1 Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Seruminstitut, Copenhagen, Denmark.
2 International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
Peter Aaby, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark. E-mail: psb{at}sol.gtelecom.gw
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Abstract |
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Methods and Data We re-analysed an existing data set from Matlab, Bangladesh. During 19821985, measles immunization was used from 9 months of age in half of the study area, and the other half was used as an unvaccinated control area. A total of 8134 immunized children had been matched by age with 8134 non-immunized children; 578 children died during the follow-up period of 3 years. Using these data, we calculated the vaccine effectiveness against death (VED) controlling for significant factors in a matched analysis. In the absence of measles, there should be no difference in mortality between immunized, uninfected children and non-immunized, uninfected children. We therefore calculated VED after the exclusion of all measles cases in the survival analysis. To assess the long-term effects of measles, we compared survival of unvaccinated children after measles disease with children who had not yet contracted measles.
Results Prior to immunization and again after 1985, childhood mortality rates were 10% lower in the area that had received immunization. Though measles deaths only constituted 12.4% of the non-accidental deaths, the VED controlling for significant factors was 49% (95% CI: 3858%). The vaccine was protective against measles death throughout the study, but it also had a marked effect against other causes of death, particularly diarrhoea and oedema. This effect may have been particularly strong in the first 6 months after immunization (VED = 74, 95% CI: 5784%). The VED was only reduced from 49% to 43% (95% CI: 3154%) when measles cases were excluded in the survival analysis. Controlling for background factors, mortality among measles cases was increased during the acute phase (045 days) (mortality ratio [MR] = 17.35, 95% CI: 11.925.3) and in the following 1 months (MR = 2.35, 95% CI: 0.955.84). However, post-measles cases had significantly lower mortality than uninfected, non-immunized children in the following 9 months (MR = 0.40, 95% CI: 0.16, 0.98).
Conclusions The non-randomized character of the original study and the possibility of uncontrolled confounding between the two areas prevent a precise estimate of the effectiveness of measles vaccine, but it is likely to have been substantial. Though there may have been some underreporting of cases of measles, the prevention of measles infection can only explain a limited part of the observed impact of measles immunization in Bangladesh. Furthermore, mortality may be reduced after the acute phase of measles infection. The observations from Bangladesh are consistent with recent research from Africa suggesting that measles immunization may have non-specific beneficial effects on survival.
Accepted 23 July 2002
Community studies from India and Bangladesh have reported relatively low case fatality rates (CFR) in measles disease1 and measles control has not been a priority in this part of the world.2 For example, in Matlab, Bangladesh, the CFR has been 13% in different studies,35 and measles deaths only represented a small proportion of all deaths.6 Nonetheless, two studies from Matlab have estimated that measles immunization reduced mortality against all causes by 36% and 46%, respectively.6,7 Similarly, investigations from Guinea-Bissau,810 Senegal,11,12 Benin,13 Zaire,14 Nigeria,15 Burundi,16 and Haiti,17 have reported much greater reductions in mortality than should be expected.18 It has therefore been speculated that measles disease was associated with post-measles excess mortality that would also be prevented by measles vaccination.5,6,8
Few studies have analysed the long-term survival impact of measles disease. Earlier studies from West Africa8,19 reported increased mortality among post-measles cases. However, these studies did not control for potential confounding factors, particularly measles vaccination status, and they compared survival of children after measles infection with children who had been immunized against measles.18 Recent studies from Guinea-Bissau,20 Senegal,21 Burundi16 and Ghana22 have found no difference or lower mortality for post-measles cases when the immunization status of controls was taken into consideration. If the prevention of acute and post-measles mortality does not explain the reduction in mortality associated with measles immunization, measles immunization may have non-specific beneficial effects.18
The Matlab field station of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), has maintained a demographic and health surveillance system since 1966 in the Matlab rural district. The worlds largest study on the impact of measles immunization was conducted in this area between 1982 and 19857 when the population under surveillance counted 190 000 individuals (1985).23 Since the understanding of the impact of measles immunization and the long-term effects of measles infection may have major implications for disease control programmes, we requested permission to re-analyse the existing data set to examine to what extent the prevention of measles infection may explain the impact of measles vaccination.
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Subject and Methods |
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Design of original study and modifications
The data set has been described in detail elsewhere.7 The introduction of measles vaccine in the Matlab area was phased; children aged 960 months living in two of the four sub-areas (blocks A and C) were offered Schwarz measles vaccine in March 1982 and onwards, the coverage reaching more than 80% in 19831984.6 In November 1985, measles vaccination was extended to blocks B and D and reached a similar coverage. In blocks A and C, a total of 9133 children between 9 and 60 months of age were immunized against measles during the period of the study. These vaccinated children were matched individually with non-immunized children from blocks B and D with date of birth (+/ 1 month) as the only matching criterion.7 Unvaccinated children were alive at the day of immunization of the matching case. Unvaccinated children from blocks B and D could only be found for 8135 of the immunized children. Only eight children in B and D had been immunized, and thus no real selection was involved among the unvaccinated children. The 998 vaccinated children for whom a matched child could not be found were not included in the analysis.
The present analysis is restricted by the available data previously presented7 and we are therefore subject to the same potential confounding factors.7second pair with this child was excluded and our analysis has therefore 8134 pairs instead of 8135 pairs.
Definitions and concepts
The identification of measles cases depended on the parents perception. This had been found to be adequate when the study started.4 Measles onset has been defined by the date of the rash. In the present study, deaths within 45 days of the rash have been ascribed to measles unless they were due to accidents. Long-term effects of measles refer to factors affecting mortality after the acute phase of infection and could be due to persistent measles virus infection as occurs in some individuals, permanent damage like blindness, or changes in susceptibility to other infections due to nutritional or immunological changes initiated during measles infection.
Measles surveillance
Surveillance of measles disease in the study area has been conducted by two different and partly overlapping systems. Firstly, an epidemiological study of all measles cases was initiated in October 1979 and continued until December 1984. Data from the first year of this study have been analysed previously.4 Cases of measles were reported to field assistants of the Demographic Surveillance System (DSS) through community health workers who visited all households in the study area every second week. Field assistants had been trained to fill in questionnaires containing simple information on onset of measles rash and symptoms.4 Cases were defined on the basis of the simultaneous presence of rash and fever. Initially, a random sample of 108 cases were examined by a medical doctor and verified in all but two cases.
Secondly, community health workers visited all households in the study area twice a month to provide free health services and maintain records of demographic events, immunizations, and morbidity episodes, including measles, for children <5 years of age.5 The two systems were not cross-referenced at the time, and they sometimes differed with respect to date of measles disease. We have assumed the first date to be correct. For the period when both systems were in operation, the majority of cases were reported by the morbidity surveillance system.
Causes of death and death from measles
Information on causes of death was obtained from the DSS where field supervisors complete a death form based on information from parents. In previous studies of measles in Bangladesh, deaths within either 45 days or 3 months of a measles rash have been considered to be due to measles.4,5 However, death reports in the DSS have not necessarily followed these definitions. Deaths classified as measles that occurred more than 45 days after measles disease (N = 7) have been reclassified as other causes. Likewise deaths for which there was no report of measles disease (N = 10) have been reclassified as other causes since these deaths are either misclassified or correspond to surviving measles cases which have remained unreported.
Statistical methods
The main analyses are based on the original paired design; 16 268 children were included, 8431 boys and 7837 girls. Boys were not paired more frequently with boys than with girls or vice versa (2 = 3.24,1 d.f.; P = 0.072). Using a proportional hazards model for paired survival data, the mortality ratio (MR) between vaccinated and unvaccinated children is the ratio of the number of pairs in which the vaccinated child dies first to the number of pairs in which the unvaccinated child dies first. The standard error and the test statistic for no effect can also be calculated from the two numbers.24
The data have been presented previously in an unmatched analysis7 and statistical efficiency can be improved by considering the matching variable, month and year of birth, as a confounding factor25 in a proportional hazards model with age as the time scale. Follow-up time after the first death or withdrawal of a pair can be included in the analysis while still only comparing children of the same age. By this procedure, the data can be analysed unpaired, but still controlling for month and year of birth and age. Immunized children were evaluated from age at 1 October 1982, or from the age at vaccination, if occurring later (left truncation), and until death, moving, or 31 October 1985, respectively (right censoring). The unvaccinated childrens date of entry is set from their matched vaccinated childs date of entry. Using similar catagorizations, the background factors used in previous analyses7 were examined for confounding as time-independent variables (e.g. sex, number of siblings, maternal education, size of dwelling) or as time-dependent variables (e.g. measles, season). In these analyses, 635 children were excluded due to missing information regarding number of siblings, maternal education, or size of dwelling.
The analyses of measles incidence and acute measles mortality were limited to cases occurring from 1 October 1982, and after entry into the study. Within the unvaccinated areas (B + D), the age-adjusted mortality of children who contracted measles during the study was compared with that of all uninfected, unvaccinated children using an unmatched multivariate proportional hazards model with age as the underlying time. In this analysis children who had measles before the study were excluded. Children with measles were included in the measles group from the day of the rash. Uninfected children were included in this analysis from the day of entry into the study and were censored when they got measles, moved, or died, or on 31 October 1985, whichever came first.
Survival information for individuals in the vaccination study was available until December 1991 and this information has been used to compare mortality after the measles vaccination had been introduced in the previously unvaccinated area.
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Results |
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Measles prior to immunization or matching was reported for similar numbers of individuals in both groups (Table 2). During the study (Figure 1
), vaccine effectiveness against measles disease was 93.7% (95% CI: 91.895.1%) in a paired analysis. The cumulative incidence of reported measles was 25.3% (95% CI: 22.428.2%) between 9 and 48 months of age for unvaccinated children in blocks B and D, and 3.9% had had measles prior to entry at 9 months of age. The incidence among immunized children was 2.3% (95% CI: 0.75.7%). Measles accounted for 7.4% of all deaths (43/578) and constituted 12.4% of the non-accidental deaths in the non-immunized area (Table 3
).
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Figure 2 indicates the number of deaths over time in the two groups. During the first year, there were 60 immunized and 90 non-immunized deaths (VED = 33.3%, 95% CI: 7.651.9%). A marked excess of deaths was noted in the second year (68 immunized versus 178 non-immunized deaths) when epidemic outbreaks of shigella dysentery and measles occurred in the community (VED = 61.8%, 95% CI: 49.571.1%). In the last 13 months from October 1984 to October 1985, 69 immunized and 89 non-immunized children died (VED = 22.5% (95% CI: 6.2%, 43.4%).
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Studies from a later period in Matlab26 have suggested that the validity of measles diagnoses is lower among infants (53%) than among children aged 14 years (88%). Even though this may not apply to the period under study, we conducted a separate, paired analysis in which reported cases among infants were not taken into consideration. With 142 deaths among vaccinated and 247 deaths among unvaccinated children, VED was still 43% (95% CI: 2953%).
Vaccine effectiveness against death after immunization of previous measles cases
There were 136 pairs in which both had had measles prior to immunization or matching. Six of the 136 non-immunized children died a non-accidental death, whereas none of the immunized children died while both children in a pair were under observation (P < 0.05). In an unpaired, adjusted analysis including 924 immunized (13 died) and 891 non-immunized children (27 died) who had measles prior to entry into the study, VED was 55% (95% CI: 1077%).
Post-measles mortality
High post-measles mortality has been suggested as a possible explanation for the marked effect of measles immunization.58 Data from the present study suggested rather the opposite; among measles cases occurring during the study and surviving the first 3 months, there were only 4 deaths compared with 11 deaths among their immunized, paired controls (MR = 0.36, 95% CI: 0.121.14, exact two-sided P = 0.118).
In the two non-immunized blocks B and D, we therefore compared post-measles non-accidental mortality of the 1133 children who had measles during the study period (Table 2) with the mortality of all the 8134 children who had not yet had measles. The CFR within 45 days of measles disease was 3.6% (40/1120) and 4.0% (45/1120) within 3 months. Controlled for age, sex, number of siblings, maternal education, and housing area, measles cases had higher mortality during the first 45 days after measles and even in the following 1
months (Table 6
) than children who had not yet had measles. However, in the following 9 months, the measles cases had significantly lower mortality than the children who had not yet had measles (MR = 0.40, 95% CI: 0.160.98).
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Discussion |
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It is essential that these tendencies are not the result of methodological flaws. None of the studies comparing immunized and non-immunized children have been double-blind placebo studies, nor could they have been. Authors have therefore tried to control for potential confounding factors and selection bias in different ways.18 The Matlab study may be the most satisfactory because it compared the effect of introducing measles immunization in one of two areas which had similar mortality levels prior to the intervention, and it is clearly the largest of the studies.18 It is important that its potential limitations are considered.
Limitations of the Matlab study
Comparability of the two areas
Prior to immunization, there was only a small difference of 310% in mortality of 14 year old children and no difference in the number of reported measles cases in the two populations being compared. There was a slightly bigger difference of 1015% in the years after the introduction of vaccine in B and D (Table 1) but the vaccination programme was somewhat less effective in B and D since measles continued to be more frequent in B and D (Table 2
). The BCG coverage was also lower in B + D and we have found BCG to be associated with reduced mortality.27 The likelihood of the two areas being relatively similar was strengthened by the fact that there was no difference in mortality between the two cohorts after the introduction of immunization in the control area. Likewise, it mitigates against an inherently higher mortality in the unvaccinated area that there was no difference between vaccinated and unvaccinated children 2 years after vaccination (Table 5
), and that unvaccinated children who had survived measles tended to have lower mortality than their matched vaccinated control.
Localized epidemics not related to measles could have had an impact on the area-to-area comparison, for example, the shigellosis epidemic (Figure 2). What precise role these epidemics may have played is impossible to assess as there is no incidence data by area. Some of the effect during the second year of the study can probably be ascribed to the shigellosis epidemic. However, it should be noted that measles vaccinations were associated with beneficial effects in all three years and there was a particularly strong effect during the first 6 months after vaccination. It would not be possible to explain this pattern with reference to localized epidemics.
Differences in compliance
Since the children immunized in areas A and C were a compliant group accepting immunization, whereas controls from areas B and D were unselected, a systematic bias cannot be totally excluded. However, acceptance for all children <5 years of age was high in areas A and C, with 82% of the children reaching 9 months being vaccinated.7 In a previous analysis including the 18% non-immunized children in areas A and C, the difference between A + C and B + D only changed from 46% to 40%.7 Furthermore, adjustment for risk factors for child mortality did not lead to any modification of the VED. It is therefore unlikely that a selection bias is a major cause of the observed difference in mortality between immunized and non-immunized children from blocks A + C and B + D, respectively.
Reporting of measles infection
The measles surveillance system was not perfect. With a cumulative incidence of 28.2% before 4 years of age, measles infection may have been underreported. There is no previous study of cumulative incidence in a non-immunized population in the Matlab area with which to compare. However, in a previous study3 of a major epidemic in the pre-vaccination period, the age-specific annual attack rates suggested that 50% would have had measles between 4 and 5 years of age. In the present study, there had been a strong epidemic just before the vaccinations were initiated6 and there was therefore very little measles during the first year of the study (Figure 1). The high immunization coverage in Blocks A and C may also have contributed to herd immunity and lower incidence in Blocks B and D. The number of measles deaths among children not reported to have had measles compared with the number of measles deaths among known cases suggests that there may have been 23% (10/43) more cases not detected by the surveillance system. Given the degree of herd immunity when the study started, a 2025% underreporting of measles cases may be a fair estimate.
Exclusion of the known cases of measles explained 12% ([49% 43%]/49%) of the reduction in mortality associated with measles immunization. Adding 2550% more cases would presumably only increase the proportion of vaccine efficacy explained to 1518%. There may also have been some invalid reports of measles cases and the fact that measles vaccination of children with previous measles infection reduced mortality is likely to raise such concerns. However, misreporting is unlikely to have been substantial. A subsequent study from the immunization era, when knowledge of measles would have been less, indicated an 88% validity of reported measles cases aged 14 years.26 Major misreporting seems unlikely given the mortality profile of post-measles cases; were many case reports false, the decline in mortality among post measles cases would be even more extreme.
Potential impact of study limitations
We have pointed out a number of limitations of the data collected and of differences between the areas; for example, we found differences in coverage for maternal tetanus immunization. The possibility that uncontrolled differences exist questions the absolute estimate of VED, but hardly the foundation for the study. Assuming for example a 15% effect of differences in compliance and mortality levels as may have existed prior to 1982 (Table 1), measles immunized children would still have a reduction in mortality considerably larger than the proportion of deaths due to measles infection (12%) in the period 19821985. Given that measles cases had lower mortality after the acute phase, the 12% would actually overestimate the proportion of deaths due to measles.
Had incomplete and inaccurate detection of measles cases been a major factor behind the strong effect of measles immunization on non-measles mortality, the VED should have been much lower in the first year of the study when there was little measles (Figure 1) due to the strong epidemic in 1982. There was no such effect, the VED being as strong in 19821983 as in later years with a high incidence of measles (data not shown).
Furthermore, it should be noted that even if further uncontrolled differences exist between the two areas, these would not invalidate the conclusions that the impact of measles immunization6,7 has little to do with the specific prevention of measles, that the non-specific impact of immunization was temporary, and that post-measles cases had a reduction in mortality compared with uninfected children in blocks B and D where children had not been immunized. These tendencies correspond closely to observations made in West Africa.18,20,21
Post-measles mortality: selection bias or immune activation?
In contrast to previous hypotheses,5,6,8 mortality was increased only in the second and third months after measles, mainly due to diarrhoea. After the third month, post-measles cases had significantly lower mortality than uninfected individuals. This is contrary to usual assumptions1,6 about the impact of measles disease on long-term mortality. A small underreporting of measles cases as may well have existed in the present study would have contributed minimally to exaggerate the mortality level in the large group of non-immunized, uninfected children since less than half of the deaths among measles cases were excess deaths (Table 6). Furthermore, underreporting would not affect the time-dependent mortality profile of previous measles cases and it seems therefore unlikely it would change the conclusion that previous measles cases may have lower mortality after measles. Better post-measles survival could be due to selection of stronger individuals among measles survivors. In both Bangladesh and West Africa,4,28 intensive exposure as a secondary case is a major risk factor for acute measles mortality and if selection was the main reason, post-measles mortality should be particularly low among secondary cases. In studies from Senegal and Guinea-Bissau, index cases of measles had both lower acute and significantly lower post-measles mortality than secondary cases (ref. 21, unpublished data). As low post-measles mortality follows low acute mortality, selection of stronger individuals is not the best explanation. Instead a better survival after measles infection could be due to a beneficial immune activation as suggested for measles immunization.18,29
Studies from Guinea-Bissau20 and Senegal21 have shown reduced mortality among post-measles cases and larger than expected mortality reduction after measles immunization.18,27 The reduction in mortality has been temporary, being strongest in the first period after immunization18 or infection. The Bangladesh study was consistent with previous studies from Bissau, Senegal, and Burundi, showing that exclusion of measles disease had very little impact on the estimated VED.18,27 Data do not support a disease-specific interpretation. The simplest explanation would be that measles vaccination and measles disease stimulate the immune system, providing protection against other infections. Though both measles and measles immunization are associated with immune suppression in the acute phase, there is growing evidence that in the longer term they stimulate a Th1 cytokine profile.2932 For example, measles immunization stimulates interferon production, providing protection against subsequent challenge with vaccinia virus.30 In animal studies a Th1 profile induced by live-vaccine leads to mild infection whereas a Th2 profile due to inactivated vaccination leads to severe disease when challenged with respiratory syncitial virus or influenza.3335
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Conclusion |
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The suggestion that measles disease could lead to immune stimulation reducing mortality in the post-acute phase may raise concerns about natural infection and unnatural immunizations. However, measles has a high acute mortality and there is no doubt that measles immunization has a more beneficial effect on survival than measles disease18 as it can be distributed to everybody at an earlier and specific age and with less risk of adverse effects. Nevertheless, there may be reasons to question the culture of eradication which assumes that vaccines have only specific effects and that they can be withdrawn later to save production and distribution costs once diseases such as smallpox, measles, and polio have been eradicated. If measles vaccine does have non-specific beneficial effects, child mortality may increase again should measles vaccine be withdrawn after the eradication of measles.
KEY MESSAGES
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Acknowledgments |
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References |
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