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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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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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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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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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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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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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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.
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