Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

Opioid-specific medication-assisted therapy and its impact on criminal justice and overdose outcomes.

Background: The overlap between justice system involvement and drug use is well-documented. Justice-involved people who misuse opioids are at high risk for relapse and criminal recidivism. Criminal justice policymakers consider opioid-specific medication-assisted therapies (MATs) one approach for improving outcomes for this population. More research is needed that explores the impacts of opioid-specific MATs for justice-involved people. Objectives: This study sought to assess the effects of opioid-specific MAT for reducing the frequency and likelihood of criminal justice and overdose outcomes for current or formerly justice-involved individuals. Search Methods: Records were searched between May 7, 2021 and June 23, 2021. We searched a total of sixteen proprietary and open access databases that included access to gray literature and conference proceedings. The bibliographies of included studies and relevant reviews were also searched. Selection Criteria: Studies were eligible for inclusion in the review if they: (a) assessed the effects of opioid-specific MATs on individual-level criminal justice or overdose outcomes; included (b) a current or formerly justice-involved sample; and (c) a randomized or strong quasi-experimental design; and c) were published in English between January 1, 1960 and October 31, 2020. Data Collection and Analysis: We used the standard methodological procedures as expected by The Campbell Collaboration. Main Results: Twenty studies were included, representing 30,119 participants. The overall risk of bias for the experimental studies ranged from "some" to "high" and for quasi-experimental studies ranged from "moderate" to "serious." As such, findings must be interpreted against the backdrop of less-than-ideal methodological contexts. Of the 20 included studies, 16 included outcomes that were meta-analyzed using mean log odds ratios (which were reported as mean odds ratios). Mean effects were nonsignificant for reincarceration (odds ratio [OR] = 0.93 [0.68, 1.26], SE = .16), rearrest (OR = 1.47 [0.70, 3.07], SE = 0.38), and fatal overdose (OR = 0.82 [0.56, 1.21], SE = 0.20). For nonfatal overdose, the average effect was significant (OR = 0.41 [0.18, 0.91], SE = 0.41, p < 0.05), suggesting that those receiving MAT had nearly 60% reduced odds of a nonfatal overdose. Implications for Policy Practice and Research: The current review supports some utility for adopting MAT for the treatment of justice-involved people with opioid addiction, however, more studies that employ rigorous methodologies are needed. Researchers should work with agencies to improve adherence to medication regimens, study design, and collect more detailed information on participants, their criminal and substance use histories, onset, and severity. This would help clarify whether treatment and control groups are indeed comparable and provide better insight into the potential reasons for participant dropout, treatment failure, and the occurrence of recidivism or overdose. Outcomes should be assessed in multiple ways, if possible (e.g., self-report and official record), as reliance on official data alone may undercount participants' degree of criminal involvement.

Post-immunotherapy imaging in lung cancer.

By boosting the immune system, immunotherapy with immune checkpoint inhibitors (ICIs) has altered the management of patients with various cancers including those with metastatic non-small cell lung cancer (NSCLC). As a result of immune system activation, ICIs are associated with unique response patterns (that are not addressed by traditional response criteria) and inflammatory side effects termed immune-related adverse events. In this article, we will review the role of immunotherapy in cancer treatment, specifically ICIs used in NSCLC treatment, radiological response criteria of immunotherapy, and the imaging spectrum of immune-related adverse events.

The postoperative chest in lung cancer.

Most of the complications following lung cancer surgery occur in the early postoperative period and can result in significant morbidity and mortality. Delayed complications can also occur. Diagnosing these complications can be challenging because clinical manifestations are non-specific. Imaging plays an important role in detecting these complications in a timely manner and facilitates prompt interventions. Hence, it is important to have knowledge of the expected anatomical alterations following lung cancer surgeries, and the spectrum of post-surgical complications and their respective imaging findings to avoid misinterpretations or delay in diagnosis.

Imaging of the post-radiation chest in lung cancer.

Radiation therapy using conventional fractionated external-beam or high-precision dose techniques including three-dimensional conformal radiotherapy, stereotactic body radiation therapy, intensity-modulated radiation therapy, and proton therapy, is a key component in the treatment of patients with lung cancer. Knowledge of the radiation technique used, radiation treatment plan, expected temporal evolution of radiation-induced lung injury and patient-specific parameters, such as previous radiotherapy, concurrent chemoradiotherapy, and/or immunotherapy, is important in imaging interpretation. This review discusses factors that affect the development and severity of radiation-induced lung injury and its radiological manifestations with emphasis on the differences between conventional radiation and high-precision dose radiotherapy techniques.

PROTOCOL: Opioid-specific medication-assisted therapy and its impact on criminal justice and overdose outcomes.

Background: The overlap between criminal justice system involvement and drug use is well-documented, and criminal justice agencies have been particularly overwhelmed by the recent opioid epidemic. Treating opioid (and other substance) addiction as a means to reduce risk for future criminality and improve public safety is inherently a responsibility for the criminal justice system. In turn, the criminal justice system has a responsibility to manage and treat addiction among the individuals under its purview.  Policy recommendations place emphasis on the use of medication-assisted treatments (MAT) as a front-line defense among correctional populations, because its efficacy and effectiveness has been well-established in other contexts.  Despite this, criminal justice agencies have been reluctant or slow to do so. Objectives: The current review will provide criminal justice and substance use treatment decision-makers with information regarding the efficacy and effectiveness of opioid-specific MAT on offending and overdose outcomes. Specifically, the authors will address the following research questions: Do opioid-specific MATs reduce the frequency or likelihood of criminal justice outcomes, as defined by official or self-reported indices of criminal reconviction or rearrest, revocation of community supervision, mandated treatment failure, and specialized court docket failure? Do opioid-specific MATs reduce the frequency of opioid overdose among individuals with current or prior self-reported or official record of criminal justice system involvement? Inclusion Criteria: Studies were required to use strong quasi-experimental or randomized experimental designs. All studies used individual level unit of analysis and examined adults and adolescents who are male, female, or nonbinary and racially/ethnically diverse, with current opioid use and who have current or prior criminal justice involvement. Studies had to prospectively test the effects of heroin and methadone maintenance, buprenorphine, or naltrexone on criminal conviction, arrest, revocation of community supervision, technical probation or parole violation, mandated treatment failure, and specialized court docket failure. Overdose outcomes were also examined for samples in criminal justice settings such as jails, prisons, probation, and parole. Search Strategy and Data Collection: This review builds upon a prior review conducted by Egli et al. (2009) and examined studies meeting the inclusion criteria above published between 1960 and October 31, 2020. The following platforms and databases (in parentheticals) were used: EBSCOhost (Criminal Justice Abstracts, SocINDEX with Full Text, Legal Collection, Wilson Omnifile, PsycINFO, Social Work Abstracts, and Women's Studies International [includes grey literature]); ProQuest (Criminal Justice Database, PAIS [includes grey literature], Dissertations and Theses Global [includes grey literature]); Gale (Expanded Academic ASAP, Opposing Viewpoints Resource Center); FirstSearch (GPO Monthly Catalog, PapersFirst [includes grey literature]); ISI Web of Knowledge (Web of Science Core Collection); Office of Justice Programs (National Criminal Justice Reference Service); Summon; and Nexis Uni. The following open access platforms and databases will also be consulted: Elsevier (Scopus [includes grey literature]); Science.gov; ClinicalTrials.gov; WHO International Clinical Trials Registry Platform (ICTRP) portal; and Google Scholar. Search terms were harvested according to their demonstrated success in drawing out relevant and complete results for studies regarding the effectiveness of opioid-specific medication-assisted therapies (MATs). From this process 5 core search strings were created, each one with the same general base terms, but unique outcome measure(s). Analysis: For binary offending outcomes (e.g., arrest, conviction, incarceration, specialty court failure, mandated treatment failure, or community supervision failure) and overdose outcomes, odds ratios were computed, and for continuous or quasi-continuous outcomes (e.g., total number of arrests), a standardized mean difference type effect size was computed and then transformed into an odds ratio. We used the χ 2 test that goes with the forest plot and computed the I 2 statistic to assess heterogeneity. Risk of bias was assessed with (1) the revised Cochrane risk-of-bias tool for randomized trials; and (2) the risk of bias in non-randomized studies of interventions assessment tool.

Cyst-based measurements for assessing lymphangioleiomyomatosis in computed tomography.

PURPOSE: To investigate the efficacy of a new family of measurements made on individual pulmonary cysts extracted from computed tomography (CT) for assessing the severity of lymphangioleiomyomatosis (LAM). METHODS: CT images were analyzed using thresholding to identify a cystic region of interest from chest CT of LAM patients. Individual cysts were then extracted from the cystic region by the watershed algorithm, which separates individual cysts based on subtle edges within the cystic regions. A family of measurements were then computed, which quantify the amount, distribution, and boundary appearance of the cysts. Sequential floating feature selection was used to select a small subset of features for quantification of the severity of LAM. Adjusted R(2) from multiple linear regression and R(2) from linear regression against measurements from spirometry were used to compare the performance of our proposed measurements with currently used density based CT measurements in the literature, namely, the relative area measure and the D measure. RESULTS: Volumetric CT data, performed at total lung capacity and residual volume, from a total of 49 subjects enrolled in the MILES trial were used in our study. Our proposed measures had adjusted R(2) ranging from 0.42 to 0.59 when regressing against the spirometry measures, with p < 0.05. For previously used density based CT measurements in the literature, the best R(2) was 0.46 (for only one instance), with the majority being lower than 0.3 or p > 0.05. CONCLUSIONS: The proposed family of CT-based cyst measurements have better correlation with spirometric measures than previously used density based CT measurements. They show potential as a sensitive tool for quantitatively assessing the severity of LAM.

Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline.

Alpha-1 antitrypsin (A1AT) functions primarily to inhibit neutrophil elastase, and deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD). Severe A1AT deficiency occurs in one in 5000 to one in 5500 of the North American population. While the exact prevalence of A1AT deficiency in patients with diagnosed COPD is not known, results from small studies provide estimates of 1% to 5%. The present document updates a previous Canadian Thoracic Society position statement from 2001, and was initiated because of lack of consensus and understanding of appropriate patients suitable for targeted testing for A1AT deficiency, and for the use of A1AT augmentation therapy. Using revised guideline development methodology, the present clinical practice guideline document systematically reviews the published literature and provides an evidence-based update. The evidence supports the practice that targeted testing for A1AT deficiency be considered in individuals with COPD diagnosed before 65 years of age or with a smoking history of <20 pack years. The evidence also supports consideration of A1AT augmentation therapy in nonsmoking or exsmoking patients with COPD (forced expiratory volume in 1 s of 25% to 80% predicted) attributable to emphysema and documented A1AT deficiency (level ≤11 µmol/L) who are receiving optimal pharmacological and nonpharmacological therapies (including comprehensive case management and pulmonary rehabilitation) because of benefits in computed tomography scan lung density and mortality.

Development of predictive models for airflow obstruction in alpha-1-antitrypsin deficiency.

Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV(1)) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV(1) and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV(1) explained 50% of the variance in FEV(1), and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).

Heritability of lung function in severe alpha-1 antitrypsin deficiency.

Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV1/FVC demonstrated significant heritability (0.26 +/- 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV1 demonstrated significant heritability (0.47 +/- 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV1 decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency.

Hepatopulmonary syndrome occurring after orthotopic liver transplantation.

Hepatopulmonary syndrome (HPS) is an infrequent complication of liver cirrhosis. Orthotopic liver transplantation (OLT) has gained increasing acceptance as a treatment modality for HPS, although there have been reports of HPS developing after OLT with documented recurrence of cirrhosis. We describe the case of a 9-year-old boy who underwent OLT at 7 months of age because of biliary atresia. He subsequently developed HPS in the setting of chronic rejection without cirrhosis or evidence of portal hypertension. Re-OLT resulted in resolution of HPS and a good clinical outcome.

Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis.

It is not known if a surgical lung biopsy is necessary in all patients for the diagnosis of idiopathic pulmonary fibrosis (IPF). We conducted a blinded, prospective study at eight referring centers. Initially, cases were evaluated by clinical history and examination, transbronchial biopsy, and high-resolution lung computed tomography scans. Pulmonologists at the referring centers then assessed their certainty of the diagnosis of IPF and provided an overall diagnosis, before surgical lung biopsy. The lung biopsies were reviewed by a pathology core and 54 of 91 patients received a pathologic diagnosis of IPF. The positive predictive value of a confident (certain) clinical diagnosis of IPF by the referring centers was 80%. The positive predictive value of a confident clinical diagnosis was higher, when the cases were reviewed by a core of pulmonologists (87%) or radiologists (96%). Lung biopsy was most important for diagnosis in those patients with an uncertain diagnosis and those thought unlikely to have IPF. These studies suggest that clinical and radiologic data that result in a confident diagnosis of IPF by an experienced pulmonologist or radiologist are sufficient to obviate the need for a lung biopsy. Lung biopsy is most helpful when clinical and radiologic data result in an uncertain diagnosis or when patients are thought not to have IPF.

Management of spontaneous pneumothorax: an American College of Chest Physicians Delphi consensus statement.

OBJECTIVE: Provide explicit expert-based consensus recommendations for the management of adults with primary and secondary spontaneous pneumothoraces in an emergency department and inpatient hospital setting. The use of opinion was made explicit by employing a structured questionnaire, appropriateness scores, and consensus scores with a Delphi technique. The guideline was designed to be relevant to physicians who make management decisions for the care of patients with pneumothorax. OPTIONS: Decisions for observation, chest tube placement, surgical interventions, and radiographic imaging. OUTCOMES: Effectiveness of pneumothorax resolution, duration of and patient tolerance of care, and pneumothorax recurrence. EVIDENCE: Literature review from 1967 to January 1999 and Delphi questionnaire submitted in three iterations to a multidisciplinary physician panel. VALUES: The guideline development group determined by consensus the relevant outcomes to be considered in developing the Delphi questionnaire. BENEFITS, HARMS, AND COSTS: The type and magnitude of benefits, harms, and costs expected for patients from guideline implementation. RECOMMENDATIONS: Management decisions vary between patients with primary or secondary pneumothoraces, with observation of small pneumothoraces being appropriate only for primary pneumothoraces. The level of consensus varies regarding the specific interventions indicated, but agreement exists for the general principles of care. VALIDATION: Recommendations were peer reviewed by physician experts and were reviewed by the American College of Chest Physicians (ACCP) Health and Science Policy Committee. IMPLEMENTATION: The guideline recommendations will be published in printed and electronic form with distribution of synopses for patients and health care providers. Contents of the guideline will be incorporated into continuing medical education programs. SPONSORS: The ACCP.

Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension.

STUDY OBJECTIVES: To determine the cause of pulmonary hypertension (PH) in systemic sclerosis (SSc) patients since PH can occur because of pulmonary arteriopathy, pulmonary parenchymal destruction, and left ventricular cardiac dysfunction. DESIGN AND SETTING: Consecutive case series in a university hospital. PATIENTS: Nine SSc patients with PH (mean pulmonary artery pressure, 41 mm Hg), with (n = 6) or without (n = 3) concomitant interstitial lung disease (ILD). METHODS: Acute infusion of epoprostenol was begun at 2 ng/kg/min and was titrated upward at a rate of 2 ng/kg/min every 30 min until symptomatic complications developed or pulmonary artery vascular resistance (PVR) was reduced by 50%. RESULTS: Eight of nine patients demonstrated a reduction of > or = 20% in PVR, suggesting that vasoreactivity is common despite the presence of significant ILD. A single patient had no response to infusion with unchanged hemodynamics and oxygenation. One patient developed hypoxemia as cardiac output increased, suggesting a worsening of ventilation/perfusion matching or the presence of an anatomic shunt. Acute pulmonary edema developed in one patient at an infusion rate of 6 ng/kg/min. The results of cardiac catheterization suggested that pulmonary edema was caused by SSc heart disease. CONCLUSION: SSc patients with ILD have diverse and sometimes multiple causes of PH that can be determined by short-term epoprostenol infusion. Beneficial effects can be obtained from epoprostenol despite extensive ILD.

Pleural complications in the intensive care unit.

In summary pleural complications in the ICU are common. Pneumothorax in a mechanically ventilated patient is a medical emergency that requires prompt diagnosis and therapy. Correct diagnosis and therapy of pleural effusions will assist in improving pulmonary physiology and outcome in the ICU patient.

The definitions and epidemiology of pleural space infection.

Infections of the pleural space are caused by a diverse group of clinical conditions that include trauma, post-operative states, and pneumonia. Although pleural effusions accompany bacterial pneumonia in up to 60% of patients, they uncommonly influence management because the effusion in most patients disappears with antibiotic administration. Unfortunately, the large number of patients with pneumonia provide an abundant supply of patients who fail to respond to antibiotic administration alone and subsequently present with pleural fluid loculation, pleural sepsis, or empyema. This article provides an overview of the classification schemes that have been used to characterize pleural space infections and highlight the epidemiology of those patients who present with complicated parapneumonic effusions and empyema.

Bullous sarcoidosis: a report of three cases.

Three cases of pulmonary sarcoidosis presented as bullous emphysema with severe airflow obstruction, and the diagnosis of sarcoidosis was unsuspected for at least 2 years. Potential mechanisms of bullous emphysema from sarcoidosis are discussed. The physician should suspect sarcoidosis as the cause of bullous emphysema when young patients who have smoked relatively few pack-years present with emphysema or severe airflow obstruction. Additional clues are the presence of mediastinal adenopathy on a chest radiograph or a CT scan and a history consistent with extrapulmonary sarcoidosis.

Comparison of train-of-four and best clinical assessment during continuous paralysis.

Train-of-four (TOF) monitoring is recommended in published guidelines during use of continuous-infusion neuromuscular blocking agents (NMB) in the intensive care unit (ICU). To test that recommendation, dual protocols were established in a medical ICU after intensive nursing education. Paralyzed patients received either TOF monitoring with a goal of three twitches or best clinical assessment while receiving atracurium by continuous infusion. Demographics and mean duration of paralysis of 20 patients in the TOF group were no different than that of the 16 patients in the best clinical assessment group. Although most patients demonstrated atracurium tolerance over time, there was no difference between groups in total mg (+/- SEM) infused (10,460 +/- 2,409 versus 9,201 +/- 3,237) or mean microgram/kg/min (15.2 +/- 1.5 versus 12.0 +/- 1.1). The time to clinical recovery was no different between groups (50 +/- 10 versus 45 +/- 12 min). Two complications occurred in the TOF group, with pulmonary emboli despite prophylaxis and an unrecognized cerebrovascular accident in one patient each. We conclude that careful titration of NMB using clinical bedside markers should remain the standard of care with these drugs.