BACKGROUND: After the introduction of PCV7 and PCV13, the number of cases of pneumonia in children caused by vaccine serotypes has decreased significantly. Children with comorbidities, however, are still at high risk for IPD. This study aims to compare children with comorbidities to healthy children in an urban setting to assess current risk factors and potential risk factors for pneumonia. METHODS: Existing clinical data of Boston Medical Center patients under 7 years of age were used to compare age, gender, race, comorbidities, and immune status of children with pneumonia to those of children without pneumonia. A representative random sample of 150 patients with pneumonia and 150 patients without pneumonia was selected. Medical record and chart information were reviewed in order to obtain clinical and demographic data. RESULTS: In our study cohort, 120 of 300 (40%) children whose charts were reviewed had at least one comorbidity. Among 150 children with pneumonia, 76 (50.7%) cases were found to have at least one underlying condition, whereas in children without pneumonia 44 (29.3%) of 150 cases had at least one underlying clinical condition (chi-square value 14.2; p-value <0.001). Children with comorbidities were 2.47 times more likely to have pneumonia compared to children without any chronic conditions (OR 2.47, 95% CI 1.54 - 3.98). The risk of having pneumonia among children who are not Hispanic/Latino/Spanish was approximately 40% less compared to children of Hispanic origin (OR 0.61; 95% CI 0.31 - 1.19; p-value 0.14). CONCLUSIONS: Our study shows that children with underlying conditions are at greater risk for pneumonia compared to healthy children without chronic conditions. Ethnicity is also associated with pneumonia cases, with Hispanic children at increased risk for pneumonia compared to non-Hispanic children.

No description available.

ABSTRACT Introduction Invasive pneumococcal disease (IPD) is an important cause of morbidity and mortality in many parts of the world. It is estimated that pneumococcal disease causes more than one million-childhood deaths every year and the burden of disease is greater in developing countries. The main aim of this study was to analyze risk factors associated with mortality in invasive pneumococcal disease in all ages in South Africa. Materials and Methods We performed an analytical cross-sectional analysis of secondary data from national population-based surveillance for invasive Streptococcus pneumoniae infection in South Africa. The study period was 1 January 2003 to 31 December 2005, and the mortality analysis used a subset of laboratory-confirmed cases who had a completed case report form and available mortality data. Multiple logistic regression models were constructed to identify risk factors significantly associated with the increased risk of death in patients with invasive pneumococcal disease. Separate models were used to evaluate risk factors for death in patients with meningitis and those with other IPD. Results There were 1154 (24%) cases of Streptococcus pneumoniae meningitis and 3736 (76%) cases of other invasive disease. The overall case fatality rate was 1360/4890 (27.8%) of which 911 (67%) patients died within 2 days of admission and 449 (33%) died between 2 days and 30 days of admission. Variables associated with mortality in a logistic regression analysis of all IPD patients included meningitis (OR 2.8, CI 1.9 – 3.9, P=<0.001), HIV-infection (OR 2.8, CI 1.6 – 4.6, P=<0.001), acute severe illness measured by Pitt bacteraemia score >=4 (OR 4.7, CI 2.8 – 7.7, P=<0.001) and prior antibiotic use within 2 months before first positive culture (OR 2.1, CI 1.4 – 3.1, P=<0.001). In addition to this children less than 1 year and adults ≥45 years were more likely to die compared to other age groups. Patients from Western Cape Province were significantly less likely to die (OR 0.27, CI 0.15 – 0.50, P=<0.001) compared to other provinces. Amongst HIV-positive patients severe immunosuppression (low CD4+ count) was a risk factor for death. Risk factors for death were similar in patients with other IPD and meningitis except for HIV which was associated with death in the meningitis group but not in the other IPD group. Antibiotic resistance and vaccine-serotype disease were not associated with increased risk of death. Discussion and Conclusions IPD is associated with a high mortality in South Africa. Our findings of increased risk of death in HIV-positive patients especially those with low CD4+ count are of importance given the high prevalence of HIV amongst patients with IPD. Introduction of the pneumococcal conjugate vaccine as part of the national expanded program for immunization (EPI) and ensuring access to antiretroviral therapy for HIV-positive patients where indicated should be prioritized.

Streptococcus pneumoniae is a major bacterial pathogen which causes pneumoniae, meningitis, otitis media, and bacteremia. Currently there are two vaccines available, Pneumococcal Polysaccharide Vaccine (PPV) for adults and the Pneumococcal Conjugate Vaccine (PCV) for children. The PCV vaccine was developed in 2000 specifically for children and infants due to the ineffectiveness of the PPV vaccine in children. This is a cross sectional study of invasive S. pneumoniae in Florida during 2003. This study is designed to determine the population characteristics, clinically relevant antibiotic resistance patterns and specific risk factors for development of antibiotic resistance of invasive S. pneumoniae. Participants for the study of antimicrobial resistance will be selected if they are positive for invasive S. pneumoniae, and have been reported to the Florida Department of Health, Bureau of Epidemiology with a laboratory specimen collection date in 2003. A total of 1056 cases were reported. The incidence of invasive S. pneumoniae was calculated. Logistic regression was used to find an association between each risk factor and invasive S. pneumoniae. 95% Confidence Intervals were calculated to determine statistical significance. The incidence of invasive pneumococcal disease was calculated to be 6.61 per 100,000 persons (95% CI 6.21 -- 7.01). The incidence of drug resistant S. pneumoniae was calculated to be 3.3 per 100,000 persons (95% CI 3.03 -- 3.59).The incidence of penicillin resistant S. pneumoniae (PRSP) was estimated to be 2.6 per 100,000 persons (95% CI 2.37 -- 2.87). Fifty percent of the cases qualified as Drug Resistant S. pneumoniae (DRSP), being non-susceptible to one or more antibiotics as defined by the National Committee for Clinical Laboratory Standards (NCCLS). Age, race, gender, county and month of occurrence were evaluated as risk factors for DRSP. Only month of occurrence was determined to be a risk factor. Compared to current studies and previous results for Florida, it appears that Florida has a decreasing incidence of antibiotic resistant Streptococcus pneumoniae. I believe that this is due to the use of the PCV vaccine.

Masters of Science / Invasive pneumococcal disease (IPD), which includes potentially fatal conditions such as meningitis, septicaemia and pneumonia poses a threat in children aged <5 years, pneumonia being the leading cause of child mortality worldwide. Even though capsular polysaccharides are the main antigens involved in the immunity to encapsulated bacteria, it was found that in children in that age group, the immune system was unresponsive. Conjugate vaccines however induce immunologic memory and provide long-term protective immunity. Therefore the aim of this project was to develop novel conjugation strategies towards a pneumococcal conjugate vaccines and focuses mainly on the serotypes that are a burden to the African continent. The chemistry involved in developing a conjugate vaccine is of importance beacuse while some polysaccharides contain chemical grouping which can be conveniently utilized for conjugation, many medically important ones require derivatization before they can be coupled to protein. Derivatization of which can be achieved through various strategies, important to note is through hypervalent iodine oxidants. Two hypervalent iodine reagents, O-Methyl substituted-1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (Me-IBX)and modified 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (mIBX)were successfully synthesized in preparation for the use in polysaccharide, polyribitol phosphate, (PRP) oxidation. The polysaccharide to be oxidised was first size reduced by microfluidisation to allow maximum oxidation. However, the extent to which oxidisation was achieved was not enough to conjugate the polysaccharide to the protein of preference, Bovine Serum Albumin, (BSA).

INTRODUÇÃO: A doença pneumocócica invasiva (DPI) tem alta mortalidade sendo o pulmão órgão de intenso acometimento. Na DPI caracterizou-se localmente importante processo inflamatório agudo com expressivo aumento de macrófagos, polimorfonucleares e fenômenos exsudativos como edema e hemorragia intra-alveolar. Concretizou-se uma resposta inflamatória proeminente com redução dos fenômenos de apoptose que se traduziu por aumento significativo de citocinas pró-inflamatórias, exceto IL-6 e IL-8, aumento de Toll-2, ativação do complemento, aumento de expressão de ICAM- 1 e CD 14 que em conjunto favorecem o estabelecimento dos fenômenos inflamatórios. A diminuição significativa das células NK e das células de Langherhans, IL-6 e IL-8 reflete comprometimento da imunidade inata. Tal comprometimento poderia ser responsável pela diminuição dos linfócitos TCD4+ e TCD8+ com consequente baixa produção de IFN. Em resumo, as lesões teciduais graves na DPI seriam decorrentes do comprometimento parcial da imunidade inata, em especial das células NK e das células de Langherhans, do prejuízo da imunidade adaptativa e da redução da apoptose como possível estratégia defensiva do pneumococo / INTRODUCTION: Invasive pneumococcal disease (IPD) is a condition with high mortality rates, the lungs being intensely attacked. The in situ immune response was determined, in blocks recovered from 22 necropsies of adults who died from IPD in the lungs, by quantitative immune cell phenotype (CD57-NK, CD1a, CD68, antigen S-100, TCD4, TCD8, CD20), Complement-C3, ICAM-1, CD14, Caspase-3 and cytokine (interferon , TNF, TGF, interleukin - IL-1, IL-2, IL-4, IL-6, IL-8, IL- 10), Toll-2 and SP-A (surfactant). A locally important acute inflammation process was characterized in IPD, with significant rise in macrophages, neutrophils and exsudative phenomena such as edema and intra-alveolar hemorrhage. Compared with the lungs from age-matched controls, results from patients with IPD showed significant depletion of NK, CD1a,CD4+, CD8+, CD20+ cells, interferon , IL-4, IL- 6 , IL-8, TGF and Caspase-3 (apoptosis). On the other hand, S-100, Toll-2, IL-1, IL-2R, IL-10, ICAM-1, CD14 and SP-A were more frequently seen in the alveoli of patients with IPD than in controls. A pronounced inflammatory response was detected, with decrease in apoptosis phenomena that translated into significant increase of pro-inflammatory cytokines, except for IL-6 and IL-8, increase in Toll-2, complement activation, increased ICAM-1 and CD-14 expression, which altogether favored installation of the inflammatory processes. A significant decrease in NK and Langherhans cells, IL-6 and IL-8 reflect the harm to the innate immune system. This could respond for the decrease in TCD4+ and TCD8+ lymphocytes, with a consequent low IFNy output. Briefly, the severe tissue lesions in IPD could be a consequence of the partial damage to the innate immunity, particularly of NK and Langherhans cells, of adaptive immune dysfunction, and of apoptosis reduction possibly as a defense strategy of the pneumococcus

INTRODUÇÃO: A doença pneumocócica invasiva (DPI) tem alta mortalidade sendo o pulmão órgão de intenso acometimento. Na DPI caracterizou-se localmente importante processo inflamatório agudo com expressivo aumento de macrófagos, polimorfonucleares e fenômenos exsudativos como edema e hemorragia intra-alveolar. Concretizou-se uma resposta inflamatória proeminente com redução dos fenômenos de apoptose que se traduziu por aumento significativo de citocinas pró-inflamatórias, exceto IL-6 e IL-8, aumento de Toll-2, ativação do complemento, aumento de expressão de ICAM- 1 e CD 14 que em conjunto favorecem o estabelecimento dos fenômenos inflamatórios. A diminuição significativa das células NK e das células de Langherhans, IL-6 e IL-8 reflete comprometimento da imunidade inata. Tal comprometimento poderia ser responsável pela diminuição dos linfócitos TCD4+ e TCD8+ com consequente baixa produção de IFN. Em resumo, as lesões teciduais graves na DPI seriam decorrentes do comprometimento parcial da imunidade inata, em especial das células NK e das células de Langherhans, do prejuízo da imunidade adaptativa e da redução da apoptose como possível estratégia defensiva do pneumococo / INTRODUCTION: Invasive pneumococcal disease (IPD) is a condition with high mortality rates, the lungs being intensely attacked. The in situ immune response was determined, in blocks recovered from 22 necropsies of adults who died from IPD in the lungs, by quantitative immune cell phenotype (CD57-NK, CD1a, CD68, antigen S-100, TCD4, TCD8, CD20), Complement-C3, ICAM-1, CD14, Caspase-3 and cytokine (interferon , TNF, TGF, interleukin - IL-1, IL-2, IL-4, IL-6, IL-8, IL- 10), Toll-2 and SP-A (surfactant). A locally important acute inflammation process was characterized in IPD, with significant rise in macrophages, neutrophils and exsudative phenomena such as edema and intra-alveolar hemorrhage. Compared with the lungs from age-matched controls, results from patients with IPD showed significant depletion of NK, CD1a,CD4+, CD8+, CD20+ cells, interferon , IL-4, IL- 6 , IL-8, TGF and Caspase-3 (apoptosis). On the other hand, S-100, Toll-2, IL-1, IL-2R, IL-10, ICAM-1, CD14 and SP-A were more frequently seen in the alveoli of patients with IPD than in controls. A pronounced inflammatory response was detected, with decrease in apoptosis phenomena that translated into significant increase of pro-inflammatory cytokines, except for IL-6 and IL-8, increase in Toll-2, complement activation, increased ICAM-1 and CD-14 expression, which altogether favored installation of the inflammatory processes. A significant decrease in NK and Langherhans cells, IL-6 and IL-8 reflect the harm to the innate immune system. This could respond for the decrease in TCD4+ and TCD8+ lymphocytes, with a consequent low IFNy output. Briefly, the severe tissue lesions in IPD could be a consequence of the partial damage to the innate immunity, particularly of NK and Langherhans cells, of adaptive immune dysfunction, and of apoptosis reduction possibly as a defense strategy of the pneumococcus

Background: S. pneumoniae is a major cause of meningitis, pneumonia and sepsis in children. In 2006 universal pneumococcal vaccination was recommended in Germany for all children up to their second birthday. We have compared the prevalence and outcome of IPD at a single hospital before and after the introduction of vaccination. Findings: 55 cases of IPD were identified over an 11 year period. Almost half of the patients were younger than 2 years of age. Most of the children were affected by pneumonia. The second highest incidence seen was for meningitis and sepsis. 17 patients exhibited additional complications. Significant pre-existing and predisposing disorders, such as IRAK 4 defect, ALPS or SLE were identified in 4 patients. Complete recovery was seen in 78% of affected children; 11% had a fatal outcome and 11% suffered from long term complications. Only 31% overall had been vaccinated. The most common serotype was 14. Serotypes not covered by any of the current vaccines were also found. Antibiotic treatment commenced with cephalosporins in over 90%. Conclusion: Frequency of IPD in our hospital did not decrease after initiation of the pneumococcal vaccination. This might be due to vaccinations not being administered satisfactorily as well as to poor education about the need of the vaccination. Pre-existing diseases must be monitored and treated accordingly and rare deficiencies taken into account when IPD takes a foudroyant course. In addition, antibiotic stewardship has been initiated at this hospital centre as a consequence of the high cephalosporin use detected in this study.

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No. of bitstreams: 2 Tese - Sheila Elke Araújo Nunes - 2014.pdf: 4139252 bytes, checksum: 113368e043fc53148e1cd7b8b50b2632 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2014-12-18 / Introduction: Estimate the costs of treatment of pneumococcal diseases can aid the understanding of reduced economic burden of these after introduction of the pneumococcal conjugate vaccine (PCV), as run in Brazil, in March 2010, which introduced the PCV10 valiant in the National Program Immunization (NPI) for children between 2 and 23 months of age. Cost-effectiveness analysis (CEA) before the introduction indicated that the vaccine was cost-effective (R $ 24.930 / Daly avoided - Disability Adjusted Life Years), in the SUS perspective. Disease burden and the cost of the vaccine were identified as the main drivers of the results for sensitivity analysis. Objectives: Estimate the costs of pneumococcal disease and to evaluate the ratio of incremental cost-effectiveness (ICER) of implementing the PCV-10 brave after introduction into INP Brazil. Methods: Three steps have been performed in the SUS perspective: 1) cost of illness study: medical charts of children 28 days to 35 months of age hospitalized with clinical suspicion of bacterial pneumonia were reviewed to estimate the costs of pneumonia and to other syndromes costs were estimated by therapeutic guidelines; 2) comparison between the three methods of funding: (i) bottom-up / micro-costing by chart review; (ii) top-down / micro-costing through therapeutic guidelines; and (iii) top-down / gross-costing, through reimbursement paid by the SUS. 3) CEA: the strategy to vaccinate with PCV-10 was compared to the non-vaccination. The model used was the PneuModel. In acute otitis media from all causes, pneumococcal meningitis, pneumococcal sepsis and pneumococcal pneumonia were considered. Costs were obtained by microcusteio, epidemiological data from primary studies of population-based, dose costs and vaccination coverage in INP. The discount rate was 5%. Sensitivity analysis was conducted to test the robustness and variability of the model parameters. Results: The cost of study of hospitalized pneumonia records of 52 cases of severe pneumonia and 7 of very serious pneumonia were reviewed. Statistical analyzes of severe pneumonia data revealed that there is difference between the costing methodologies (p=0,015) and to compare the estimated costs by these methods there was no difference between the cost of compensation and the cost for therapeutic guideline (p=0,241). At ACE, annually, vaccination with PCV-10 would prevent 3,942 cases of the disease and 16,514 years of life lost in a cohort of children <1 year. The ICER was R $ 14,230 per DALY averted. In sensitivity analysis, the model was sensitive to variations in incidence and mortality of pneumonia and pneumococcal meningitis. Conclusions: The cost for therapy guideline, uncommonly used in disease cost estimates, was an alternative to funding for compensation, heavily used technique and lower accuracy. After introduction of ICER, using primary data revealed that PCV-10 is a low-cost intervention, as suggested by WHO (<1GDP / per capita - in Brazil, in 2010, US $ 10.933) and, ICER less than previous ACE. Despite uncertainties in critical parameters of the model, using secondary data, ACE can provide evidence to support decision making. After the implementation analysis can result in more accurate estimates and provide evidence to continue vaccination. / Introdução: Estimar os custos do tratamento das doenças pneumocócicas podem auxiliar no conhecimento da redução da carga econômica destas após introdução da vacina anti-pneumocócica conjugada (VPC), como corrido no Brasil, em março de 2010, que introduziu a VPC-10 valente no Programa Nacional de Imunização (PNI), para crianças entre 2 e 23 meses de idade. Análise de custo-efetividade (ACE) antes da introdução indicou que a vacina era custo-efetiva (R$ 24,930/Daly evitado – do inglês, Disability Adjusted Life Years), na perspectiva do SUS. Carga da doença e os custos da vacina foram identificados como os principais direcionadores do resultado para análise de sensibilidade. Objetivos: Estimar os custos da doença pneumocócica e avaliar a razão de custo-efetividade incremental (RCEI) da implementação da VPC-10 valente após introdução no PNI do Brasil. Métodos: Três etapas foram executadas, aplicadas a perspectiva do SUS: 1º) estudo de custo de doenças: prontuários de crianças com 28 dias a 35 meses de idade internadas por suspeita clínica de pneumonia bacteriana foram revisados para estimar os custos da pneumonia e para demais síndromes os custos foram estimados por diretrizes terapêuticas; 2º) comparação entre as três metodologias de custeio: (i) bottom-up/micro-costing através da revisão de prontuários; (ii) top-down/micro-costing através de diretriz terapêutica; e (iii) top-down/gross-costing através de ressarcimento pago pelo SUS. 3º) ACE: a estratégia de vacinar com a VPC-10 foi comparada com a não vacinação. O modelo empregado foi o PneuModel. Neste, otite média aguda por todas as causas, meningite pneumocócica, sepse pneumocócica e pneumonia pneumocócica foram consideradas. Os custos foram obtidos por microcusteio, dados epidemiológicos a partir de estudos primários de base populacional, custos da dose e de cobertura vacinal no PNI. A taxa de desconto aplicada foi de 5%. Análise de sensibilidade foi conduzida para testar a robustez e variabilidade de parâmetros do modelo. Resultados: No estudo de custo da pneumonia hospitalizada prontuários de 52 casos de pneumonias graves e 7 de pneumonias muito graves foram revisados. Análises estatísticas dos dados de pneumonias graves revelaram que há diferença entre as metodologias de custeio (p=0,015) e ao comparar os custos estimados por estas metodologias não houve diferença entre o custeio por ressarcimento e o custeio por diretriz terapêutica (p=0,241). Na ACE, anualmente, a vacinação com VPC-10 evitaria 3.942 casos da doença e 16.514 anos de vida perdidos em uma coorte de crianças <1 ano. A RCEI foi de R$ 14.230 por DALY evitado. Na análise de sensibilidade, o modelo foi sensível às variações de incidência e letalidade de pneumonia e meningite pneumocócica. Conclusões: O custeio por diretriz terapêutica, pouco empregado nas estimativas de custo de doença, se mostrou uma alternativa ao custeio por ressarcimento, técnica muito utilizada e de menor acurácia. A RCEI pós introdução, com dados primários, revelou que a VPC-10 é uma intervenção de baixo custo, como sugerido pela OMS (<1PIB/per capita – no Brasil, em 2010, R$ 10,933) e, com menor RCEI que ACE anterior. Mesmo com incertezas em parâmetros críticos do modelo, usando dados secundários, ACE podem fornecer evidências para apoiar tomadas de decisões. Analise pós-introdução pode resultar em estimativas mais precisas e fornecer evidências para continuar a vacinação.

Background: S. pneumoniae is a major cause of meningitis, pneumonia and sepsis in children. In 2006 universal pneumococcal vaccination was recommended in Germany for all children up to their second birthday. We have compared the prevalence and outcome of IPD at a single hospital before and after the introduction of vaccination. Findings: 55 cases of IPD were identified over an 11 year period. Almost half of the patients were younger than 2 years of age. Most of the children were affected by pneumonia. The second highest incidence seen was for meningitis and sepsis. 17 patients exhibited additional complications. Significant pre-existing and predisposing disorders, such as IRAK 4 defect, ALPS or SLE were identified in 4 patients. Complete recovery was seen in 78% of affected children; 11% had a fatal outcome and 11% suffered from long term complications. Only 31% overall had been vaccinated. The most common serotype was 14. Serotypes not covered by any of the current vaccines were also found. Antibiotic treatment commenced with cephalosporins in over 90%. Conclusion: Frequency of IPD in our hospital did not decrease after initiation of the pneumococcal vaccination. This might be due to vaccinations not being administered satisfactorily as well as to poor education about the need of the vaccination. Pre-existing diseases must be monitored and treated accordingly and rare deficiencies taken into account when IPD takes a foudroyant course. In addition, antibiotic stewardship has been initiated at this hospital centre as a consequence of the high cephalosporin use detected in this study.