662,000 Latin America 57,235 100,220 214,415 25,130 397,000 Oceania 822 1,285 2,620 273 5,000 Total 498,559 909,366 1,954,728 232,347 3,595,000 aDerived by applying the proportions of the 1980 population in various age groups to the mid-1984 population projections. See Chapter 4, Table 4.4, for the countries included. million deaths). This total reasonably agrees with the estimated 3.5 million derived by the foregoing approach. Tables C.6 and C.7 show the estimated distribution of the diarrheal disease burden by etiology. These estimates were derived from expert judgment after a review of available publications and from personal field experience. Only those etiologies for which vaccine prospects are reasonably promising were considered. Salmonella was subsequently dropped from consideration.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE C.3 Estimated Annual Number of Diarrheal Episodes for Various Regions (thousands)   Age Group (years) Region Under 5 5–14 15–59 60 and Over Africa 484,010 141,459 79,635 8,186 Asia 1,031,100 333,201 294,448 35,931 Latin America 228,940 100,220 53,604 6,283 Oceania 1,644 643 524 55 Total 1,745,694 575,523 428,211 50,455 TABLE C.4 Estimated Proportion of Diarrheal Episodes by Severity and Consequences, Assuming Current Levels of Interventiona   Age Group (years) Category Under 5 5–14 15–59 60 and Over A (mild) 0.9 0.99 0.99 0.95 B (moderate) 0.08 0.008 0.008 0.04 C (severe) 0.02 0.002 0.002 0.01 H (death) 0.002 0.0004 0.0003 0.0005 aThese values are estimated average proportions for all diarrheal etiologies. The number of episodes, which was ultimately derived by the methods presented here, reflects that for some pathogens severe cases are relatively more common than for all diarrheas aggregated (see Table C.9). TABLE C.5 Morbidity Episodes and Mortality Arising from Diarrheal Disease   Age Group (years) Category Under 5 5–14 15–59 60 and Over A (mild) 1,571,125 569,768 423,929 47,932 B (moderate) 139,656 4,604 3,426 2,018 C (severe) 34,914 1,151 856 505 H (death) 3,491 230 128 25

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE C.6 Distribution of Mild and Moderate Diarrheal Episodes by Etiology (percent)a   Age Group (years) Pathogen Under 2 2–4 Under 5 5–14 15–59 60 and Over E. coli (enterotoxigenic) 25 20 22.5 25 20 20 Rotavirus 10 5 7 1 1 1 Salmonella 2 1 1 1 1 2 Shigella 5 10 8 10 10 15 aPercentages do not total 100 because some pathogens that cause diarrhea are not included due to poor vaccine prospects. TABLE C.7 Distribution of Severe Diarrheal Episodes and Deaths by Etiology (percent)a   Age Group (years) Pathogen Under 2 2–4 Under 5 5–14 15–59 60 and Over E. coli (enterotoxigenic) 20 20 20 20 20 20 Rotavirus 30 10 25 0 0 0 Salmonella 2 1 1 1 1 1 Shigella 10 20 15 20 20 25 aPercentages do not total 100 because some pathogens that cause diarrhea are not included due to poor vaccine prospects. Combining estimates in Tables C.5, C.6, and C.7 yields (for enterotoxigenic E. coli, rotavirus, and shigella) distributions of illness burden shown in Tables C.8, C.9, and C.10, respectively. These estimates are used in the calculation of total disease burden values (see Chapter 4).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE C.8 Disease Burden: Enterotoxigenic E. coli   Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Mild diarrhea 353,503,000 4 142,442,000 4 84,786,000 4 9,586,000 4 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Moderately severe diarrhea 31,423,000 5 1,151,000 5 685,000 5 404,000 5 C Severe pain, severe short-term impairment, or hospitalization Severe diarrhea 6,983,000 6 230,000 6 171,000 6 101,000 6 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   n.a.   n.a.   n.a.   n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   698,000 n.a. 46,000 n.a. 26,000 n.a. 5,000 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE C.9 Disease Burden: Rotavirus   Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Mild diarrhea 109,979,000 6 5,698,000 4 4,239,000 4 479,000 4 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Moderately severe diarrhea 9,776,000 6 46,000 6 34,300 5 20,200 6 C Severe pain, severe short-term impairment, or hospitalization Severe diarrhea 8,729,000 7   7   7   7 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   n.a.   n.a.   n.a.   n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   873,000 n.a.   n.a.   n.a.   n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE C.10 Disease Burden: Shigella   Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Mild diarrhea 125,690,000 5 56,977,000 5 42,393,000 5 7,190,000 5 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Moderately severe diarrhea 11,172,000 7 460,000 7 342,000 7 303,000 7 C Severe pain, severe short-term impairment, or hospitalization Severe diarrhea 5,237,000 11 230,000 10 171,000 10 126,000 10 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   52,370 n.a.   n.a.   n.a.   n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   576,000 n.a. 46,000 n.a. 26,000 n.a. 6,000 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries MODIFICATION OF DISEASE BURDENS BY APPLICATION OF CURRENTLY AVAILABLE REMEDIES The burdens of illness shown in Tables C.8, C.9, and C.10 are those thought to occur with the present level of intervention. The committee examined how these burdens might be altered by increased application of currently available therapeutic intervention. Among the interventions considered to be of potential major impact were general access to health care and, particularly, the use of oral rehydration therapy (ORT). The committee felt that by the time vaccines became available, the burden of diarrheal illness from enterotoxigenic E. coli and rotavirus might be reduced by increased use of ORT. To assess the effect of therapeutic intervention on the vaccine candidate priority rankings, the committee calculated the potential health benefits of vaccines for enterotoxigenic E. coli. and rotavirus under two assumptions. The first assumption did not change the current level of intervention. The second one increased ORT (and general access to health care) and resulted in a reduction of deaths from these diseases by 50 percent of current levels. The disease burdens assuming increased ORT use are shown in Tables C.11 (enterotoxigenic E. coli) and C.12 (rotavirus). For shigellosis, the committee believed that ORT would not have major influence on the disease consequences but that increased use of antibiotics could potentially reduce the mortality resulting from this disease. Realizing this benefit may be impeded by the increasing prevalence of antibiotic-resistant strains of shigella; the consequent need for accurate diagnosis/resistance testing, which may not be available; and in some cases, the need for more expensive antibiotics, which may not be affordable to developing countries. If desired, the effect of wider antibiotic use on the shigellosis disease burden and the ultimate rankings of vaccine benefits can be tested in a manner similar to that used for E. coli and rotavirus. SECOND-ORDER EFFECTS OF DISEASES The committee and subgroups had much discussion on the interaction of diseases causing mortality, and whether or how to quantitatively incorporate these interactions into the calculation of potential vaccine benefits. A notable example is the enhanced mortality among children with diarrhea and measles. Few attempts have been made to evaluate quantitatively this type of interaction (e.g., Feachem and Koblinsky, 1983). The committee developed a questionnaire to evaluate possible second-order effects of reducing diseases, including the “replacement” of one cause of mortality by another. For diarrheal diseases, the committee judged that the available data, in general, were not precise and could not suggest the possible effects of disease interactions on a vaccine’s potential health benefit. The capacity of all diarrheal disease to debilitate patients and enhance

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE C.11 Disease Burden: Enterotoxigenic E.coli, Assuming Increased Use of Oral Rehydration Therapy   Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Mild diarrhea 353,503,000 4 142,442,000 4 84,786,000 4 9,586,000 4 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Moderately severe diarrhea 31,423,000 5 1,151,000 5 685,000 5 404,000 5 C Severe pain, severe short-term impairment, or hospitalization Severe diarrhea 6,983,000 6 230,000 6 171,000 6 101,000 6 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   n.a.   n.a.   n.a.   n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   349,000 n.a. 23,000 n.a. 13,000 n.a. 2,500 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE C.12 Disease Burden: Rotavirus, Assuming Increased Use of Oral Rehydration Therapy   Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Mild diarrhea 109,979,000 6 5,698,000 4 4,239,000 4 479,000 4 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Moderately severe diarrhea 9,776,000 5.5 46,000 5.5 34,300 5 20,200 5.5 C Severe pain, severe short term impairment, or hospitalization Severe diarrhea 8,729,000 7   7   7   7 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)   n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   n.a.   n.a.   n.a.   n.a. F Total impairment   n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility   n.a.   n.a.   n.a.   n.a. H Death   436,500 n.a.   n.a.   n.a.   n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries their susceptibility to other diseases should be weighed in the final choice of priorities. UNCERTAINTY IN THE DISEASE BURDEN ESTIMATES The estimated number of diarrheal episodes caused by specific pathogens (attempted above) is based largely on expert judgments, and committee advisers had different opinions on certain estimates. For example, some individuals disagreed with the majority opinion on the numbers of diarrheal episodes per individual in Asia and Latin America, under 5 years, believing that these numbers should be reversed. Such estimate modifications and their effect on the ultimate ranking can be evaluated. Preliminary calculations of the example cited above suggest an increase in disease burdens of less than 20 percent. The effects on vaccine benefits would be proportional, and the effects on the rankings easily calculated. REFERENCES Feachem, R.G., and M.A.Koblinsky. 1983. Interventions for the control of diarrhoeal diseases among children: Measles immunization. Bull. WHO 61:641–652. Programme for Control of Diarrhoeal Diseases. 1984. Interim Program Report. WHO/CDD/84.10. Geneva: World Health Organization. United Nations Children’s Fund. 1983. Statistics. Pp. 174–197 in The State of the World’s Children 1984. New York: Oxford University Press.