a Reference Center Hélio Frega, National Health Foundation, Ministry of Health, Brazil.
b National School of Public Health, Oswaldo Cruz Foundation (IMS/UERJ), Ministry of Health, Brazil and IMS/VERJ.
Reprint requests to: Claudio J Struchiner, av. Brasil 4365, Residencia Oficial 21045.900, Rio de Janeiro, RJ Brazil. E-mail: stru{at}procc.fiocruz.br
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Abstract |
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Methods A retrospective cohort study based on the cases of acute flaccid paralysis (AFP) reported to the Ministry of Health (MoH) was designed, with the objective of studying cases of VAPP in Brazil between 1989 and 1995. Clinical, laboratory and epidemiological data from 3656 acute flaccid paralysis (AFP) cases, 30 of them diagnosed as VAPP, were analysed.
Results An 8.88 risk ratio of VAPP (95% CI : 4.3718.03) was found when comparing individuals who received oral poliovirus vaccine (OPV) between 4 and 40 days before the onset of paralysis and individuals who did not receive the vaccine within this period. A risk of 1 case/2.39 million first doses and 1 case/13.03 million OPV doses administered was estimated for the general population.
Conclusions Cases of AFP who received OPV between 4 and 40 days before the onset of paralysis and had fever, a prodrome of gastrointestinal symptoms, history of first dose of OPV, isolation of vaccine poliovirus type 2, and young age deserve careful investigation, since they are at increased risk for the condition studied.
Keywords Vaccine, poliomyelitis, oral poliomyelitis vaccine, adverse effect
Accepted 2 February 2000
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Introduction |
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In Brazil and other countries most VAPP cases are due to type 2 and 3 strains.4 Although the reversal towards neurovirulence happens frequently in strains 2 and 3, recent studies have confirmed the isolation of type 1 poliovirus from samples from patients with VAPP, demonstrating the occurrence of mutations in this strain.5
Vaccine-associated paralytic poliomyelitis was observed soon after the introduction of attenuated poliovirus vaccines. In the US, between 19801994, it was demonstrated that the risk of VAPP was of approximately 1 case/2.4 million OPV doses; this has remained relatively constant since 1965. With regard to the first dose, it is estimated that there is one case of VAPP per 750 000 doses distributed.6 In individuals with immunodeficiency, a 7- to 21-fold higher risk is reported for first doses in comparison to subsequent ones.2
Until 1989 in Brazil, cases of acute flaccid paralysis (AFP) with (1) neurological sequellae compatible with poliomyelitis still present 60 days after the onset of paralysis, (2) isolation of vaccine poliovirus from stool samples and (3) a history of vaccination between 4 and 30 days before the onset of the paralysis were classified as VAPP. In 1990, the criteria were changed, excluding the history of vaccination (since contacts of vaccinees can develop VAPP), and determining that the isolation of vaccine poliovirus strains should be done from stool samples collected up to 14 days after the onset of paralysis.7
This study aimed to estimate the incidence of VAPP in infants and the risk of this condition in relation to the first dose and to the total number of doses of OPV administered, and to analyse VAPP cases in Brazil, comparing OPV recipients (exposed) with contacts of vaccinees (non-exposed). Predictive models were designed, based on a cohort of individuals with AFP, trying to identify possible risk factors for this condition.
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Methods |
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Study design, variables and biases
The study design proposed is a retrospective cohort of the AFP cases where the outcome observed is the occurrence of VAPP. The main exposure variable (exposed) was having received OPV between 4 and 40 days before the onset of AFP.8 All individuals who had not received the vaccine or who received it outside of this period were classified as non-exposed. The other independent variables analysed were: gender, fever, gastrointestinal (GI) and upper respiratory signs and/or symptoms, month of onset, extremit(y/ies) paralysed, number of OPV doses received before the paralysis (in the exposed individuals), type of vaccine poliovirus isolated and age in years.
Since the database analysed was a secondary source, it had some limitations, mainly related to the lack of information concerning some variables. As to the possibility of selection bias, given the underreporting of AFP, the likelihood of inclusion in this cohort is related to the quality of the epidemiological surveillance and not to the exposure or the disease. As to classification bias, since the classification criteria for VAPP are very strict, they could only lead to a smaller number of VAPP cases, probably randomly distributed between exposed and non-exposed, and to an underestimation of the effect.
Statistical analysis
The incidence of VAPP in infants, the risk of VAPP occurrence in relation to the first OPV dose and the total number of vaccine doses given, and the crude relative risk (RR) of VAPP in relation to exposure to OPV and other covariates were calculated.
The construction of a parsimonious multivariate model to study the determination of VAPP occurrence from the covariates observed was done using logistic regression.9 The adequacy of the regression models proposed was investigated using the diagnosis of deviance residuals.9,10 The logistic regression model allows the estimation of the odds ratio (OR) as a measure of association, which provides a good approximation of the relative risk in studies with rare outcomes like the present one.11
In the logistic regression models used in this study, the dichotomous dependent variable represents the occurrence of VAPP, while exposure to the vaccine is the independent main variable, also analysed dichotomously. The other independent variables included in the predictive model were categorical, with the exception of age, which was treated as a continuous variable. The option was made for building models including the main independent variable and two or three covariates, with the objective of obtaining more robust models and more accurate estimates. Later, the multivariate models were selected on the basis of the statistical tests, accuracy of the estimates found, and the biological plausibility of each model.
For each variable in the model the regression coefficient and its standard error, the exponential of the regression coefficient and its CI, and the deviance were calculated, as well as statistical significance tests to evaluate the adjustment of the models.9 For the association between age and the occurrence of VAPP, the generalized additive model (GAM)10 was also used. Figures containing the observed values and the probability predicted by the model for the occurrence or non-occurrence of VAPP were used to evaluate the predictive models chosen.
The statistical analyses considered 95% CI and a 5% error912 and used the S-Plus software, version 3.3, Copyright 1988 (1995 Math Soft, Inc. S. Copyright AT&T).
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Results |
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Table 1 shows that about 50% of VAPP had no exposure to OPV between 4 and 40 days prior to paralysis. On the other hand, 90% of individuals without VAPP had no exposure to OPV in this time. Fever appeared in 60% of AFP cases, albeit in 93% of VAPP.
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Table 2 shows that individuals with AFP have an increased risk of VAPP under certain conditions. When the crude RR were analysed, exposure to OPV, a history of fever and particularly the isolation of type 2 vaccine poliovirus were shown to be significantly associated to the condition studied.
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Discussion |
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The results found in this study corroborate data in the international literature concerning the low risk of VAPP occurrence. Nonetheless, the risks and incidence rates found in Brazil are even lower than those found in other studies,6,1618 even when compared to the Latin American study,19 which includes the Brazilian data. However, one must take into account the heterogeneity of the diagnostic criteria used throughout the world for the classification of VAPP.
Moreover, other plausible hypotheses must be considered so that these discrepancies can be understood. Considering that sometimes there are double entries, with doses distributed in vaccine campaigns also recorded as routine doses due at that time, one can hypothesize an underestimation of risk, secondary to an overestimation of the number of doses distributed. Underclassification of VAPP cases is also possible, since Brazil follows strict criteria requiring isolation of vaccine poliovirus from stool samples collected up to 14 days after the onset of paralysis.
In addition to these factors, the vaccination campaigns carried out since 1980, with wide dissemination of vaccine poliovirus in the population, must be considered. This assumes that, at the time of case analysis, older individuals already had several opportunities for contact with the vaccine poliovirus and were likely to be immunized. The effect of the frequent vaccination campaigns could overcome the decreased seroconversion to polioviruses seen in warm climates and in developing countries, as well as the interference created by diarrhoeal diseases mentioned in several studies.3,2025
The results of vaccine poliovirus isolation demonstrate a larger association with the isolation of type 2 vaccine poliovirus. These findings agree with reports in the literature concerning the greater occurrence of poliovirus types 2 and 3 in VAPP, while the type 1 strain is considered more stable in the attenuation/virulence process.4,16,26
The analysis of risk of VAPP occurrence in relation to vaccine exposure demonstrated a significant association, i.e. the risk of individuals exposed to the vaccine was significantly higher than that of individuals who did not receive the vaccine between 4 and 40 days before the onset of paralysis. Few references in the literature use this approach. Nevertheless, other studies, presenting percentage data, are consistent with the results found in Brazil. In these studies it can be noted that most cases of VAPP occur in vaccine recipients, when compared to contacts of vaccinees.6,17,2729 Some discrepancies in relation to these findings were found in studies in Romania,29 in the US, analysing the 19731984 historical series16 and in Washington,30 where the largest number of cases was among contacts of vaccinees.
As to the age group of VAPP occurrence, the risk decreases with increasing age. This finding agrees with the literature, where it is noted that most cases occur in the youngest age groups.16,29,31
In the models presented, an approximately three times higher risk is observed for the first dose of OPV in relation to subsequent doses. When the first, second, third or more vaccine doses were analysed, the last two appear to be protective factors for the condition. The increased risk for the first dose of OPV has already been clearly demonstrated in several other studies analysing cases of VAPP.1618,29,31
Acute flaccid paralyses presenting with a prodromic phase of fever and GI symptoms are associated with VAPP. The studies reviewed lacked this analysis, which prevented their comparison with the present results. Nevertheless, the literature describes, among the clinical manifestations of poliomyelitis, the minor illness, characterized by fever, vomiting, diarrhoea, etc.32 This description alone allows us to consider them relevant when faced with a case of paralytic poliomyelitis.
The other variables analysed did not show statistical significance when the crude relative risk data were analysed and when they were included in the models.
The construction of a predictive model for the outcome studied had some limiting factors. Since the event studied is rare, and therefore has a small number of cases, estimates are not very accurate, and several analyses demonstrated a lack of statistical significance of the factors examined. However, the analysis of the data demonstrated that some variables are important, allowing us to identify which, among the risk factors studied, are more relevant for the occurrence of the condition.
To our knowledge, no other studies using multivariate analysis for determining the occurrence of VAPP have been conducted, rendering the comparison of our findings to published data hard to achieve.
The important risk factors to be considered when a case of AFP is reported are: previous exposure to the vaccine (between 4 and 40 days before the onset of paralysis), presence of fever and a GI prodrome, number of vaccine doses and age group. Given the results found, it seems evident that the first dose of OPV is more strongly associated with the occurrence of VAPP than the others, while two or more doses of vaccine would appear to be a protective factor, as previously commented.
For almost all the observations, the predictive probability of the multivariate models developed was too low. In all the models, the predicted risk of developing VAPP was very close to zero, even among those who had actually become ill. The predictive model which included vaccine exposure, first dose of vaccine, fever and age had the highest median and a peak probability of 0.18. However, when the model included only the number of vaccine doses and fever, the peak estimated risk, by logistic regression, was 0.20. Among the models tested, these would be the best for predicting the risk of VAPP when AFP is reported.
The results found are consistent with the literature, in spite of the limitations mentioned before. As to the validity of our findings, it must be considered that, at least in principle, the whole population of AFP occurring in the period 19891995 in the country was analysed. This allows us to believe that our results faithfully portray events in this population in this period regardless of the statistical significance or precision of the model parameter estimates.
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Acknowledgments |
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References |
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