1 Institute of Tropical Pathology and Public Health, Federal University of Goias, Brazil
2 University Hospital, Federal University of Goias, Brazil
3 Secretariat of Health, Municipality of Goiânia, Brazil
4 Pan American Health OrganizationDivision of Vaccines and Immunization, USA/WDC
Correspondence: Ana Lucia SS Andrade, Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás-Brasil. Rua Delenda R Melo, S/N, Setor Universitário, Goiânia, Brasil74605050. E-mail: ana{at}iptsp.ufg.br
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Abstract |
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Methods A matched case-control study was built into an ongoing prospective population-based surveillance of pneumonia, enrolling 1293 participants between May 2000 and August 2001. Cases (n = 431) were children 2 years old hospitalized with radiologically definite pneumonia according to the World Health Organization standard criteria for the interpretation of radiographs for the diagnosis of pneumonia. Two controls (n = 862) without previous hospitalization for pneumonia were identified among children from the same neighbourhood and matched to cases by age stratum (±4 months). The Hib vaccination effectiveness was estimated as 1 minus odds ratio (OR).
Results The greatest risk factor for pneumonia among children <2 years of age was day-care centre attendance (P < 0.001). Of the study participants, 83.3% (1072/1287) were classified as vaccinated according to immunization card and 16.7% (215/1287) were considered unvaccinated. By using conditional logistic regression the vaccine effectiveness was estimated as 31.0% (95% CI: −9.0%, 57.0%) after adjusting for sex, previous flu-like illnesses, day-care attendance, smokers at home, house ownership, mother's education, and age as continuous variable.
Conclusion Under programme conditions the effectiveness of Hib conjugate vaccine in infants with radiologically confirmed pneumonia was 31% (95% CI: −9%, 57%) showing the potential benefit of Hib immunization in the prevention of likely non-bacteraemic pneumonia.
Accepted 28 August 2003
Bacterial pneumonia is a relevant cause of morbidity and mortality in children especially in developing countries where approximately 4 million children under 5 years of age die of this disease every year.1 The aetiology of childhood pneumonia has been considered a critical issue in clinical practice and particularly for research purposes. Only a small proportion of cases yield positive bacterial isolation in blood culture specimens, since microbiological diagnostic tests lack sensitivity. Furthermore, in many developing areas, the widespread use of antibiotics prior to health service access is a common practice decreasing the odds of recovering bacteria.
Haemophilus influenzae type b (Hib) causes a wide variety of clinical manifestations and is a leading agent of invasive infections among children, such as meningitis, pneumonia, epiglottitis, septicaemia, osteomyelitis, and arthritis. In developing regions, pneumonia is the most important manifestation of Hib while meningitis is the major invasive Hib disease in industrialized countries.24 In a recent systematic review of H. influenzae based on laboratory surveillance data in Latin America over the last 10 years, type b was predominant among 5362 H. influenzae isolates of invasive diseases, mainly in children under 5 years old.5
The burden of Hib pneumonia in children has been proven by lung aspiration in large studies conducted in Africa and Asia and in case series in Latin America, making non-bacteraemic pneumonia probably the principal Hib disease worldwide.68 The evidence base of the efficacy of Hib conjugate vaccine for the prevention of pneumonia in infants comes from the large randomized trial of Gambia.9 In Chile, a post-license Hib vaccination study showed 80% of effectiveness against Hib bacteraemic pneumonia.10 The impact of the Hib vaccine on pneumonia after the vaccine introduction was also assessed by linking a retrospective evaluation of hospitalization for pneumonia with the previous dataset of the Hib vaccine effectiveness study.11
Conjugate Hib vaccine has been available for more than a decade, and it is estimated that close to 20% of the world's children will have this vaccine included in the immunization schedule. In the Americas, more than 95% of the children born in the year 2002 will have Hib vaccine as part of their regular immunization schedule.12 The cost of the vaccine has hampered mass scale vaccine implementation, especially in other non-industrialized countries.13,14 Meningitis prevention has been the main target for the vaccine and it has been highly efficacious in reducing H. influenzae type b meningitis.15 In 1999, the Hib conjugate vaccine was introduced into the Infant Immunization Program as routine in Brazil. In a highly urbanized city in Central Brazil, a prospective population-based surveillance of pneumonia among children was initiated immediately after Hib vaccine implementation. Taking advantage of this ongoing surveillance we designed a matched case-control study to evaluate the effectiveness of Hib vaccination in the reduction of radiologically confirmed pneumonia among children.
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Patients and Methods |
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Population-based surveillance of pneumonia
This prospective surveillance to detect new cases of community-acquired pneumonia is part of a major project to assess the burden of H. influenzae and Streptococcus pneumoniae infection in childhood.17 This network comprised 20 paediatric hospitals, responsible for almost 90% of the pneumonia admission in the city. At outpatient level, children with cough or difficulty breathing were sent to chest X-ray if they presented one of the following signs:1 (1) breathing >40/minute and no chest indrawing; or (2) chest indrawing and/or any danger sign (unable to feed, vomiting, cyanosis, lethargy, or unconsciousness). The radiographs were initially examined by the paediatricians and, according to their interpretation, children with an X-ray compatible with bacterial pneumonia (potential cases) were referred for hospitalization regardless of disease severity (mild, moderate, or severe) (Figure 1). In our city all requests for hospital admission must be authorized by a Call Center System (Hospital Admission Electronic Information System) located at the Secretariat of Health of Goiânia, where the research team closely monitored and recorded the baseline data of all the hospitalized pneumonia cases on a daily basis. At hospital admission the radiographs of all potential cases were photographed with digital cameras (Mavica® FD90) following technical procedures previously defined.18 Soon after a child's hospitalization, two radiologists, allocated to the project, reviewed independently all the digital photos. They were trained to use the standard World Health Organization (WHO) criteria for interpretation of radiographs and diagnosis of pneumonia.19 There was 85% of concordance on the pneumonia pattern between the two radiologists and the remaining discordant readings (15%) were reviewed by a senior radiologist. Coded forms were used to record the location, type of the infiltrates, and presence of atelectasis, cavitations/abscess, airways and/or airspace disease, hyperinflation, and pleural effusion. The features examined focused on alveolar consolidation and interstitial infiltrate with or without hyperinflation. Cases with both alveolar and interstitial patterns were coded as mixed. For the purpose of this study, a pneumonia case was defined by the presence of alveolar consolidation and/or pleural effusion and/or mixed pattern, herein called radiologically definite pneumonia. The clinical case definition for children with radiologically definite pneumonia was established according to the signs present during the clinical assessment at the time of the hospital admission and followed the WHO guidelines.1,20 In addition to cough and difficulty breathing (mild pneumonia) children with no chest indrawing and fast breathing were considered as moderate pneumonia while those concurrently with chest indrawing or danger signs (unable to drink or breastfeed, vomiting, convulsions, lethargy, or unconsciousness) were considered as severe pneumonia.
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The households of cases and controls were visited and parents were interviewed to obtain information on socioeconomic data, history of previous illness, and potential confounding variables. Day-care attendance meant full time (i.e. 8 hours/day), therefore there was no difference between length of time of day-care attendance between cases and controls. Since this case-control study was matched by neighbourhood, type of day-care attendance did not differ between cases and controls. The institutions in charge of day-care attendance are public and the child admission policy gives priority to those resident in the vicinity. Hib conjugate vaccination status was obtained by checking the immunization card during the house visits. The vaccination history of controls was considered until the age at which the matched case developed disease. The research was approved by the Regional and National Ethics Committee. The field investigators outlined the study to parents or guardians of the participants, to obtain the written informed consent to participate. No refusal was reported.
Data analysis
Data were analysed using the statistical package EpiInfoTM 2000 (Version 1.1.2).21 The required sample size was estimated as 400 cases and 800 controls, assuming an expected reduction of less than 30% in pneumonia between vaccinated and unvaccinated group with 80% power, ratio of controls per case of 2:1, and 5% significance level (two-tailed) for a vaccination coverage of 70%. Categorical data were compared using 2 test or Fisher's exact test and continuous covariates by using the Student's t test. Conditional logistic regression (CLR) was performed to assess the odds ratio (OR) with respective 95% CI of the independent effect of conjugate vaccination on reduction of radiologically definite pneumonia (EGRET software, version 0.19.6). Variables statistically associated with pneumonia in univariate analysis were adjusted for in the multivariate model. Although controls were matched to cases by age stratum, age as a continuous variable entered into the final CLR model since it was regarded as a confounder and therefore was adjusted for irrespective of its level of significance.22 Analysis of vaccination effectiveness was performed based upon documented information on the immunization card. Records with missing information on immunization status were excluded from the analysis. The effectiveness of Hib vaccine was estimated as 1 minus adjusted OR.23 Vaccine effectiveness was calculated assuming non-vaccinated as reference group including children with zero or a single dose of Hib vaccine (administered at age <12 months). It has been demonstrated that a single dose at under one year old is not enough to mount a protective immune response.9,24 The vaccinated group pooled children who received two or three doses or a single dose after 12 months. OR with 95%CI that did not include 1.0 and P-values <0.05 were considered statistically significant.
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Results |
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Discussion |
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In our study no child diagnosed with pneumonia developed severe invasive disease manifestations such as meningitis, septic arthritis, and epiglottitis. In the Gambia study, cases of pneumonia, meningitis, septic arthritis, and septicaemia were detected among the episodes of culture-proven invasive Hib denoting the bactaeremic pattern of the H. influenzae disease in that country. Other studies in the Gambia have confirmed the presence of H. influenzae serotype b by recovery from percutaneous lung aspirates of children with pneumonia.25,26 In this sense, the epidemiological profile of Hib disease in our setting could be expected to be less invasive, i.e. non-bacteraemic disease, when compared with poorer countries.27 The diversity of the epidemiological profile of H. influenzae causing bacteraemic and non-bacteraemic pneumonia should be considered when interpreting the study findings.
We found that the greatest risk factor for pneumonia among children <2 years of age was day-care attendance, a well-established risk factor for pneumonia.28 The case definition of pneumonia in children adopted by this study based upon radiographic evidence of alveolar consolidation and/or pleural effusion followed the standardized criteria proposed by the WHO for epidemiological purposes.19 This is considered a useful indicator of pneumonia likely to be bacterial in aetiology.11,25,2931 Children with chest radiographs compatible with a viral aetiology were excluded from this study. In our study only 11 children (2.5%) out of 431 recruited cases had severe lobar consolidation with effusion, and no pericarditis was seen; these being considered indicators of disease severity. Therefore, most of our pneumonia cases were moderate or mild according to clinical evaluation and chest X-ray patterns. It would be desirable to assess the protective effect of Hib vaccination stratifying pneumonia cases by severity; however, severe cases were few, limiting the study power for such a stratified analysis. There are some possible explanations for this local epidemiological scenario where most mild and moderate pneumonia cases in children are referred for hospitalization. First, chest X-ray is available for all children with clinical signs suspicious of pneumonia who attend the paediatric ambulatory clinic within the urban area. Second, the majority of children with chest radiograph compatible with pneumonia are referred for hospitalization. Furthermore, official Medicare allows cost reimbursement for all hospitalized pneumonia (Brazilian Health Care Security System).
According to our data, 34% of children received antimicrobial treatment before hospital admission. A recent systematic review of lung tap culture including studies conducted in all six continents has shown different proportions of isolation of H. influenzae depending on the region. In South America as a whole, H. influenzae has been found to vary widely (range: 550%) among children with pneumonia, while in Brazil it has been recovered in up to 38% of children who had received no antibiotics prior to hospital admission.6 Unfortunately, H. influenzae serotyping was performed in just one of these studies7 making it difficult to evaluate the real burden of type b and non-type b H. influenzae in childhood pneumonia in Latin America.
Childhood pneumonia is not a notifiable disease and therefore lacks reliable epidemiological baseline data before Hib vaccine implementation. The beforeafter design was not feasible for monitoring the impact of this intervention on pneumonia in contrast to the appropriateness of this methodology for evaluating meningitis under field conditions.3234 In this case-control study we opted for matching controls by neighbourhood in order to deal in the design phase with the similar socioeconomic parameters between cases and controls related to the likelihood of getting both pneumonia and hospital admission. The selection of controls is always a crucial issue in case-control design and subject to debate, especially when assessing vaccine effectiveness.35 Case-control studies would be ideal in a situation where factors affecting the risk of Hib disease (particularly socioeconomic status) were equally distributed in vaccinated and in unvaccinated children. This is seldom the situation, but rather poor high-risk children tend to be unvaccinated biasing in favour of vaccine effectiveness unless this is not adequately controlled for. Neighbourhood controls go some way to rectifying this problem, as neighbourhoods tend to have similar socioeconomic parameters. It is worthwhile mentioning that the study setting is a highly urbanized area where there is a complete access to health care facilities for this age group.
When the study protocol was designed the Hib vaccine had just been introduced into the routine programme. A high immunization rate of around 90% was achieved in the first year of vaccine implementation. It may be difficult to predict to what extent herd immunity could affect the estimation of the Hib vaccine effectiveness in our study area.36 Issues concerning the herd effect following implementation of Hib immunization have been highlighted in the light of the reappearance of H. influenzae b in some regions, especially in the UK.37,38 For instance, some authors have pointed to evidence about low or lack of herd immunity such as: (1) the presence of invasive Hib disease among unvaccinated or incompletely vaccinated children even 2 years after the introduction of the Hib vaccine into the national immunization programme in The Gambia;39 (2) the recent published threat of Hib disease in the UK,40 and (3) the lack of indirect effect of the vaccine after the 3-year nationwide vaccination campaign in The Netherlands.41
In a recent review of child mortality from preventable causes, pneumonia ranks second in a shortlist of causes and is responsible for 21% of the total deaths in children under 5 years of age in low-income countries.42 Given the current state of the interventions capable of reducing child mortality, Hib vaccine is part of the arsenal of childhood interventions with a sufficient level of evidence of reducing the burden of childhood mortality due to pneumonia. Although immunization with Hib vaccine represents an unquestionably powerful tool for reducing infant mortality in poor countries where the burden of Hib disease has been documented, the global estimated coverage of the target population for Hib immunization is 1%.42 The ongoing studies in Lombok and Bangladesh will certainly add important insights to the impact of the Hib vaccination in less developed countries of Asia, where mortality associated with pneumonia is high.43,44
In conclusion, the present investigation pointed out the potential impact of Hib vaccine on community-acquired pneumonia when measured under real conditions of immunization in Brazil. Our result is similar to previous observational investigations performed within immunization programmes in South America and with the clinical trial conducted in Africa, and confirm the relevance of the Hib vaccination as part of the regular childhood immunization schedule in developing regions.
KEY MESSAGES
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References |
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