A dificuldade de realização de estudos clínicos com a população pediátrica favorece a prescrição off-label de medicamentos. Paralelamente, existe uma grande diversidade de fontes de informações sobre medicamentos disponíveis para consulta e diferentes formas de expressar doses para a pediatria, podendo resultar em padrões variados no uso de medicamentos. Este estudo avaliou a concordância de fontes de informação, em nível nacional e internacional, que orientam a prescrição pediátrica de antimicrobianos para faringotonsilite, otite média aguda (OMA) e rinossinusite, em relação ao fármaco de escolha, à posologia e aos tipos de referências utilizadas para sua elaboração. Foram selecionados documentos de entidades brasileiras e estrangeiras e as bulas dos medicamentos neles mencionados, totalizando 23 documentos diferentes para as três doenças avaliadas. A classe das penicilinas foi prevalente como terapia de primeira escolha nas três doenças estudadas, contudo houve grande variação nas doses indicadas e no modo como elas são expressas. A idade mínima para uso foi informada em 51,2% das fontes, sendo menos recorrente nas fontes nacionais. A duração do tratamento esteve presente em 66,7% dos fármacos indicados nas fontes. De forma geral, as fontes analisadas para as três doenças avaliadas citam principalmente referências classificadas como artigos de revisão e estudos experimentais, seguidos dos formulários e listas oficiais e consensos, diretrizes e manuais para embasar seus dados. Os resultados encontrados neste estudo reforçam a necessidade de estimular a realização de ensaios clínicos e/ ou estudos de farmacometria para a definição de doses de antimicrobianos para a pediatria, assim como, a harmonização das informações disponibilizadas para orientar a prescrição. / The difficulty of conducting clinical studies with the pediatric population favors off-label prescribing. At the same time, there is easy access to a great diversity of sources of information about drugs and different ways of expressing pediatric doses. These factors have impact on drug prescription and may result in varying standards in the use of medications. The present study assessed, at national and international levels, the agreement of information sources that guide pediatric prescription of antimicrobials for pharyngotonsillitis, acute otitis media (AOM) and rhinosinusitis, in relation to the drug of choice, dosage and types of references used in its preparation. Documents from Brazilian and international entities and the package inserts of the medications mentioned in these documents were selected. To three diseases, was analyzed 23 differents documents. The penicillin class was prevalent as first-line therapy in the three diseases investigated. However, there was great variation in the doses indicated and in the way they are expressed. The minimum age for use was reported in only 51,2% of the sources, being less recurrent in the national sources. Duration of treatment was present in 66,7% of the drugs indicated in the sources. In general, the sources analyzed for the three disorders investigated most often cite references classified as review articles and experimental studies, followed by formularies and official lists and consensus, guidelines and manuals to support their data. The results obtained reinforce the need to encourage clinical trials and/or pharmacometrics studies for establishing dosing recommendations of antimicrobials for pediatric patients, as well as to harmonize the information provided to guide prescriptions.

Abstract The purpose was to study respiratory infections in a cold environment among young Finnish men. The seasonal variation in the occurrence of respiratory tract infections is well-known, but the impact of cold exposure is obscure. The burden of respiratory tract infections is especially apparent during military service, but the possible risk factors for infections are not. A total of 892 young military conscripts, 224 men with physician-diagnosed asthma, from the intake groups of July 2004 and January 2005 in Kainuu Brigade, were recruited for the study. In Kajaani area, the average daily temperature is above 10°C only from June to August and all conscripts serve during the cold season, too. The previous history of respiratory tract symptoms, infections, smoking habits and cold sensations were obtained with a questionnaire. Blood samples were taken for determination of the markers of inflammation and infection and peak expiratory flow, height and weight were measured. Data on respiratory tract infections requiring a physician consultation and results of a 12-min running test were collected. The temperature data was obtained from the nearest meteorological station located ca. 15 km from the garrison. At the beginning of the service, asthmatic men reported to have experienced more respiratory tract symptoms and were in poorer physical condition according to the 12-min running test compared to non-asthmatic men. However, 48% of men with asthma were without medication. After the 180–362 -day service, both men with and without asthma had enhanced their physical fitness as determined with the 12-min running test. At the same time, the levels of high sensitive C-reactive protein as a marker of low-grade inflammation, decreased. Infection episodes requiring physician consultation were more common among men with, rather than without, asthma. Chlamydia pneumoniae infections were mostly mild upper respiratory tract infections, common cold and sinusitis, and were as common in asthmatic as in non-asthmatic men. However, prolonged Chlamydia pneumoniae infections were more common among asthmatic men. Obesity and previous respiratory tract infections were independent risk factors for frequent infections among men with 180-day service. There was a typical seasonal variation in respiratory tract infections among conscripts: most infections occurred in the wintertime. The men with 180-day service had most infections during the first three months of the service, both in the July and January intake groups. Temperature was significantly associated with the occurrence of respiratory infection episodes. The most common temperature for the onset of an episode was in the outdoor temperature range of 0°C to –5°C. Respiratory tract infections were preceded by linearly decreasing outdoor temperature, the coldest day being the day before physician consultation.

Pseudomonas aeruginosa (PA) is a gram-negative bacillus well known for colonizing human respiratory airways and causing opportunistic infections. Children with neuromuscular disease (NMD) including cerebral palsy (CP) and severe upper airway obstruction who get infected with PA, their chances of experiencing a severe illness, being admitted to a pediatric intensive care unit, and extended or repeated hospital stays increase dramatically. These patients often need a surgical procedure called tracheostomy which act as a channel for microbes to enter lower respiratory tract and increase infections, despite its well documented impact as an opportunistic pathogen comprehensive investigation into the diversity of PA in such vulnerable populations is limited. To fill this gap in knowledge we perform whole genome sequencing (WGS) and phenotypic analysis of 40 PA isolates from the respiratory tract of this susceptible population with and without tracheotomies. Pangenome analysis showed highly variable genome content with 16,212 total genes of which 2326 are core genes. MLST revealed diverse sequence types (STs) among the studied population with 21 known and 10 new STs. Genotypic analysis revealed moderate variations in the antimicrobial resistance determinants and virulence factors among all isolates. In total 8 serogroups were identified, with serogroups O6 and O11 accounting for 70% of all the isolates. Genotypic diversity was observed in overall population however comparative analysis among tracheostomized and non-tracheostomized patient groups showed significant similarity which aligns with the phenotypic analysis revealing significant similarity with minor differences in biofilm formation, motility, hemolysis production, and pigment production. Last, we explored putative healthcare transmission and identified three potential transmission events. These findings provide insight into how WGS along with phenotypic analysis can help us better understand population dynamics, epidemiology, virulence profile and antibiotic resistance profile of PA contributing to respiratory infections which has valuable therapeutic implications for epidemiology and disease management.

<p><i>Chlamydia pneumoniae</i> is a human respiratory tract pathogen. Seroepidemiological studies indicate that <i>C. pneumoniae</i> infection is most common in school-aged children and infrequently detected in younger children.</p><p>The aims of this study were to further elucidate the prevalence of <i>C. pneumoniae</i> in paediatric populations and to describe the clinical implications of these infections.</p><p>The study population consisted of 367 children with respiratory tract diseases, 453 presumed healthy children at day-care, 69 children undergoing adenoidectomy and 1585 children from a population based cohort. Family members to infected day-care children were investigated. The laboratory methods used were polymerase chain reaction (PCR) on specimen from upper respiratory tract, serology by microimmunofluorescence (MIF), and immunohistochemistry (IHC) on adenoid tissue specimen. Personal data and medical history were obtained by the means of questionnaires and by the study of patient records.</p><p>In children younger than five years, the prevalence of <i>C. pneumoniae</i> was 17% as detected by PCR. This prevalence started to increase with increasing age from two years of age. The corresponding increase in serology as detected by MIF started at the age of four years. The prevalence at day-care centres varied from 4 to 39%. Both PCR and MIF underestimated the prevalence of <i>C. pneumoniae</i> detected by IHC. Families to infected children were investigated: mothers were more often infected than fathers were.</p><p>Most <i>C. pneumoniae</i> infections in small children were confined to the upper respiratory tract. These infections were usually mild or asymptomatic. Symptomatic disease may be of prolonged nature. No subsequent illness after <i>C. pneumoniae</i> infection was detected at follow-up after four years. In general, no association between <i>C. pneumoniae</i> and asthma was found, but <i>C. pneumoniae</i> may be of importance for asthma in some susceptible individuals. Previous <i>C. pneumoniae</i> infection reduced the risk for later atopy.</p><p>In conclusion, <i>C. pneumoniae</i> is a common finding in small children and most often causes relatively mild disease. If the acquisition of this infection early in life will have any implications for future health remains to be investigated.</p>

Chlamydia pneumoniae is a human respiratory tract pathogen. Seroepidemiological studies indicate that C. pneumoniae infection is most common in school-aged children and infrequently detected in younger children. The aims of this study were to further elucidate the prevalence of C. pneumoniae in paediatric populations and to describe the clinical implications of these infections. The study population consisted of 367 children with respiratory tract diseases, 453 presumed healthy children at day-care, 69 children undergoing adenoidectomy and 1585 children from a population based cohort. Family members to infected day-care children were investigated. The laboratory methods used were polymerase chain reaction (PCR) on specimen from upper respiratory tract, serology by microimmunofluorescence (MIF), and immunohistochemistry (IHC) on adenoid tissue specimen. Personal data and medical history were obtained by the means of questionnaires and by the study of patient records. In children younger than five years, the prevalence of C. pneumoniae was 17% as detected by PCR. This prevalence started to increase with increasing age from two years of age. The corresponding increase in serology as detected by MIF started at the age of four years. The prevalence at day-care centres varied from 4 to 39%. Both PCR and MIF underestimated the prevalence of C. pneumoniae detected by IHC. Families to infected children were investigated: mothers were more often infected than fathers were. Most C. pneumoniae infections in small children were confined to the upper respiratory tract. These infections were usually mild or asymptomatic. Symptomatic disease may be of prolonged nature. No subsequent illness after C. pneumoniae infection was detected at follow-up after four years. In general, no association between C. pneumoniae and asthma was found, but C. pneumoniae may be of importance for asthma in some susceptible individuals. Previous C. pneumoniae infection reduced the risk for later atopy. In conclusion, C. pneumoniae is a common finding in small children and most often causes relatively mild disease. If the acquisition of this infection early in life will have any implications for future health remains to be investigated.

The aim of this thesis was to analyse possible effects of prenatal arsenic exposure on foetal and infant health. The setting is Bangladesh, where two cohorts were studied, both part of a health and demographic surveillance system in Matlab. A historical cohort 1991-2000 included 29,134 pregnant women with information on drinking water sources and arsenic testing of tube well water. A prospective cohort study included pregnant women 2002 - 2003 where urinary arsenic concentrations were assessed twice during pregnancy; 2,924 women and their pregnancy outcomes were evaluated for foetal loss, perinatal and infant mortality; 1,578 mother-infant pairs were analysed for size at birth; and 1,552 were analysed for morbidity during infancy. Women exposed to arsenic levels ≥ 50 µg/L in water had an increased risk of foetal loss and infant death in comparison with women exposed to arsenic levels &lt; 50 µg/L. These findings were confirmed in the prospective cohort study. Women with urine arsenic concentrations at the 5th quintile had 62% increased risk of spontaneous abortion (OR 1.62, 95% CI 1.04 - 2.55) in comparison with women who had arsenic concentrations at the 1st quintile level. Increased risks of perinatal morality (RR 3.01, 95% CI 1.07 - 8.45) and infant mortality (RR 5.01; 95% CI: 1.41 - 17.84) were also observed at the 5th quintile of exposure. Significant negative dose-effect associations were found between arsenic exposure and birth weight, head and chest circumferences at a relatively low level of exposure (&lt;100 µg/L in urine). In this range of exposure birth weight decreased by 1.68 g (SE 0.62) for each 1 µg/L increase of arsenic in urine. In comparison with exposure at the 1st quintile level the risk of lower respiratory tract infection was significantly increased (RR 1.68, 95% CI 1.35-2.07) for women who had urinary arsenic concentrations at the 5th quintile level. The risk was also increased for diarrhoeal diseases. The study findings highlight the negative effects of arsenic exposures on pregnancy outcomes and infant health. Mitigation programs need to be strengthened and women of reproductive ages should be prioritized in arsenic affected regions worldwide.

Maternal obesity has significant consequences on the lifelong health of the developing child and rising global incidences make it one of the most common comorbidities during pregnancy. Offspring of obese mothers are at an increased risk of hospitalization for respiratory infections throughout childhood, which predispose these children to non-communicable respiratory diseases in later life. Animal models of maternal high fat diet (mHFD) feeding have observed common inflammatory outcomes with obesogenic models, but the effect on offspring varies with timing of the nutritional challenge and diet composition across studies. These studies demonstrate significant alterations to circulating and lung specific immune cells but the sequence of events that link maternal diet to these fetal outcomes are unclear, nor have they been tested in the context of a bacterial respiratory infection. Streptococcus pneumonaie is the most common causative pathogen of bacterial pneumonia and meningitis, making it of high clinical relevance. We aimed to investigate the effect of a mHFD (45% kcal from fat) during gestation and lactation, on offspring outcome and recovery from Streptococcus pneumoniae infection. Immunophenotyping, both before and after infection, revealed a hypo-inflammatory phenotype in circulating monocytes of the mHFD offspring with a decreased capacity to both initiate and terminate inflammatory responses. These offspring had significantly higher bacterial counts in lung tissues during infection and sustained cellular inflammation in survivors. In this thesis, we present foundational work on the detrimental influence of excess maternal nutrition on offspring immune function and infection outcomes, which may be involved in susceptibility to inflammatory and chronic disease in later life. A better understanding of this deep and lasting influence of the maternal environment will allow us to target preconception health as a form of harm reduction, informing stake holders and institutions to direct efforts towards DOHaD knowledge translation. / Thesis / Master of Science (MSc)

<p>Recent evidence suggests that vitamin D may be important for immune function. Canadian studies have reported varying prevalences of low levels of vitamin D. Whether these low vitamin D levels are associated with susceptibility to respiratory tract infections (RTIs) and infection severity remains unclear given the inconsistent association in recent studies. Influenza virus as a cause of RTI is of particular interest given its prevalence, morbidity and economic burden. Vaccination is a key strategy in prevention, but little is known about the effect of vitamin D on influenza vaccine response.</p> <p>A prospective cohort study of children 3 to 15 years old living in Hutterite communities in Alberta, Saskatchewan and Manitoba was conducted to assess the prevalence and predictors of low vitamin D levels and evaluate the association between vitamin D and the incidence and severity of laboratory proven respiratory tract infections. In those who received influenza vaccination, the relationship between vitamin D and influenza vaccine immunogenicity was examined.</p> <p>A total of 743 children were included in the study. The median serum 25-hydroxyvitamin D level (25[OH]D) was 62.0 nmol/L (interquartile range 51.0, 74.0). Levels lower than 50 nmol/L were present in 152 children (20.5%) and lower than 75 nmol/L in 565 children (76%). Lower serum 25(OH)D levels were associated with increased risk of RTI. No association was found between serum 25(OH)D level and disease severity. There was also no relationship found between serum 25(OH)D level and seroprotection or seroconversion from inactivated influenza vaccine.</p> <p>In conclusion, low serum 25(OH)D levels are a significant problem in Canadian Hutterite communities. Furthermore, low serum 25(OH)D levels were associated with increased risk of proven upper RTIs. Studies evaluating the role of vitamin D supplementation to reduce the burden of disease are warranted, and strategies to improve vitamin D status in rural communities in Canada are needed.</p> / Master of Science (MSc)

As infecções respiratórias agudas contribuem para elevada morbimortalidade na infância, destacando o Parainfluenza (HPIV) nos quadros de crupe viral. Pouco é conhecido a influência dos fatores ambientais (meteorológicos e de poluição atmosférica) nas infecções respiratórias. De 21/10/2004 a 01/06/2007 foi conduzido um estudo ecológico de séries temporais, em menores de 15 anos, com sintomas respiratórios atendidos na Santa Casa de São Paulo e no Hospital Universitário de Jundiaí para determinar a freqüência de HPIV, pela imunofluorescência indireta e verificar a relação entre poluentes atmosféricos, variáveis meteorológicas na infecção respiratória. Os dados meteorológicos e de poluição ambiental foram coletados diariamente. Das 1464 amostras o HPIV foi detectado em 49 (5,5%) amostras (SCSP) e em 29(5,0%) amostras (HUFMJ),sendo o HPIV3 mais prevalente.O Ozônio e Dióxido de Nitrogênio tiveram relação com vírus respiratórios em São Paulo. Em Jundiaí observou-se relação com material particulado (lag3) e HPIV. / Acute respiratory infections contribute to high infant morbidity and mortality, highlighting the parainfluenza (HPIV) in the frames of viral croup. Little is known the influence of environmental factors (meteorological and air pollution) in respiratory infections. From 21/10/2004 to 01/06/2007 was an ecological study of time series, for children under 15 years, with respiratory symptoms treated at Santa Casa de São Paulo and the University Hospital of Jundiaí to determine the frequency of HPIV by immunofluorescence and verify the relationship between air pollutants, meteorological variables in respiratory infection. The meteorological and environmental pollution were collected daily. 1464 samples of the HPIV was detected in 49 (5.5%) samples (SCSP) and 29 (5.0%) samples (HUFMJ) and the HPIV3 more prevalente.O Ozone and nitrogen dioxide were associated with respiratory viruses in Sao Paulo. In Jundiaí was observed relationship with particulate matter (lag3) and HPIV.

As infecções respiratórias agudas contribuem para elevada morbimortalidade na infância, destacando o Parainfluenza (HPIV) nos quadros de crupe viral. Pouco é conhecido a influência dos fatores ambientais (meteorológicos e de poluição atmosférica) nas infecções respiratórias. De 21/10/2004 a 01/06/2007 foi conduzido um estudo ecológico de séries temporais, em menores de 15 anos, com sintomas respiratórios atendidos na Santa Casa de São Paulo e no Hospital Universitário de Jundiaí para determinar a freqüência de HPIV, pela imunofluorescência indireta e verificar a relação entre poluentes atmosféricos, variáveis meteorológicas na infecção respiratória. Os dados meteorológicos e de poluição ambiental foram coletados diariamente. Das 1464 amostras o HPIV foi detectado em 49 (5,5%) amostras (SCSP) e em 29(5,0%) amostras (HUFMJ),sendo o HPIV3 mais prevalente.O Ozônio e Dióxido de Nitrogênio tiveram relação com vírus respiratórios em São Paulo. Em Jundiaí observou-se relação com material particulado (lag3) e HPIV. / Acute respiratory infections contribute to high infant morbidity and mortality, highlighting the parainfluenza (HPIV) in the frames of viral croup. Little is known the influence of environmental factors (meteorological and air pollution) in respiratory infections. From 21/10/2004 to 01/06/2007 was an ecological study of time series, for children under 15 years, with respiratory symptoms treated at Santa Casa de São Paulo and the University Hospital of Jundiaí to determine the frequency of HPIV by immunofluorescence and verify the relationship between air pollutants, meteorological variables in respiratory infection. The meteorological and environmental pollution were collected daily. 1464 samples of the HPIV was detected in 49 (5.5%) samples (SCSP) and 29 (5.0%) samples (HUFMJ) and the HPIV3 more prevalente.O Ozone and nitrogen dioxide were associated with respiratory viruses in Sao Paulo. In Jundiaí was observed relationship with particulate matter (lag3) and HPIV.