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OCR for page 149
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
Appendix B
The Burden of Disease Resulting from Acute Respiratory Illness
This appendix reports estimates of the burden of illness (particularly mortality) associated with three vaccine development candidates that cause acute respiratory illness (ARI) in children in developing countries. These pathogens are respiratory syncytial virus (RSV), the parainfluenza viruses, H. influenzae type b, and S. pneumoniae.
Table B.1 shows the population distribution in regions where developing countries predominate. Table B.2 shows the estimated mortality resulting from acute respiratory infections. Application of the rates in Table B.2 to the population data in Table B.1 yields the ARI mortality distribution shown in Table B.3.
The number of ARI deaths estimated by this method accounts for about 13.5 percent of the 10.4 million infant deaths (under 1 year of age) and 22 percent of the 4.4 million child deaths (1 to 4 years of age) estimated to occur in developing countries in 1984 (United Nations Children’s Fund, 1983). Combined, they represent about 18 percent of all deaths in the under 5 years age group.
Bulla and Hitze (1978) reported that about 10 percent of all ARI deaths were attributable to influenza. Of the remainder, most were viral and bacterial pneumonias (80 percent), and the balance involved acute upper respiratory tract infections. Table B.4 shows the estimated total noninfluenza ARI mortality for children.
Little information from developing countries is available on the etiology of lower respiratory tract infections or their impact on mortality rates. Even less is available on serious or fatal upper respiratory tract infections. One of the difficulties in obtaining data on the etiology of lower respiratory tract infections is that ethical requirements dictate that lung aspiration (to identify pathogens) is performed only for medical indications (e.g., to aid in selection of appropriate treatment of patients with selected bacterial pneumonia). Accordingly, this procedure is not used routinely.
The committee gratefully acknowledges the advice and assistance of F.W.Denny, W.P.Glezen, and A.S.Monto. 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 B.1 Population Distribution in Regions Where Developing Countries Predominate (thousands)
Age Group (years)
Region
Under 1
1–4
Total Under 5
5–14
15–59
60 and Over
Africa
23,040
73,762
96,802
141,459
265,451
27,288
Asia
73,400
270,300
343,700
666,402
1,472,242
179,656
Latin America
12,736
44,499
57,235
100,220
214,415
25,130
Oceania
187
635
822
1,285
2,620
273
Total
109,363
389,196
498,559
909,366
1,954,728
232,347
TABLE B.2 Estimated Mortality in Developing Countries Due to Acute Respiratory Infections (deaths/100,000 population/yeara)
Age Group (years)
Region
Under 1
1–4
5–14
15–59b
60 and Over
Africa
1,500
500
20
—
150
Asia
1,200
200
20
—
150
Latin America
1,300
130
13
—
400
Oceania
200
10
1
—
100
aModified from Bulla and Hitze (1978). Rates in some categories are based on a small number of reporting countries.
bNot calculated.
Pio et al. (1985) reviewed the results of bacteriological studies on lung aspirates from children (birth to 8 years of age) in developing countries who had pneumonia and no previous antimicrobial treatment. About 55 percent of these aspirates were culture positive for bacteria. Of these, 22.5 percent contained S. pneumoniae, and 11.5 percent contained H. influenzae. Staphylococcus aureus (4.4 percent), mixed infections, or other bacteria accounted for the balance of positive cultures. These proportions may be underestimates because the appropriate lung lesion may not have been reached with the aspiration needle or because laboratory methods may have been inadequate. Lung aspirate sampling may overestimate the significance of bacterial pathogens because of the kinds of patients selected for testing (see above). However, it is not possible to estimate how much these considerations affect the accuracy of available data.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
TABLE B.3 Deaths due to Acute Respiratory Infections in Developing Countries (thousands)a
Age Group (years)
Region
Under 1
1–4
Total Under 5
5–14
Africa
345.6
368.810
714.41
28.3
Asia
880.8
540.6
1,421.4
133.3
Latin America
165.6
57.8
223.4
13.0
Oceania
0.374
0.064
0.44
0.0129
Total
1,392.4
967.3
2,359.7
174.6
aDerived by application of the rates shown in Table B.2 to the population estimates shown in Table B.1.
Few studies have been undertaken on viruses as a cause of lower respiratory tract infection or mortality in developing countries. Denny and Clyde (1983) reported on the isolation of viruses and mycoplasma from children with lower respiratory tract disease in the United States. No isolate was obtained in 74 percent of cases. Parainfluenza viruses were isolated in 9.4 percent of cases and RSV in 5.2 percent of cases. A variety of other viruses and Mycoplasma pneumoniae accounted for the balance of identified agents.
TABLE B.4 Annual Deaths from Acute Respiratory Infections Other than Influenza
Age Group (years)
Pathogen
Proportion of Deaths (percent)a
Under 5
5–14
H. influenzae
11.5
244,260
18,071
Parainfluenza viruses
5.5
116,820
8,643
Respiratory syncytial virus
7
148,680
11,000
S. pneumoniae
22.5
477,900
35,357
Totalb
2,124,000
157,140
aThese proportions are based on a very limited number of reports and assume that the distribution of deaths parallels the isolation of pathogens from individuals with lower respiratory tract infection.
bThe total includes deaths caused by other pathogens for which vaccine prospects are considered poor, or for which an etiologic agent is not yet identified.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
Berman et al. (1983) reported data on acute lower respiratory tract infections in children under 5 years of age attending ambulatory clinics in Colombia. A viral diagnosis was reported in 20 percent of cases: RSV was found in 9 percent and parainfluenza viruses in 2.1 percent. Serologic data reported by Monto and Johnson (1968) for three areas in Latin America suggest that the behavior and distribution of viral respiratory disease agents in the tropics are generally similar to those of the same agents in the temperate zones.
The data discussed above appear to be the best basis on which to estimate the disease burden proportion of noninfluenza ARI that can be attributed to the pathogens that are candidates for vaccine development. No direct information is available on the proportions of deaths due to the various pathogens incriminated in ARIs. To estimate deaths, it is therefore assumed that the proportion of deaths due to each agent parallels its isolation in lower respiratory tract illness/pneumonia cases. This assumed relationship is likely to be imprecise because certain agents, like respiratory syncytial virus, are more virulent than others, such as parainfluenza virus type 1.
The proportion of lower respiratory tract illness/pneumonia cases attributed to a particular pathogen sometimes differed between studies. In these instances, intermediate values have been used in the calculations if reported figures vary considerably. The resulting distribution of deaths due to noninfluenza ARI is assumed to be as follows: RSV, 7 percent; parainfluenza viruses, 5.5 percent; H. influenzae, 11.5 percent; and S. pneumoniae, 22.5 percent.
Table B.4 shows the results of combining the above assumptions with the estimates of annual noninfluenza ARI mortality.
To complete the disease burden estimates in the format required for the disease comparison method used in this report, it is necessary to estimate the number of disease episodes at various levels of severity. No specific information on the ratio of deaths to severe cases of ARI is available. However, the number of severe cases of parainfluenza and RSV disease can be calculated by presuming a case fatality rate of 10 percent for severe cases of these diseases. The relative distributions of less severe episodes are assumed to be the same as those estimated
TABLE B.5 Relative Case Frequenciesa
Category
H. influenzae
Parainfluenza Viruses
Respiratory Syncytial Virus
S. pneumoniae
Mild (A)
500
300
Moderate (B)
100
100
Severe (C)
7
10
10
7
Death (H)
1
1
1
1
aThese ratios are assumed from limited data (see text).
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
TABLE B.6 Disease Burden Estimates by Morbidity Category, Disease, and Age Group (years)
H. influenzae
Parainfluenza Viruses
Respiratory Syncytial Virus
S. pneumoniae
Morbidity Category
Under 5
5–14
Under 5
5–14
Under 5
5–14
Under 5
5–14
A
—
—
58,410,000
4,321,500
44,604,000
3,300,000
—
—
B
—
—
11,682,000
864,300
14,868,000
1,100,000
—
—
C
1,709,820
126,497
1,168,200
86,430
1,486,800
110,000
3,345,300
247,500
H
244,260
18,071
116,820
8,643
148,680
11,000
477,900
35,357
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
TABLE B.7 Disease Burden: Hemophilus influenzae—Respiratory Component
Under 5 Years
5–14 Years
15–59 Years
60 Years and Over
Morbidity Category
Description
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
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
C
Severe pain, severe short-term impairment, or hospitalization
1,709,820
7
126,497
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
244,260
n.a.
18,071
n.a.
n.a.
n.a.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
TABLE B.8 Disease Burden: Parainfluenza Viruses
Under 5 Years
5–14 Years
15–59 Years
60 Years and Over
Morbidity Category
Description
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
58,410,000
3
4,321,500
3
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
11,682,000
5
864,300
5
C
Severe pain, severe short-term impairment, or hospitalization
1,168,200
7
86,430
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
116,820
n.a.
8,643
n.a.
n.a.
n.a.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
TABLE B.9 Disease Burden: Respiratory Syncytial Virus
Under 5 Years
5–14 Years
15–59 Years
60 Years and Over
Morbidity Category
Description
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
44,604,000
3
3,300,000
3
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
14,868,000
5
1,100,000
5
C
Severe pain, severe short-term impairment, or hospitalization
1,486,800
7
110,000
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 resticting 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
148,680
n.a.
11,000
n.a.
n.a.
n.a.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
TABLE B.10 Disease Burden: S. Pneumoniae—Respiratory Component in Children
Under 5 Years
5–14 Years
15–59 Years
60 Years and Over
Morbidity Category
Description
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
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
C
Severe pain, severe short-term impairment, or hospitalization
3,345,300
247,500
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
477,900
n.a.
35,357
n.a.
n.a.
n.a.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries
for the diseases domestically (Institute of Medicine, 1985): for parainfluenza, 50 mild and 10 moderate episodes for each severe case, and for RSV, 30 mild and 10 moderate episodes for each severe case. In the absence of pathogen-specific data for developing countries, a case fatality rate (CFR) of 15 percent is assumed for H. influenzae and S. pneumoniae (based on CFRs for untreated and hospitalized ARIs; Pio et al., 1985). Hence, seven severe cases are presumed to occur for each death. All H. influenzae and S. pneumoniae episodes are assumed to be severe.
The relative case frequencies shown in Table B.5 are based on these assumptions. They were used to derive the disease burden distributions shown in Table B.6, and in Tables B.7, B.8, B.9, and B.10 for the individual pathogens.*
UNCERTAINTY IN THE DISEASE BURDEN ESTIMATES
Advisers to the committee expressed concerns about the limited knowledge from which the estimates described above are derived. Certain features of acute respiratory infections led the committee to conclude that the available data are probably not entirely reliable because of suspected bias.
For example, many children with pneumonia may not reach the hospital, and those who do may represent a skewed sample. How to adjust available data for suspected biases is not known; hence, the procedures described above represent the only practical approach to developing the disease burden estimates needed for the overall assessment.
REFERENCES
Berman, S., A.Duenas, A.Bedoya, V.Constain, S.Leon, I.Borrero, and J.Murphy. 1983. Acute lower respiratory tract illness in Cali, Colombia: A two-year ambulatory study. Pediatrics 71:210–218.
Bulla, A., and K.L.Hitze. 1978. Acute respiratory infections: a review. Bull. WHO 56:481–498.
Denny, F.W., and W.A.Clyde. 1983. Acute respiratory tract infections: An overview. Pediatr. Res. 17:1026–1029.
Institute of Medicine. 1985. New Vaccine Development: Establishing Priorities, Volume 1. Diseases of Importance in the United States. Washington, D.C.: National Academy Press.
Monto, A.S., and K.M.Johnson. 1968. Respiratory infections in the American tropics. Am. J.Trop. Med. Hyg. 17:867–874.
Pio, A., J.Leowski, and H.G.ten Dam. 1985. The magnitude of the problem of acute respiratory infections. Pp. 3–16 in Acute Respiratory Infections in Childhood, R.M.Douglas and E.Kerby-Eaton, eds. Adelaide, Aust.: University of Adelaide.
United Nations Children’s Fund. 1983. Statistics. Pp. 174–197 in The State of the World’s Children 1984. New York: Oxford University Press.
*
The disease burdens for disease caused by H. influenzae type b and S. pneumonia have also been computed separately in Appendixes D-3 and D-17.
Representative terms from entire chapter:
acute respiratory
