An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

An official American Thoracic Society/European Respiratory Society statement: research questions in COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes.

COPD uncovered: an international survey on the impact of chronic obstructive pulmonary disease [COPD] on a working age population.

BACKGROUND: Approximately 210 million people are estimated to have chronic obstructive pulmonary disease [COPD] worldwide. The burden of disease is known to be high, though less is known about those of a younger age. The aim of this study was to investigate the wider personal, economic and societal burden of COPD on a cross country working-age cohort. METHODS: A cross-country [Brazil, China, Germany, Turkey, US, UK] cross-sectional survey methodology was utilised to answer the research questions. 2426 participants aged 45-67 recruited via a number of recruitment methods specific to each country completed the full survey. Inclusion criteria were a recalled physician diagnosis of COPD, a smoking history of > 10 pack years and the use of COPD medications in the previous 3 months prior to questioning. The survey included items from the validated Work Productivity and Activity Impairment [WPAI] scale and the EuroQoL 5 Dimension [EQ-5D] scale. Disease severity was measured using the 5-point MRC [Medical Research Council] dyspnoea scale as a surrogate measure. RESULTS: 64% had either moderate [n = 1012] or severe [n = 521] COPD, although this varied by country. 75% of the cohort reported at least one comorbid condition. Quality of life declined with severity of illness [mild, mean EQ-5D score = 0.84; moderate 0.58; severe 0.41]. The annual cost of healthcare utilisation [excluding treatment costs and diagnostic tests] per individual was estimated to be $2,364 [£1,500]. For those remaining in active employment [n: 677]: lost time from work cost the individual an average of $880 [£556] per annum and lifetime losses of $7,365 [£4,661] amounting to $596,000 [£377,000] for the cohort. 447 [~40%] of the working population had retired prematurely because of COPD incurring individual estimated lifetime income losses of $316,000 [£200,000] or a combined total of $141 m [£89.6 m]. As the mean age of retirees was 58.3 and average time since retirement was 4 years, this suggests the average age of retirement is around 54. This would mean a high societal and economic impact in all study countries, particularly where typical state retirement ages are higher, for example in Brazil, Germany and the UK [65] and the US [65,66,67], compared to Turkey [58 for women, 60 for men] and China [60]. CONCLUSIONS: Although generalisation across a broader COPD population is limited due to the varied participant recruitment methods, these data nevertheless suggest that COPD has significant personal, economic and societal burden on working age people. Further efforts to improve COPD diagnosis and management are required.

Reduced mRNA Expression of RGS2 (Regulator of G Protein Signaling-2) in the Placenta Is Associated With Human Preeclampsia and Sufficient to Cause Features of the Disorder in Mice.

Cascade-specific termination of G protein signaling is catalyzed by the RGS (regulator of G protein signaling) family members, including RGS2. Angiotensin, vasopressin, and endothelin are implicated in preeclampsia, and RGS2 is known to inhibit G protein cascades activated by these hormones. Mutations in RGS2 are associated with human hypertension and increased risk of developing preeclampsia and its sequelae. RGS family members are known to influence maternal vascular function, but the role of RGS2 within the placenta has not been explored. Here, we hypothesized that reduced expression of RGS2 within the placenta represents a risk factor for the development of preeclampsia. Although cAMP/CREB signaling was enriched in placentas from human pregnancies affected by preeclampsia compared with clinically matched controls and RGS2 is known to be a CREB-responsive gene, RGS2 mRNA was reduced in placentas from pregnancies affected by preeclampsia. Experimentally reducing Rgs2 expression within the feto-placental unit was sufficient to induce preeclampsia-like phenotypes in pregnant wild-type C57BL/6J mice. Stimulation of RGS2 transcription within immortalized human HTR8/SVneo trophoblasts by cAMP/CREB signaling was discovered to be dependent on the activity of histone deacetylase activity, and more specifically, HDAC9 (histone deacetylase-9), and HDAC9 expression was reduced in placentas from human pregnancies affected by preeclampsia. We conclude that reduced expression of RGS2 within the placenta may mechanistically contribute to preeclampsia. More generally, this work identifies RGS2 as an HDAC9-dependent CREB-responsive gene, which may contribute to reduced RGS2 expression in placenta during preeclampsia.

Responsible patient advocacy: perspectives from the Alpha-1 Foundation.

Patient advocacy groups play an increasingly prominent role in patient care and clinical research. To help manage some of the unique challenges associated with the involvement of patient-centered organizations in the delivery of medical services and conduct of clinical research, patient advocacy groups may wish to establish an ethics advisory board. Although hospitals and government agencies often adopt this approach, ethics advisory boards have not been widely used by patient advocacy groups. We report on the experiences of an ethics advisory board for a patient advocacy group actively involved in genetic testing and clinical research. Drawing on the experiences of this organization, we examine the potential advantages and limitations of this approach to navigating the complex moral terrain of contemporary medicine and biomedical research.

Postoperative cranial fasciitis. Report of two cases and review of the literature.

The authors report two cases of cranial fasciitis occurring at prior craniotomy sites. They review the presentation and pathological features associated with cranial fasciitis and describe two unusual cases and their treatment. The first case is that of a 16-year-old girl who underwent suboccipital craniectomy for resection of medulloblastoma and 14 months later was found to have a 4-cm nontender mass at the incision site, with evidence of skull erosion on neuroimaging. Resection of the mass revealed cranial fasciitis. The patient later developed two more lesions in the cranial region, as well as lesions on the chest wall and abdomen consistent with nodular fasciitis; all of the lesions were resected. The second case is that of a 61-year-old man who underwent suboccipital craniectomy for hypertensive hemorrhage and 2 years later was found to have an enlarging mass at the incision site, causing compression of the cerebellum. The mass was resected and found to be consistent with cranial fasciitis. Cranial fasciitis is a rare, benign lesion of the cranial region. It is histologically identical to nodular fasciitis, a self-limiting fibroblastic process of the superficial and deep fascia. Although most cases of cranial fasciitis are reported to occur spontaneously in the very young, the two cases reported here involved older patients and lesions that developed at prior craniotomy sites in a delayed fashion, a phenomenon not previously reported. Interestingly, one patient exhibited lesions in other areas as well.

Recurrent lymphocytic hypophysitis and bilateral intracavernous carotid artery occlusion. an observation and review of the literature.

OBJECTIVES: Bilateral carotid artery occlusion associated with lymphocytic hypophysitis is exceedingly rare. We describe this association and review the literature. METHODS: The authors describe a 38-year-old woman with a history of severe headaches. Magnetic resonance (MR) imaging showed an intrasellar mass with invasion of both cavernous sinuses. Lymphocytic hypophysitis was diagnosed by transphenoidal biopsy. In the course of the disease, she developed symptoms of cerebral ischemia attributable to bilateral occlusion of her internal carotid arteries in both cavernous sinuses. She underwent bilateral superficial temporal artery-middle cerebral artery bypass surgery. RESULTS: The patient experienced progressive neurological recovery after surgery. A literature search revealed no other cases describing this unique association. CONCLUSIONS: Bilateral carotid artery occlusion may develop in the course of lymphocytic hypophysitis with cavernous sinus involvement. If indicated, cerebral revascularization should be performed to reverse cerebral ischemia.

A review of the alpha-1 foundation: its formation, impact, and critical success factors.

Patient-advocacy organizations have proliferated because they can be an effective method to advance research and clinical care for those with the index condition, and can produce substantial benefits for the affected community, especially when the condition is uncommon. To clarify critical success factors in organizing a patient-advocacy organization and to provide a blueprint for others, including the respiratory-care advocacy community, this report examines features of one highly successful organization, the Alpha-1 Foundation, which is committed to helping those with the genetic condition alpha-1 antitrypsin deficiency. Features of the Alpha-1 Foundation that underlie its success include: consistently creating partnerships with key stakeholders, including the scientific and clinical communities, government, and pharmaceutical manufacturers; bringing passion to the cause (eg, by assuring that organizational leadership is provided by individuals affected by alpha-1 antitrypsin deficiency); and developing strategic business partnerships, as with a company that administers alpha-1 antitrypsin treatment (so-called intravenous augmentation therapy) and employs individuals with alpha-1 antitrypsin deficiency. Funds allocated by the company help to underwrite the foundation's research-funding commitment. The foundation also recruits and retains talent, including alpha-1 patients, to leadership roles (eg, on the board of directors) and has a voluntary group of committed scientists and clinicians. We believe that attention to these factors can help assure the success of patient-advocacy groups.

Tuberculosis infection presenting as brain abscess in an immunocompromised host.

Despite advances in modern treatment, tuberculosis remains an ever-present problem. With the HIV epidemic, the prevalence of tuberculosis has risen. Contributing to this trend has been the development of multi-resistant tuberculosis strains, as well as rising immigration from nations where tuberculosis is endemic. Although tuberculosis most commonly manifests as a pulmonary process, milary tuberculosis is also on the rise. Neurotuberculosis, a rare but dangerous progression of pulmonary tuberculosis, remains a difficult diagnostic and treatment dilemma to practitioners both in the United States and abroad. We describe an unusual presentation of neurotuberculosis infection in a previously asymptomatic patient. Early recognition and treatment of intracranial tuberculosis is important if mortality is to be prevented.

High-Dose Versus Low-Dose Systemic Steroids in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Systematic Review.

Background: Treatment of an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with systemic steroids reduces treatment failure, shortens hospital length of stay, improves lung function, and reduces dyspnea. However, it can also cause hyperglycemia, delirium, fluid retention, and other side effects. The balance of these desirable and undesirable effects probably varies according to the steroid dose. Methods: We asked the question, "Should patients having an AECOPD receive low-dose or high-dose systemic steroids?" We searched Medline and the Cochran Central Register of Controlled Trials (CENTRAL) using a sensitive search strategy built around the medical subject heading, "COPD," and variations of the keywords exacerbation, steroids, and randomized trials. Our search yielded 1702 articles in Medline and 885 articles in CENTRAL; we reviewed the full text of 35 articles and selected 11 studies that met the following conditions: randomized trial, enrolled patients having an AECOPD, compared one systemic steroid regimen to another, measured clinical outcomes, and was published in a peer-reviewed journal. Results: None of the selected trials directly compared the effects of different systemic steroid doses on clinical outcomes in patients with AECOPD. Four trials compared durations of steroid treatment, 3 trials compared types of steroids, 1 trial compared routes of steroid delivery, and 3 trials compared multiple variables. Conclusion: There is a paucity of data to support the selection of a systemic steroid dose in patients having an AECOPD. Randomized trials that measure patient-centered outcomes and compare doses of systemic steroids in patients having an AECOPD are needed.

Insight into Best Variables for COPD Case Identification: A Random Forests Analysis.

RATIONALE: This study is part of a larger, multi-method project to develop a questionnaire for identifying undiagnosed cases of chronic obstructive pulmonary disease (COPD) in primary care settings, with specific interest in the detection of patients with moderate to severe airway obstruction or risk of exacerbation. OBJECTIVES: To examine 3 existing datasets for insight into key features of COPD that could be useful in the identification of undiagnosed COPD. METHODS: Random forests analyses were applied to the following databases: COPD Foundation Peak Flow Study Cohort (N=5761), Burden of Obstructive Lung Disease (BOLD) Kentucky site (N=508), and COPDGene® (N=10,214). Four scenarios were examined to find the best, smallest sets of variables that distinguished cases and controls:(1) moderate to severe COPD (forced expiratory volume in 1 second [FEV1] <50% predicted) versus no COPD; (2) undiagnosed versus diagnosed COPD; (3) COPD with and without exacerbation history; and (4) clinically significant COPD (FEV1<60% predicted or history of acute exacerbation) versus all others. RESULTS: From 4 to 8 variables were able to differentiate cases from controls, with sensitivity ≥73 (range: 73-90) and specificity >68 (range: 68-93). Across scenarios, the best models included age, smoking status or history, symptoms (cough, wheeze, phlegm), general or breathing-related activity limitation, episodes of acute bronchitis, and/or missed work days and non-work activities due to breathing or health. CONCLUSIONS: Results provide insight into variables that should be considered during the development of candidate items for a new questionnaire to identify undiagnosed cases of clinically significant COPD.

Patient-Centered Research Priorities for Pulmonary Nontuberculous Mycobacteria (NTM) Infection. An NTM Research Consortium Workshop Report.

Nontuberculous mycobacteria (NTM) cause an increasingly important chronic and debilitating lung disease in older adults. Diagnosis is often delayed, although awareness among clinicians and patients is increasing. When necessary, treatment often lasts 18-24 months and consists of three or four antibiotics that can have serious side effects. Relapses are common and commonly require resumption of prolonged therapy. Given the need for improved diagnostic techniques and clinical trials to identify new therapies or to improve existing therapies, a group of North American clinicians and researchers formed the NTM Research Consortium (NTMRC) in 2014. The NTMRC recognized the importance of including the patient voice in determining research priorities for NTM. In November 2015, patients, caregivers, patient advocates, clinical experts, and researchers gathered for a 1-day meeting in Portland, Oregon funded by the Patient-Centered Outcomes Research Institute. The meeting goal was to define patient-centered research priorities for NTM lung infections. Patients expressed frustration with the number of people who have endured years of missed diagnoses or inadequate treatment of NTM. Participants identified as top research priorities the prevention of NTM infection; approval of more effective treatments with fewer side effects and easier administration; understanding the best chest physiotherapy methods; validating and using tools to measure quality of life; and developing a disease-specific activity and severity assessment tool. Workshop participants agreed that two complementary objectives are critical to ensure the best achievable outcomes for patients: (1) additional clinician education to improve screening and diagnosis of NTM infections; and (2) development of a geographically distributed network of experts in NTM disease to offer consultation or direct therapy after a diagnosis is made.

Intrathecal colistin for treatment of highly resistant Pseudomonas ventriculitis. Case report and review of the literature.

Nosocomial infections with organisms resistant to multiple antibiotic agents represent an evolving challenge in the intensive care setting, particularly in patients requiring surgical diversion of cerebrospinal fluid. The authors present the case of a 51-year-old woman who endured protracted hospitalization and required multiple surgeries including placement of a ventriculoperitoneal shunt. The shunt subsequently became colonized with Pseudomonas aeruginosa, which demonstrated intermediate sensitivity to amikacin and full resistance to all other antibiotics tested 'After failing to respond to intravenous imipenem as well as intravenous and intrathecal amikacin, the patient was successfully treated with intravenous and intrathecal colistin. Colistin is a polymyxin-type antibiotic, rarely used outside of topical application because of reported nephrotoxicity associated with parenteral administration. With activity limited to Gram-negative organisms, colistin is bactericidal by directly disrupting the structure of cell membranes. Authors of a few case reports in the literature have described successful treatment of various ventriculitis with the intrathecal administration of colistin. With bacterial resistances outpacing the pharmaceutical industry's ability to develop novel antibiotics, colistin represents an important alternative in situations involving multidrug-resistant organisms.

Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure.

Risperidone is a second-generation antipsychotic that causes weight gain. We hypothesized that risperidone-induced shifts in the gut microbiome are mechanistically involved in its metabolic consequences. Wild-type female C57BL/6J mice treated with risperidone (80 µg/day) exhibited significant excess weight gain, due to reduced energy expenditure, which correlated with an altered gut microbiome. Fecal transplant from risperidone-treated mice caused a 16% reduction in total resting metabolic rate in naïve recipients, attributable to suppression of non-aerobic metabolism. Risperidone inhibited growth of cultured fecal bacteria grown anaerobically more than those grown aerobically. Finally, transplant of the fecal phage fraction from risperidone-treated mice was sufficient to cause excess weight gain in naïve recipients, again through reduced energy expenditure. Collectively, these data highlight a major role for the gut microbiome in weight gain following chronic use of risperidone, and specifically implicates the modulation of non-aerobic resting metabolism in this mechanism.

Identifying Patients with Undiagnosed COPD in Primary Care Settings: Insight from Screening Tools and Epidemiologic Studies.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, yet research suggests this disease is greatly underdiagnosed. This literature review sought to summarize the most common and significant variables associated with case-finding or missed cases of COPD to inform more effective and efficient detection of high-risk COPD patients in primary care. METHODS: PubMed and EMBASE were searched for articles describing case-finding and epidemiologic research to detect or characterize new cases of COPD. International studies in primary and non-primary care settings, published in English from 2002-2014, were eligible for inclusion. Studies related to risk factors for development of COPD were excluded. RESULTS: Of the 33 studies identified and reviewed, 21 were case-finding or screening and 12 were epidemiological, including cross-sectional, longitudinal, and retrospective designs. A range of variables were identified within and across studies. Variables common to both screening and epidemiological studies included age, smoking status, and respiratory symptoms. Seven significant predictors from epidemiologic studies did not appear in screening tools. No studies targeted discovery of higher risk patients such as those with reduced lung function or risks for exacerbations. CONCLUSION: Variables used to identify new cases of COPD or differentiate COPD cases and non-cases are wide- ranging, (from sociodemographic to self-reported health or health history variables), providing insight into important factors for case identification. Further research is underway to develop and test the best, smallest variable set that can be used as a screening tool to identify people with undiagnosed, high-risk COPD in primary care.

Identifying cases of undiagnosed, clinically significant COPD in primary care: qualitative insight from patients in the target population.

BACKGROUND: Many cases of chronic obstructive pulmonary disease (COPD) are diagnosed only after significant loss of lung function or during exacerbations. AIMS: This study is part of a multi-method approach to develop a new screening instrument for identifying undiagnosed, clinically significant COPD in primary care. METHODS: Subjects with varied histories of COPD diagnosis, risk factors and history of exacerbations were recruited through five US clinics (four pulmonary, one primary care). Phase I: Eight focus groups and six telephone interviews were conducted to elicit descriptions of risk factors for COPD, recent or historical acute respiratory events, and symptoms to inform the development of candidate items for the new questionnaire. Phase II: A new cohort of subjects participated in cognitive interviews to assess and modify candidate items. Two peak expiratory flow (PEF) devices (electronic, manual) were assessed for use in screening. RESULTS: Of 77 subjects, 50 participated in Phase I and 27 in Phase II. Six themes informed item development: exposure (smoking, second-hand smoke); health history (family history of lung problems, recurrent chest infections); recent history of respiratory events (clinic visits, hospitalisations); symptoms (respiratory, non-respiratory); impact (activity limitations); and attribution (age, obesity). PEF devices were rated easy to use; electronic values were significantly higher than manual (P<0.0001). Revisions were made to the draft items on the basis of cognitive interviews. CONCLUSIONS: Forty-eight candidate items are ready for quantitative testing to select the best, smallest set of questions that, together with PEF, can efficiently identify patients in need of diagnostic evaluation for clinically significant COPD.

An official American Thoracic Society/European Respiratory Society statement: research questions in COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers and patient advocates believe will have the greatest impact on patient-centred outcomes.