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.

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.

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.

Streptococcus pneumoniae (S. pneumoniae) és un colonitzador habitual del tracte respiratori superior dels humans. Es tracta d’un patogen comú de l’espècie humana que presenta una elevada taxa de morbiditat i mortalitat arreu del món. El bacteri pot causar otitis mitjana, sinusitis o infeccions de tracte respiratori superior, (per contigüitat) però també pot causar malaltia invasiva, quan habita en un territori habitualment estèril, produint pneumònia, bacterièmia, septicèmies i meningitis, entre d’altres. La malaltia pneumocòccica és un important problema de salut pública i és la principal causa individual de mortalitat infantil en el món. Segons dades de la Organització Mundial de la Salut (OMS), s’estima que a l’any 2000 es van produir 14.5 milions d’episodis greus de malaltia pneumocòccica, que va resultar en 826 000 morts en nens menors de dos anys. Un 61% d’aquestes morts es van produir a l’Àfrica subsahariana i al sud-est asiàtic. Tanmateix, en aquests països i, en especial a les zones rurals, les capacitats de diagnòstic són limitades o inexistents i la identificació de l’agent etiològic es basa en signes i símptomes clínics. És molt important aïllar l’agent etiològic causant de malaltia per tal de poder avaluar el millor tractament possible. No obstant, les tècniques actuals per al diagnòstic de la malaltia presenten una limitada sensibilitat i especificitat. El cultiu microbiològic, com a mètode de diagnòstic clàssic, té una baixa sensibilitat per a detectar el pneumococ. L’objectiu d’aquesta tesi és avaluar el potencial de les tècniques moleculars per al diagnòstic i caracterització de la malaltia pneumocòccica i discernir si l’ús de tècniques moleculars com la reacció en cadena de la polimerasa (PCR) poden suposar un avantatge tant per la rapidesa del mètode com per la detecció del patogen present en una mostra a baixa concentració. L’aplicació d’aquest tipus de tècniques en mostres biològiques impregnades en paper de filtre (dried-spot) i conservades a temperatura ambient poden ser un excel•lent sistema per a la detecció i serotipat de S. pneumoniae en països en vies de desenvolupament on la falta de recursos econòmics esdevé una de les principals limitacions. La capacitat del pneumococ de causar malaltia depèn de la presència d’una càpsula polisacàrida que impedeix la fagocitosi. Tot i que la presència de la càpsula és un requisit perquè produeixi malaltia, no és suficient per conferir virulència, sinó que són necessaris una varietat de factors determinants addicionals, com ara les adhesines, les proteases, les toxines, els sistemes de transport i enzims que modifiquen el medi extracel•lular. Recentment, s’ha descobert un determinant de virulència del pneumococ que és la proteïna rica en repeticions de serina, PsrP (Pneumococcal-serine rich protein). Es tracta d’una adhesina que intervé en l’adhesió del pneumococ a les cèl•lules pulmonars. PsrP és un important factor de virulència capaç de causar malaltia i un potencial candidat a una nova vacuna proteica. / Streptococcus pneumoniae (S. pneumoniae) is a common colonizer of the upper respiratory tract of humans. This is a major human pathogen and leading cause of morbidity and mortality worldwide. The bacteria can cause otitis media, sinusitis or upper respiratory tract infections (contiguity) but can also cause invasive disease, when living in an area usually sterile, causing pneumonia, bacteraemia, sepsis and meningitis, among others. According to the World Health Organization, in 2000, pneumococcal disease was estimated to have caused about 14.5 million severe episodes. There were approximately 826 000 deaths from pneumococcal disease in children under five years and 61% of these deaths occurred in sub-Saharan Africa and Southeast Asia. However, in these countries, especially in rural areas, diagnostic capabilities are limited or nonexistent and agent identification is based on clinical signs and symptoms. It is very important to isolate the etiologic agent of disease in order to assess the best treatment possible. However, present techniques for the diagnosis of the disease have a limited sensitivity and specificity. Microbiological culture, considered the “gold-standard” in microbiological diagnosis has low sensitivity to detect pneumococcus. The aim of this Thesis is to evaluate the potential of molecular techniques for diagnosis and characterization of pneumococcal disease and to discern whether the use of molecular techniques such as PCR, can be an advantage both for the speed of method as for the detection of the pathogen present in a sample in low concentration. The application of these techniques in biological samples impregnated filter paper (dried-spot) and kept at room temperature can be an excellent system for the detection and serotyping of S. pneumoniae in developing countries where lack of financial resources is a major constraint. The ability of the pneumococcus to cause disease depends on the presence of a polysaccharide capsule that prevents phagocytosis. Although the presence of the capsule is a requirement to produce disease, is not sufficient to confer virulence, but need a large number of additional factors such as adhesins, proteases, toxins, transportation systems and enzymes that modify the extracellular medium. One recently identified pneumococcal virulence determinant is the pneumococcal serine-rich repeat protein (PsrP). This is an adhesin involved in adherence of pneumococci to lung cells. PsrP is an important virulence factor capable of causing disease and a potential new vaccine candidate protein.

No description available.