Dynamics of antimicrobial resistance of Streptococcus pneumoniae following PCV10 introduction in Brazil: Nationwide surveillance from 2007 to 2019.

BACKGROUND: Brazil introduced 10-valent pneumococcal conjugate vaccine (PCV10) into its immunization program in 2010. We assessed antimicrobial susceptibility of Streptococcus pneumoniae (Spn) obtained from a national surveillance system for invasive pneumococcal diseases (IPD) before/after PCV10 introduction. METHODS: Antimicrobial non-susceptible isolates were defined as intermediate or resistant. Minimum inhibitory concentrations (MICs) to penicillin and ceftriaxone were analyzed by year. Antimicrobial susceptibility rates were assessed for each three-year-period using the pre-PCV10-period as reference. Susceptibility of vaccine-types was evaluated for 2017-2019. RESULTS: 11,380 isolates were studied. Spn with penicillin ≥ 0.125 mg/L and ceftriaxone ≥ 1.0 mg/L decreased in the three-years after PCV10 introduction (2011-2013: penicillin, 28.1-22.5%; ceftriaxone, 11.3%-7.6%) versus pre-PCV10-years (2007-2009: penicillin, 33.8-38.1%; ceftriaxone, 17.2%-15.6%). After 2013, the proportion of Spn with those MICs to penicillin and ceftriaxone increased to 39.4% and 19.7% in 2019, respectively. Non-susceptibility to penicillin and ceftriaxone increased in 2014-2016, and again in 2017-2019 especially among children < 5 years with meningitis (penicillin, 53.9%; ceftriaxone, 28.0%); multidrug-resistance reached 25% in 2017-2019. Serotypes 19A, 6C and 23A were most associated with antimicrobial non-susceptibility. CONCLUSIONS: Antimicrobial non-susceptible Spn decreased in the three-years after vaccination but subsequently increased and was associated with non-PCV10-types. Antimicrobial susceptibility surveillance is fundamental for guiding antibiotic therapy policies.

Modeling the cost-effectiveness of maternal acellular pertussis immunization (aP) in different socioeconomic settings: A dynamic transmission model of pertussis in three Brazilian states.

OBJECTIVES: Using dynamic transmission models we evaluated the health and cost outcomes of adding acellular pertussis (aP) vaccination of pregnant women to infant vaccination in three Brazilian states that represent different socioeconomic conditions. The primary objective was to determine whether the same model structure could be used to represent pertussis disease dynamics in differing socioeconomic conditions. METHODS: We tested three model structures (SIR, SIRS, SIRSIs) to represent population-level transmission in three socio-demographically distinct Brazilian states: São Paulo, Paraná and Bahia. Two strategies were evaluated: infant wP vaccination alone versus maternal aP immunization plus infant wP vaccination. Model projections for 2014-2029 include outpatient and inpatient pertussis cases, pertussis deaths, years of life lost, disability-adjusted life-years (DALYs) lost, and costs (in 2014 USD) of maternal aP vaccination, infant vaccination, and pertussis medical treatment. Incremental cost per DALY averted is presented from the perspective of the Brazilian National Health System. RESULTS: Based on goodness-of-fit statistics, the SIRSIs model fit best, although it had only a modest improvement in statistical quantitative assessments relative to the SIRS model. For all three Brazilian states, maternal aP immunization led to higher costs but also saved infant lives and averted DALYs. The 2014 USD cost/DALY averted was $3068 in Sao Paulo, $2962 in Parana, and $2022 in Bahia. These results were robust in sensitivity analyses with the incremental cost-effectiveness ratios exceeding per capita gross regional product only when the probability that a pertussis case is reported was assumed higher than base case implying more overt cases and deaths and therefore more medical costs. CONCLUSIONS: The same model structure fit all three states best, supporting the idea that the disease behaves similarly across different socioeconomic conditions. We also found that immunization of pregnant women with aP is cost-effective in diverse Brazilian states.

The data used to build the models: Pertussis morbidity and mortality burden considering various Brazilian data sources.

BACKGROUND: Pertussis is associated with significant disease burden in children worldwide. In addition to its cyclical nature, resurgences of pertussis cases, hospitalizations and deaths have been reported by many countries. We describe the dynamics of pertussis in Brazil, a middle-income country that has experienced a resurgence and that provides good quality data to allow building a dynamic transmission disease model. METHODS: We conducted a descriptive analysis of pertussis burden considering data from the national disease surveillance system, national hospitalization information system and national mortality registry. Study period was 2000-2016. Absolute numbers and rates per 100,000 inhabitants over time, by age sub-groups and geographical regions are presented. RESULTS: From 2000 to 2016, a total of 37,299 reported pertussis cases, 25,240 hospitalizations, and 601 deaths due to pertussis were reported. Although the outcomes - pertussis cases, hospitalizations, and deaths - come from independent information systems, our results document low disease burden with periodic increases every 3-4 years during the years 2000-2010, followed by a sharp increase which peaked in 2014. In both periods, disease burden is concentrated in young children, while its more serious outcomes - hospitalizations and deaths, are concentrated in infants. Pre-outbreak and outbreak disease burden as well as timing of peak during the outbreak period vary by states and within geographical regions, representing valuable resources of data for modelling purposes. CONCLUSION: Consistent disease burden patterns were observed over time in Brazil using a variety of data sources. Given the scarcity of good epidemiological data on pertussis available from low- and middle-income countries, our reported data provide valuable information for the assessment of the public health impact and cost-effectiveness modelling studies of newer strategies to prevent and control pertussis. These data were used to build and calibrate a national dynamic transmission model, which was used to evaluate the cost-effectiveness of maternal immunization. Clinical Trial registry name and registration number: Not applicable.

Cost-effectiveness of maternal pertussis immunization: Implications of a dynamic transmission model for low- and middle-income countries.

OBJECTIVE: This study evaluates the cost-effectiveness of maternal acellular pertussis (aP) immunization in low- and middle-income countries using a dynamic transmission model. METHODS: We developed a dynamic transmission model to simulate the impact of infant vaccination with whole-cell pertussis (wP) vaccine with and without maternal aP immunization. The model was calibrated to Brazilian surveillance data and then used to project health outcomes and costs under alternative strategies in Brazil, and, after adjusting model parameter values to reflect their conditions, in Nigeria and Bangladesh. The primary measure of cost-effectiveness is incremental cost (2014 USD) per disability-adjusted life-year (DALY). RESULTS: The dynamic model shows that maternal aP immunization would be cost-effective in Brazil, a middle-income country, under the base-case assumptions, but would be very expensive at infant vaccination coverage in and above the threshold range necessary to eliminate the disease (90-95%). At 2007 infant coverage (DTP1 90%, DTP3 61% at 1 year of age), maternal immunization would cost < $4,000 per DALY averted. At high infant coverage, such as Brazil in 1996 (DTP1 94%, DTP3 74% at 1 year), cost/DALY increases to $1.27 million. When the model's time horizon was extended from 2030 to 2100, cost/DALY increased under both infant coverage levels, but more steeply with high coverage. The results were moderately sensitive to discount rate, maternal vaccine price, and maternal aP coverage and were robust using the 100 best-fitting parameter sets. Scenarios representing low-income countries showed that maternal aP immunization could be cost-saving in countries with low infant coverage, such as Nigeria, but very expensive in countries, such as Bangladesh, with high infant coverage. CONCLUSION: A dynamic model, which captures the herd immunity benefits of pertussis vaccination, shows that, in low- and middle-income countries, maternal aP immunization is cost-effective when infant vaccination coverage is moderate, even cost-saving when it is low, but not cost-effective when coverage levels pass 90-95%.

The direct effect of pneumococcal conjugate vaccines on invasive pneumococcal disease in children in the Latin American and Caribbean region (SIREVA 2006-17): a multicentre, retrospective observational study.

BACKGROUND: Streptococcus pneumoniae isolated from patients with invasive pneumococcal disease has been subjected to laboratory-based surveillance in Latin American and Caribbean countries since 1993. Invasive pneumococcal diseases remain a major cause of death and disability worldwide, particularly in children. We therefore aimed to assess the direct effect of pneumococcal conjugate vaccines (PCVs) on the distribution of pneumococcal serotypes causing invasive pneumococcal disease in children younger than 5 years before and after PCV introduction. METHODS: We did a multicentre, retrospective observational study in eight countries that had introduced PCV (ie, PCV countries) in the Latin American and Caribbean region: Argentina, Brazil, Chile, Colombia, Dominican Republic, Mexico, Paraguay, and Uruguay. Cuba and Venezuela were also included as non-PCV countries. Isolate data for Streptococcus pneumoniae were obtained between 2006 and 2017 from children younger than 5 years with an invasive pneumococcal disease from local laboratories or hospitals. Species' confirmation and capsular serotyping were done by the respective national reference laboratories. Databases from the Sistema Regional de Vacunas (SIREVA) participating countries were managed and cleaned in a unified database using Microsoft Excel 2016 and the program R (version 3.6.1). Analysis involved percentage change in vaccine serotypes between pre-PCV and post-PCV periods and the annual reporting rate of invasive pneumococcal diseases per 100 000 children younger than 5 years, which was used as a population reference to calculate percentage vaccine type reduction. FINDINGS: Between 2006 and 2017, 12 269 isolates of invasive pneumococcal disease were collected from children younger than 5 years in the ten Latin American and Caribbean countries. The ten serotypes included in ten-valent pneumococcal conjugate vaccine (PCV10) decreased significantly (p<0·0001) after any PCV introduction, except for the Dominican Republic. The percentage change for the ten vaccine serotypes in PCV10 countries was -91·6% in Brazil (530 [72·9%] of 727 before, 27 [6·1%] of 441 after); -85·0% in Chile (613 [72·6%] of 844 before, 44 [10·9%] of 404] after); -84·7% in Colombia (231 [63·1%] of 366 before, 34 [9·7%] of 352 after); and -73·8% in Paraguay (127 [77·0%] of 165 before, 22 [20·2%] of 109 after). In the 13-valent pneumococcal conjugate vaccine (PCV13) countries, the percentage change for the 13 vaccine serotypes was -59·6% in Argentina (853 [85·0%] of 1003 before, 149 [34·3%] of 434 after); -16·5% in the Dominican Republic (95 [80·5%] of 118 before, 39 [67·2%] of 58 after); -43·7% in Mexico (202 [73·2%] of 276 before, 63 [41·2%] of 153 after); and -45·9% in Uruguay (138 [80·7%] of 171 before, 38 [43·7%] of 87 after). Annual reporting rates showed a reduction from -82·5% (6·21 before vs 1·09 after per 100 000, 95% CI -61·6 to -92·0) to -94·7% (1·15 vs 0·06 per 100 000, -89·7 to -97·3) for PCV10 countries, and -58·8% (2·98 vs 1·23 per 100 000, -21·4 to -78·4) to -82·9% (7·80 vs 1·33 per 100 000, -76·9 to -87·4) for PCV13 countries. An increase in the amount of non-vaccine types was observed in the eight countries after PCV introduction together with an increase in their percentage in relation to total invasive strains in the post-PCV period. INTERPRETATION: SIREVA laboratory surveillance was able to confirm the effect of PCV vaccine on serotypes causing invasive pneumococcal disease in the eight PCV countries. Improved monitoring of the effect and trends in vaccine type as well as in non-vaccine type isolates is needed, as this information will be relevant for future decisions associated with new PCVs. FUNDING: None. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

Genomic surveillance of Neisseria meningitidis serogroup B invasive strains: Diversity of vaccine antigen types, Brazil, 2016-2018.

BACKGROUND: Neisseria meningitidis serogroup B remains a prominent cause of invasive meningococcal disease (IMD) in Brazil. Because two novel protein-based vaccines against serogroup B are available, the main purpose of this study was to provide data on the diversity and distribution of meningococcal vaccine antigen types circulating in Brazil. METHODOLOGY: Genetic lineages, vaccine antigen types, and allele types of antimicrobial-associated resistance genes based on whole-genome sequencing of a collection of 145 Neisseria meningitidis serogroup B invasive strains recovered in Brazil from 2016 to 2018 were collected. RESULTS: A total of 11 clonal complexes (ccs) were identified among the 145 isolates, four of which were predominant, namely, cc461, cc35, cc32, and cc213, accounting for 72.0% of isolates. The most prevalent fHbp peptides were 24 (subfamily A/variant 2), 47 (subfamily A/variant 3), 1 (subfamily B/variant 1) and 45 (subfamily A/variant 3), which were predominantly associated with cc35, cc461, cc32, and cc213, respectively. The NadA peptide was detected in only 26.2% of the isolates. The most frequent NadA peptide 1 was found almost exclusively in cc32. We found seven NHBA peptides that accounted for 74.5% of isolates, and the newly described peptide 1390 was the most prevalent peptide exclusively associated with cc461. Mutated penA alleles were detected in 56.5% of the isolates, whereas no rpoB and gyrA mutant alleles were found. CONCLUSION: During the study period, changes in the clonal structure of circulating strains were observed, without a predominance of a single hyperinvasive lineage, indicating that an epidemiologic shift has occurred that led to a diversity of vaccine antigen types in recent years in Brazil.

Nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in a Brazilian elderly cohort.

We aimed to investigate the nasopharyngeal colonization (NPC) by Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in the elderly population and to assess the demographic factors associated with NPC. This was an observational cohort study in which outpatients aged ≥60 years were enrolled from April to August 2017, with a follow-up visit from September through December 2017. Nasopharyngeal (NP) swabs were collected, bacteria were detected and isolated, and isolates were subjected to phenotypic and molecular characterization using standard microbiological techniques. At enrolment, the rates of S. aureus, methicillin-resistant S. aureus (MRSA), H. influenzae, and S. pneumoniae among 776 elderly outpatients were 15.9%, 2.3%, 2.5%, and 2.2%, respectively. Toxin production was detected in 21.1% of methicillin-susceptible S. aureus, and three SCCmec types were identified: II/IIb, IVa, and VI. At the follow-up visit, all carriage rates were similar (p > 0.05) to the rates at enrolment. Most of S. pneumoniae serotypes were not included in pneumococcal conjugate vaccines (PCVs), except for 7F, 3, and 19A. All strains of H. influenzae were non-typeable. Previous use of antibiotics and 23-valent pneumococcal polysaccharide vaccination (p < 0.05) were risk factors for S. aureus and MRSA carriage; S. aureus colonization was also associated with chronic kidney disease (p = 0.021). S. pneumoniae carriage was associated with male gender (p = 0.032) and an absence of diabetes (p = 0.034), while not receiving an influenza vaccine (p = 0.049) and chronic obstructive pulmonary disease (p = 0.031) were risk factors for H. influenzae colonization. The frailty of study participants was not associated with colonization status. We found a higher S. aureus carriage rate compared with the S. pneumoniae- and H. influenzae-carriage rates in a well-attended population in a geriatric outpatient clinic. This is one of the few studies conducted in Brazil that can support future colonization studies among elderly individuals.

Long-term effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae in children in Brazil.

Brazil introduced the 10-valent pneumococcal vaccine (PCV10) to the routine national immunization program (NIP) in March 2010. In 2017, we investigated the effects of PCV10 on nasopharyngeal carriage of vaccine-types (VT) and non-vaccine-types (NVT) of Streptococcus pneumoniae (Spn) among children living in São Paulo city. We also compared the prevalence of VT and NVT with previous carriage surveys performed in 2010 (baseline) and 2013. METHOD: The carriage survey was conducted among 531 children, aged 12 months to <24 months, recruited from public Primary Health Units during the immunization campaign, using previous surveys methodology, except for qPCR, which was performed in the 2017 survey only. RESULTS: No statistical difference was found in the prevalence of Spn either by culture (59.7%) or by qPCR (61.2%). Spn carriage increased from 40.3% (baseline) to 59.7% (2017 survey) (p < 0.001). Colonization by VT isolates significantly decreased by 90.9% (19.8-1.8%) and 95.5% (19.8-0.9%) in the 2013 and 2017 surveys, respectively, compared to that at baseline. NVT isolates increased significantly by 128% (19.6-44.8%) and 185% (19.6-55.9%) in the respective post-PCV10 surveys, most led to high prevalence of serotypes 6C (27%), 15B (9.8%), 19A (9.2%), 15A (6.0%), and 16F (5.7%). In 2017, reduction in serotype 6A (4.2-0.6%, p < 0.001) and increase in serotype 19A (1.8-6.0%, p = 0.001) were found; serotype 3 isolate was not detected in the present survey. We identified the emergence of 19A isolates CC320, associated with high penicillin (MIC ≥ 2.0 mg/L) and cefotaxime (MIC ≥ 1.0 mg/L) values. CONCLUSION: After 7 years of PCV10 introduction in the NIP, colonization by VT among toddlers decreased substantially to a residual level, along with substantial serotype replacement by novel serotypes not present in any current conjugated pneumococcal vaccine and serotype 19A. The present findings can assist policy decisions in Brazil.

Long-term effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae in children in Brazil

Brazil introduced the 10-valent pneumococcal vaccine (PCV10) to the routine national immunization program (NIP) in March 2010. In 2017, we investigated the effects of PCV10 on nasopharyngeal carriage of vaccine-types (VT) and non-vaccine-types (NVT) of Streptococcus pneumoniae (Spn) among children living in São Paulo city. We also compared the prevalence of VT and NVT with previous carriage surveys performed in 2010 (baseline) and 2013. Method: The carriage survey was conducted among 531 children, aged 12 months to <24 months, recruited from public Primary Health Units during the immunization campaign, using previous surveys methodology, except for qPCR, which was performed in the 2017 survey only. Results: No statistical difference was found in the prevalence of Spn either by culture (59.7%) or by qPCR (61.2%). Spn carriage increased from 40.3% (baseline) to 59.7% (2017 survey) (p < 0.001). Colonization by VT isolates significantly decreased by 90.9% (19.8­1.8%) and 95.5% (19.8­0.9%) in the 2013 and 2017 surveys, respectively, compared to that at baseline. NVT isolates increased significantly by 128% (19.6­44.8%) and 185% (19.6­55.9%) in the respective post-PCV10 surveys, most led to high prevalence of serotypes 6C (27%), 15B (9.8%), 19A (9.2%), 15A (6.0%), and 16F (5.7%). In 2017, reduction in serotype 6A (4.2­0.6%, p < 0.001) and increase in serotype 19A (1.8­6.0%, p = 0.001) were found; serotype 3 isolate was not detected in the present survey. We identified the emergence of 19A isolates CC320, associated with high penicillin (MIC 2.0 mg/L) and cefotaxime (MIC 1.0 mg/L) values. Conclusion: After 7 years of PCV10 introduction in the NIP, colonization by VT among toddlers decreased substantially to a residual level, along with substantial serotype replacement by novel serotypes not present in any current conjugated pneumococcal vaccine and serotype 19A. The present findings can assist policy decisions in Brazil

Expansion of the multidrug-resistant clonal complex 320 among invasive Streptococcus pneumoniae serotype 19A after the introduction of a ten-valent pneumococcal conjugate vaccine in Brazil.

BACKGROUND: In 2010, a ten-valent pneumococcal conjugate vaccine (PCV10) was introduced in the routine infant national immunization program in Brazil. Invasive pneumococcal disease (IPD) caused by serotype 19A (Spn19A) increased after the introduction of PCVs in several countries. We compared the frequency, antimicrobial resistance and molecular patterns of invasive Spn19A strains before and after PCV10 introduction in Brazil using data from the national laboratory-based surveillance. METHODS: We analyzed invasive Spn19A strains isolated from 2005-2009 (pre-PCV10 period), 2011-2015 and 2016-2017 (post-PCV10 periods). Antimicrobial susceptibility was performed for all Spn19A strains, and multilocus sequence typing (MLST) was performed for strains isolated in the age groups <5 years and ≥50 years. RESULTS: Among the study period, a total of 9,852 invasive Spn strains were analyzed, and 673 (6.8%) belonged to serotype 19A. Overall, the proportion of Spn19A among the total number of IPD strains increased from 2.8% in 2005-2009 to 7.0% and 16.4% in 2011-2015 and 2016-2017, respectively. The relative increase in Spn19A was observed especially in children <5 years old (2005-2009: 3.2%; 2011-2015: 15.5%; 2016-2017: 31.2%). The percentage of penicillin resistance (MIC 2.0-4.0 µg/mL), erythromycin resistance and multidrug resistance (MDR) increased after PCV10 introduction due to the expansion of the MDR clonal complex CC320 (2005-2009: 8.6%; 2011-2015: 56.1%; 2016-2017: 66.5%). CONCLUSION: We observed an expansion of MDR-CC320 among invasive Spn19A strains after PCV10 introduction in Brazil, probably related to a combination of factors, such as vaccination and antimicrobial pressure. Continued surveillance of Spn19A strains is necessary to monitor the sustainability of this clonal complex in the Brazilian population.

Increased risk of death and readmission after hospital discharge of critically ill patients in a developing country: a retrospective multicenter cohort study.

PURPOSE: To describe long-term mortality and hospital readmissions of patients admitted to Brazilian intensive care units (ICU). METHODS: Retrospective cohort study of adult patients admitted to Brazilian hospitals affiliated to the Public Healthcare System from 10 state capitals. ICU patients were paired to non-ICU patients by frequency matching (ratio 1:2), according to postal code and admission semester. Hospitalization records were linked through deterministic linkage to national mortality data. Primary outcome was mortality up to 1 year. Other outcomes were mortality and readmissions at 30 and 90 days and 3 years. Multiple Cox regressions were used adjusting for age, sex, cancer diagnosis, type of hospital, and surgical status. RESULTS: We included 324,594 patients (108,302 ICU and 216,292 non-ICU). ICU patients had increased hospital length of stay [9 (5-17) vs. 3 (1-6) days, p < 0.001] and mortality (18.5 vs. 3.6%, p < 0.001) versus non-ICU patients. One year after discharge, ICU patients were more frequently readmitted to hospital (25.4 vs. 17.4%, p < 0.001) and to ICU (31.4 vs. 7.3%, p < 0.001) than controls. Mortality up to 1 year was also higher for ICU patients (14.3 vs. 3.9%, p < 0.001). A significant interaction between surgical status and mortality was found, with adjusted hazard ratios (HRs) up to 1 year of 2.7 [95% confidence interval (CI) 2.5-2.9] for surgical patients, and 3.4 (95%CI 3.3-3.5) for medical patients. The risk for death and readmission diminished over time up to 3 years. CONCLUSIONS: In a public healthcare system of a developing country, ICU patients have excessive long-term mortality and frequent readmissions. The ICU burden tended to reduce over time after hospital discharge.

Distribution of invasive Streptococcus pneumoniae serotypes before and 5 years after the introduction of 10-valent pneumococcal conjugate vaccine in Brazil.

BACKGROUND: In March 2010, the 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the routine immunization program in Brazil. We describe the pneumococcal serotypes that caused invasive pneumococcal diseases (IPD) before and after the introduction of PCV10 using data from a national laboratory-based surveillance system. METHOD: We compared the prevalence of vaccine types (VT) and non-vaccine types (NVT) of Streptococcus pneumoniae in three periods, pre-PCV10 (January/2005-December/2009), early post-PCV10 (January/2010-December/2013), and late post-PCV10 (January/2014-December/2015), by episode in meningitis and non-meningitis cases and by age group. Changes in serotype prevalence in the early and late post-PCV10 periods were determined using pre-PCV10 period as a reference. RESULTS: A total of 8971 IPD isolates from patients aged 2 months to 99 years were analyzed. In the late post-PCV10 period, the VT-IPD reduction in the 2-month to 4-year age group was 83.4% for meningitis and 87.4% for non-meningitis cases; in the age groups 5-17 years, 18-64 years, and ≥65 years, VT declined by 56.1%, 54.1%, and 47.4%, respectively, in meningitis cases, and by 60.9%, 47.7%, and 53.4%, respectively, in non-meningitis cases. NVT-IPD increased throughout the study period, driven mainly by serotypes 3, 6C, and 19A, which remained the predominant types causing IPD in the late post-PCV10 period. CONCLUSION: We observed direct and indirect PCV10 protection against IPD caused by VT and a shift in the distribution of serotypes 5 years after the introduction of PCV10. Continued IPD surveillance is needed to evaluate the sustainability of the high prevalence of serotypes 3, 6C, and 19A, which were not included in PCV10.

Combined effect of PCV10 and meningococcal C conjugate vaccination on meningitis mortality among children under five years of age in Brazil.

The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in the Brazilian National Immunization Program in March 2010, scheduled at 2, 4, and 6 months, with a booster at 12-15 months of age. The meningococcal C conjugate vaccine (MCC) was introduced in November 2010, scheduled at 3 and 5 months, with a booster dose at 12-15 months of age and no catch-up for older age groups. In this interrupted time-series analysis study, we used Brazilian mortality data from 2005 to 2015 for children under five years of age (excluding data from the state of Bahia) to assess the combined impact of these vaccines on the overall burden of meningitis mortality among children aged 0-23 months and 2-4 years, as defined using meningitis and meningococcemia specific International Classification of Diseases - tenth revision codes. Secular trends and seasonality were taken into account. We found significant reductions for both age groups relative to those observed for the comparison group of diseases, with immediate effects after the transition period (2010-2011) of 29.2% and 27.5% for children aged 0-23 months and 2-4 years, respectively. These immediate effects were sustained throughout the post-vaccination period (2012-2015). In total, 337 deaths were averted by the combined effect of both vaccines, 238 (95%CI 169-319) for children aged 0-23 months and 99 (95%CI 56-144) for those aged 2-4 years. These results add strong evidence in support of investments in these vaccines by low and middle-income countries.

Single-dose varicella vaccine effectiveness in Brazil: A case-control study.

BACKGROUND: Varicella vaccine was introduced into the Brazilian Immunization Program in October 2013, as a single-dose schedule administered at 15 months of age. Its effectiveness had not yet been assessed in the country. METHODS: A matched case-control study was carried out in São Paulo and Goiânia (Southeast and Midwest regions, respectively), Brazil. Suspected cases, were identified through a prospective surveillance established in the study sites. All cases had specimens from skin lesion collected for molecular laboratory testing. Cases were confirmed by either clinical or PCR of skin lesions and classified as mild, moderate, and severe disease. Two neighborhood controls were selected for each case. Cases and controls were aged 15-32 months and interviewed at home. Evidence of prior vaccination was obtained from vaccination cards. Univariate and multivariate logistic regression models were used, and odds ratio and its respective 95% confidence intervals were estimated. Vaccine effectiveness was estimated by comparing de odds of having received varicella vaccine among cases and controls. RESULTS: A total of 168 cases and 301 controls were enrolled. Moderate and severe illness, was found in 33.3% and 9.9% of the cases. Effectiveness of a single dose varicella vaccine was 86% (95%CI 72-92%) against disease of any severity and 93% (95%CI 82-97%) against moderate and severe disease. Out of 168 cases, 81.8% had positive PCR results for wild-type strains, and 22.0% were breakthrough varicella cases. Breakthrough cases were milder compared to non-breakthrough cases (p < .001). CONCLUSIONS: Effectiveness of single dose varicella vaccine in Brazil is comparable to that in other countries where breakthrough varicella cases have also been found to occur. The goal of the varicella vaccination program, along with disease burden and affordability should be taken into consideration when considering the adoption of a second dose of varicella vaccine into national immunization programs.

Direct and indirect impact of 10-valent pneumococcal conjugate vaccine introduction on pneumonia hospitalizations and economic burden in all age-groups in Brazil: A time-series analysis.

Background: Ten-valent pneumococcal conjugate vaccine (PCV10) was introduced in the National Immunization Program of Brazil in March/2010. Although there are recent reports of PCV10 impact on pneumonia hospitalizations, there is still uncertainty regarding the indirect impact in individuals non-targeted by vaccination. We assessed both direct and indirect effect of PCV10 on pneumonia hospitalizations and the impact on the economic burden of pneumonia hospitalizations. Methods: An interrupted time-series analysis was conducted considering monthly rates of pneumonia hospitalizations and comparison groups, in all age-groups, from January/2005-December/2015. We used records of the National Hospitalizations Information System. Observed pneumonia rates in the post-vaccination period (2011­2015) were compared to predicted rates, should PCV10 had not been introduced. Relative percent difference in rates and its 95% confidence interval were estimated. The number of pneumonia hospitalizations averted by vaccination was calculated as the difference between the predicted and observed cumulative number of pneumonia hospitalizations in the post-vaccination period. The impact of PCV10 on economic burden was presented as averted costs of pneumonia hospitalization. Results: Significant decrease in rates of pneumonia hospitalization was observed in both children targeted by vaccination (17.4%­26.5%; p<0.01), and in age-groups not targeted by vaccination (11.1%­27.1%, in individuals 10­49 years; p<0.01). In contrast, PCV10 introduction did not alter the increasing trends in pneumonia hospitalization among elderly ≥65 years. A total of 457,564 pneumonia hospitalizations was averted in Brazil for individuals aged <50 years, with a total averted costs of BRL 383.2 million (Int$ 225.2 million, and USD 147 million) for the 5 year period after PCV introduction. Conclusion: Vaccination with PCV10 5 years after its introduction in Brazil was associated with a relevant reduction in pneumonia hospitalization in the target age-groups, with an indirect effect in individuals aged 10­49 years, and significant reduction in associated economic burden. The increasing trends in pneumonia hospitalization rates in the elderly is a matter of concern for public health and should be further investigated.

Hospitalization costs of severe bacterial pneumonia in children: comparative analysis considering different costing methods.

OBJECTIVE: To determine and compare hospitalization costs of bacterial community-acquired pneumonia cases via different costing methods under the Brazilian Public Unified Health System perspective. METHODS: Cost-of-illness study based on primary data collected from a sample of 59 children aged between 28 days and 35 months and hospitalized due to bacterial pneumonia. Direct medical and non-medical costs were considered and three costing methods employed: micro-costing based on medical record review, micro-costing based on therapeutic guidelines and gross-costing based on the Brazilian Public Unified Health System reimbursement rates. Costs estimates obtained via different methods were compared using the Friedman test. RESULTS: Cost estimates of inpatient cases of severe pneumonia amounted to R$ 780,70/$Int. 858.7 (medical record review), R$ 641,90/$Int. 706.90 (therapeutic guidelines) and R$ 594,80/$Int. 654.28 (Brazilian Public Unified Health System reimbursement rates). Costs estimated via micro-costing (medical record review or therapeutic guidelines) did not differ significantly (p=0.405), while estimates based on reimbursement rates were significantly lower compared to estimates based on therapeutic guidelines (p<0.001) or record review (p=0.006). CONCLUSION: Brazilian Public Unified Health System costs estimated via different costing methods differ significantly, with gross-costing yielding lower cost estimates. Given costs estimated by different micro-costing methods are similar and costing methods based on therapeutic guidelines are easier to apply and less expensive, this method may be a valuable alternative for estimation of hospitalization costs of bacterial community-acquired pneumonia in children. OBJETIVO: Determinar e comparar custos hospitalares no tratamento da pneumonia bacteriana adquirida na comunidade por diferentes metodologias de custeio, na perspectiva do Sistema Único de Saúde. MÉTODOS: Estudo de custo, com coleta de dados primários de uma amostra de 59 crianças com 28 dias a 35 meses de idade hospitalizadas por pneumonia bacteriana. Foram considerados custos diretos médicos e não médicos. Três metodologias de custeio foram utilizadas: microcusteio por revisão de prontuários, microcusteio considerando diretriz terapêutica e macrocusteio por ressarcimento do Sistema Único de Saúde. Os custos estimados pelas diferentes metodologias foram comparados utilizando o teste de Friedman. RESULTADOS: Os custos hospitalares de crianças com pneumonia grave foram R$ 780,70 ($Int. 858.7) por revisão de prontuários, R$ 641,90 ($Int. 706.90) por diretriz terapêutica e R$ 594,80 ($Int. 654.28) por ressarcimento do Sistema Único de Saúde, respectivamente. A utilização de metodologias de microcusteio (revisão de prontuários e diretriz) resultou em estimativas de custos equivalentes (p=0,405), enquanto o custo estimado por ressarcimento foi significativamente menor do que aqueles estimados por diretriz (p<0,001) e por revisão de prontuário (p=0,006), sendo, assim, significativamente diferentes. CONCLUSÃO: Na perspectiva do Sistema Único de Saúde, existe diferença significativa nos custos estimados quando se utilizam diferentes metodologias, sendo a estimativa por ressarcimento a que resulta em valores menores. Considerando que não há diferença nos valores de custos estimados por diferentes metodologias de microcusteio, a metodologia de custeio por diretriz, de mais fácil e rápida execução, é uma alternativa válida para estimativa de custos de hospitalização por pneumonias bacterianas em crianças.

Qualifying information on deaths and serious injuries caused by road traffic in five Brazilian capitals using record linkage.

INTRODUCTION: Road traffic crashes (RTC) are an important public health problem, accounting for 1.2 million deaths per year worldwide. In Brazil, approximately 40,000 deaths caused by RTC occur every year, with different trends in the Federal Units. However, these figures may be even greater if health databases are linked to police records. In addition, the linkage procedure would make it possible to qualify information from the health and police databases, improving the quality of the data regarding underlying cause of death, cause of injury in hospital records, and injury severity. OBJECTIVE: This study linked different data sources to measure the numbers of deaths and serious injuries and to estimate the percentage of corrections regarding the underlying cause of death, cause of injury, and the severity injury in victims in matched pairs from record linkage in five representative state capitals of the five macro-regions of Brazil. METHODS: This cross-sectional, population-based study used data from the Hospital Information System (HIS), Mortality Information System (MIS), and Police Road Traffic database of Belo Horizonte, Campo Grande, Curitiba, Palmas, and Teresina, for the year 2013 for Teresina, and 2012 for the other capitals. RecLink III was used to perform probabilistic record linkage by identifying matched pairs to calculate the global correction percentage of the underlying cause of death, the circumstance that caused the road traffic injury, and the injury severity of the victims in the police database. RESULTS: There was a change in the cause of injury in the HIS, with an overall percentage of correction estimated at 24.4% for Belo Horizonte, 96.9% for Campo Grande, 100.0% for Palmas, and 33.2% for Teresina. The overall percentages of correction of the underlying cause of death in the MIS were 29.9%, 11.9%, 4.2%, and 33.5% for Belo Horizonte, Campo Grande, Curitiba, and Teresina, respectively. The correction of the classification of injury severity in police database were 100.0% for Belo Horizonte and Teresina, 48.0% for Campo Grande, and 51.4% for Palmas after linkage with hospital database. The linkage between mortality and police database found a percentage of correction of 29.5%, 52.3%, 4.4%, 74.3 and 72.9% for Belo Horizonte, Campo Grande, Palmas, Curitiba and Teresina, respectively in the police records. CONCLUSIONS: The results showed the importance of linking records of the health and police databases for estimating the quality of data on road traffic injuries and the victims in the five capital cities studied. The true causes of death and degrees of severity of the injuries caused by RTC are underestimated in the absence of integration of health and police databases. Thus, it is necessary to define national rules and standards of integration between health and traffic databases in national and state levels in Brazil.

Reduction in all-cause otitis media-related outpatient visits in children after PCV10 introduction in Brazil.

Few studies have reported the effect of 10-valent pneumococcal conjugate vaccine (PCV10) on otitis media (OM) in infants. In particular, no population-based study in upper-middle income countries is available. In 2010, Brazil introduced PCV10 into its routine National Immunization Program using a 3+1 schedule. We measured the impact of PCV10 on all-cause OM in children. An interrupted time-series analysis was conducted in Goiânia/Brazil considering monthly rates (per 100,000) of all-cause OM outpatient visits in children aged 2-23 months. We used case-based data from the Outpatient Visits Information System of the Unified Health System coded for ICD-10 diagnosis for the period of August/2008 to July/2015. As a comparator, we used rates of outpatient visits due to all-other causes. The relative reduction of all-cause OM and all-other causes of outpatient visits were calculated as the difference between the predicted and observed cumulative rates of the PCV10 post-vaccination period. We then subtracted the relative reduction of all-other causes of outpatient visits from all-cause OM to obtain the impact of PCV10 on OM. In total, 6,401 OM outpatient visits were recorded in 4,793 children aged 2-23 months. Of these, 922 (19.2%) children had more than one OM episode. A significant reduction in all-cause OM visits was observed (50.7%; 95%CI: 42.2-59.2%; p = 0.013), while the reduction in visits due to all-other causes was 7.7% (95% CI 0.8-14.7%; p<0.001). The impact of PCV10 on all-cause OM was thus estimated at 43.0% (95%CI 41.4-44.5). This is the first study to show significant PCV10 impact on OM outpatient visits in infants in a developing country. Our findings corroborate the available evidence from developed countries.