Patricio Escalante

Tools for Assessing Outcomes in Studies of Chronic Cough: CHEST Guideline and Expert Panel Report

BACKGROUND Since the publication of the 2006 American College of Chest Physicians (CHEST) cough guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to (1) assess the performance of tools designed to measure cough frequency, severity, and impact in adults, adolescents, and children with chronic cough and (2) make recommendations or suggestions related to these findings. METHODS By following the CHEST methodologic guidelines, the CHEST Expert Cough Panel based its recommendations and suggestions on a recently published comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality, a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted on during a meeting of the Expert Cough Panel. RESULTS We recommend for adults, adolescents (≥ 14 years of age), and children complaining of chronic cough that validated and reliable health-related quality-of-life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough, such as the Leicester Cough Questionnaire and the Cough-Specific Quality-of-Life Questionnaire in adult and adolescent patients and the Parent Cough-Specific Quality of Life Questionnaire in children. We recommend acoustic cough counting to assess cough frequency but not cough severity. Limited data exist regarding the performance of visual analog scales, numeric rating scales, and tussigenic challenges. CONCLUSIONS Validated and reliable cough-specific health-related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by visual analog or numeric rating scales should be standardized. Previously validated QoL questionnaires or other cough assessments should not be modified unless the new version has been shown to be reliable and valid. Finally, in research settings, tussigenic challenges play a role in understanding mechanisms of cough.

Overview of the Management of Cough: CHEST Guideline and Expert Panel Report

This overview will demonstrate that cough is a common and potentially expensive health-care problem. Improvement in the quality of care of those with cough has been the focus of study for a variety of disciplines in medicine. The purpose of the Cough Guideline and Expert Panel is to synthesize current knowledge in a form that will aid clinical decision-making for the diagnosis and management of cough across disciplines and also identify gaps in knowledge and treatment options.

Methodologies for the Development of the Management of Cough: CHEST Guideline and Expert Panel Report

BACKGROUND This series of guidance documents on cough, which will be published over time, is a hybrid of two processes: (1) evidence-based guidelines and (2) trustworthy consensus statements based on a robust and transparent process. METHODS The CHEST Guidelines Oversight Committee selected a nonconflicted Panel Chair and jointly assembled an international panel of experts in each clinical area with few, if any, conflicts of interest. PICO (population, intervention, comparator, outcome)-based key questions and parameters of eligibility were developed for each clinical topic to inform the comprehensive literature search. Existing guidelines, systematic reviews, and primary studies were assessed for relevance and quality. Data elements were extracted into evidence tables and synthesized to provide summary statistics. These, in turn, are presented to support the evidence-based graded recommendations. A highly structured consensus-based Delphi approach was used to provide expert advice on all guidance statements. Transparency of process was documented. RESULTS Evidence-based guideline recommendations and consensus-based suggestions were carefully crafted to provide direction to health-care providers and investigators who treat and/or study patients with cough. Manuscripts and tables summarize the evidence in each clinical area supporting the recommendations and suggestions. CONCLUSIONS The resulting guidance statements are based on a rigorous methodology and transparency of process. Unless otherwise stated, the recommendations and suggestions meet the guidelines for trustworthiness developed by the Institute of Medicine and can be applied with confidence by physicians, nurses, other health-care providers, investigators, and patients.

Assessment of Intervention Fidelity and Recommendations for Researchers Conducting Studies on the Diagnosis and Treatment of Chronic Cough in the Adult: CHEST Guideline and Expert Panel Report

BACKGROUND Successful management of chronic cough has varied in the primary research studies in the reported literature. One of the potential reasons relates to a lack of intervention fidelity to the core elements of the diagnostic and/or therapeutic interventions that were meant to be used by the investigators. METHODS We conducted a systematic review to summarize the evidence supporting intervention fidelity as an important methodologic consideration in assessing the effectiveness of clinical practice guidelines used for the diagnosis and management of chronic cough. We developed and used a tool to assess for five areas of intervention fidelity. Medline (PubMed), Scopus, and the Cochrane Database of Systematic Reviews were searched from January 1998 to May 2014. Guideline recommendations and suggestions for those conducting research using guidelines or protocols to diagnose and manage chronic cough in the adult were developed and voted upon using CHEST Organization methodology. RESULTS A total of 23 studies (17 uncontrolled prospective observational, two randomized controlled, and four retrospective observational) met our inclusion criteria. These articles included 3,636 patients. Data could not be pooled for meta-analysis because of heterogeneity. Findings related to the five areas of intervention fidelity included three areas primarily related to the provider and two primarily related to the patients. In the area of study design, 11 of 23 studies appeared to be underpinned by a single guideline/protocol; for training of providers, two of 23 studies reported training, and zero of 23 reported the use of an intervention manual; and for the area of delivery of treatment, when assessing the treatment of gastroesophageal reflux disease, three of 23 studies appeared consistent with the most recent guideline/protocol referenced by the authors. For receipt of treatment, zero of 23 studies mentioned measuring concordance of patient-interventionist understanding of the treatment recommended, and zero of 23 mentioned measuring enactment of treatment, with three of 23 measuring side effects and two of 23 measuring adherence. The overall average intervention fidelity score for all 23 studies was poor (20.74 out of 48). CONCLUSIONS Only low-quality evidence supports that intervention fidelity strategies were used when conducting primary research in diagnosing and managing chronic cough in adults. This supports the contention that some of the variability in the reporting of patients with unexplained or unresolved chronic cough may be due to lack of intervention fidelity. By following the recommendations and suggestions in this article, researchers will likely be better able to incorporate strategies to address intervention fidelity, thereby strengthening the validity and generalizability of their results that provide the basis for the development of trustworthy guidelines.

Combinatorial Immunoprofiling in Latent Tuberculosis Infection. Toward Better Risk Stratification

RATIONALE Most immunocompetent patients diagnosed with latent tuberculosis infection (LTBI) will not progress to tuberculosis (TB) reactivation. However, current diagnostic tools cannot reliably distinguish nonprogressing from progressing patients a priori, and thus LTBI therapy must be prescribed with suboptimal patient specificity. We hypothesized that LTBI diagnostics could be improved by generating immunomarker profiles capable of categorizing distinct patient subsets by a combinatorial immunoassay approach. OBJECTIVES A combinatorial immunoassay analysis was applied to identify potential immunomarker combinations that distinguish among unexposed subjects, untreated patients with LTBI, and treated patients with LTBI and to differentiate risk of reactivation. METHODS IFN-γ release assay (IGRA) was combined with a flow cytometric assay that detects induction of CD25(+)CD134(+) coexpression on TB antigen-stimulated T cells from peripheral blood. The combinatorial immunoassay analysis was based on receiver operating characteristic curves, technical cut-offs, 95% bivariate normal density ellipse prediction, and statistical analysis. Risk of reactivation was estimated with a prediction formula. MEASUREMENTS AND MAIN RESULTS Sixty-five out of 150 subjects were included. The combinatorial immunoassay approach identified at least four different T-cell subsets. The representation of these immune phenotypes was more heterogeneous in untreated patients with LTBI than in treated patients with LTBI or unexposed groups. Patients with IGRA(+) CD4(+)CD25(+)CD134(+) T-cell phenotypes had the highest estimated reactivation risk (4.11 ± 2.11%). CONCLUSIONS These findings suggest that immune phenotypes defined by combinatorial assays may potentially have a role in identifying those at risk of developing TB; this potential role is supported by risk of reactivation modeling. Prospective studies will be needed to test this novel approach.

T-cell profiling and the immunodiagnosis of latent tuberculosis infection in patients with inflammatory bowel disease.

Background:Factors associated with performance of interferon-&ggr; release assays (IGRA) and the tuberculin skin test (TST) in screening for latent tuberculosis infection in patients with inflammatory bowel diseases (IBD) are still poorly understood. The influence of peripheral T-cell subset counts on the results also remain unclear. Methods:Prospective single-center study in 205 patients with IBD. Latent tuberculosis infection screening included a chest radiograph, TST (retest if negative), and 2 IGRAs: QuantiFERON-TB Gold In-Tube (QFT-GIT) and TSPOT-TB (TSPOT). T-cell subpopulations were determined by flow cytometry. Results:Twenty-one (10.2%) patients had an abnormal chest radiograph, 55 (26.8%) had a positive TST, 16 (7.8%) had a positive QFT-GIT, and 25 (12.6%) had a positive TSPOT. TST positivity was lower in patients on ≥2 immunosuppressants compared with the controls (5-aminosalicylic acid treatment) (10.4% versus 38.2%, respectively) (P = 0.0057). No other drugs influenced TST or IGRA positivity. In patients on corticosteroid treatment, anti-TNF treatment, or ≥2 immunosuppressants, IGRAs detected 10 cases of latent tuberculosis infection not identified by TST. TSPOT and QFT-GIT increased yield by 56% and 22%, respectively. No significant differences in T-cell subpopulations were found between patients with positive or negative TST or TSPOT results. However, patients with positive QFT-GIT findings had more CD8+ T cells (mean, 883 ± 576 versus 484 ± 385 cells per microliter in patients with negative results) (P = 0.022). Conclusions:IGRAs can improve TST-based screening in patients with IBD on immunosuppressive therapy. A low CD8+ count can affect QFT-GIT results. We suggest combining TSPOT and TST screening in patients with IBD on immunosuppressants.

Cough in the Athlete: CHEST Guideline and Expert Panel Report

Background: Cough is a common symptom experienced by athletes, particularly after exercise. We performed a systematic review to assess the following in this population: (1) the main causes of acute and recurrent cough, either exercise‐induced or not, (2) how cough is assessed, and (3) how cough is treated in this population. From the systematic review, suggestions for management were developed. Methods: This review was performed according to the CHEST methodological guidelines and Grading of Recommendations Assessment, Development and Evaluation framework until April 2015. To be included, studies had to meet the following criteria: participants had to be athletes and adults and adolescents aged ≥ 12 years and had to complain of cough, regardless of its duration or relationship to exercise. The Expert Cough Panel based their suggestions on the data extracted from the review and final grading by consensus according to a Delphi process. Results: Only 60 reports fulfilled the inclusion criteria, and the results of our analysis revealed only low‐quality evidence on the causes of cough and how to assess and treat cough specifically in athletes. Although there was no formal evaluation of causes of cough in the athletic population, the most common causes reported were asthma, exercise‐induced bronchoconstriction, respiratory tract infection (RTI), upper airway cough syndrome (UACS) (mostly from rhinitis), and environmental exposures. Cough was also reported to be related to exercise‐induced vocal cord dysfunction among a variety of less common causes. Although gastroesophageal reflux disease (GERD) is frequent in athletes, we found no publication on cough and GERD in this population. Assessment of the causes of cough was performed mainly with bronchoprovocation tests and suspected disease‐specific investigations. The evidence to guide treatment of cough in the athlete was weak or nonexistent, depending on the cause. As data on cough in athletes were hidden in a set of other data (respiratory symptoms), evidence tables were difficult to produce and were done only for cough treatment in athletes. Conclusions: The causes of cough in the athlete appear to differ slightly from those in the general population. It is often associated with environmental exposures related to the sport training environment and occurs predominantly following intense exercise. Clinical history and specific investigations should allow identification of the cause of cough as well as targeting of the treatment. Until management studies have been performed in the athlete, current guidelines that exist for the general population should be applied for the evaluation and treatment of cough in the athlete, taking into account specific training context and anti‐doping regulations.

Symptomatic Treatment of Cough Among Adult Patients With Lung Cancer: CHEST Guideline and Expert Panel Report

Background Cough among patients with lung cancer is a common but often undertreated symptom. We used a 2015 Cochrane systematic review, among other sources of evidence, to update the recommendations and suggestions of the American College of Chest Physicians (CHEST) 2006 guideline on this topic. Methods The CHEST methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework were used. The Expert Cough Panel based their recommendations on data from the Cochrane systematic review on the topic, uncontrolled studies, case studies, and the clinical context. Final grading was reached by consensus according to the Delphi method. Results The Cochrane systematic review identified 17 trials of primarily low‐quality evidence. Such evidence was related to both nonpharmacologic (cough suppression) and pharmacologic (demulcents, opioids, peripherally acting antitussives, or local anesthetics) treatments, as well as endobronchial brachytherapy. Conclusions Compared with the 2006 CHEST Cough Guideline, the current recommendations and suggestions are more specific and follow a step‐up approach to the management of cough among patients with lung cancer, acknowledging the low‐quality evidence in the field and the urgent need to develop more effective, evidence‐based interventions through high‐quality research.

Occupational and Environmental Contributions to Chronic Cough in Adults: Chest Expert Panel Report

BACKGROUND In response to occupational and environmental exposures, cough can be an isolated symptom reflecting exposure to an irritant with little physiological consequence, or it can be a manifestation of more significant disease. This document reviews occupational and environmental contributions to chronic cough in adults, focusing on aspects not previously covered in the 2006 ACCP Cough Guideline or our more recent systematic review, and suggests an approach to investigation of these factors when suspected. METHODS MEDLINE and TOXLINE literature searches were supplemented by articles identified by the cough panel occupational and environmental subgroup members, to identify occupational and environmental aspects of chronic cough not previously covered in the 2006 ACCP Cough Guideline. Based on the literature reviews and the Delphi methodology, the cough panel occupational and environmental subgroup developed guideline suggestions that were approved after review and voting by the full cough panel. RESULTS The literature review identified relevant articles regarding: mechanisms; allergic environmental causes; chronic cough and the recreational and involuntary inhalation of tobacco and marijuana smoke; nonallergic environmental triggers; laryngeal syndromes; and occupational diseases and exposures. Consensus-based statements were developed for the approach to diagnosis due to a lack of strong evidence from published literature. CONCLUSIONS Despite increased understanding of cough related to occupational and environmental triggers, there remains a gap between the recommended assessment of occupational and environmental causes of cough and the reported systematic assessment of these factors. There is a need for further documentation of occupational and environmental causes of cough in the future.

Diagnosis and Management of Tuberculosis in Candidates for Tumor Necrosis Factor Alpha Antagonists: An Experts Survey

Background: There are some controversies regarding the management of latent tuberculosis infection and tuberculosis in patients with rheumatologic indications for biologic therapy. Objectives: To describe current expert opinions and preferences regarding the evaluation and management of latent tuberculosis infection and tuberculosis in candidates and recipients of tumor-necrosis factor-alpha blocking therapy. Methods: A questionnaire addressing preferences related to management and treatment of latent tuberculosis infection and active tuberculosis in tumor-necrosis factor-alpha blocking candidates was distributed to tuberculosis and rheumatology experts across the United States between August 18, 2009, and June 21, 2010. Survey responses were formulated as a 5-point Likert scale (strongly disagree to strongly agree), or as a priority rank order list (1 to 6 or 7), and data were analyzed for percent agreement and median rankings. Measurements and main results: The tuberculin skin test and interferon-gamma release assays for latent tuberculosis infection screening were highly accepted among tuberculosis and rheumatology experts. Most participants supported the use of daily isoniazid for 9 months for latent tuberculosis infection therapy, but responses were mixed regarding timing to initiation of tumor-necrosis factor-alpha blocking therapy. Most tuberculosis experts supported standard anti-tuberculosis therapy for treatment of tuberculosis, but preferences varied among rheumatologists. In contrast, most rheumatologists believed tumor-necrosis factor-alpha blocking therapy should be stopped in individuals with active tuberculosis, while opinions varied among tuberculosis experts. Conclusions: Agreement among experts was common regarding preferences for diagnosis and management of latent tuberculosis infection and tuberculosis under hypothetical but likely common clinical scenarios, but some differences exist.