BACKGROUND AND OBJECTIVE: Pneumonia is the leading cause of death of children. Diagnostic tools include chest radiography, but guidelines do not currently recommend the use of lung ultrasound (LUS) as a diagnostic method. We conducted a meta-analysis to summarize evidence on the diagnostic accuracy of LUS for childhood pneumonia. METHODS:We performed a systematic search in PubMed, Embase, the Cochrane Library, Scopus, Global Health, World Health Organization-Libraries, and Latin American and Caribbean Health Sciences Literature of studies comparing LUS diagnostic accuracy against a reference standard. We used a combination of controlled key words for age ,18 years, pneumonia, and ultrasound. We identified 1475 studies and selected 15 (1%) for further review. Eight studies (765 children) were retrieved for analysis, of which 6 (75%) were conducted in the general pediatric population and 2 (25%) in neonates. Eligible studies provided information to calculate sensitivity, specificity, and positive and negative likelihood ratios. Heterogeneity was assessed by using Q and I 2 statistics.RESULTS: Five studies (63%) reported using highly skilled sonographers. Overall methodologic quality was high, but heterogeneity was observed across studies. LUS had a sensitivity of 96% (95% confidence interval [CI]: 94%-97%) and specificity of 93% (95% CI: 90%-96%), and positive and negative likelihood ratios were 15.3 (95% CI: 6.6-35.3) and 0.06 (95% CI: 0.03-0.11), respectively. The area under the receiver operating characteristic curve was 0.98. Limitations included the following: most studies included in our analysis had a low number of patients, and the number of eligible studies was also small. Dr Pereda conceptualized and designed the study, reviewed all abstracts and selected articles to be included in the meta-analysis, was responsible for data collection, and drafted the initial manuscript; Dr Chavez conceptualized and designed the study, reviewed all abstracts and selected articles to be included in the meta-analysis, was responsible for data collection, led the analysis, and drafted the initial manuscript; Dr Hooper-Miele participated in analysis and interpretation of results, critically revised ultrasound methods used by selected studies, and reviewed and revised the manuscript; Drs Gilman, Steinhoff, Ellington, and Tielsch participated in the analysis and interpretation of results and reviewed and revised the manuscript; Ms Gross and Ms Price conducted the literature search and reviewed and revised the manuscript; Dr Checkley conceptualized and designed the study, contributed equally to the analysis, drafted the initial manuscript, and had ultimate oversight over the study conduct, analysis plan, and writing of the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.www.pediatrics.org/cgi

BackgroundGuidelines do not currently recommend the use of lung ultrasound (LUS) as an alternative to chest X-ray (CXR) or chest computerized tomography (CT) scan for the diagnosis of pneumonia. We conducted a meta-analysis to summarize existing evidence of the diagnostic accuracy of LUS for pneumonia in adults.MethodsWe conducted a systematic search of published studies comparing the diagnostic accuracy of LUS against a referent CXR or chest CT scan and/or clinical criteria for pneumonia in adults aged ≥18 years. Eligible studies were required to have a CXR and/or chest CT scan at the time of evaluation. We manually extracted descriptive and quantitative information from eligible studies, and calculated pooled sensitivity and specificity using the Mantel-Haenszel method and pooled positive and negative likelihood ratios (LR) using the DerSimonian-Laird method. We assessed for heterogeneity using the Q and I2 statistics.ResultsOur initial search strategy yielded 2726 articles, of which 45 (1.7%) were manually selected for review and 10 (0.4%) were eligible for analyses. These 10 studies provided a combined sample size of 1172 participants. Six studies enrolled adult patients who were either hospitalized or admitted to Emergency Departments with suspicion of pneumonia and 4 studies enrolled critically-ill adult patients. LUS was performed by highly-skilled sonographers in seven studies, by trained physicians in two, and one did not mention level of training. All studies were conducted in high-income settings. LUS took a maximum of 13 minutes to conduct. Nine studies used a 3.5-5 MHz micro-convex transducer and one used a 5–9 MHz convex probe. Pooled sensitivity and specificity for the diagnosis of pneumonia using LUS were 94% (95% CI, 92%-96%) and 96% (94%-97%), respectively; pooled positive and negative LRs were 16.8 (7.7-37.0) and 0.07 (0.05-0.10), respectively; and, the area-under-the-ROC curve was 0.99 (0.98-0.99).ConclusionsOur meta-analysis supports that LUS, when conducted by highly-skilled sonographers, performs well for the diagnosis of pneumonia. General practitioners and Emergency Medicine physicians should be encouraged to learn LUS since it appears to be an established diagnostic tool in the hands of experienced physicians.

Lapatinib demonstrated clinical activity and was well tolerated as first-line therapy in ErbB2-amplified locally advanced or metastatic breast cancer. This study supports further evaluation of lapatinib in first-line and early-stage ErbB2-overexpressing breast cancer.

BackgroundPneumonia is a leading cause of morbidity and mortality in children worldwide; however, its diagnosis can be challenging, especially in settings where skilled clinicians or standard imaging are unavailable. We sought to determine the diagnostic accuracy of lung ultrasound when compared to radiographically-confirmed clinical pediatric pneumonia.MethodsBetween January 2012 and September 2013, we consecutively enrolled children aged 2–59 months with primary respiratory complaints at the outpatient clinics, emergency department, and inpatient wards of the Instituto Nacional de Salud del Niño in Lima, Peru. All participants underwent clinical evaluation by a pediatrician and lung ultrasonography by one of three general practitioners. We also consecutively enrolled children without respiratory symptoms. Children with respiratory symptoms had a chest radiograph. We obtained ancillary laboratory testing in a subset.ResultsFinal clinical diagnoses included 453 children with pneumonia, 133 with asthma, 103 with bronchiolitis, and 143 with upper respiratory infections. In total, CXR confirmed the diagnosis in 191 (42%) of 453 children with clinical pneumonia. A consolidation on lung ultrasound, which is our primary endpoint for pneumonia, had a sensitivity of 88.5%, specificity of 100%, and an area under-the-curve of 0.94 (95% CI 0.92–0.97) when compared to radiographically-confirmed clinical pneumonia. When any abnormality on lung ultrasound was compared to radiographically-confirmed clinical pneumonia the sensitivity increased to 92.2% and the specificity decreased to 95.2%, with an area under-the-curve of 0.94 (95% CI 0.91–0.96).ConclusionsLung ultrasound had high diagnostic accuracy for the diagnosis of radiographically-confirmed pneumonia. Added benefits of lung ultrasound include rapid testing and high inter-rater agreement. Lung ultrasound may serve as an alternative tool for the diagnosis of pediatric pneumonia.

Pneumonia is one of the major causes of child mortality, yet with a timely diagnosis, it is usually curable with antibiotic therapy. In many developing regions, diagnosing pneumonia remains a challenge, due to shortages of medical resources. Lung ultrasound has proved to be a useful tool to detect lung consolidation as evidence of pneumonia. However, diagnosis of pneumonia by ultrasound has limitations: it is operator-dependent, and it needs to be carried out and interpreted by trained personnel. Pattern recognition and image analysis is a potential tool to enable automatic diagnosis of pneumonia consolidation without requiring an expert analyst. This paper presents a method for automatic classification of pneumonia using ultrasound imaging of the lungs and pattern recognition. The approach presented here is based on the analysis of brightness distribution patterns present in rectangular segments (here called “characteristic vectors“) from the ultrasound digital images. In a first step we identified and eliminated the skin and subcutaneous tissue (fat and muscle) in lung ultrasound frames, and the “characteristic vectors”were analyzed using standard neural networks using artificial intelligence methods. We analyzed 60 lung ultrasound frames corresponding to 21 children under age 5 years (15 children with confirmed pneumonia by clinical examination and X-rays, and 6 children with no pulmonary disease) from a hospital based population in Lima, Peru. Lung ultrasound images were obtained using an Ultrasonix ultrasound device. A total of 1450 positive (pneumonia) and 1605 negative (normal lung) vectors were analyzed with standard neural networks, and used to create an algorithm to differentiate lung infiltrates from healthy lung. A neural network was trained using the algorithm and it was able to correctly identify pneumonia infiltrates, with 90.9% sensitivity and 100% specificity. This approach may be used to develop operator-independent computer algorithms for pneumonia diagnosis using ultrasound in young children.

The WHO algorithm disagreed with point-of-care ultrasound findings in more than one-third of children and had an overall low performance when compared with point-of-care ultrasound to identify lung consolidation. A paired approach with point-of-care ultrasound may improve case management in resource-limited settings.

Mast cells (MCs) play pivotal roles in many inflammatory conditions including infections, anaphylaxis, and asthma. MCs store immunoregulatory compounds in their large cytoplasmic granules and, upon stimulation, secrete them via regulated exocytosis. Exocytosis in many cells requires the participation of Munc18 proteins (also known as syntaxin-binding proteins), and we found that mature MCs express all three mammalian isoforms: Munc18-1, -2, and -3. To study their functions in MC effector responses and test the role of MC degranulation in anaphylaxis, we used conditional knockout (cKO) mice in which each Munc18 protein was deleted exclusively in MCs. Using recordings of plasma membrane capacitance for high-resolution analysis of exocytosis in individual MCs, we observed an almost complete absence of exocytosis in Munc18-2-deficient MCs but intact exocytosis in MCs lacking Munc18-1 or Munc18-3. Stereological analysis of EM images of stimulated MCs revealed that the deletion of Munc18-2 also abolishes the homotypic membrane fusion required for compound exocytosis. We confirmed the severe defect in regulated exocytosis in the absence of Munc18-2 by measuring the secretion of mediators stored in MC granules. Munc18-2 cKO mice had normal morphology, development, and distribution of their MCs, indicating that Munc18-2 is not essential for the migration, retention, and maturation of MC-committed progenitors. Despite that, we found that Munc18-2 cKO mice were significantly protected from anaphylaxis. In conclusion, MC-regulated exocytosis is required for the anaphylactic response, and Munc18-2 is the sole Munc18 isoform that mediates membrane fusion during MC degranulation.

The study examines the impact of the introduction of 10-valent Pneumococcal Conjugate Vaccine (PCV10) into Bangladesh’s national vaccine program. PCV10 is administered to children under 1 year-old; the scheduled ages of administration are at 6, 10, and 18 weeks. The study is conducted in ~770,000 population containing ~90,000 <5 children in Sylhet, Bangladesh and has five objectives: 1) To collect data on community-based pre-PCV incidence rates of invasive pneumococcal diseases (IPD) in 0-59 month-old children in Sylhet, Bangladesh; 2) To evaluate the effectiveness of PCV10 introduction on Vaccine Type (VT) IPD in 3-59 month-old children using an incident case-control study design. Secondary aims include measuring the effects of PCV10 introduction on all IPD in 3-59 month-old children using case-control study design, and quantifying the emergence of Non Vaccine Type IPD; 3) To evaluate the effectiveness of PCV10 introduction on chest radiograph-confirmed pneumonia in children 3-35 months old using incident case-control study design. We will estimate the incidence trend of clinical and radiologically-confirmed pneumonia in 3-35 month-old children in the study area before and after introduction of PCV10; 4) To determine the feasibility and utility of lung ultrasound for the diagnosis of pediatric pneumonia in a large sample of children in a resource-limited setting. We will also evaluate the effectiveness of PCV10 introduction on ultrasound-confirmed pneumonia in 3-35 month-old children using an incident case-control design and to examine the incidence trend of ultrasound-confirmed pneumonia in 3-35 month-old children in the study area before and after PCV10 introduction; and 5) To determine the direct and indirect effects of vaccination status on nasopharyngeal colonization on VT pneumococci among children with pneumonia .  This paper presents the methodology. The study will allow us to conduct a comprehensive and robust assessment of the impact of national introduction of PCV10 on pneumococcal disease in Bangladesh.