Antecedentes: La neumonía es una infección grave común en la infancia y principal causa de muerte en niños menores de 5 años. Se sabe poco sobre escalas que evalúen el riesgo de muerte por neumonía. Objetivos: Establecer qué escala tiene mejor desempeño como predictor de muerte por neumonía adquirida en la comunidad (NAC) en niños menores de cinco años. Métodos: Se realizo un estudio observacional, retrospectivo, analítico con un diseño de precisión diagnóstica en una cohorte de registros clínicos de pacientes con NAC entre 2013 y 2015 en las primeras 24 horas de ingreso al hospital. El desempeño de las tres escalas se evaluó comparando el área bajo la curva (ABC) como medida de capacidad discriminativa. Resultados: La escala PIRO modificada (Predisposition, Insult, Response and Organic dysfunction) tiene mayor capacidad discriminatoria con un ABC de 0,93 (IC del 95%: 0,89 a 0,96), siendo la mejor de las tres escalas evaluados. En segundo lugar, la escala RISC (Respiratory Index of Severity in Children) con ABC 0,83 (IC 95%: 0.79-0.87) y, finalmente, la escala PRESS (Pediatric Respiratory Severity Score) ABC 0.67 (IC 95% 0.61 - 0.74). Conclusión: Las escalas PIROm y RISC son buenos predictores de muerte en niños menores de 59 meses, basados en criterios clínicos, radiológicos y laboratoriales. La primera escala podría ser utilizada en centros de salud de mayor complejidad. La segunda escala netamente clínica podría ser utilizada en centros de atención primaria de salud. Se sugiere realizar más estudios en poblaciones con diversas características clínicas, demográficas y ambientales. / Background: Pneumonia is a common serious infection in childhood, being the major cause of death in children under 5 years. Little is kwon about clinical scales predicting risk of death owing to pneumonia Objectives: Establish which scale has better performance as a predictor of death due to community-acquired pneumonia (CAP) in children under five years. Methods: An observational, retrospective, analytical study with a diagnostic precision design was conducted in a cohort of clinical records of patients with CAP between 2013 and 2015 that were review in the first 24 hours of admission to the hospital. The performance of the three scales were evaluated by the comparison of the area under the curve (AUC) as a measure of discriminative capacity. Results: The PIRO modified scale (Predisposition, Insult, Response and Organic dysfunction) has greater discrimination capacity AUC of 0.93 (95% CI 0.89 - 0.96) being the best of the three evaluated. Secondly, the RISC scale (Respiratory Severity Index in children) with AUC 0.83 (95% CI: 0.79-0.87) and, finally, the PRESS scale (Pediatric Respiratory Severity Score) AUC 0.67 (95% CI 0.61 - 0.74). Conclusion: The PIROm and RISC scales are good predictors of death in children under 59 months, based on clinical, radiological and laboratory criteria. The first scale could be used in healthcare centers of higher complexity. The second scale purely clinical could be used in centers of primary health care attention. It is suggested to carry out more studies in diverse populations with different clinical, demographical and environmental characteristics. / Tesis

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 5 uppsatser.

Abstract Pneumonia is a common diagnosis for intensive care unit (ICU) admission. In 2012, 51% of the ICU-treated infections in Finland were of pulmonary origin. The ICU-treated pneumonias can be classified according to acquisition of infection as community-acquired (CAP) or hospital-acquired (HAP). Ventilator-associated pneumonia (VAP) is a subtype of HAP. Patients with severe community-acquired pneumonia (SCAP) require ICU treatment due to need of mechanical ventilation or hemodynamic support. SCAP is associated with high morbidity and high ICU and hospital mortality. The aim of this observational study was to evaluate the clinical characteristics and outcome of SCAP, with special interest on imaging, viral etiology, combination antibiotic treatment and long-term outcome. The thesis comprises three retrospective studies with altogether 392 SCAP patients, median age 55 years, 55.9% of them male. The usefulness of early chest CT and β-lactam-respiratory quinolone (βQ) versus β-lactam-macrolide (βM) therapy for SCAP treatment was evaluated. The hospital and long-term outcomes of SCAP patients were compared with 66 HAP and 25 VAP cases. A prospective study included 49 mechanically ventilated SCAP patients. The frequency of viral etiology in SCAP was analyzed. In SCAP patients, the chest CT as compared to the chest radiograph yielded new imaging findings for 58.5% of the SCAP patients. This information led to procedures or treatment changes in 43% of the cases. The severity of oxygenation disorder correlated to the extent of lung involvement. In prospective SCAP series ICU- mortality was 6.1% and hospital mortality was 12.2%. Viral etiology was found to be common in SCAP and viruses were demonstrated in 49% of patients. The outcome was similar whether SCAP patients were treated with βQ or βM combination. The type of pneumonia did not have a significant association with hospital mortality in ICU-treated SCAP, HAP and VAP patients. Among the hospital survivors, the long-term mortality was substantial, SCAP patients representing the best 1-year outcome. In conclusion, early CT might be useful in SCAP diagnostics and treatment. Viral etiology is common in SCAP. Both β-lactam-respiratory quinolone and β-lactam macrolide combinations were equally good in SCAP treatment. Hospital mortality did not differ among ICU-treated pneumonia cases, but SCAP had the best long-term survival. / Tiivistelmä Keuhkokuume on yleinen tehohoitoon johtava tulehdussairaus. Suomessa vuonna 2012 teho-osastolla hoidetuista infektioista 51 % oli keuhkoalkuisia. Keuhkokuume luokitellaan hankintapaikan mukaan kotisyntyiseksi (CAP) tai sairaalasyntyiseksi (HAP). Hengityslaitehoitoon liittyvä keuhkokuume (VAP) on sairaalasyntyisen keuhkokuumeen alatyyppi. Vakavalla kotisyntyisellä keuhkokuumeella (SCAP) tarkoitetaan vaikeaa keuhkoinfektiota, joka vaatii hengityslaitehoitoa tai verenkierron tukihoitoa teho-osastolla. SCAP:iin liittyy korkea sairastuvuus sekä tehohoito- ja sairaalakuolleisuus. Tässä havainnoivassa kliinisessä tutkimuksessa selvitettiin SCAP:n kliinistä kuvaa ja ennustetta. Erityishuomion kohteena oli varhaisvaiheessa suoritetun keuhkojen tietokonekerroskuvauksen (CT), keuhkokuumeen aiheuttajamikrobien ja antibimikrobihoidon vaikutus taudin hoitoon ja ennusteeseen sekä tehohoidettujen keuhkokuumepotilaiden pitkäaikaisennuste. Väitöskirja koostuu kolmesta retrospektiivisestä osatyöstä, joissa oli yhteensä 392 SCAP-potilasta. Potilaiden mediaani-ikä oli 55 vuotta ja heistä 55,9 % oli miehiä. Varhaisvaiheen keuhkojen CT:n sekä beetalaktaami-kinoloni- ja beetalaktaami- makrolidi-yhdistelmähoidon vaikutusta keuhkokuumeen hoitoon arvioitiin retrospektiivisesti. SCAP-potilaiden sairaalakuolleisuutta ja pitkäaikaisennustetta verrattiin 25:n VAP- ja 66:n HAP-potilaan ennusteeseen. Prospektiivisessa tutkimuksessa oli 49 hengityskonehoidettua potilasta. Tutkimuksessa tarkasteltiin virusten osuutta ja merkitystä vaikeassa SCAP:ssa. Keuhkojen CT havaitsi 58,5 %:lla SCAP-potilaista löydöksiä, joita ei todettu keuhkojen natiiviröntgentutkimuksessa. Löydökset johtivat toimenpiteisiin 43 %:lla SCAP-potilaista. Happeutumishäiriön vaikeusasteen ja CT:llä todettujen keuhkojen tulehdusmuutosten laajuuden välillä havaittiin yhteys. Virusetiologia on SCAP:ssa yleinen. Viruksia havaittiin 49 %:lla SCAP-potilaista. Beetalaktaami-kinoloni- ja beetalaktaami-makrolidi -yhdistelmähoidon välillä ei havaittu eroa SCAP-potilaiden ennusteessa. SCAP-, HAP- ja VAP-potilaiden ennustevertailussa keuhkokuumetyypin ei todettu vaikuttavan sairaalakuolleisuuteen. Paras yhden vuoden ennuste oli SCAP-potilailla. Yhteenvetona todettakoon, että varhaisvaiheen keuhkojen CT on hyödyllinen SCAP:n hoidossa. Virukset ovat yleisiä SCAP:n aiheuttajamikrobeja. Molemmat tutkitut antimikrobiyhdistelmät todettiin hyviksi SCAP:n hoidossa. Sairaalakuolleisuus ei eroa keuhkokuumealatyyppien välillä, mutta SCAP- potilailla on paras pitkäaikaisennuste.

Introduktion: Sepsis är ett livshotande tillstånd som kräver snabb behandling. Otydliga symtom, varierad sjukvårdstillgång och olika hälsolitteracitet hos inringare försvårar tidig behandling.   Syfte: Att studera handhavandet av inringare till 1177 som vid hänvisning till 112 bedömts som ”sepsis-larm” på grund av misstänkt samhällsförvärvad sepsis.    Metod: Kvantitativ retrospektiv icke-experimentell studie där data inhämtats. För de inringare som identifierades med samhällsförvärvad sepsis gjordes fallbeskrivningar. Inkluderade var personer ≥18 år som dygnen före eller efter ”sepsis-larm” under perioden maj 2017 – maj 2018 kontaktade 1177 VPT och inkom via ambulans till akutmottagningar.   Resultat: En fjärdedel av sepsislarmen (158/637) kontaktade 1177 före 112. Senare i processen identifierades 4% som samhällsförvärvad sepsis. Telefonsjuksköterskan (tssk) misstänkte sepsis i 50% av fallen och bedömde samtalen brådskande i 87% av fallen.  Komorbiditetsdokumentation saknades ofta vid korta samtal. Många inringare agerade ombud till fallen.   Konklusion: Det är få samtal till 1177 VPT från individer som senare i samma vårdförlopp identifieras med samhällsförvärvad sepsis. Det är således svårt för tssk att arbeta fram en rutin, därför behövs rådgivningsstödet som ett uppmärksamhetsstöd i samtalsanalysen. Det är viktigt i vården, inte minst inom 1177 VPT, att inte glömma bort att ospecifika symtom och allmänpåverkan kan vara sepsis, som kräver omgående behandling.  En utveckling av rådgivningsstödet med frågor om inringarens förståelse och uppfattning, eller påminnelser om fördjupad anamnes, kan förbättra utfallet. Kontinuerlig kvalitetssäkring för tssk är fundamentalt.  Studien indikerar att det kan finnas viktiga aspekter att studera vidare ur ett jämlik-vård perspektiv, såsom könsskillnader och närhet till akutvård.  I framtida forskning bör 1177 VPT inspelningar av samtal analyseras för inringare som senare erhållit sepsisdiagnos. / Introduction: Sepsis is a life-threatening condition that requires timely treatment. Unclear symptoms, varied health availability and callers’ different levels of health literacy complicate early treatment.     Purpose: To study the handling of callers to 1177 who, when referred to 112, was assessed as "sepsis alert" due to suspected community-acquired sepsis.      Method: A quantitative, retrospective non-experimental study in which data were obtained for callers identified as having community-acquired sepsis and case histories were drawn up. Individuals aged ≥18 years old who contacted the 1177 National Medical Advisory Service 24 hours before or after sepsis alerts and were taken by ambulance to emergency departments during the period May 2017 to May 2018 were included.   Results: A quarter of sepsis alert patients (158/637) contacted 1177 before contacting 112, and 4% were later identified as having community-acquired sepsis. Telephone nurse (TN) suspected sepsis in 50% of cases and assessed calls as urgent in 87% of cases.  Co-morbidity documentation was often missing during short calls. Many callers acted as agents to cases.     Conclusion: There are few calls to 1177 National Medical Advisory Service by individuals who are later identified as having community-acquired sepsis. It is therefore difficult for TNs to work out a routine, so the advice support is needed in the conversation analysis. It is important in health care, not least in terms of the 1177 National Medical Advisory Service, to remember that non-specific symptoms and general impact may be sepsis, which needs urgent treatment.  The development of counselling support with questions about callers’ understanding and perception, or reminders of in-depth medical history, can improve the outcome. Continuous quality assurance for TNs is fundamental.  The study indicates that there may be important aspects for further study from an equal care perspective, such as gender differences and proximity to emergency care.  In future research calls recorded by the 1177 National Medical Advisory Service should be analyzed to identify callers who later received sepsis diagnosis.

The transcription factor Krueppel-like factor (KLF) 4 fosters the pro-inflammatory immune response in macrophages and polymorphonuclear neutrophils (PMNs) when stimulated with Streptococcus pneumoniae, the main causative pathogen of community-acquired pneumonia (CAP). Here, we investigated the impact of KLF4 expression in myeloid cells such as macrophages and PMNs on inflammatory response and disease severity in a pneumococcal pneumonia mouse model and in patients admitted to hospital with CAP. We found that mice with a myeloid-specific knockout of KLF4 mount an insufficient early immune response with reduced levels of pro-inflammatory cytokines and increased levels of the anti-inflammatory cytokine interleukin (IL) 10 in bronchoalveolar lavage fluid and plasma and an impaired bacterial clearance from the lungs 24 hours after infection with S. pneumoniae. This results in higher rates of bacteremia, increased lung tissue damage, more severe symptoms of infection and reduced survival. Higher KLF4 gene expression levels in the peripheral blood of patients with CAP at hospital admission correlate with a favourable clinical presentation (lower sequential organ failure assessment (SOFA) score), lower serum levels of IL-10 at admission, shorter hospital stay and lower mortality or requirement of intensive care unit treatment within 28 days after admission. Thus, KLF4 in myeloid cells such as macrophages and PMNs is an important regulator of the early proinflammatory immune response and, therefore, a potentially interesting target for therapeutic interventions in pneumococcal pneumonia.

O objetivo principal dessa tese foi avaliar se o tratamento com ceftriaxona e um macrolídeo leva a melhores desfechos quando comparada a monoterapia com ceftriaxona em pacientes hospitalizados com HIV/AIDS e pneumonia adquirida na comunidade (PAC). 227 adultos com HIV hospitalizados por uma suspeita de PAC foram randomizados numa proporção 1:1 para receber um dos dois regimes, ceftriaxona mais macrolídeo ou ceftriaxona mais placebo. Houve 2 exclusões após a randomização, um paciente retirou consentimento para uso de seus dados e outro paciente já havia sido incluído previamente no estudo, perfazendo um total de 225 pacientes analisados (112 receberam ceftriaxona mais placebo e 113 receberam ceftriaxona mais macrolídeo). Os pacientes tinham HIV há um longo tempo (período mediano de 10 anos) e a maioria não fazia uso regular de terapia antirretroviral. Somente 32/202 pacientes (16%) tinham carga viral menor que 50 cópias/mL e 146/202 (72%) tinham contagem de linfócitos T CD4+ menor que 200 células/mm³. A frequência do desfecho primário, letalidade durante a internação, não foi estatisticamente distinta entre os regimes estudados: 12/112 (11%) pacientes que receberam ceftriaxona mais placebo e 17/113 (15%) que receberam ceftriaxona mais macrolídeo foram a óbito durante a hospitalização (HR: 1.22, 95% CI: 0.57-2.59). Não foram encontradas diferenças entre os regimes para os desfechos secundários: letalidade em 14 dias (RR: 2.38, 95% CI: 0.87-6.53), uso de drogas vasoativas (OR: 1.18, 95% CI: 0.60-2.29) e ventilação mecânica (OR: 1.24, 95% CI: 0.64- 2.40). A etiologia das infecções pulmonares adquiridas na comunidade nesses pacientes com infecção pelo HIV também foi estudada e determinada prospectivamente. Essa investigação também buscou analisar a contribuição de diferentes métodos diagnósticos e o impacto de diferentes abordagens de investigação microbiológica. Além disso, os achados microbiológicos foram analisados levando em consideração a contagem de linfócitos T CD4+, gravidade da doença e a situação da vacina pneumocócica. 224 pacientes foram submetidos a investigação microbiológica estendida e 143 (64%) tiveram uma etiologia determinada. Por outro lado, a investigação microbiológica de rotina foi capaz de determinar o agente etiológico em 92 (41%) pacientes. Métodos baseados na reação em cadeia da polimerase foram essenciais para o diagnóstico de bactérias atípicas e vírus, além de melhorar a detecção de Pneumocystis jirovecii. Entre os 143 pacientes com uma etiologia determinada, Pneumocystis jirovecii foi o principal agente, detectado em 52 (36%) casos, seguido pelo Mycobacterium tuberculosis responsável por 28 (20%) casos. Streptococcus pneumoniae e Rhinovírus foram diagnosticados em 22 (15%) casos cada e Influenza em 15 (10%) casos. Entre as bactérias atípicas, Mycoplasma pneumoniae foi responsável por 12 (8%) e Chlamydophila pneumoniae por 7 (5%) casos. Infecções mistas ocorreram em 48 casos (34%). Streptococcus pneumoniae foi associado com maiores escores de gravidade, sem associação com o estado vacinal. A análise de agentes etiológicos baseada na contagem de linfócitos T CD4+ demonstrou que a etiologia da pneumonia nos pacientes que estavam gravemente imunossuprimidos (CD4+ < 200 células/mm³) foi similar aos que não estavam. Pneumocystis jirovecii foi o único agente mais frequente no primeiro grupo, um achado esperado levando em consideração os critérios diagnósticos empregados / The main purpose of this thesis was to evaluate if treatment with ceftriaxone and a macrolide improved patient outcome when compared with monotherapy with ceftriaxone in hospitalized patients with HIV/AIDS with community acquired pneumonia (CAP). 227 adult patients with HIV hospitalized due to suspected CAP were randomized to receive one of two regimens, ceftriaxone plus macrolide or ceftriaxone plus placebo, at a 1:1 proportion. We had 2 exclusions after randomization, one patient who withdrew consent for data inclusion and use and one that had previously been included, leaving a total of 225 patients to analyse (112 received ceftriaxone plus placebo and 113 received ceftriaxone plus macrolide). Patients had prolonged HIV infection, the median period was twelve years, and most of them did not make regular use of antiretroviral therapy. Only 32/202 patients (16%) had viral load below 50 copies/mL and 146/202 (72%) had a CD4+ T cell count below 200 cells/mm³. The frequency of the primary outcome, in-hospital mortality, was not statistically different between the studied regimens: 12/112 (11%) patients who received ceftriaxone plus placebo and 17/113 (15%) who received ceftriaxone plus macrolide died during hospitalization (HR: 1.22, 95% CI: 0.57-2.59). We did not find differences between the regimens for the secondary outcomes: mortality within 14 days (RR: 2.38, 95% CI: 0.87-6.53), need for vasoactive drug (OR: 1.18, 95% CI: 0.60-2.29) or mechanical ventilation (OR: 1.24, 95% CI: 0.64-2.40). The etiology of community-acquired pulmonary infections in these hospitalized patients with HIV was also studied and determined prospectively. This investigation also aimed to analyze the contribution of different diagnostic methods as well of the impact of different approaches to microbiological evaluation and to evaluate the microbiological findings in relation to the CD4+ T cell count, the severity of disease and pneumococcal vaccine status. 224 patients underwent the extended microbiological investigation of which 143 (64%) had an etiology determined. On the other hand, the microbiological routine investigation was able to determine the etiological agents in 92 (41%) patients. Polymerase chain reaction-based methods were essential for the diagnosis of atypical bacteria and viruses, besides contributing to ameliorate Pneumocystis jirovecii detection. Among the 143 patients with a determined etiology, Pneumocystis jirovecii was the main agent, detected in 52 (36%) cases and followed by Mycobacterium tuberculosis accounting for 28 (20%) cases. Streptococcus pneumoniae and Rhinovirus were diagnosed in 22 (15%) cases each and Influenza in 15 (10%) cases. Among atypical bacteria, Mycoplasma pneumoniae was responsible for 12 (8%) and Chlamydophila pneumoniae for 7 (5%) cases. Mixed infections occurred in 48 cases (34%). Streptococcus pneumoniae was associated with higher severity scores and not associated with vaccine status. Performing an analysis of causative agents based on CD4+ T cell count, we found that the etiology of pneumonia in those severely immunosuppressed (CD4+ < 200 cells/mm³) was similar to those who were not. Pneumocystis jirovecii is the only agent more frequent in the former group, an expected finding considering our diagnostic criteria

O Streptococcus pneumoniae (pneumococo) constitui um dos mais importantes patógenos bacterianos do trato respiratório, podendo causar infecções invasivas e não invasivas, levando a altas taxas de morbimortalidade, particularmente em crianças menores de cinco anos de idade. A bactéria ganha acesso ao hospedeiro através da colonização da nasofaringe, que representa um importante reservatório para a transmissão deste patógeno na comunidade, contribuindo para a disseminação horizontal de pneumococo entre os indivíduos de uma população. As doenças respiratórias causadas por pneumococo constituem em uma das prioridades atuais em Saúde Pública, recebendo atenção destacada das organizações internacionais da área da saúde, como a Organização Mundial da Saúde. No presente trabalho procura-se conhecer e avaliar a ocorrência da pneumonia adquirida na comunidade (PAC) antes e após a implantação no Calendário Vacinal da Vacina Pneumocócica-10 Valente Conjugada em 2010, na área de abrangência da Superintendência Regional de Saúde (SRS) de Alfenas/MG. Foi realizado um estudo ecológico com componente temporal que incluiu registros de crianças menores que um ano de idade, vacinadas e não vacinadas com a vacina antipneumocócica 10-valente conjugada, no período pré e pós inclusão da vacina no PNI nos municípios da Superintendência Regional de Saúde (SRS) de Alfenas/MG, sendo a vacinação o fator de exposição e a ocorrência de PAC o desfecho, utilizando dados anuais secundários por município para cálculo da cobertura vacinal e das taxas de morbidade por pneumonia em menores de um ano no período de 2007 a 2013. Considerando se os 26 municípios da SRS de Alfenas, houve redução significativa do número de casos de PAC em crianças abaixo de um ano de idade, cuja Razão de Prevalência foi de 0,81 (IC95%: 0,74 0,89; p<0,05). Mesmo com um tempo reduzido de uso, a vacina pneumocócica conjugada 10 valente apresentou um impacto relevante na redução de PAC em crianças, ajustada por cobertura vacinal no período pós vacinação (2011-2013), sendo estatisticamente significativa na maioria dos municípios, o que sugere a efetividade da vacina PCV-10 na prevenção de casos da doença em crianças menores de um ano de idade. / The Streptococcus pneumoniae (pneumococcus) is one of the most important bacterial pathogens of the respiratory tract, may cause invasive and non-invasive infections, leading to high morbidity and mortality rates, particularly in children under five years of age. The bacteria gain access to the host through the nasopharyngeal colonization, which is an important reservoir for the transmission of this pathogen in the community, contributing to the horizontal spread among individuals in a population. Respiratory diseases caused by pneumococcus are in one of the current priorities in Public Health, receiving outstanding attention of international organizations in the health field, such as the World Health Organization. In the present study we aimed to understand and evaluate the occurrence of community acquired pneumonia (CAP) before and after implantation in 10- valent pneumococcal conjugate vaccine in 2010, on the coverage area of the Regional Health Service (SRS) of Alfenas / MG. An ecological study with temporal component was conducted which included records of children under one year old, vaccinated and not vaccinated with 10-valent pneumococcal conjugate vaccine, before and after period inclusion of the vaccine in PNI, in the municipalities of SRS of Alfenas / MG, with vaccination the exposure factor and the occurrence of CAP the outcome, using annual data side by municipality to calculate vaccination coverage and pneumonia morbidity in children under one year old, in the period 2007 to 2013. Considering the 26 municipalities of SRS Alfenas, there was a significant reduction in the number of CAP cases in children under one year old. The prevalence ratio was 0.81 (95%CI: 0.74 - 0.89; p<0.05). Even with a short period of use, the 10-valent pneumococcal conjugate vaccine had a significant impact on the reduction of CAP in children, adjusted for immunization coverage in the post vaccination period (2011-2013) and was statistically significant in most municipalities, which suggests the effectiveness of PCV-10 vaccine in preventing cases of the disease in children under one year of age.

O Streptococcus pneumoniae (pneumococo) constitui um dos mais importantes patógenos bacterianos do trato respiratório, podendo causar infecções invasivas e não invasivas, levando a altas taxas de morbimortalidade, particularmente em crianças menores de cinco anos de idade. A bactéria ganha acesso ao hospedeiro através da colonização da nasofaringe, que representa um importante reservatório para a transmissão deste patógeno na comunidade, contribuindo para a disseminação horizontal de pneumococo entre os indivíduos de uma população. As doenças respiratórias causadas por pneumococo constituem em uma das prioridades atuais em Saúde Pública, recebendo atenção destacada das organizações internacionais da área da saúde, como a Organização Mundial da Saúde. No presente trabalho procura-se conhecer e avaliar a ocorrência da pneumonia adquirida na comunidade (PAC) antes e após a implantação no Calendário Vacinal da Vacina Pneumocócica-10 Valente Conjugada em 2010, na área de abrangência da Superintendência Regional de Saúde (SRS) de Alfenas/MG. Foi realizado um estudo ecológico com componente temporal que incluiu registros de crianças menores que um ano de idade, vacinadas e não vacinadas com a vacina antipneumocócica 10-valente conjugada, no período pré e pós inclusão da vacina no PNI nos municípios da Superintendência Regional de Saúde (SRS) de Alfenas/MG, sendo a vacinação o fator de exposição e a ocorrência de PAC o desfecho, utilizando dados anuais secundários por município para cálculo da cobertura vacinal e das taxas de morbidade por pneumonia em menores de um ano no período de 2007 a 2013. Considerando se os 26 municípios da SRS de Alfenas, houve redução significativa do número de casos de PAC em crianças abaixo de um ano de idade, cuja Razão de Prevalência foi de 0,81 (IC95%: 0,74 0,89; p<0,05). Mesmo com um tempo reduzido de uso, a vacina pneumocócica conjugada 10 valente apresentou um impacto relevante na redução de PAC em crianças, ajustada por cobertura vacinal no período pós vacinação (2011-2013), sendo estatisticamente significativa na maioria dos municípios, o que sugere a efetividade da vacina PCV-10 na prevenção de casos da doença em crianças menores de um ano de idade. / The Streptococcus pneumoniae (pneumococcus) is one of the most important bacterial pathogens of the respiratory tract, may cause invasive and non-invasive infections, leading to high morbidity and mortality rates, particularly in children under five years of age. The bacteria gain access to the host through the nasopharyngeal colonization, which is an important reservoir for the transmission of this pathogen in the community, contributing to the horizontal spread among individuals in a population. Respiratory diseases caused by pneumococcus are in one of the current priorities in Public Health, receiving outstanding attention of international organizations in the health field, such as the World Health Organization. In the present study we aimed to understand and evaluate the occurrence of community acquired pneumonia (CAP) before and after implantation in 10- valent pneumococcal conjugate vaccine in 2010, on the coverage area of the Regional Health Service (SRS) of Alfenas / MG. An ecological study with temporal component was conducted which included records of children under one year old, vaccinated and not vaccinated with 10-valent pneumococcal conjugate vaccine, before and after period inclusion of the vaccine in PNI, in the municipalities of SRS of Alfenas / MG, with vaccination the exposure factor and the occurrence of CAP the outcome, using annual data side by municipality to calculate vaccination coverage and pneumonia morbidity in children under one year old, in the period 2007 to 2013. Considering the 26 municipalities of SRS Alfenas, there was a significant reduction in the number of CAP cases in children under one year old. The prevalence ratio was 0.81 (95%CI: 0.74 - 0.89; p<0.05). Even with a short period of use, the 10-valent pneumococcal conjugate vaccine had a significant impact on the reduction of CAP in children, adjusted for immunization coverage in the post vaccination period (2011-2013) and was statistically significant in most municipalities, which suggests the effectiveness of PCV-10 vaccine in preventing cases of the disease in children under one year of age.

Le pneumocoque est une cause majeure d'infections bactériennes communautaires dans le monde. D'après la littérature, la consommation d'antibiotiques pourrait influer sur le risque de colonisation ou d'infection par pneumocoque à sensibilité diminuée aux antibiotiques spécifiques. La France, grande consommatrice d'antibiotiques, a mis en place, à l'automne 2002, un plan national pour préserver l'efficacité des antibiotiques et améliorer leur usage. Cette campagne a conduit à une diminution significative de la consommation d'antibiotiques durant les périodes hivernales. En 2003, une vaccination anti-pneumococcique des enfants de moins de deux ans a été recommandée afin de réduire les infections communautaires à pneumocoque chez l'enfant. Au vu du contexte français, il paraît important d'étudier la dynamique des infections invasives communautaires à pneumocoque en prenant en compte les deux interventions de santé publique. L'étude de l'association entre deux ou plusieurs séries temporelles saisonnières doit être effectuée sur des séries stationnarisées afin d'éliminer tout risque de confusion. Les différentes méthodes de désaisonnalisation ont été comparées à travers une étude de simulations afin d'identifier la stratégie optimale. De plus, le modèle de régression linéaire adapté aux séries temporelles repose sur l'hypothèse de la linéarité du lien. Cependant, cette hypothèse est critiquable en particulier lorsqu'on s'intéresse au lien associé à une série de type épidémique. Une deuxième étude de simulations a été réalisée afin d'étudier l'impact de l'hypothèse de la linéarité du lien lors de son estimation.A partir des stratégies permettant d'étudier le lien entre plusieurs séries saisonnières identifiées à partir des études de simulations, la dynamique des infections invasives communautaires à pneumocoque a été étudiée en France entre janvier 2002 et décembre 2009. / Streptococcus pneumoniae is a leading cause of communitary-acquired pneumococcal invasive infections worldwide. Recent surveys studied the association between pneumococcal carriage and antibiotic consumption. Reducing antibiotic consumption migth reduce pneumococcal carriage. In France, a national campaign was launched in 2002 in order to reduce antibiotic consumption mainly in the community. In 2003, the seven-valent pneumococcal conjugate vaccine was introduced and recommanded for to children in order to reduce the risk of invasive pneumococcal infections. In this contexte, it is worth investigating the evolution of communitary-acquired pneumococcal invasive infections in France.When examining the association between two monthly time series data with some common seasonal pattern, we are faced with the problem of eliminating this seasonal variation. Indeed this common seasonal feature will act as a confounder if not removed. Even if several methods exist, such as the use of semi-parametric or trigonometric functions, no optimal method has been yet identified. Hence, we compared performances of available smoothing approaches to estimate a temporal link between two series using extensive simulations. The linear regression usually used to estimate the link between two time series is based on the hypothesis of a linear link. However, such a link might not be linear when considering an association with an epidemic time series. In order to check whether this linear model can also manage non linear relationships, a simulation study was also settled. Finally, from these simulation studies, we identified strategies that where implemented to estimate the association between community-acquired pneumococcal invasive infections and antibiotic exposure.

Treatment failure in community-acquired pneumonia (CAP) is the failure to normalize the clinical features (eg, fever, cough, sputum production), or nonresolving image in chest radiograph, despite antimicrobial therapy. The incidence of treatment failure in CAP has not been clearly established; according to several studies it ranges between 6% and 15%. The rate of mortality increases significantly, especially in those patients with severe CAP. It is important to be able to identify what patients are at risk for progressive or treatment failure pneumonia that may make them candidates for a more careful monitoring. This doctoral thesis has been structured following the guidelines of the rules for submission of doctoral theses as a compendium of publications, adopted by the Council, Department of Medicine, University of Barcelona. The studies are part of this thesis belong to the same line of research, validated the current guidelines of pneumonia-community acquired and hospital acquired. The results of the studies have provided relevant and innovative in this field and were collected in 2 original articles published in international journals with a widespread global impact factor of 16,37 points.