Predicting Usual Interstitial Pneumonia Histopathology From Chest CT Imaging With Deep Learning.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal form of interstitial lung disease (ILD) characterized by the absence of a known cause and usual interstitial pneumonitis (UIP) pattern on chest CT imaging and/or histopathology. Distinguishing UIP/IPF from other ILD subtypes is essential given different treatments and prognosis. Lung biopsy is necessary when noninvasive data are insufficient to render a confident diagnosis. RESEARCH QUESTION: Can we improve noninvasive diagnosis of UIP be improved by predicting ILD histopathology from CT scans by using deep learning? STUDY DESIGN AND METHODS: This study retrospectively identified a cohort of 1,239 patients in a multicenter database with pathologically proven ILD who had chest CT imaging. Each case was assigned a label based on histopathologic diagnosis (UIP or non-UIP). A custom deep learning model was trained to predict class labels from CT images (training set, n = 894) and was evaluated on a 198-patient test set. Separately, two subspecialty-trained radiologists manually labeled each CT scan in the test set according to the 2018 American Thoracic Society IPF guidelines. The performance of the model in predicting histopathologic class was compared against radiologists' performance by using area under the receiver-operating characteristic curve as the primary metric. Deep learning model reproducibility was compared against intra-rater and inter-rater radiologist reproducibility. RESULTS: For the entire cohort, mean patient age was 62 ± 12 years, and 605 patients were female (49%). Deep learning performance was superior to visual analysis in predicting histopathologic diagnosis (area under the receiver-operating characteristic curve, 0.87 vs 0.80, respectively; P < .05). Deep learning model reproducibility was significantly greater than radiologist inter-rater and intra-rater reproducibility (95% CI for difference in Krippendorff's alpha did not include zero). INTERPRETATION: Deep learning may be superior to visual assessment in predicting UIP/IPF histopathology from CT imaging and may serve as an alternative to invasive lung biopsy.

Observer Performance for Detection of Pulmonary Nodules at Chest CT over a Large Range of Radiation Dose Levels.

Background There is a wide variation in radiation dose levels that can be used with chest CT in order to detect indeterminate pulmonary nodules. Purpose To compare the performance of lower-radiation-dose chest CT with that of routine dose in the detection of indeterminate pulmonary nodules 5 mm or greater. Materials and Methods In this retrospective study, CT projection data from 83 routine-dose chest CT examinations performed in 83 patients (120 kV, 70 quality reference mAs [QRM]) were collected between November 2013 and April 2014. Reference indeterminate pulmonary nodules were identified by two nonreader thoracic radiologists. By using validated noise insertion, five lower-dose data sets were reconstructed with filtered back projection (FBP) or iterative reconstruction (IR; 30 QRM with FBP, 10 QRM with IR, 5 QRM with FBP, 5 QRM with IR, and 2.5 QRM with IR). Three thoracic radiologists circled pulmonary nodules, rating confidence that the nodule was a 5-mm-or-greater indeterminate pulmonary nodule, and graded image quality. Analysis was performed on a per-nodule basis by using jackknife alternative free-response receiver operating characteristic figure of merit (FOM) and noninferiority limit of -0.10. Results There were 66 indeterminate pulmonary nodules (mean size, 8.6 mm ± 3.4 [standard deviation]; 21 part-solid nodules) in 42 patients (mean age, 51 years ± 17; 21 men and 21 women). Compared with the FOM for routine-dose CT (size-specific dose estimate, 6.5 mGy ± 1.8; FOM, 0.86 [95% confidence interval: 0.80, 0.91]), FOM was noninferior for all lower-dose configurations except for 2.5 QRM with IR. The sensitivity for subsolid nodules at 70 QRM was 60% (range, 48%-72%) and was significantly worse at a dose of 5 QRM and lower, whether or not IR was used (P < .05). Diagnostic image quality decreased with decreasing dose (P < .001) and was better with IR at 5 QRM (P < .05). Conclusion CT images reconstructed at dose levels down to 10 quality reference mAs (size-specific dose estimate, 0.9 mGy) had noninferior performance compared with routine dose in depicting pulmonary nodules. Iterative reconstruction improved subjective image quality but not performance at low dose levels. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by White and Kazerooni in this issue.

Pulmonary hyalinising granuloma: a rare and elusive cause of multiple lung nodules.

A 72-year-old woman was referred with incidentally detected multiple lung nodules, one of which was identified as 18F-fluorodeoxyglucose (FDG)-avid on positron emission tomography. Extensive workup followed, including numerous radiographs, surveillance scans and a CT-guided biopsy which demonstrated chronic inflammation only. Following a wedge-resection, a diagnosis of pulmonary hyalinising granuloma (PHG) was made. PHG is a cause of FDG-avid single or multiple pulmonary nodules and can mimic lung cancer or metastatic disease radiologically. The diagnosis is often difficult to make with minimally invasive techniques such as needle-guided biopsies which do not tend to yield the diagnosis and requires surgical resection for definitive diagnosis and exclusion of malignancy.

Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection.

BACKGROUNDRespiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T cells play a key role in antiviral immunity, but they have been little studied in the human lung.METHODSHealthy adult volunteers were inoculated i.n. with RSV A Memphis 37. CD4+ T cells in blood and the lower airway were analyzed by flow cytometry and immunohistochemistry. Bronchial soluble mediators were measured using quantitative PCR and MesoScale Discovery. Epitope mapping was performed by IFN-γ ELISpot screening, confirmed by in vitro MHC binding.RESULTSActivated CD4+ T cell frequencies in bronchoalveolar lavage correlated strongly with local C-X-C motif chemokine 10 levels. Thirty-nine epitopes were identified, predominantly toward the 3' end of the viral genome. Five novel MHC II tetramers were made using an immunodominant EFYQSTCSAVSKGYL (F-EFY) epitope restricted to HLA-DR4, -DR9, and -DR11 (combined allelic frequency: 15% in Europeans) and G-DDF restricted to HLA-DPA1*01:03/DPB1*02:01 and -DPA1*01:03/DPB1*04:01 (allelic frequency: 55%). Tetramer labeling revealed enrichment of resident memory CD4+ T (Trm) cells in the lower airway; these Trm cells displayed progressive differentiation, downregulation of costimulatory molecules, and elevated CXCR3 expression as infection evolved.CONCLUSIONSHuman infection challenge provides a unique opportunity to study the breadth of specificity and dynamics of RSV-specific T-cell responses in the target organ, allowing the precise investigation of Trm recognizing novel viral antigens over time. The new tools that we describe enable precise tracking of RSV-specific CD4+ cells, potentially accelerating the development of effective vaccines.TRIAL REGISTRATIONClinicalTrials.gov NCT02755948.FUNDINGMedical Research Council, Wellcome Trust, National Institute for Health Research.

Prospective Pilot Evaluation of Radiologists and Computer-aided Pulmonary Nodule Detection on Ultra-low-Dose CT With Tin Filtration.

PURPOSE: The aim of this study was to evaluate the ability of computer-aided detection (CAD) and human readers to detect pulmonary nodules ≥5 mm using 100 kV ultra-low-dose computed tomography (ULDCT) utilizing a tin filter. MATERIALS AND METHODS: After informed consent, 55 patients prospectively underwent standard-dose chest CT (SDCT) using 120 kV followed by ULDCT using 100 kV/tin. Reference nodules ≥5 mm were identified by a thoracic radiologist using SDCT. Four thoracic radiologists marked detected nodules on SDCT and ULDCT examinations using a dedicated computer workstation. After a 6-month memory extinction, readers were shown the same ULDCT cases with all CAD markings as well as their original detections, and characterized CAD detections as true positive or false positive. RESULTS: Volume CT Dose index (CTDIvol) for SDCT and ULDCT were 5.3±2 and 0.4±0.2 mGy (P<0.0001), respectively. Forty-five reference nodules were detected in 30 patients. Reader sensitivity varied widely but similarly for SDCT (ranging from 45% to 87%) and ULDCT (45% to 83%). CAD sensitivity was 76% (34/45) for SDCT and 71% (32/45) for ULDCT. After CAD, reader sensitivity substantially improved by 19% and 18% for 2 readers, and remained nearly unchanged for the other 2 readers (0% and 2%), despite reader perception that many more nodules were identified with CAD. There was a mean of 2 false-positive CAD detections/case. CONCLUSIONS: ULDCT with 100 kV/tin reduced patient dose by over 90% without compromising pulmonary nodule detection sensitivity. CAD can substantially improve nodule detection sensitivity at ULDCT for some readers, maintaining interobserver performance.

The flip-flop fungus sign: an FDG PET/CT sign of benignity.

Benign granulomatous processes such as fungal infection may mimic metastatic lung cancer on FDG PET/CT. We found that these processes often have draining lymph node(s) with equal or greater FDG activity than associated lung nodule(s), a "flip-flop" of what is commonly seen in lung cancer. The aim of this study was to examine the utility of this "flip-flop fungus" (FFF) sign for diagnosing benign pulmonary disease. FDG PET/CT scans performed between 9/09-3/13 for the indications of pulmonary nodule or mass were reviewed. Scans with at least one hilar or mediastinal FDG avid draining node were included. Patients with a history of cancer, lack of pathologic confirmation, or without at least two years of imaging follow-up were excluded. A total of 209 FDG PET/CT exams were included and reviewed in a blinded fashion. A positive FFF sign had a sensitivity of 60.0% (95% CI: 47.6-71.5%) and specificity of 84.9% (95% CI: 77.8-90.4%) (P<0.0001) for benign disease. With additional strict imaging criteria applied, the FFF sign had a specificity of 98.6% (95% CI: 94.9-99.8%) (P<0.0001) and a positive predictive value of 90.0% (95% CI: 68.3-98.5%). A positive FFF sign was predominately due to granulomatous disease (91%), mostly histoplasmosis (73%). A positive FFF sign combined with positive fungal serology (n=16) had a specificity of 100% for benign disease. The FFF sign predicts benign disease in patients with a lung nodule(s) and an FDG avid draining lymph node(s) that would otherwise be considered worrisome for cancer.

Rhinovirus induction of fractalkine (CX3CL1) in airway and peripheral blood mononuclear cells in asthma.

Rhinovirus infection is associated with the majority of asthma exacerbations. The role of fractalkine in anti-viral (type 1) and pathogenic (type 2) responses to rhinovirus infection in allergic asthma is unknown. To determine whether (1) fractalkine is produced in airway cells and in peripheral blood leucocytes, (2) rhinovirus infection increases production of fractalkine and (3) levels of fractalkine differ in asthmatic compared to non-asthmatic subjects. Fractalkine protein and mRNA levels were measured in bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMCs) from non-asthmatic controls (n = 15) and mild allergic asthmatic (n = 15) subjects. Protein levels of fractalkine were also measured in macrophages polarised ex vivo to give M1 (type 1) and M2 (type 2) macrophages and in BAL fluid obtained from mild (n = 11) and moderate (n = 14) allergic asthmatic and non-asthmatic control (n = 10) subjects pre and post in vivo rhinovirus infection. BAL cells produced significantly greater levels of fractalkine than PBMCs. Rhinovirus infection increased production of fractalkine by BAL cells from non-asthmatic controls (P<0.01) and in M1-polarised macrophages (P<0.05), but not in BAL cells from mild asthmatics or in M2 polarised macrophages. Rhinovirus induced fractalkine in PBMCs from asthmatic (P<0.001) and healthy control subjects (P<0.05). Trends towards induction of fractalkine in moderate asthmatic subjects during in vivo rhinovirus infection failed to reach statistical significance. Fractalkine may be involved in both immunopathological and anti-viral immune responses to rhinovirus infection. Further investigation into how fractalkine is regulated across different cell types and into the effect of stimulation including rhinovirus infection is warranted to better understand the precise role of this unique dual adhesion factor and chemokine in immune cell recruitment.

Estimation of Observer Performance for Reduced Radiation Dose Levels in CT: Eliminating Reduced Dose Levels That Are Too Low Is the First Step.

RATIONALE AND OBJECTIVES: This study aims to estimate observer performance for a range of dose levels for common computed tomography (CT) examinations (detection of liver metastases or pulmonary nodules, and cause of neurologic deficit) to prioritize noninferior dose levels for further analysis. MATERIALS AND METHODS: Using CT data from 131 examinations (abdominal CT, 44; chest CT, 44; head CT, 43), CT images corresponding to 4%-100% of the routine clinical dose were reconstructed with filtered back projection or iterative reconstruction. Radiologists evaluated CT images, marking specified targets, providing confidence scores, and grading image quality. Noninferiority was assessed using reference standards, reader agreement rules, and jackknife alternative free-response receiver operating characteristic figures of merit. Reader agreement required that a majority of readers at lower dose identify target lesions seen by the majority of readers at routine dose. RESULTS: Reader agreement identified dose levels lower than 50% and 4% to have inadequate performance for detection of hepatic metastases and pulmonary nodules, respectively, but could not exclude any low dose levels for head CT. Estimated differences in jackknife alternative free-response receiver operating characteristic figures of merit between routine and lower dose configurations found that only the lowest dose configurations tested (ie, 30%, 4%, and 10% of routine dose levels for abdominal, chest, and head CT examinations, respectively) did not meet criteria for noninferiority. At lower doses, subjective image quality declined before observer performance. Iterative reconstruction was only beneficial when filtered back projection did not result in noninferior performance. CONCLUSION: Opportunity exists for substantial radiation dose reduction using existing CT technology for common diagnostic tasks.

Addition of the Fleischner Society Guidelines to Chest CT Examination Interpretive Reports Improves Adherence to Recommended Follow-up Care for Incidental Pulmonary Nodules.

RATIONALE AND OBJECTIVES: The study aimed to determine whether the addition of the Fleischner Society guidelines to chest computed tomography (CT) reports identifying incidental pulmonary nodules affects follow-up care. PATIENTS AND METHODS: Beginning in 2008, a template containing the Fleischner Society guidelines was added at the interpreting radiologist's discretion to chest CT reports describing incidental solid pulmonary nodules at our institution. The records of all medical centers in Olmsted county were used to capture the complete medical history of local patients >35 years old diagnosed with a pulmonary nodule from April 1, 2008 to October 1, 2011. Patients with a history of cancer or previously diagnosed nodule, or who died before follow-up, were excluded. Patients were categorized according to whether they did ("template group") or did not ("control group") have the template added. Nodule size and smoking history were used to determine recommended follow-up care. Differences in follow-up were compared between groups using Pearson's chi-square test. RESULTS: A total of 510 patients (276 in the template group, 234 in the control group) were included in the study. Only 198 patients (39%) received their recommended follow-up care. Template group patients were significantly more likely to receive recommended follow-up care compared to control group patients (45% vs 31%, P = .0014). Most patients whose management did not adhere to Fleischner Society guidelines did not receive a recommended follow-up chest CT (210 out of 312, 67%). CONCLUSIONS: The addition of the Fleischner Society guidelines to chest CT reports significantly increases the likelihood of receiving recommended follow-up care for patients with incidental pulmonary nodules. Additional education is needed to improve appropriate guideline utilization by radiologists and adherence by ordering providers.

18F-FDG PET/CT assessment of histopathologically confirmed mediastinal lymph nodes in non-small cell lung cancer using a penalised likelihood reconstruction.

PURPOSE: To investigate whether using a Bayesian penalised likelihood reconstruction (BPL) improves signal-to-background (SBR), signal-to-noise (SNR) and SUVmax when evaluating mediastinal nodal disease in non-small cell lung cancer (NSCLC) compared to ordered subset expectation maximum (OSEM) reconstruction. MATERIALS AND METHODS: 18F-FDG PET/CT scans for NSCLC staging in 47 patients (112 nodal stations with histopathological confirmation) were reconstructed using BPL and compared to OSEM. Node and multiple background SUV parameters were analysed semi-quantitatively and visually. RESULTS: Comparing BPL to OSEM, there were significant increases in SUVmax (mean 3.2-4.0, p<0.0001), SBR (mean 2.2-2.6, p<0.0001) and SNR (mean 27.7-40.9, p<0.0001). Mean background SNR on OSEM was 10.4 (range 7.6-14.0), increasing to 12.4 (range 8.2-16.7, p<0.0001). Changes in background SUVs were minimal (largest mean difference 0.17 for liver SUVmean, p<0.001). There was no significant difference between either algorithm on receiver operating characteristic analysis (p=0.26), although on visual analysis, there was an increase in sensitivity and small decrease in specificity and accuracy on BPL. CONCLUSION: BPL increases SBR, SNR and SUVmax of mediastinal nodes in NSCLC compared to OSEM, but did not improve the accuracy for determining nodal involvement. KEY POINTS: • Penalised likelihood PET reconstruction was applied for assessing mediastinal nodes in NSCLC. • The new reconstruction generated significant increases in signal-to-background, signal-to-noise and SUVmax. • This led to an improvement in visual sensitivity using the new algorithm. • Higher SUV max thresholds may be appropriate for semi-quantitative analyses with penalised likelihood.

Magnetic Resonance Imaging of Part-solid Nodules: A Pilot Study.

PURPOSE: The aim of the study was to assess whether magnetic resonance imaging (MRI) characteristics can distinguish benign from malignant part-solid pulmonary nodules and predict the aggressiveness of the latter. We also sought to compare MRI-derived parameters with morphologic and physiological values derived from conventional examinations such as computed tomography and positron emission tomography/computed tomography. MATERIALS AND METHODS: This was an institutional review board-approved pilot study of 28 participants (23 women, mean age 73.5±13.8 y) with 32 biopsy-proven lesions. 3-T unenhanced pulmonary MRI examinations were performed with regions of interest drawn around lesions for T1, T2, T2*, and diffusion-weighted sequences. Apparent diffusion coefficient (ADC) and T2* values were calculated. Two weeks later the regions of interest were redrawn. MRI parameters were compared with lesion pathology, maximal standard uptake value (SUVmax), and Hounsfield units (HU). MRI lesion visibility was correlated with solid component size and the percentage of solid component. Intraobserver and interobserver agreements were determined. RESULTS: Only ADC values correlated with malignancy (P<0.05). ADC≥1.28 µm/ms predicted malignancy with 83.3% sensitivity (area under the curve 0.79). ADC and T2* correlated with adenocarcinoma subtypes (P<0.05). No MRI parameters predicted tumor differentiation (P>0.11). SUVmax did not correlate with any MRI parameters (P>0.56). Visibility on T1-weighted images correlated with the percentage of solid components (P<0.03). T1 and T2 values showed significant correlation with HU measurements of the entire nodule (P<0.001 and P<0.024, respectively) and HU measurements of solid components (P=0.031 and 0.008, respectively). CONCLUSIONS: 3 T MRI with quantitative ADC values demonstrated potential for discriminating benign part-solid pulmonary nodules from malignant lesions. ADC and T2* values correlated with adenocarcinoma subtypes. No MRI parameters correlated with SUVmax. T1 and T2 values showed significant correlation with HU measurements of the entire nodule and of the solid components.

Amyloid-associated Cystic Lung Disease.

BACKGROUND: Amyloid-associated cystic lung disease is rare. It can be associated with collagen vascular disease (CVD). We aimed to describe the clinical, radiology, and pathology findings of this entity. METHODS: We reviewed the records of subjects having biopsy-proven pulmonary amyloidosis with cystic lung disease demonstrated at high-resolution computed tomography (HRCT). Demographic characteristics, association with CVD and lymphoproliferative disorders, pulmonary function, and pathology results were reviewed. HRCT appearance was analyzed for number, size, distribution, and morphology of cysts and nodules. RESULTS: Twenty-one subjects (13 female, eight male; median age, 61 years) with cystic pulmonary amyloidosis were identified. The most common pulmonary function patterns were normal (42%) and obstructive (32%). The most common associated CVD was Sjögren syndrome (10 of 12). Nine subjects had no CVD. Cysts tended to be multiple (≥ 10 in 14 of 21, 67%), round (21 of 21, 100%), or lobulated (20 of 21, 95%); thin-walled (< 2 mm in 17 of 21, 81%); and of small (< 1 cm in 21 of 21, 100%) to moderate (1-2 cm in 17 of 21, 81%) size. Peribronchovascular (19 of 21, 90%) and subpleural (19 of 21, 90%) cysts were typically present. Seventeen (81%) subjects had lung nodules, which tended to be numerous (≥ 10 in 10 of 17, 59%; 4-9 in six of 17, 35%). At least one calcified nodule was present in 14 of 17 subjects (82%). Pulmonary mucosa-associated lymphoid tissue lymphoma (MALToma) was diagnosed in seven subjects (33%). CONCLUSIONS: Amyloid-associated cystic lung disease can occur with or without underlying CVD. Cystic lesions in the lung are commonly numerous, often are peribronchovascular or subpleural, and are frequently associated with nodular lesions that are often calcified. MALToma was a relatively frequent association.

RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection.

In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T-cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyse phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. While these have a more highly differentiated phenotype, they express fewer cytotoxicity markers than in blood. Nevertheless, their abundance before infection correlates with reduced symptoms and viral load, implying that CD8+ Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome.

Intercostal chest drain insertion by general physicians: attitudes, experience and implications for training, service and patient safety.

BACKGROUND: Intercostal chest drain (ICD) insertion is considered a core skill for the general physician. Recent guidelines have highlighted the risks of this procedure, while UK medical trainees have reported a concurrent decline in training opportunities and confidence in their procedural skills. OBJECTIVES: We explored clinicians' attitudes, experience and knowledge relating to pleural interventions and ICD insertion in order to determine what changes might be needed to maintain patient safety and quality of training. METHODS: Consultants and trainees delivering general medical services across five hospitals in England were invited to complete a questionnaire survey over a 5-week period in July and August 2014. RESULTS: 117 general physicians (32.4% of potential participants; comprising 31 consultants, 48 higher specialty trainees, 38 core trainees) responded. Respondents of all grades regarded ICD insertion as a core procedural skill. Respondents were asked to set a minimum requirement for achieving and maintaining independence at ICD insertion; however, only 25% of higher specialty trainees reported being able to attain this self-imposed standard. A knowledge gap was also revealed, with trainees managing clinical scenarios correctly in only 51% of cases. CONCLUSIONS: Given the disparity between clinical reality and what is expected of the physician-in-training, it is unclear whether ICD insertion can remain a core procedural skill for general physicians. Consideration should be given to how healthcare providers and training programmes might address issues relating to clinical experience and knowledge given the implications for patient safety and service provision.

Ultrasound-guided pneumothorax induction prior to local anaesthetic thoracoscopy.

Local anaesthetic thoracoscopy (LAT) is performed by a growing number of respiratory physicians in the context of an expanding population with pleural disease. Most LATs occur in patients with moderate to large effusions where the presence of fluid allows safe access to the pleural space. Patients with little or no fluid, but other features concerning for pleural disease, are usually investigated by surgical means. Advanced LAT practitioners can also provide this service through pneumothorax induction, although there is little published data on the safety or efficacy of this technique. We present data from a series of 77 consecutive patients in whom ultrasound-guided pneumothorax induction and LAT were attempted. 67 procedures (87.0%) were successful, with the most common histopathological diagnoses being chronic pleuritis (58.2%) and mesothelioma (16.4%). No adverse events were reported secondary to the procedure. These findings demonstrate the utility of this approach and should inform future practice and guidelines.

Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons.

BACKGROUND: Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/ß/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown. OBJECTIVE: We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients. METHODS: We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes. RESULTS: We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients. CONCLUSION: We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.

Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study.

BACKGROUND: The relationship between early-life antibiotic use and the development of wheeze and asthma has been reported in several studies but might arise as a consequence of bias rather than causal relationship. We investigated the association between antibiotic prescription and subsequent development of atopy, wheeze, and asthma exacerbations, and the relation of early life antibiotic prescription with anti-infective immunity and genetic variants on asthma susceptibility locus 17q21. METHODS: Children in a population-based birth cohort were followed from birth to age 11 years. Information on antibiotic prescription, wheeze, and asthma exacerbations was extracted from medical records, and the effect of antibiotic prescription assessed with longitudinal analyses. We assessed immune responses of peripheral blood mononuclear cells, taken at age 11 years, to viruses (rhinovirus and respiratory syncytial virus; RSV) and bacteria (Haemophilus influenzae and Streptococcus pneumoniae) in children who either received at least one or no antibiotic prescriptions in infancy. Finally, we assessed the association of 17q21 polymorphisms with antibiotic prescription. FINDINGS: Of 984 families who gave consent, we extracted data for 916 children. We noted significantly higher risk of physician-confirmed wheezing after antibiotic prescription (hazard ratio [HR] 1·71, 95% CI 1·32-2·23; p<0·0001) and severe wheeze or asthma exacerbation after antibiotic prescription (HR 2·26, 95% CI 1·03-4·94; p=0·041). In children who wheezed, the hazards of exacerbations (2·09, 1·51-2·90; p<0·0001) and admissions to hospital (2·64, 1·49-4·70; p=0·0009) were significantly increased in the 2 years after the first antibiotic prescription. Children who received antibiotics in infancy had significantly lower induction of cytokines, which are important in host defence against virus infections to both RSV and rhinovirus; there were no differences in antibacterial responses. Variants in 17q21 were associated with an increased risk of early life antibiotic prescription. INTERPRETATION: The association between antibiotics and asthma might arise through a complex confounding by indication. Hidden factors that may increase the likelihood of both early life antibiotic prescription and later asthma are an increased susceptibility to viral infections consequent upon impaired antiviral immunity and genetic variants on 17q21. FUNDING: Moulton Charitable Foundation and Medical Research Council.

Establishing a chest MRI practice and its clinical applications: our insight and protocols.

Despite its nonionizing technique and exquisite soft tissue characterization, noncardiovascular, and nonmusculoskeletal magnetic resonance imaging (MRI) of the chest has been considered impractical due to various challenges such as respiratory motion, cardiac motion, vascular pulsatility, air susceptibility, and paucity of signal in the lung. With advances in MRI, it is now possible to perform diagnostically useful and good quality MRIs of the chest, but literature on subspecialized chest MRI practices is limited. The purpose of this manuscript is to describe the rationale, nuances, and logistics that went into developing such a practice in the Division of Thoracic Radiology at our institution. The topics addressed include technical and clinical considerations, support at administrative and clinical levels, protocol development, and economic considerations compared with conventional practices. Various MRI techniques are also specifically discussed to facilitate chest MRI at other sites. Although chest MRI is used in a relatively small number of patients at this point, in certain patients, chest MRI can provide additional information to optimize medical management. A few clinical cases illustrate the quality and clinical utility of chest MRI. Given recent advances in MRI techniques, it is now an opportune time to develop a chest MRI practice.