Vaccine trial as “probe” to define the burden of pneumococcal pneumonia disease [Comment]

In today's Lancet, Felicity Cutts and colleagues present their findings on the randomised double-blind placebo controlled trial on the efficacy of a nine-valent pneumococcal conjugate-vaccine (9PCV) against radiologically confirmed pneumonia and invasive pneumococcal disease in children immunised before 12 months of age in The Gambia. The study site is a rural African setting with high child-mortality, a low prevalence of HIV-1 infection in pregnant mothers, and with endemic malaria. The authors report a vaccine efficacy of 37% (95% CI 27–45%) against first-episodes of radiological pneumonia in a per-protocol analysis. Intention-to-treat analysis showed similar results. The investigators also found that the vaccine could significantly reduce the incidence of vaccine-type invasive pneumococcal disease by 77%, by 50% for all-serotype invasive pneumococcal disease, by 15% for all-cause health-facility admissions, and by 16% for overall child mortality.

Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study.

PURPOSE To develop a score predicting the risk of adverse events (AEs) in pediatric patients with cancer who experience fever and neutropenia (FN) and to evaluate its performance. PATIENTS AND METHODS Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of future AEs (ie, serious medical complication, microbiologically defined infection, radiologically confirmed pneumonia) was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. Results An AE was reported in 122 (29%) of 423 FN episodes. In 57 episodes (13%), the first AE was known only after reassessment after 8 to 24 hours of inpatient management. Predicting AE at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The score predicting future AE in 358 episodes without known AE at reassessment used the following four variables: preceding chemotherapy more intensive than acute lymphoblastic leukemia maintenance (weight = 4), hemoglobin > or = 90 g/L (weight = 5), leukocyte count less than 0.3 G/L (weight = 3), and platelet count less than 50 G/L (weight = 3). A score (sum of weights) > or = 9 predicted future AEs. The cross-validated performance of this score exceeded the performance of published risk prediction rules. At an overall sensitivity of 92%, 35% of the episodes were classified as low risk, with a specificity of 45% and a negative predictive value of 93%. CONCLUSION This score, based on four routinely accessible characteristics, accurately identifies pediatric patients with cancer with FN at risk for AEs after reassessment.

Predicting Adverse Events in Children with Fever and Chemotherapy-Induced Neutropenia. Results of the Prospective Multicenter SPOG 2003 FN Study

PURPOSE To develop a score predicting the risk of adverse events (AEs) in pediatric patients with cancer who experience fever and neutropenia (FN) and to evaluate its performance. PATIENTS AND METHODS Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of future AEs (ie, serious medical complication, microbiologically defined infection, radiologically confirmed pneumonia) was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. Results An AE was reported in 122 (29%) of 423 FN episodes. In 57 episodes (13%), the first AE was known only after reassessment after 8 to 24 hours of inpatient management. Predicting AE at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The score predicting future AE in 358 episodes without known AE at reassessment used the following four variables: preceding chemotherapy more intensive than acute lymphoblastic leukemia maintenance (weight = 4), hemoglobin > or = 90 g/L (weight = 5), leukocyte count less than 0.3 G/L (weight = 3), and platelet count less than 50 G/L (weight = 3). A score (sum of weights) > or = 9 predicted future AEs. The cross-validated performance of this score exceeded the performance of published risk prediction rules. At an overall sensitivity of 92%, 35% of the episodes were classified as low risk, with a specificity of 45% and a negative predictive value of 93%. CONCLUSION This score, based on four routinely accessible characteristics, accurately identifies pediatric patients with cancer with FN at risk for AEs after reassessment.

Beyond malaria--causes of fever in outpatient Tanzanian children.

BACKGROUND: As the incidence of malaria diminishes, a better understanding of nonmalarial fever is important for effective management of illness in children. In this study, we explored the spectrum of causes of fever in African children. METHODS: We recruited children younger than 10 years of age with a temperature of 38°C or higher at two outpatient clinics--one rural and one urban--in Tanzania. Medical histories were obtained and clinical examinations conducted by means of systematic procedures. Blood and nasopharyngeal specimens were collected to perform rapid diagnostic tests, serologic tests, culture, and molecular tests for potential pathogens causing acute fever. Final diagnoses were determined with the use of algorithms and a set of prespecified criteria. RESULTS: Analyses of data derived from clinical presentation and from 25,743 laboratory investigations yielded 1232 diagnoses. Of 1005 children (22.6% of whom had multiple diagnoses), 62.2% had an acute respiratory infection; 5.0% of these infections were radiologically confirmed pneumonia. A systemic bacterial, viral, or parasitic infection other than malaria or typhoid fever was found in 13.3% of children, nasopharyngeal viral infection (without respiratory symptoms or signs) in 11.9%, malaria in 10.5%, gastroenteritis in 10.3%, urinary tract infection in 5.9%, typhoid fever in 3.7%, skin or mucosal infection in 1.5%, and meningitis in 0.2%. The cause of fever was undetermined in 3.2% of the children. A total of 70.5% of the children had viral disease, 22.0% had bacterial disease, and 10.9% had parasitic disease. CONCLUSIONS: These results provide a description of the numerous causes of fever in African children in two representative settings. Evidence of a viral process was found more commonly than evidence of a bacterial or parasitic process. (Funded by the Swiss National Science Foundation and others.).

Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study

PURPOSE To develop a score predicting the risk of adverse events (AEs) in pediatric patients with cancer who experience fever and neutropenia (FN) and to evaluate its performance. PATIENTS AND METHODS Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of future AEs (ie, serious medical complication, microbiologically defined infection, radiologically confirmed pneumonia) was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. Results An AE was reported in 122 (29%) of 423 FN episodes. In 57 episodes (13%), the first AE was known only after reassessment after 8 to 24 hours of inpatient management. Predicting AE at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The score predicting future AE in 358 episodes without known AE at reassessment used the following four variables: preceding chemotherapy more intensive than acute lymphoblastic leukemia maintenance (weight = 4), hemoglobin > or = 90 g/L (weight = 5), leukocyte count less than 0.3 G/L (weight = 3), and platelet count less than 50 G/L (weight = 3). A score (sum of weights) > or = 9 predicted future AEs. The cross-validated performance of this score exceeded the performance of published risk prediction rules. At an overall sensitivity of 92%, 35% of the episodes were classified as low risk, with a specificity of 45% and a negative predictive value of 93%. CONCLUSION This score, based on four routinely accessible characteristics, accurately identifies pediatric patients with cancer with FN at risk for AEs after reassessment.

Nasopharyngeal carriage of individual Streptococcus pneumoniae serotypes during pediatric radiologically confirmed community acquired pneumonia following PCV7 introduction in Switzerland.

BACKGROUND: Community-acquired pneumonia (CAP) is a serious cause of morbidity among children in developed countries. The real impact of 7-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal pneumonia is difficult to assess accurately. METHODS: Children aged ≤16 years with clinical and radiological pneumonia were enrolled in a multicenter prospective study. Children aged ≤16 years admitted for a minor elective surgery was recruited as controls. Nasopharyngeal samples for PCR serotyping of S. pneumoniae were obtained in both groups. Informations on age, gender, PCV7 vaccination status, day care/school attendance, siblings, tobacco exposure were collected. RESULTS: In children with CAP (n=236), 54% of the nasopharyngeal swabs were PCR-positive for S. pneumoniae compared to 32% in controls (n=105) (p=0.003). Serotype 19A was the most common pneumococcal serotype carried in children with CAP (13%) and in controls (15%). Most common serotypes were non-vaccine types (39.4% for CAP and 47.1% for controls) and serotypes included only in PCV13 (32.3% for CAP and 23.5% for controls). There was no significant difference in vaccine serotype distribution between the two groups. In fully vaccinated children with CAP, the proportion of serotypes carried only in PCV13 was higher (51.4%) than in partially vaccinated or non vaccinated children (27.6% and 28.6% respectively, p=0.037). CONCLUSIONS: Two to 4 years following introduction of PCV7, predominant S. pneumoniae serotypes carried in children with CAP were non PCV7 serotypes, and the 6 new serotypes included in PCV13 accounted for 51.4% of carried serotypes in fully vaccinated children.

Abnormal expression of telomerase/apoptosis limits type II alveolar epithelial cell replication in the early remodeling of usual interstitial pneumonia/idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a distinctive, usually fatal, type of chronic fibrosing interstitial pneumonia of unknown cause that increases in prevalence with advanced age, characterized by failure of alveolar re-epithelization and progressive scar formation. Recently, limitation of the replicative capacity of tissues determined by telomerase/apoptosis balance has been implicated in pathogenesis of age-related diseases. In this study, we validated the importance of the expression of type 2 alveolar epithelial cells telomerase protein and studied the relationships between telomerase and apoptosis in early remodeling of usual interstitial pneumonia. We determined type 2 alveolar epithelial cells density, telomerase expression, and apoptosis in surgical lung biopsies from 24 patients with usual interstitial pneumonia, and in normal lung tissues from 18 subjects. We used immunohistochemistry, deoxynucleotidyl transferase method of end labeling, electron microscopy, and histomorphometry to evaluate the amount of type 2 alveolar epithelial cells staining for surfactant-A, telomerase, and in situ detection of apoptotic cells. Unaffected areas of usual interstitial pneumonia and normal lung tissue had similar densities of type 2 alveolar epithelial cells, but a significant minor subpopulation of type 2 alveolar epithelial cells was telomerase positive and a large population was telomerase negative. A significant inverse association was found between low type 2, alveolar. epithelial cell telomerase expression and high apoptosis in unaffected areas of usual interstitial pneumonia. Although type 2 alveolar epithelial cell telomerase expression was higher than apoptosis in NLT group, no significant association was found between them. Electron microscopy confirmed epithelial apoptosis, alveolar collapse, and initial fibroplasia. We conclude that abnormal type 2 alveolar epithelial cells telomerase/apoptosis balance may reduce alveolar epithelial regenerative capacity, thus contributing to the early remodeling response in usual interstitial pneumonia. (C) 2010 Elsevier Inc. All rights reserved.

Secondary bronchiolitis obliterans organizing pneumonia during treatment of chronic hepatitis C: role of pegylated interferon alfa-2a

The treatment of chronic hepatitis C has frequent side effects such as cytopenias and neuropsychiatric symptoms. However, pulmonary toxicity associated with interferon is rarely described. This paper describes the clinical case of a 67-year-old female patient with chronic hepatitis C who presented an acute onset of dry cough, dyspnoea, and fever 36 weeks after the use of pegylated interferon alfa-2a and ribavirin. The lung biopsy confirmed the diagnosis of a bronchiolitis obliterans organizing pneumonia (BOOP). Corticotherapy was initiated, with clinical and radiological improvement. This paper aims to advise physicians to this occasional, though severe, adverse event related to hepatitis C virus (HCV) treatment.

Morphological and virological studies in six autopsies of children with adenovirus pneumonia

Pulmonary lesions compatible with adenovirus infection were detected by gross and microscopic examination of autopsy tissues children aged from 5 to 34 months. Hepatic lesions indicative of systemic infection were also found in four of the chisldren. The viral etiology was confirmed in three cases by in-situ hibridization, electro-microscopy and immunofluorescence performed in parafin-embedded tissues, and in one case by cell culture isolation of adenovirus type 2 from nasopharyngeal exudate. Routine testing by methods additional to conventional light microscopy would probably have revealed a larger number of adenovirus infections among the 1.103 autopsy records analyzed in this study.

Immunity to pneumococcal surface proteins in children with community-acquired pneumonia: a distinct pattern of responses to pneumococcal choline-binding protein A.

Clin Microbiol Infect ABSTRACT: The aetiological diagnosis of community-acquired pneumonia (CAP) is challenging in children, and serological markers would be useful surrogates for epidemiological studies of pneumococcal CAP. We compared the use of anti-pneumolysin (Ply) antibody alone or with four additional pneumococcal surface proteins (PSPs) (pneumococcal histidine triad D (PhtD), pneumococcal histidine triad E (PhtE), LytB, and pneumococcal choline-binding protein A (PcpA)) as serological probes in children hospitalized with CAP. Recent pneumococcal exposure (positive blood culture for Streptococcus pneumoniae, Ply(+) blood PCR finding, and PSP seroresponse) was predefined as supporting the diagnosis of presumed pneumococcal CAP (P-CAP). Twenty-three of 75 (31%) children with CAP (mean age 33.7 months) had a Ply(+) PCR finding and/or a ≥2-fold increase of antibodies. Adding seroresponses to four PSPs identified 12 additional patients (35/75, 45%), increasing the sensitivity of the diagnosis of P-CAP from 0.44 (Ply alone) to 0.94. Convalescent anti-Ply and anti-PhtD antibody titres were significantly higher in P-CAP than in non P-CAP patients (446 vs. 169 ELISA Units (EU)/mL, p 0.031, and 189 vs. 66 EU/mL, p 0.044), confirming recent exposure. Acute anti-PcpA titres were three-fold lower (71 vs. 286 EU/mL, p <0.001) in P-CAP children. Regression analyses confirmed a low level of acute PcpA antibodies as the only independent predictor (p 0.002) of P-CAP. Novel PSPs facilitate the demonstration of recent pneumococcal exposure in CAP children. Low anti-PcpA antibody titres at admission distinguished children with P-CAP from those with CAP with a non-pneumococcal origin.

Pseudomonas aeruginosa serotypes in nosocomial pneumonia: prevalence and clinical outcomes.

INTRODUCTION: Pseudomonas aeruginosa frequently causes nosocomial pneumonia and is associated with poor outcome. The purpose of this study was to assess the prevalence and clinical outcome of nosocomial pneumonia caused by serotype-specific P. aeruginosa in critically ill patients under appropriate antimicrobial therapy management. METHODS: A retrospective, non-interventional epidemiological multicenter cohort study involving 143 patients with confirmed nosocomial pneumonia caused by P. aeruginosa. Patients were analyzed for a period of 30 days from time of nosocomial pneumonia onset. Fourteen patients fulfilling the same criteria from a phase IIa studyconducted at the same time/centers were included in the prevalence calculations but not in the clinical outcome analysis. RESULTS: The prevalence of serotypes was: O6 (29%), O11 (23%), O10 (10%), O2 (9%), and O1 (8%). Serotypes with a prevalence of less than 5% were found in 13% of patients, 8% were classified as not typeable. Across all serotypes, 19% mortality, 70% clinical resolution, 11% clinical continuation, and 5% clinical recurrence were recorded. Age and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) were predictive risk factors associated with probability of death and lower clinical resolution for P. aeruginosa nosocomial pneumonia. Mortality tends to be higher with O1 (40%) and lower with O2 (0%); clinical resolution tends to be better with O2 (82%) compared to other serotypes. Persisting pneumonia with O6 and O11 was, respectively, 8% and 21%; clinical resolution with O6 and O11 was, respectively, 75% and 57%. CONCLUSIONS: In P. aeruginosa nosocomial pneumonia, the most prevalent serotypes were O6 and O11. Further studies including larger group sizes are needed to correlate clinical outcome with virulence factors of P. aeruginosa in patients with nosocomial pneumonia caused by various serotypes; and to compare O6 and O11, the two serotypes most frequently encountered in critically ill patients.

Modeling pulmonary fibrosis by abnormal expression of telomerase/apoptosis/collagen V in experimental usual interstitial pneumonia

Limitations on tissue proliferation capacity determined by telomerase/apoptosis balance have been implicated in pathogenesis of idiopathic pulmonary fibrosis. In addition, collagen V shows promise as an inductor of apoptosis. We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration. Two groups of mice were analyzed: 20 mice received BHT, and 10 control mice received corn oil. Telomerase expression, apoptosis, collagen I, III, and V fibers, and hydroxyproline were evaluated by immunohistochemistry, in situ detection of apoptosis, electron microscopy, immunofluorescence, and histomorphometry. Electron microscopy confirmed the presence of increased alveolar epithelial cells type 1 (AEC1) in apoptosis. Immunostaining showed increased nuclear expression of telomerase in AEC type 2 (AEC2) between normal and chronic scarring areas of usual interstitial pneumonia (UIP). Control lungs and normal areas from UIP lungs showed weak green birefringence of type I and III collagens in the alveolar wall and type V collagen in the basement membrane of alveolar capillaries. The increase in collagen V was greater than collagens I and III in scarring areas of UIP. A significant direct association was found between collagen V and AEC2 apoptosis. We concluded that telomerase, collagen V fiber density, and apoptosis evaluation in experimental UIP offers the potential to control reepithelization of alveolar septa and fibroblast proliferation. Strategies aimed at preventing high rates of collagen V synthesis, or local responses to high rates of cell apoptosis, may have a significant impact in pulmonary fibrosis.

Eficácia da fisioterapia respiratória em pacientes pediátricos hospitalizados com pneumonia adquirida na comunidade : um ensaio clínico randomizado

Objetivo: Avaliar a eficácia da fisioterapia respiratória como tratamento adjuvante em pacientes pediátricos com pneumonia adquirida na comunidade. Delineamento: Ensaio clínico randomizado Local do estudo: Hospital da Criança Santo Antônio – Complexo Hospitalar Santa Casa, Porto Alegre, Brasil. Participantes e métodos: Foram arroladas crianças com idade entre 1 e 12 anos, com diagnóstico clínico e radiológico confirmado de pneumonia, hospitalizadas no período de setembro de 2001 a setembro de 2002. Os pacientes que preencheram os critérios de inclusão foram randomizados para receber fisioterapia respiratória três vezes ao dia (grupo intervenção) ou para receber, uma vez ao dia, orientações para respirar profundamente, expectorar a secreção e manter preferencialmente o decúbito lateral (grupo controle). As variáveis analisadas na linha de base, no primeiro e no segundo períodos de seguimento e no dia da alta hospitalar foram: escore de gravidade (composto pela freqüência respiratória anormal para a idade, tiragem supra-esternal, intercostal, e subcostal, febre, saturação de oxigênio da hemoglobina e raio-x de tórax), duração da hospitalização, freqüência respiratória, temperatura e saturação do oxigênio. Resultados: Setenta e dois pacientes foram randomizados para os grupos intervenção ou controle. Destes, sete foram retirados devido a complicações como atelectasia ou drenagem pleural. Dentre os 65 pacientes estudados no primeiro seguimento (terceiro dia), a febre foi mais prevalente no grupo intervenção (34,4%) do que no grupo controle (12,5%), bem como o escore de gravidade 9,63 ± 1,62 e 8,71 ± 0,86 pontos, respectivamente. No segundo seguimento, entre o quarto e sexto dia, a diferença entre os grupos teve tendência à significância apenas para febre, 31,6% no grupo intervenção e 6,7% no grupo controle (P= 0,07). A duração média da hospitalização foi de 7,41 ± 6,58 dias para o grupo intervenção e 4,52 ± 2,21 dias para o controle. Conclusão: Neste ensaio clínico, a fisioterapia prolongou a hospitalização e a duração da febre nos pacientes pediátricos com pneumonia adquirida na comunidade. Nestes pacientes, a fisioterapia é prejudicial e não deveria ser prescrita até que evidências de benefício estejam disponíveis.

Pneumonia and bacteremia in a golden-headed lion tamarin (Leontopithecus chrysomelas) caused by Klebsiella pneumoniae subsp pneumoniae during a translocation program of free-ranging animals in Brazil

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Human bocavirus infection diagnosed serologically among children admitted to hospital with community-acquired pneumonia in a tropical region

Human bocavirus (HBoV) is a human virus associated with respiratory disease in children. Limited information is available on acute infection with HBoV among children admitted to hospital with community-acquired pneumonia in tropical regions and the current diagnosis is inadequate. The aims were to diagnose and describe acute HBoV infections among children hospitalized for community-acquired pneumonia. In Salvador, Brazil, 277 children with community-acquired pneumonia were prospectively enrolled. Paired serum samples were tested by IgG, IgM, and IgG-avidity enzyme immunoassays (EIAs) using recombinant HBoV VP2. HBoV DNA was detected in nasopharyngeal aspirates and serum by a quantitative polymerase-chain reaction (PCR). HBoV DNA was detected in nasopharyngeal aspirates of 62/268 (23%) children and 156/273 (57%) were seropositive. Acute primary HBoV infection was reliably diagnosed (bearing at least two acute markers: Positive IgM, a fourfold increase/conversion of IgG, low IgG avidity or viremia) in 21 (8%) of 273 patients, 90% of 20 had HBoV DNA in nasopharyngeal aspirates, 83% with a high DNA load. The median age of infection with HBoV was 16 months, range 5-36.Community-acquired pneumonia was confirmed radiographically in 85% of 20 patients with acute HBoV infection diagnosed serologically. HBoV DNA was found in nasopharyngeal aspirates of 42/246(17%) children without an acute primary HBoV infection and available nasopharyngeal aspirate. Four children with HBoV secondary immune responses were detected, lacking both IgM and viremia. HBoV infection was diagnosed accurately in children aged 5-36 months with community-acquired pneumonia confirmed radiographically. PCR of nasopharyngeal aspirates is not a reliable marker of acute HBoV infection. J. Med. Virol. 84:253-258, 2012. (C) 2011 Wiley Periodicals, Inc.