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Background: Cough characteristics vary between patients, and this can impact clinical diagnosis and care. The purpose of part two of this state-of-the-art review is to update the American College of Chest Physicians (CHEST) 2006 guideline on global physiology and pathophysiology of cough. Study Design and Methods: A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 using prespecified search terms. Results: We describe the demographics of typical patients with cough in the clinical setting, including how cough characteristics change across age. We summarize the effect of common clinical conditions impacting cough mechanics and the physical properties of mucus on airway clearance. Interpretation: This is the second of a two-part update to the 2006 CHEST cough guideline; it complements part one on basic phenomenology of cough by providing an extended clinical picture of cough along with the factors that alter cough mechanics and efficiency in patients. A greater understanding of the physiology and pathophysiology of cough will improve clinical management.

The purpose of this state-of-the-art review is to update the American College of Chest Physicians 2006 guideline on global physiology and pathophysiology of cough. A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 and using prespecified search terms. We describe the basic phenomenology of cough patterns, behaviors, and morphological features. We update the understanding of mechanical and physiological characteristics of cough, adding a contemporary view of the types of cough and their associated behaviors and sensations. New information about acoustic characteristics is presented, and recent insights into cough triggers and the patient cough hypersensitivity phenotype are explored. Lastly, because the clinical assessment of patients largely focuses on the duration rather than morphological features of cough, we review the morphological features of cough that can be measured in the clinic. This is the first of a two-part update to the American College of Chest Physicians 2006 cough guideline; it provides a more global consideration of cough phenomenology, beyond simply the mechanical aspects of a cough. A greater understanding of the typical features of cough, and their variations, may allow a more informed interpretation of cough measurements and the clinical relevance for patients.

Background This is an update of the section on complications that are associated with coughing in the 2006 CHEST cough guidelines that addresses two aims: (1) to systematically identify and thematically categorize the diverse complications of cough by providing a guide for future studies and (2) to identify gaps in the literature for future research. Research Question What are the potential complications that are associated with the act of coughing that have been reported in infants, children, adolescents, and adults? Study Design and Methods A scoping review was performed with the use of PubMed and SCOPUS databases that were searched from their beginning until September 6, 2019. Results Two hundred forty-seven publications met our inclusion criteria. To these, we added 38 articles from the 2006 complications paper that were not identified in the literature search plus the paper itself for a final total of 286 publications that formed the basis of this review. Since 2006, three new categories of complications have been reported: ear, nose and throat; disease transmission; and laboratory testing. Multiple additional complications that fall outside of these three categories have also been identified and included in the following categories: cardiovascular, constitutional symptoms, dermatologic, GI, genitourinary, musculoskeletal, neurologic, ophthalmologic, psychosocial/quality of life, and respiratory. Not previously highlighted is that some of the complications led to serious morbidity that included death, especially in patients with comorbid conditions, and potentially resulted in harm to others when cough resulted in a motor vehicle accident. Interpretation Our work identified a large number of cough complications that we thematically categorized primarily by organ system so that future studies of each system or each complication can be conducted. The gap in the literature that future studies should address is to identify the frequency of the complications and the strength of their association with cough. Only then will one be able to describe the findings in a manner that allows specific recommendations for avoiding these complications. In the meantime, patients with cough should be evaluated and treated according to evidence-based guidelines to mitigate or prevent the myriad of potential complications that are associated with coughing.

Background Chronic cough due to chronic bronchitis (CB) causes significant impairment in quality of life, and effective treatment strategies are needed. We conducted a systematic review on the management of chronic cough due to CB to update the recommendations and suggestions of the American College of Chest Physicians (CHEST) 2006 guideline on this topic. Methods This systematic review asked three questions: (1) What are the clinical features of the history that suggest a patient's cough-phlegm syndrome is due to CB? (2) Can treatment of stable CB improve or eliminate chronic cough? (3) Can therapy that targets chronic cough due to CB prevent or reduce the occurrence of acute CB exacerbations? Studies of adult patients with CB were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using the CHEST organization methodology. Results The search strategy used an assortment of descriptors and assessments to identify studies of chronic cough due to CB. Conclusions The evidence supporting the management of chronic cough due to CB is limited overall and of low quality. This article provides guidance on treatment by presenting suggestions based on the best currently available evidence and identifies gaps in our knowledge and areas for future research.

Background Cough is one of the most common presenting symptoms to general practitioners. The objective of this article is to collate the pediatric components of the CHEST chronic cough guidelines that have recently updated the 2006 guidelines to assist general and specialist medical practitioners in the evaluation and management of children who present with chronic cough. Methods We reviewed all current CHEST Expert Cough Panel's statements and extracted recommendations and suggestions relating to children aged ≤ 14 years with chronic cough (> 4 weeks duration). Additionally, we undertook systematic reviews to update other sections we considered relevant and important. Results The eight recent CHEST guidelines relevant to children, based on systematic reviews, reported some high-quality evidence in the management of chronic cough in children (eg, use of algorithms and management of wet/productive cough using appropriate antibiotics). However, much evidence is still inadequate, particularly in the management of non-specific cough in the community. Conclusions The recommendations and suggestions related to the management of chronic cough in the pediatric age group have been based upon high-quality systematic reviews and are summarized in this article. Compared to the 2006 Cough Guidelines, there is now high-quality evidence for some aspects of the management of chronic cough in children. However, further studies particularly in primary health care are required.

Background The long-term clinical course of asthma in patients with eosinophilic granulomatosis with polyangiitis (EGPA) remains unclear. We aimed to characterize long-term asthma in EGPA and to identify baseline predictors of long-term asthma severity. Methods This retrospective cohort study included patients who fulfilled standardized criteria for EGPA who were followed up in a single referral center between 1990 and 2017. Baseline and 3 (± 1) years of follow-up clinical, laboratory, and pulmonary function data were analyzed. Results Eighty-nine patients with EGPA and a documented asthma assessment at baseline and at 3 years from diagnosis were included. Severe/uncontrolled asthma was observed in 42.7% of patients at diagnosis and was associated with previous history of respiratory allergy (P Conclusions In patients with asthma with EGPA, long-term severe/uncontrolled asthma is associated with baseline pulmonary and ear, nose, and throat manifestations but not with clear-cut vasculitic features.

Rituximab (RTX) treatment is used for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, but its benefits in eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. Our aim was to characterize asthma control and glucocorticoid (GC) sparing after RTX treatment.A retrospective, computer-assisted search was performed to identify patients with EGPA and GC-dependent asthma diagnosed between 2000 and 2017 who received RTX for remission induction. Demographic and clinical features were analyzed.Of the 17 patients included, the majority were myeloperoxidase-ANCA positive (n = 13, 76.5%). Uncontrolled asthma symptoms and atopy were present in 13 patients (76.5%). RTX was used for initial remission induction in patients with new onset of severe disease (n = 5, 29.4%) and after failed remission induction with other immunosuppression (n = 12, 70.6%). It was used for remission maintenance in nine patients (52.9%). GCs were used for maintenance at a median dose of 25 mg/day (interquartile range, 16.25-37.5). At the end of follow-up, 13 patients (76.5%) had non-severe or controlled asthma, and remission was achieved in 12 (70.6%). Median serum eosinophil and C-reactive protein values decreased (1.06 vs 0.10 × 10RTX seems to be safe and have GC-sparing efficacy for asthma control in EGPA. Randomized controlled trials are needed for detailed study of RTX for treating EGPA.Key Points• In this retrospective study we have concluded that rituximab (RTX) might be considered for the control of severe corticosteroid-dependent asthma in eosinophilic granulomatosis polyangiitis (EGPA) patients especially when myeloperoxidase antibodies are positive.• Rituximab has not been studied particularly for asthma control in EGPA patients.• The most noticeable effect of RTX was the decrease in the use of corticosteroids for the control of asthma.

Objective To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors. Methods VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV). Results VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P

Background The decision to treat a suspected case of pertussis with antibiotics is usually based on a clinical diagnosis rather than waiting for laboratory confirmation. The current guideline focuses on making the clinical diagnosis of pertussis-associated cough in adults and children. Methods The American College of Chest Physicians (CHEST) methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework were used. The Expert Cough Panel based their recommendations on findings from a systematic review that was recently published on the topic; final grading was reached by consensus according to Delphi methodology. The systematic review was carried out to answer the Key Clinical Question: In patients presenting with cough, how can we most accurately diagnose from clinical features alone those who have pertussis-associated cough as opposed to other causes of cough? Results In adults, after pre-specified meta-analysis exclusions, pooled estimates of sensitivity and specificity were generated for only 4 clinical features: paroxysmal cough, post-tussive vomiting, inspiratory whooping, and absence of fever. Both paroxysmal cough and absence of fever had high sensitivity (93.2% [95% CI, 83.2-97.4] and 81.8% [95% CI, 72.2-88.7], respectively) and low specificity (20.6% [95% CI, 14.7-28.1] and 18.8% [95% CI, 8.1-37.9]). Inspiratory whooping and posttussive vomiting had a low sensitivity (32.5% [95% CI, 24.5-41.6] and 29.8% [95% CI, 18.0-45.2]) but high specificity (77.7% [95% CI, 73.1-81.7] and 79.5% [95% CI, 69.4-86.9]). In children, after pre-specified meta-analysis exclusions, pooled estimates of sensitivity and specificity were generated for only 1 clinical feature in children (0-18 years): posttussive vomiting. Posttussive vomiting in children was only moderately sensitive (60.0% [95% CI, 40.3-77.0]) and specific (66.0% [95% CI, 52.5-77.3]). Conclusions In adults with acute (

Background Patients commonly present to primary care services with upper and lower respiratory tract infections, and guidelines to help physicians investigate and treat acute cough due to suspected pneumonia and influenza are needed. Methods A systematic search was carried out with eight patient, intervention, comparison, outcome questions related to acute cough due to suspected pneumonia or influenza. Results There was a lack of randomized controlled trials in the setting of outpatients presenting with acute cough due to suspected pneumonia or influenza who were not hospitalized. Both clinical suggestions and research recommendations were made on the evidence available and CHEST Expert Cough Panel advice. Conclusions For outpatient adults with acute cough due to suspected pneumonia, we suggest the following clinical symptoms and signs are suggestive of pneumonia: cough; dyspnea; pleural pain; sweating, fevers, or shivers; aches and pains; temperature ≥ 38°C; tachypnea; and new and localizing chest examination signs. Those suspected of having pneumonia should undergo chest radiography to improve diagnostic accuracy. Although the measurement of C-reactive protein levels strengthens both the diagnosis and exclusion of pneumonia, there was no added benefit of measuring procalcitonin levels in this setting. We suggest that there is no need for routine microbiological testing. We suggest the use of empiric antibiotics according to local and national guidelines when pneumonia is suspected in settings in which imaging cannot be performed. Where there is no clinical or radiographic evidence of pneumonia, we do not suggest the routine use of antibiotics. There is insufficient evidence to make recommendations for or against specific nonantibiotic, symptomatic therapies. Finally, for outpatient adults with acute cough and suspected influenza, we suggest that initiating antiviral treatment (according to Centers for Disease Control and Prevention advice) within 48 hours of symptoms could be associated with decreased antibiotic use and hospitalization and improved outcomes.

To determine the efficacy of IL-5 inhibitory therapy in severe, refractory asthma in a real-world clinical setting from a tertiary referral center.A retrospective chart review of patients with severe asthma treated with IL-5 biologic therapy for ≥ 6 months at Mayo Clinic in Rochester, Minnesota between January 1, 2013 and August 31, 2019.Over the study period, we identified 63 patients with a mean age of 54 who received an IL-5 inhibitor for ≥ 6 months. A total of 55 patients received mepolizumab, 2 received benralizumab, and 9 patients received both. Patients were followed up for a mean of 25 months. The mean number of months of oral prednisone use prior to biologic initiation was 64. There was a significant reduction in the median dose of prednisone in the 24 months after drug initiation (15 mg vs. 0 mg; p = 0.0001). Similarly; there was a significant decline in the median number of asthma exacerbations in the 24 months before and after drug initiation (7 vs. 2; p = 0.0001). The mean number of emergency room (ER) visits and hospitalizations decreased from 5.1 and 2.0 to 1.6 and 0.4 in the 24 months before and after therapy initiation (p 0.0001 and p = 0.007, respectively) CONCLUSIONS: IL-5 inhibitory therapy is associated with significant and long-term sustained reductions in asthma exacerbation frequency, ER visits, hospitalizations, as well as oral steroid usage in a patient population with refractory steroid-dependent asthma referred to a tertiary referral center.

Background Chronic cough in interstitial lung disease (ILD) causes significant impairment in quality of life. Effective treatment approaches are needed for cough associated with ILD. Methods This systematic review asked: Is there evidence of clinically relevant treatment effects for therapies for cough in ILD? Studies of adults aged > 18 years with a chronic cough ≥ 8 weeks' duration were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using CHEST guideline methodology. Results Eight randomized controlled trials and two case series (≥ 10 patients) were included that reported data on patients with idiopathic pulmonary fibrosis, sarcoidosis, and scleroderma-related ILD who received a variety of interventions. Study quality was high in all eight randomized controlled trials. Inhaled corticosteroids were not supported for cough associated with sarcoidosis. Cyclophosphamide and mycophenolate were not supported for solely treating cough associated with scleroderma-associated ILD. A recommendation for thalidomide to treat cough associated with idiopathic pulmonary fibrosis did not pass the panel vote. In view of the paucity of antitussive treatment options for refractory cough in ILD, the guideline panel suggested that the CHEST unexplained chronic cough guideline be followed by considering options such as the neuromodulator gabapentin and speech pathology management. Opiates were also suggested for patients with cough refractory to alternative therapies. Conclusions The evidence supporting the management of chronic cough in ILD is limited. This guideline presents suggestions for managing and treating cough on the best available evidence, but future research is clearly needed.

Background Acute bronchiolitis is common in young children, and some children develop chronic cough after their bronchiolitis. We thus undertook systematic reviews based on key questions (KQs) using the PICO (Population, Intervention, Comparison, Outcome) format. The KQs were: Among children with chronic cough (> 4 weeks) after acute viral bronchiolitis, how effective are the following interventions in improving the resolution of cough?: (1) Antibiotics. If so what type and for how long? (2) Asthma medications (inhaled steroids, beta2 agonist, montelukast); and (3) Inhaled osmotic agents like hypertonic saline? Methods We used the CHEST expert cough panel's protocol and the American College of Chest Physicians (CHEST) methodological guidelines and GRADE framework. Data from the systematic reviews in conjunction with patients' values and preferences and the clinical context were used to form these suggestions. Delphi methodology was used to obtain consensus. Results Several studies and systematic reviews on the efficacy of the three types of interventions listed in the introduction were found but no data were relevant to our KQs. Thus, no recommendations on using the interventions above could be formulated. Conclusions The panel made several consensus-based suggestions and identified directions for future studies to advance the field of managing chronic cough post-acute bronchiolitis in children.

Objective To evaluate the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) measurement in individuals with suspected asthma. Methods We searched MEDLINE, EMBASE, PsycINFO, Cochrane databases, and SciVerse Scopus from the databases' inception through April 4, 2017, for studies that enrolled patients aged 5 years and older with suspected asthma and evaluated FeNO diagnostic accuracy. Independent reviewers selected studies and extracted data. We used the symmetric hierarchical summary receiver operating characteristic models to estimate test performance. Results We included 43 studies with a total of 13,747 patients. In adults, using FeNO cutoffs of less than 20, 20 to 29, 30 to 39, and 40 or more parts per billion, FeNO testing had sensitivities of 0.80, 0.69, 0.53, and 0.41, respectively, and specificities of 0.64, 0.78, 0.85, and 0.93, respectively. In children, using FeNO cutoffs of less than 20 and 20 to 29 parts per billion, FeNO testing had sensitivities of 0.78 and 0.61, respectively, and specificities of 0.79 and 0.89, respectively. Depending on the FeNO cutoff, the posttest odds of having asthma with a positive FeNO test result increased by 2.80- to 7.00-fold. Diagnostic accuracy was modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the overall population. Conclusion Fractional exhaled nitric oxide measurement has moderate accuracy to diagnose asthma in individuals aged 5 years and older. Test performance may be modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the general population with suspected asthma. Trial Registration International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42016047887

Background Cough is common in pulmonary TB and other chronic respiratory infections. Identifying features that predict whether pulmonary TB is the cause would help target appropriate individuals for rapid and cost-effective screening, potentially limiting disease progression and preventing transmission to others. Methods A systematic literature search for individual studies to answer eight key questions (KQs) was conducted according to established Chest Organization methods by using the following databases: MEDLINE via PubMed, Embase, Scopus, and the Cochrane Database of Systematic Reviews from January 1, 1984, to April 2014. Searches for KQ 1 and KQ 3 were updated in February 2016. An updated KQ 2 search was undertaken in March 2017. Results Even where TB prevalence is greatest, most individuals with cough do not have pulmonary TB. There was no evidence that 1, 3, or 4 weeks' duration were better predictors than cough lasting ≥ 2 weeks to screen for pulmonary TB. In people living with HIV (PLWHIV), screening for fever, night sweats, hemoptysis, and/or weight loss in addition to cough (any World Health Organization [WHO]-endorsed symptom) increases the diagnostic sensitivity for TB. Although the diagnostic accuracy of symptom-based screening remains low, the negative predictive value of the WHO-endorsed symptom screen in PLWHIV may help to risk-stratify individuals who are not close TB contacts and who do not require further testing for pulmonary TB in resource-limited settings. However, pregnant PLWHIV are more likely to be asymptomatic, and the WHO-endorsed symptom screen is not sensitive enough to be reliable. Combined with passive case finding (PCF), active case finding (ACF) identifies pulmonary TB cases earlier and possibly when less advanced. Whether outcomes are improved or transmission is reduced is unclear. Screening asymptomatic patients is cost-effective only in populations with a very high TB prevalence. The Xpert MTB/RIF assay on sputum is more cost-effective than clinical diagnosis. To our knowledge, no published comparative studies addressed whether the rate of cough resolution is a reliable determinant of the response to treatment or whether the rate of cough resolution was faster in the absence of cavitary lung disease. All studies on cough prevalence in Mycobacterium avium complex (MAC) lung disease, other nontuberculous mycobacterial infections, fungal lung disease, and paragonimiasis were of poor quality and were excluded from the evidence review. Conclusions On the basis of relatively few studies of fair to good quality, we conclude that most individuals at high risk and household contacts with cough ≥ 2 weeks do not have pulmonary TB, but we suggest screening them regardless of cough duration. In PLWHIV, the addition of the other WHO-endorsed symptoms increases the diagnostic sensitivity of cough. Earlier screening of patients with cough will help diagnose pulmonary TB sooner but will increase the cost of screening. The addition of ACF to PCF will increase the number of pulmonary TB cases identified. Screening asymptomatic individuals is cost-effective only in groups with a very high TB prevalence. Data are insufficient to determine whether cough resolution is delayed in individuals with cavitary lung disease or in those for whom treatment fails because of drug resistance, poor adherence, and/or drug malabsorption compared with results in other individuals with pulmonary TB. Cough is common in patients with lung infections due to MAC, other nontuberculous mycobacteria, fungal diseases, and paragonimiasis.

Background We performed systematic reviews using the population, intervention, comparison, outcome (PICO) format to answer the following key clinical question: Are the CHEST 2006 classifications of acute, subacute and chronic cough and associated management algorithms in adults that were based on durations of cough useful? Methods We used the CHEST Expert Cough Panel's protocol for the systematic reviews and the American College of Chest Physicians (CHEST) methodological guidelines and Grading of Recommendations Assessment, Development, and Evaluation framework. Data from the systematic reviews in conjunction with patient values and preferences and the clinical context were used to form recommendations or suggestions. Delphi methodology was used to obtain the final grading. Results With respect to acute cough ( 8 weeks), 11 studies met our criteria for quality assessment, and all had a high risk of bias. As predicted by the 2006 guidelines, the most common causes were UACS from rhinosinus conditions, asthma, gastroesophageal reflux disease, nonasthmatic eosinophilic bronchitis, combinations of these four conditions, and, less commonly, a variety of miscellaneous conditions and atopic cough in Asian countries. The subjects resided on four continents: North America, South America, Europe, and Asia. Conclusions Although the quality of evidence was low, the published literature since 2006 suggests that CHEST's 2006 Cough Guidelines and management algorithms for acute, subacute, and chronic cough in adults appeared useful in diagnosing and treating patients with cough around the globe. These same algorithms have been updated to reflect the advances in cough management as of 2017.

Background Cough is a common symptom prompting patients to seek medical care. Like patients in the general population, patients with compromised immune systems also seek care for cough. However, it is unclear whether the causes of cough in immunocompromised patients who are deemed unlikely to have a life-threating condition and a normal or unchanged chest radiograph are similar to those in persons with cough and normal immune systems. Methods We conducted a systematic review to answer the question: What are the most common causes of cough in ambulatory immunodeficient adults with normal chest radiographs? Studies of patients ≥ 18 years of age with immune deficiency, cough of any duration, and normal or unchanged chest radiographs were included and assessed for relevance and quality. Based on the systematic review, suggestions were developed and voted on using the American College of Chest Physicians (CHEST) methodology framework. Results The results of the systematic review revealed no high-quality evidence to guide the clinician in determining the likely causes of cough specifically in immunocompromised ambulatory patients with normal chest radiographs. Conclusions Based on a systematic review, we found no evidence to assess whether or not the proper initial evaluation of cough in immunocompromised patients is different from that in immunocompetent persons. A consensus of the panel suggested that the initial diagnostic algorithm should be similar to that for immunocompetent persons but that the context of the type and severity of the immune defect, geographic location, and social determinants be considered. The major modifications to the 2006 CHEST Cough Guidelines are the suggestions that TB should be part of the initial evaluation of patients with cough and HIV infection who reside in regions with a high prevalence of TB, regardless of the radiographic findings, and that specific causes and immune defects be considered in all patients in whom the initial evaluation is unrevealing.

Background There is no published systematic review on the etiologies of chronic cough or the relationship between OSA and chronic cough in children aged ≤ 14 years. We thus undertook a systematic review based on key questions (KQs) using the Population, Intervention, Comparison, Outcome format. The KQs follow: Among children with chronic (> 4 weeks) cough (KQ 1) are the common etiologies different from those in adults? (KQ 2) Are the common etiologies age or setting dependent, or both? (KQ 3) Is OSA a cause of chronic cough in children? Methods We used the CHEST Expert Cough Panel's protocol and the American College of Chest Physicians (CHEST) methodological guidelines and Grading of Recommendations Assessment, Development, and Evaluation framework. Data from the systematic reviews in conjunction with patients' values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain consensus. Results Combining KQs 1 and 2, we found moderate-level evidence from 10 prospective studies that the etiologies of cough in children are different from those in adults and are setting dependent. Data from three studies found that common etiologies of cough in young children were different from those in older children. However, data relating sleep abnormalities to chronic cough in children were found only in case studies. Conclusions There is moderate-quality evidence that common etiologies of chronic cough in children are different from those in adults and are dependent on age and setting. As there are few data relating OSA and chronic cough in children, the panel suggested that these children should be managed in accordance with pediatric sleep guidelines.

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.

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.

Background We updated the 2006 ACCP clinical practice guidelines for management of reflux-cough syndrome. Methods Two population, intervention, comparison, outcome (PICO) questions were addressed by systematic review: (1) Can therapy for gastroesophageal reflux improve or eliminate cough in adults with chronic and persistently troublesome cough? and (2) Are there minimal clinical criteria to guide practice in determining that chronic cough is likely to respond to therapy for gastroesophageal reflux? Results We found no high-quality studies pertinent to either question. From available randomized controlled trials (RCTs) addressing question #1, we concluded that (1) there was a strong placebo effect for cough improvement; (2) studies including diet modification and weight loss had better cough outcomes; (3) although lifestyle modifications and weight reduction may be beneficial in suspected reflux-cough syndrome, proton pump inhibitors (PPIs) demonstrated no benefit when used in isolation; and (4) because of potential carryover effect, crossover studies using PPIs should be avoided. For question #2, we concluded from the available observational trials that (1) an algorithmic approach to management resolved chronic cough in 82% to 100% of instances; (2) cough variant asthma and upper airway cough syndrome (UACS) (previously referred to as postnasal drip syndrome) from rhinosinus conditions were the most commonly reported causes; and (3) the reported prevalence of reflux-cough syndrome varied widely. Conclusions The panelists (1) endorsed the use of a diagnostic/therapeutic algorithm addressing causes of common cough, including symptomatic reflux; (2) advised that although lifestyle modifications and weight reduction may be beneficial in suspected reflux-cough syndrome, PPIs demonstrated no benefit when used in isolation; and (3) suggested that physiological testing be reserved for refractory patients being considered for antireflux surgery or for those in whom there is strong clinical suspicion warranting diagnostic testing.

The long-term clinical course of asthma in patients with eosinophilic granulomatosis with polyangiitis (EGPA) remains unclear. We aimed to characterize long-term asthma in EGPA and to identify baseline predictors of long-term asthma severity.This retrospective cohort study included patients who fulfilled standardized criteria for EGPA who were followed up in a single referral center between 1990 and 2017. Baseline and 3 (± 1) years of follow-up clinical, laboratory, and pulmonary function data were analyzed.Eighty-nine patients with EGPA and a documented asthma assessment at baseline and at 3 years from diagnosis were included. Severe/uncontrolled asthma was observed in 42.7% of patients at diagnosis and was associated with previous history of respiratory allergy (P .01), elevated serum total IgE levels (P .05), and increased use of high-dose inhaled corticosteroids (ICSs; P .05) and oral corticosteroids (OCSs; P .001) for respiratory symptoms the year before the EGPA diagnosis. During follow-up, an improvement or worsening in asthma severity was noted in 12.3% and 10.1% of patients, respectively. Severe/uncontrolled asthma was present in 40.5% of patients at 3 years and was associated with increased airway resistance on pulmonary function tests (PFTs; P .05). Long-term PFTs did not improve during long-term follow-up regardless of ICS or OCS therapy. Multivariate binary logistic regression results indicated that severe rhinosinusitis (P = .038), pulmonary infiltrates (P = .011), overweight (BMI ≥ 25 kg/mIn patients with asthma with EGPA, long-term severe/uncontrolled asthma is associated with baseline pulmonary and ear, nose, and throat manifestations but not with clear-cut vasculitic features.

Background: Bronchial asthma in Eosinophilic Granulomatosis with Polyangiitis (EGPA) patients is commonly present before, at and after the diagnosis of vasculitis, often requiring high doses of oral corticosteroid (OCS) to be controlled. Objectives: We aimed to better characterize long-term asthma in EGPA and to identify predictors of long-term asthma severity. Methods: Retrospective cohort study of anti-neutrophil cytoplasmic antibodies associated vasculitis patients who fulfilled standardized criteria for EGPA (American College of Rheumatology 1990 and/or Lanham criteria and/or Chapel Hill Consensus Conference 2012) that were followed in a single referral center from 1990-2017. Baseline and 3 (±1) years of follow-up clinical, laboratory and pulmonary function data were analyzed. The definition from American Thoracic Society Workshop was used to identify patients with severe/uncontrolled asthma. Severe rhinosinusitis was defined as rhinosinusitis that needed sinus surgery to control nasal polyps and/or reduce symptoms (≥1 surgery). Results: One-hundred-eighty-seven patients with EGPA were identified, from which 89 patients with documented asthma assessment at baseline and after 3 years from diagnosis were included. Severe/uncontrolled asthma was observed in 42.7% of patients at diagnosis and was associated with a previous history of respiratory allergy (p 0.05). Using multivariate binary logistic regressions, severe rhinosinusitis, pulmonary infiltrates, overweight and severe/uncontrolled asthma at vasculitis diagnosis independently predicted severe/uncontrolled asthma at the 3-year endpoint (Table below). Conclusion: In this large cohort of patients with EGPA, long-term severe/uncontrolled asthma is frequent, and patients affected display a higher proportion of bronchial obstruction and have more severe airway resistance. Overall, pulmonary function does not improve during the follow-up regardless of ICS and OCS therapy. Finally, long-term severe/uncontrolled asthma is associated with baseline pulmonary and ENT manifestations, but not with vasculitic features. References [1] Cottin V, et al. Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). The European respiratory journal. 2016;48(5):1429-41. [2] Berti A, et al. Severe/uncontrolled asthma and overall survival in atopic patients with eosinophilic granulomatosis with polyangiitis. Respiratory medicine. 2018;142:66-72. Disclosure of Interests: Alvise Berti: None declared, Divi Cornec: None declared, Marta Casal Moura: None declared, Robert Smith: None declared, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI., Ulrich Specks: None declared, Karina Keogh: None declared

Background In this study we aim to describe presenting characteristics and identify prognostic factors for disease resolution in patients with chronic rhinosinusitis (CRS) in the setting of eosinophilic granulomatosis with polyangiitis (EGPA). Methods Patients evaluated at a tertiary care center with diagnoses of EGPA and CRS were identified. Descriptive statistics were obtained. Univariate analysis was used to search for prognostic factors associated with higher Lund-Mackay score at presentation and disease resolution. Results Forty-four patients were included with a mean age of 52.7 (standard deviation, 14) years. Twenty-one patients (47.7%) were female, all had a diagnosis of asthma, and 36 (83.7%) had eosinophils >10%. Common presenting symptoms for CRS included nasal discharge (87.9%) followed by nasal congestion (83.9%) and facial pain and pressure (83.8%). Medical management of CRS included systemic corticosteroids (93.2%) and systemic antibiotics (75%). Surgical intervention occurred in 29 patients (67%). Nine patients (20.5%) had resolution of sinus symptoms, including 4 with imaging confirmation. Fourteen patients (31.8%) had continued CRS, but with improved symptoms, whereas 9 patients (20.5%) had continued CRS with no improvement in symptoms. Eleven patients (25%) were lost to follow-up and 4 (9.1%) died. Univariate analysis did not show antineutrophil cytoplasmic antibody positivity, presence of peripheral eosinophilia, gender, age, or absence of systemic therapy to be predictive of higher Lund-Mackay score at presentation or predictive of disease resolution. Conclusion CRS in patients with EGPA is often refractory to medical and surgical management. Treatment of these patients should occur in a multidisciplinary setting.

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.

Background Unexplained chronic cough (UCC) causes significant impairments in quality of life. Effective assessment and treatment approaches are needed for UCC. Methods This systematic review of randomized controlled trials (RCTs) asked: What is the efficacy of treatment compared with usual care for cough severity, cough frequency, and cough-related quality of life in patients with UCC? Studies of adults and adolescents aged > 12 years with a chronic cough of > 8 weeks' duration that was unexplained after systematic investigation and treatment were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using the American College of Chest Physicians organization methodology. Results Eleven RCTs and five systematic reviews were included. The 11 RCTs reported data on 570 participants with chronic cough who received a variety of interventions. Study quality was high in 10 RCTs. The studies used an assortment of descriptors and assessments to identify UCC. Although gabapentin and morphine exhibited positive effects on cough-related quality of life, only gabapentin was supported as a treatment recommendation. Studies of inhaled corticosteroids (ICS) were affected by intervention fidelity bias; when this factor was addressed, ICS were found to be ineffective for UCC. Esomeprazole was ineffective for UCC without features of gastroesophageal acid reflux. Studies addressing nonacid gastroesophageal reflux disease were not identified. A multimodality speech pathology intervention improved cough severity. Conclusions The evidence supporting the diagnosis and management of UCC is limited. UCC requires further study to establish agreed terminology and the optimal methods of investigation using established criteria for intervention fidelity. Speech pathology-based cough suppression is suggested as a treatment option for UCC. This guideline presents suggestions for diagnosis and treatment based on the best available evidence and identifies gaps in our knowledge as well as areas for future research.

Although asthma, rhinitis/rhinosinusitis and peripheral eosinophilia are present in virtually all patients with eosinophilic granulomatosis with polyangiitis (EGPA), the role of atopy in these patients is not well defined.To clarify the role of atopy in patients affected with EGPA.Clinical, laboratory and standard spirometry data have been abstracted from medical records. Only patients who underwent skin and/or specific IgE testing for common aeroallergens before the vasculitic phase were included.Overall, 33.5% (63) of our patients underwent skin and/or specific IgE testing to aeroallergens. Atopy related to aeroallergens was confirmed in 22.3% (two-third of those tested), and was associated with more severe/uncontrolled asthma (p 0.001), including a greater use of oral glucocorticoids for respiratory manifestations the year before the diagnosis of EGPA (p = 0.013). Atopic patients with EGPA had higher total serum IgE levels and less renal disease at EGPA diagnosis compared to non-atopic patients (p 0.05). Among atopic patients, the majority had multiple sensitizations (76%); dust mite and grass pollen were the most common respiratory allergens identified. The number of allergens did not correlate with peripheral eosinophilia, total serum IgE, ESR, or measures of airway obstruction (p 0.05 in all cases). The presence of atopy increased the risk of severe/uncontrolled asthma, but not the risk of severe vasculitis (Five Factor Score≥1). Atopic patients had a better overall survival (p = 0.027).In EGPA, atopy is associated with better prognosis and more severe/uncontrolled asthma manifestations in the year before the development of vasculitis, but not with more severe vasculitis at presentation.

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.

BACKGROUND We conducted a systematic review on the management of psychogenic cough, habit cough, and tic cough to update the recommendations and suggestions of the 2006 guideline on this topic. METHODS We followed the American College of Chest Physicians (CHEST) methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework. The Expert Cough Panel based their recommendations on data from the systematic review, patients' values and preferences, and the clinical context. Final grading was reached by consensus according to Delphi methodology. RESULTS The results of the systematic review revealed only low-quality evidence to support how to define or diagnose psychogenic or habit cough with no validated diagnostic criteria. With respect to treatment, low-quality evidence allowed the committee to only suggest therapy for children believed to have psychogenic cough. Such therapy might consist of nonpharmacologic trials of hypnosis or suggestion therapy, or combinations of reassurance, counseling, and referral to a psychologist, psychotherapy, and appropriate psychotropic medications. Based on multiple resources and contemporary psychologic, psychiatric, and neurologic criteria ( Diagnostic and Statistical Manual of Mental Disorders , 5th edition and tic disorder guidelines), the committee suggests that the terms psychogenic and habit cough are out of date and inaccurate. CONCLUSIONS Compared with the 2006 CHEST Cough Guidelines, the major change in suggestions is that the terms psychogenic and habit cough be abandoned in favor of somatic cough syndrome and tic cough, respectively, even though the evidence to do so at this time is of low quality.

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.

Bronchopulmonary C-fibers and a subset of mechanically sensitive, acid-sensitive myelinated sensory nerves play essential roles in regulating cough. These vagal sensory nerves terminate primarily in the larynx, trachea, carina, and large intrapulmonary bronchi. Other bronchopulmonary sensory nerves, sensory nerves innervating other viscera, as well as somatosensory nerves innervating the chest wall, diaphragm, and abdominal musculature regulate cough patterning and cough sensitivity. The responsiveness and morphology of the airway vagal sensory nerve subtypes and the extrapulmonary sensory nerves that regulate coughing are described. The brainstem and higher brain control systems that process this sensory information are complex, but our current understanding of them is considerable and increasing. The relevance of these neural systems to clinical phenomena, such as urge to cough and psychologic methods for treatment of dystussia, is high, and modern imaging methods have revealed potential neural substrates for some features of cough in the human.

Purpose of review This review aims to give an overview of efficacy and safety of the therapeutic options for eosinophilic granulomatosis with polyangiitis (EGPA). Recent findings There are few current treatments beyond glucocorticoids for the successful induction and maintenance of remission in EGPA, and glucocorticoids remain the cornerstone of treatment. Life-threatening manifestations likely benefit from the addition of cytotoxic agents, although results of studies investigating cyclophosphamide or azathioprine have shown mixed efficacy results and high adverse event rates. More recently, targeted therapies including rituximab and mepolizumab have shown encouraging results. Since bronchial asthma often persists beyond the control of vasculitis disease manifestations, inhaled respiratory therapy and a multispecialty management approach are advocated. Summary EGPA has been the subject of very few randomized controlled trials. Glucocorticoids remain the cornerstone of treatment. Among others, evidence of efficacy for mepolizumab and rituximab is accumulating. The optimization of asthma control is recommended.

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.

Introduction Disease relapses are frequent in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). We evaluated the outcomes of patients re-treated with rituximab (RTX) and prednisone for severe disease relapses.

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.

Objective Diffuse alveolar hemorrhage (DAH) is an uncommon complication of primary antiphospholipid syndrome (APS). We aimed to describe the clinical characteristics, treatment, and outcomes of primary APS–associated DAH in a single center. Methods We conducted a retrospective review of all adults with primary APS–associated DAH evaluated at Mayo Clinic over a 15-year period. DAH was defined as bilateral pulmonary infiltrates and bronchoalveolar lavage (BAL) fluid documenting progressively bloody returns and/or the presence of >20% hemosiderin-laden macrophages. Patients with other causes of DAH were excluded. Results Eighteen patients were identified (median age 43 years). Capillaritis was present in surgical lung biopsy samples of 3 patients. BAL differential cell counts revealed predominantly neutrophils. All patients were treated initially with glucocorticoids. Cyclophosphamide (CYC) was used in 8 patients; complete remission was achieved in 3 patients treated with CYC alone and in 1 patient receiving combination therapy with rituximab (RTX). RTX was used in 9 patients; 2 patients achieved remission with RTX alone, whereas 3 patients required combination therapy with CYC or mycophenolate mofetil (MMF). No patient achieved complete remission while receiving single therapy with MMF, azathioprine, or plasma exchange. Intravenous gamma globulin therapy was administered in 5 patients; no patient achieved control of the disease. Six patients died, all because of complications related to uncontrolled DAH or its therapy. Conclusion We present the largest case series of primary APS–associated DAH reported in the literature. DAH carries a very poor prognosis and therapeutic options are limited. Immunosuppression with either CYC or RTX is associated with the highest likelihood of remission induction and should be considered early.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare systemic disease characterized by asthma, peripheral and tissue eosinophilia & systemic vasculitis. Cardiovascular manifestations have been reported in past smaller studies, but the prevalence and spectrum of cardiac disease in EGPA is

Granulomatosis with polyangiitis (GPA) (Wegener's) may mimic IgG4-related disease (IgG4-RD) on histologic examination of some biopsies, especially those from head and neck sites. IgG4 immunostaining is often performed in this context for differential diagnosis with IgG4-RD. Herein, we report the results of IgG4-positive (IgG4+) cells in 43 cases of GPA including 26 previously published cases as well as the newly added cases from the lung and kidney. We also included 20 control cases without any clinical evidence of GPA or IgG4-RD that consisted of chalazion (n = 8), chronic sinusitis (n = 8), and chronic tonsillitis (n = 4). Forty-three biopsies diagnosed as GPA were from sinonasal mucosa/oral cavity/nasopharynx (n = 14), orbit/periorbital tissue (n = 7), lung/pleura (n = 14), kidney (n = 4), skin (n = 3), and dura (n = 1). Of 43 biopsies, 8 (18.6%) revealed increased IgG4+ cells (>30 per high-power field and >40% in IgG4+/IgG+ ratio) and originated from sinonasal (n = 4) or orbital/periorbital (n = 4) regions. The IgG4+ cells and IgG4+/IgG+ ratio in these cases ranged from 37 to 139 per high-power field and 44% to 83%, respectively. None of the control cases had increased IgG4+ cells. In conclusion, increased IgG4+ cells can be seen in sinonasal or orbital/periorbital biopsies of GPA, which could pose as a pitfall in the diagnosis of IgG4-RD. However, GPA in other organs and controls did not show increased IgG4+ cells when using the above threshold. The biologic or clinical importance of increased IgG4+ cells in GPA cases involving head and neck region is uncertain, and a further study might be warranted to address the potential pathogenic relationship between IgG4-RD and GPA in those cases.

Objective. To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). Methods. The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). Results. Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. Conclusion. Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3- ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Background The long-term safety of patient-administered nebulized lidocaine for control of chronic cough has not been established. Methods We performed a retrospective study of adults who received a prescription and nurse education for nebulized lidocaine for chronic cough between 2002 and 2007. A survey questionnaire inquiring about adverse reactions and the effectiveness of nebulized lidocaine was developed and administered to these individuals after the nebulized lidocaine trial. We conducted two mailings and a postmailing phone follow-up to nonresponders. When adverse events were reported in the questionnaire response, a structured phone interview was conducted to obtain additional details. Results Of 165 eligible patients, 99 (60%) responded to the survey. Responders were a median age of 62 years (range, 29–87 years); 77 (79%) were women, and 80 (82%) were white. The median duration of cough was 5 years before treatment with nebulized lidocaine. Of the patients who used nebulized lidocaine (93% of survey responders), 43% reported an adverse event. However, none of these events required an emergency visit, hospitalization, or antibiotic therapy for aspiration pneumonia. The mean (SD) of the pretreatment cough severity score was 8.4 (1.6) and posttreatment was 5.9 (3.4) ( P Conclusions Adults tolerated self-administration of nebulized lidocaine for difficult-to-control chronic cough. No serious adverse effects occurred while providing symptomatic control in 49% of patients.

Obliterative bronchiolitis (OB) is a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Our objective was to perform a systematic review and meta-analysis of the impact of azithromycin on change in forced expiratory volume in 1 second (FEV1). We searched MEDLINE, EMBASE, Web of Science, Cochrane CENTRAL and Scopus databases and included studies that compared azithromycin with placebo or no intervention in the treatment of OB or bronchiolitis obliterans syndrome (BOS) in patients who had undergone allogeneic HSCT. Ninety-one unique publications were identified, and 4 studies met inclusion criteria, with a total of 90 patients. Changes in FEV1 were measured between 12 and 24 weeks after initiation of treatment. The meta-analysis demonstrated a mean increase in FEV1 of 30 mL (95% confidence interval, −260 to +330 mL; P = .82) after initiation of azithromycin. One patient death was reported but not attributed to azithromycin therapy. In conclusion, current evidence can neither support nor refute the use of azithromycin in the treatment of patients who develop OB/BOS after HSCT. Further studies are needed to determine whether azithromycin is beneficial for the treatment of OB/BOS in this setting.

Importance Refractory chronic cough is a debilitating condition with limited therapeutic options. Laryngeal botulinum toxin type A (BtxA) has been anecdotally reported to benefit patients with chronic cough. We report on our experience with the use of BtxA for the treatment of patients with refractory chronic cough. Objective To describe the effects of electromyography (EMG)-guided thyroarytenoid (TA) BtxA injection for the treatment of refractory chronic cough. Design, Setting, and Participants For this single tertiary referral center retrospective case series, we included all patients with refractory chronic cough who received bilateral EMG-guided TA BtxA injections (n = 22) between July 1, 2013, and July 31, 2014, at the Mayo Clinic in Rochester, Minnesota. Intervention Bilateral TA BtxA injection. Main Outcomes and Measures The primary outcome is a self-reported improvement of 50% or more in cough severity and/or symptoms by a 2-month follow-up telephone call. Adverse events and patient-reported quality measures were also assessed. Results A total of 22 patients (median [interquartile range] age 61 [57.5-85] years; 19 of 22 women) underwent 31 distinct laryngeal BtxA treatment sessions. The primary outcome of self-reported improvement of 50% or more of cough severity and/or symptoms was achieved in 16 of 31 (52%) treatment sessions. Eleven patients (50%) reported greater than 50% improvement after the first BtxA injection. No major complications occurred. Postprocedural liquid dysphagia had a positive predictive value of 84% and negative predictive value of 100% for response to therapy. Conclusions and Relevance In this case series, laryngeal BtxA injection was well tolerated in patients with refractory chronic cough with half of participants experiencing at least short-term improvement in their cough. The occurrence of liquid dysphagia after a BtxA injection appeared to be predictive of a beneficial response. The durability of response, patient selection criteria, and optimal BtxA dosage remains to be determined.

The vasculitic syndromes are a heterogeneous group of rare disorders characterized by degrees of inflammation and necrosis of blood vessels with a wide variety of clinical manifestations. Intensive care treatment is most commonly required for vasculitis involving small blood vessels, including capillaries. Involvement of these vessels in the lung causes alveolar haemorrhage, which may lead to respiratory failure. In the kidneys it may cause glomerulonephritis leading to renal failure. Severe cardiac, neurological, and gastrointestinal manifestions can also be seen. Non-vasculitic manifestations may also be present, such as pulmonary nodules secondary to granulomatous inflammation in granulomatosis with polyangiitis. Diagnosis is based primarily on history and physical exam in conjunction with radiographic and serological testing. Intensive care unit admission is typically secondary to end organ damage due to inflammation, or because of side effects from the cytotoxic therapies, particularly infection. Treatment of vasculitis includes supportive management in conjunction with immunosuppression. Standard treatment of severe disease consists of corticosteroids and cytotoxic drugs.

Purpose To determine the association of antineutrophil cytoplasmic antibodies (ANCA) and leukotriene receptor antagonists with disease activity in a large series of patients with Churg-Strauss syndrome. Methods Potential subjects were identified by a computerized search of the Mayo Clinic Rochester database for the years 1990 to 2000. Patients meeting one of three classification schemes for Churg-Strauss syndrome were included. Results Ninety-one patients met the inclusion criteria. Clinical manifestations were similar to those in previous reports. Mortality was similar to that in the general population. ANCA testing was performed in 74 patients. Seventy-three percent (n = 22) of the 30 patients tested before therapy were ANCA positive, as were 75% (n = 12) of the 16 patients tested during a disease flare. In comparison, 16% (n = 8) of the 49 tested during remission were ANCA positive. Serial measurements indicated a correlation of ANCA levels with disease activity. Central nervous system involvement was the only clinical manifestation that correlated with ANCA status ( P = 0.05). Twenty-three patients received leukotriene receptor antagonists, of whom 16 (70%) began treatment before diagnosis and 6 (27%) began during remission. Two of those treated after diagnosis relapsed. In 1 patient the relation between disease and leukotriene receptor antagonist use could not be determined. Use of leukotriene receptor antagonists did not affect the time between onset of asthma and manifestations of vasculitis, and was not correlated with organ manifestations, except sinus disease. Conclusion No one classification scheme identified all patients. Churg-Strauss syndrome has a better prognosis than other ANCA-associated vasculitides. ANCA status correlates with disease activity, whereas a pathogenic role for leukotriene receptor antagonists in the development of Churg-Strauss syndrome was not noted.