What's New in Pulmonary and Critical Care Medicine (UpToDate) PDF

10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate Official reprint from UpToDate® www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. What's new in pulmonary and critical care medicine AUTHORS: Paul Dieffenbach, MD, April F Eichler, MD,...

10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate Official reprint from UpToDate® www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. What's new in pulmonary and critical care medicine AUTHORS: Paul Dieffenbach, MD, April F Eichler, MD, MPH, Geraldine Finlay, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Sep 2023. This topic last updated: Oct 09, 2023. The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection. COPD Significance of airway dilation on computed tomography and symptoms in patients at risk for COPD (October 2023) Smokers and former smokers without airway obstruction but with respiratory symptoms or pulmonary imaging abnormalities are considered at risk for COPD, but their long-term prognosis is uncertain. In a recent study of over 3200 smokers and former smokers with normal spirometry, individuals with a computed tomography (CT)-derived marker of airway dilation and clinical symptoms (cough, phlegm production, dyspnea, or respiratory exacerbations) had increased 10-year mortality compared with those without CT-derived airway dilation (23 versus 11 percent, adjusted mortality difference 15 percent) [1]. These investigational data suggest that clinical and imaging features of airway disease have prognostic significance in patients at risk for COPD, but further study is needed to determine the value of detecting airway dilation in this population. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Additional testing'.) Pulmonary embolism in patients with severe COPD exacerbation (September 2023) Pulmonary embolism (PE) is an important potential trigger for COPD exacerbation. In a recent multicenter study, 1580 patients with COPD who were admitted to the hospital with acute worsening of respiratory symptoms were all screened for PE with computed tomography pulmonary angiogram within 48 hours of admission [2]. PE was identified in 266 (17 percent), with 166 patients (11 percent) having PE involving the main or lobar pulmonary https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 1/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate arteries. Purulent sputum production decreased the odds of PE by 60 percent. We suggest obtaining imaging for PE in patients requiring admission for COPD exacerbation who do not have evidence of other triggers (eg, infection or heart failure). (See "COPD exacerbations: Clinical manifestations and evaluation", section on 'Triggers' and "COPD exacerbations: Clinical manifestations and evaluation", section on 'Additional testing'.) Longitudinal risk of airway obstruction in symptomatic current or former smokers (August 2023) Whether current or former smokers with early respiratory symptoms have a different risk for COPD development or complications is not well understood. In one longitudinal cohort of patients aged 40 to 80 years with a >20 pack-year smoking history, the risk of developing airway obstruction over five years was 30 to 35 percent regardless of the presence of respiratory symptoms [3]. However, patients with symptoms were significantly more likely to have respiratory exacerbations during follow-up. (See "Chronic obstructive pulmonary disease: Risk factors and risk reduction", section on 'Cigarette smoking'.) Ensifentrine for moderate-severe COPD (July 2023) Ensifentrine is a novel inhaled selective dual phosphodiesterase-3 (PDE3) and phosphodiesterase-4 (PDE4) inhibitor with bronchodilator and anti-inflammatory properties. In two concomitant placebo-controlled phase 3 trials totaling approximately 1500 patients with COPD, dyspnea, and moderate-severe airway obstruction, nebulized ensifentrine was well tolerated and improved lung function, dyspnea, and rates of moderate-severe exacerbations compared with placebo [4]. Patients were on a mix of baseline therapies during the trial, but none were receiving dual bronchodilator therapy. Although the optimal strategy for use of this agent requires further study, this first-in-class inhaled bronchodilator/anti-inflammatory agent may, pending regulatory approval, lead to additional therapeutic options for COPD management. (See "Stable COPD: Follow-up pharmacologic management", section on 'Future directions'.) Dupilumab for refractory chronic obstructive pulmonary disease (June 2023) Biologic therapies have been proposed for patients with chronic obstructive pulmonary disease (COPD) and evidence of eosinophilic inflammation who continue to have frequent exacerbations despite optimized standard therapy. In a phase 3 blinded trial of over 930 patients with COPD, chronic bronchitis, and peripheral eosinophilia, with recurrent moderate to severe exacerbations despite optimal inhaled therapy, individuals assigned to receive dupilumab subcutaneously every two weeks demonstrated modest reductions in exacerbations and improvements in pulmonary function at one year compared with those assigned to placebo [5]. These findings suggest that a trial of dupilumab (off-label) is reasonable for patients with COPD and eosinophilia who have frequent exacerbations https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 2/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate despite optimized therapy for COPD including inhaled therapy and trials of azithromycin and/or roflumilast. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Frequent exacerbations despite azithromycin or roflumilast'.) Pneumothorax after endobronchial valve placement (June 2023) Postoperative pneumothorax is a frequent complication of endobronchial valve placement (EVP) for the treatment of emphysema, occurring in up to one-third of patients. One possible mechanism for pneumothorax involves rapid reabsorption atelectasis, which may be worsened by high levels of inspired oxygen. In a recent cohort study of 74 patients undergoing EVP, use of an intraoperative protocol to minimize the level of inspired oxygen during the procedure was associated with a marked reduction in the frequency of pneumothorax pre- versus post-protocol initiation (31 percent versus 7 percent) [6]. If generalizable, this strategy has the potential to greatly improve tolerability and outcomes of endobronchial valve therapy. (See "Bronchoscopic treatment of emphysema", section on 'Complications of endobronchial valve placement'.) Mucus plugging on CT scan and COPD mortality (May 2023) In patients with chronic obstructive pulmonary disease (COPD), excess production and reduced clearance of mucus in the airways lead to an accumulation of occlusive mucus plugs. There is growing evidence that mucus plugging impacts lung function, symptoms, and COPD prognosis. In a study of over 4000 patients with COPD who were evaluated for mucus plugging in medium-to-large airways by high-resolution computed tomography (CT) scan and followed for a median of 9.5 years, higher levels of mucus plugging correlated with increased risk of mortality, even after controlling for other clinical risk factors [7]. It remains to be seen whether therapeutic targeting of these occlusive mucus plugs can favorably impact COPD outcomes. (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions", section on 'Mucus plugging'.) Elexacaftor-tezacaftor-ivacaftor for children ≥2 years with cystic fibrosis (May 2023) Elexacaftor-tezacaftor-ivacaftor is an important therapy for most patients with cystic fibrosis (CF), but its use has been limited to individuals ≥6 years. The drug combination was evaluated in a 24-week open-label study in 75 children ≥2 to 6 years old with at least one F508del mutation [8]. The safety profile was similar to that in older age groups, and children had significant decreases in sweat chloride and improvement in lung clearance index, a sensitive measure of pulmonary function. Based on these findings, the US Food and Drug Administration approved this drug for children ≥2 years with CF and eligible genotypes ( algorithm 1) [9]. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Adverse effects'.) https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 3/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate CRITICAL CARE No benefit of routine V-A ECMO in patients with AMI-related cardiogenic shock (September 2023) Venoarterial extracorporeal membrane oxygenation (V-A ECMO) can increase survival for patients with refractory cardiogenic shock caused by a variety of conditions. However, benefit from the routine use of V-A ECMO for cardiogenic shock due to acute myocardial infarction (AMI) is unproven. In a meta-analysis of four randomized trials (nearly 570 patients with AMI-related cardiogenic shock), routine V-A ECMO use showed no mortality benefit and increased rates of both major bleeding and peripheral vascular ischemia compared with medical care alone [10]. Limitations of this meta-analysis include crossover between groups and a low rate of active left ventricular uploading during ECMO therapy, which may have biased the study in favor of the control group. These findings suggest no meaningful benefit for the routine use of V-A ECMO for patients with AMI-related cardiogenic shock but does not preclude benefit in selected patients who are candidates for salvage procedures such as heart transplant. (See "Extracorporeal life support in adults: Management of venoarterial extracorporeal membrane oxygenation (V-A ECMO)", section on 'Refractory cardiogenic shock'.) Adjunctive immunomodulators for severe COVID-19 (August 2023) For patients hospitalized for COVID-19 who require high-flow oxygen or ventilatory support, we suggest adding baricitinib or tocilizumab to dexamethasone to further reduce mortality. Other immunomodulatory agents may also improve outcomes. In a randomized trial of patients with severe COVID-19, most of whom were on remdesivir and glucocorticoids, infliximab and abatacept each reduced 28-day mortality compared with placebo (10 and 11 versus 15 percent) but did not improve time to clinical improvement [11]. The trial did not detect a benefit with cenicriviroc. Despite their potential efficacy, we do not routinely use infliximab or abatacept for COVID-19, because they do not offer clear advantages over baricitinib or tocilizumab, which have more established benefit and, in the United States, are approved for this indication. (See "COVID-19: Management in hospitalized adults", section on 'Limited roles for alternative immunomodulators'.) No benefit for continuous antibiotic infusion in critically ill patients with sepsis (August 2023) Whether the continuous infusion of antibiotics has improved clinical efficacy compared with traditional intermittent infusion is unclear. In a randomized trial of over 600 patients with sepsis, meropenem, given either as a continuous or intermittent infusion, resulted in similar rates of the composite outcome of 28-day mortality and emergence of pandrug bacterial https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 4/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate resistant (47 versus 49 percent [mortality 30 versus 33 percent]) [12]. Other outcomes were also similar, including 90-day mortality and length of stay. Lack of therapeutic monitoring and common prescription of other antimicrobials may have limited the ability to detect a between-group difference. We continue to prescribe intermittent infusions of antibiotics, unless otherwise indicated. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Dosing'.) High-flow oxygen for acute hypoxemic respiratory failure (August 2023) In adult patients with acute nonhypercapnic hypoxemic respiratory failure, the benefits of high-flow oxygen delivered via nasal cannulae (HFNC) compared with conventional low-flow oxygen (COT) are unclear. A recent meta-analysis of six trials (over 2700 patients with acute hypoxemic respiratory failure) reported that while HFNC did not reduce 28-day mortality compared with COT, it did significantly reduce the rate of reintubation (relative risk 0.89, 95% CI 0.81-0.97) [13]. These data support the use of HFNC in patients with acute hypoxemic respiratory failure who have escalating oxygen needs. (See "Evaluation and management of the nonventilated, hospitalized adult patient with acute hypoxemia", section on 'Humidified, high-flow oxygen delivered via nasal cannulae (HFNC)'.) Mild hypercarbia not associated with improved outcomes after sudden cardiac arrest (August 2023) In adults who are resuscitated after sudden cardiac arrest (SCA), hypercarbia has been proposed to induce cerebral vasodilation and improve cerebral perfusion. In a randomized trial of 1700 patients with coma after SCA, there was no significant difference in seizures, neurologic outcome, or survival, when ventilation was targeted to normocarbia (PaCO2 35 to 45 mm Hg) or mild hypercapnia (PaCO2 50 to 55 mmHg) [14]. Limitations of the trial include lack of blinding and a high percentage of patients with hypercapnia at study entry, which may have attenuated between-group differences. We continue to suggest targeting normocarbia in patients with SCA. (See "Intensive care unit management of the intubated post-cardiac arrest adult patient", section on 'Airway, ventilation, and oxygen targets'.) Variable response to sugammadex (June 2023) The sugammadex doses recommended for reversal of neuromuscular block are based on the train-of-four response to nerve stimulation. However, the efficacy varies with such fixed doses. In a prospective study of 97 surgical patients who received rocuronium for paralysis, 13 percent had residual neuromuscular block after reversal with the recommended sugammadex doses [15]. This finding reinforces the need to confirm complete reversal of block with neuromuscular monitoring before extubation at the end of surgery. (See "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Sugammadex'.) Racial bias in communication during family/caregiver meetings (June 2023) https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 5/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate The impact of race on shared decision-making is poorly studied. In a post-hoc analysis of a randomized trial, one study examined the impact of race on shared decision-making behaviors during family/caregiver meetings [16]. In general, ICU physicians appeared to approach both Black and White families/caregivers similarly (eg, discussion of information and prognosis) but provided less validation about those decisions to Black than White families/caregivers (27 versus 50 percent). The latter may have implications for emotional support following ICU meetings. While encouraging, more work is needed to address any potential for bias during communication with families/caregivers of critically ill patients. (See "Communication in the ICU: Holding a meeting with families and caregivers", section on 'Impact of race'.) Video laryngoscopy improves first-pass attempt success for emergency department and intensive care unit intubations (June 2023) Compared with direct laryngoscopy (DL), video laryngoscopy (VL) has been shown to increase first-pass attempt success in patients undergoing tracheal intubation, but most trials have been performed in the elective surgery setting. In a multi-center trial, over 1400 critically-ill adult patients undergoing tracheal intubation in the emergency department or intensive care unit were randomized to VL or DL for the first attempt (92 percent were performed by trainees) [17]. Successful first-attempt intubation was more common using VL (85 versus 71 percent) as was first-pass attempt without severe complications (69 versus 59 percent). There was no difference in the total number of severe complications, esophageal intubation, teeth injury, and aspiration. These findings support our recommendation of using VL if available, instead of DL, in a patient who is undergoing emergency intubation. (See "Overview of advanced airway management in adults for emergency medicine and critical care", section on 'Choice of laryngoscopy technique'.) Extracorporeal versus conventional cardiopulmonary resuscitation (May 2023) Limited and largely observational data suggest benefit from extracorporeal cardiopulmonary resuscitation (ECPR). However, a recent randomized trial in 160 adults with witnessed out-ofhospital cardiac arrest found no significant difference in the rate of survival with good neurologic outcome at 30 days for ECPR compared with conventional CPR (20 percent versus 16 percent, respectively) [18]. A longer time to implementation or differences in practice among the participating centers may account for discrepancies with previous studies that reported improved outcomes with ECPR. Further trials are needed to determine which subgroups may benefit from ECPR. (See "Extracorporeal life support in adults: Management of venoarterial extracorporeal membrane oxygenation (V-A ECMO)", section on 'Sudden cardiac arrest (ECPR)'.) Clinical characteristics of myxedema coma (April 2023) https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 6/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate Myxedema coma is a rare manifestation of hypothyroidism. In a recent multicenter cohort study including 82 cases over 18 years, common clinical findings included hypothermia, hemodynamic instability, and central nervous system involvement (somnolence, coma) [19]. While thyroiditis and thyroidectomy were common causes of preexisting hypothyroidism, 54 percent of patients did not have a prior known diagnosis of hypothyroidism. Precipitating events included discontinuing thyroid hormone (28 percent), sepsis (15 percent), and amiodarone (11 percent). The mortality rate in the intensive care unit (ICU) was 26 percent. This study emphasizes the importance of early diagnosis and prompt initiation of thyroid hormone and supportive measures (eg, hemodynamic monitoring in ICU, mechanical ventilation if needed, treatment of any underlying cause). (See "Myxedema coma", section on 'Epidemiology and risk factors'.) INTERSTITIAL LUNG DISEASE Sirolimus-related survival in lymphangioleiomyomatosis (August 2023) The impact of sirolimus on the survival of patients with lymphangioleiomyomatosis (LAM) is unclear. One retrospective study recently reported an improved eight-year cumulative survival rate in LAM patients treated with sirolimus compared with patients not on sirolimus (90 versus 78 percent) [20]. Improved survival occurred despite worse baseline lung function in the sirolimus group. These data support our recommendation for sirolimus as the first-line agent in patients with moderate to severe lung dysfunction due to LAM. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Mortality'.) Immunosuppressant therapy for rheumatoid arthritis-associated interstitial lung disease (May 2023) The optimal treatment for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has not been determined. Generally, treatment strategies parallel treatments that have been used for the underlying type of interstitial pneumonia, based on clinical presentation and radiographic features. However, in a recent observational study of 212 patients with RA-ILD treated with immunosuppressant agents (mycophenolate, azathioprine, or rituximab), initiation of immunosuppression correlated with stabilization in lung function trajectory [21]. Importantly, this improvement in lung function trajectory was seen regardless of the radiographic characteristics, including the presence of usual interstitial pneumonia [UIP] or probable UIP on imaging. These data suggest that a trial of immunosuppressive therapy is reasonable in most patients with RA-ILD who have progressive disease. (See "Interstitial lung disease in rheumatoid arthritis", section on 'Approach to treatment with glucocorticoids and immunosuppressants'.) https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 7/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate INTERVENTIONAL PULMONOLOGY Bleeding control during bronchoscopy (August 2023) When topical application of ice-cold saline fails to control bleeding during bronchoscopy, topical epinephrine is usually administered. The role of topical tranexamic acid (TXA) as a hemostatic agent in this setting is unknown. In a recent randomized trial of topical epinephrine versus TXA in 130 patients with bleeding during bronchoscopy, the rate of hemostasis was 83 percent in both groups [22]. There were no adverse events in either group. Although this is a single trial and larger studies are needed, topical TXA may be considered a third-line agent for bronchoscopic bleeding if epinephrine fails. (See "Flexible bronchoscopy in adults: Preparation, procedural technique, and complications", section on 'Bleeding'.) LUNG TRANSPLANTATION Lung transplant outcomes for COVID-19 end-stage lung disease (September 2023) COVID-19 end-stage lung disease is a new indication for lung transplantation with limited outcome data. Two groups have recently analyzed overlapping cohorts of approximately 400 patients who underwent lung transplantation in the United States for COVID-19-associated end-stage lung disease between March 2020 and August 2022 and who comprised almost 9 percent of all lung transplants performed during this time period [23,24]. Compared with other lung transplant recipients, these patients were generally younger and more likely to need mechanical ventilation or extracorporeal membrane oxygenation support before transplantation. Despite longer hospital stays, overall survival over the first 12 months was similar to that seen in patients who received lung transplantation for other causes (86 to 87 percent). Lung transplantation provides effective treatment for carefully selected patients with irreversible end-stage lung disease caused by COVID-19. (See "Lung transplantation: General guidelines for recipient selection", section on 'Lung disease due to COVID-19'.) New scoring system for lung transplantation (May 2023) As of March 9, 2023, the allocation of donor lungs for transplantation in the United States relies on a new lung Composite Allocation Score (CAS), which was developed to further improve waitlist mortality and provide more lung transplants to the most medically urgent candidates [25]. The CAS score has a theoretical maximum score of 100 points and has the following individual components: ● Candidate expected waitlist survival ● Likelihood of survival over five years posttransplant https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 8/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate ● Biologic compatibility (ie, candidate blood type, height, and immune sensitivity) ● Extra point allocation for pediatric candidates and prior living organ donors ● Placement efficiency, based on logistics of preserving and transporting the lungs between donor and transplant hospitals The impact of this scoring system on lung allocation and transplant outcomes remains to be seen. (See "Lung transplantation: An overview", section on 'Lung allocation'.) PULMONARY VASCULAR DISEASE Direct oral anticoagulants for cancer-related venous thromboembolism (August 2023) In patients with cancer-related venous thromboembolism (VTE), accumulating evidence suggests that direct oral anticoagulants (DOACS) and subcutaneous low molecular weight heparin (LMWH) have similar efficacy and safety. In a recent randomized trial of over 670 patients with cancer-related VTE, there were no significant differences between rates at six months for recurrent VTE (6.1 [DOACs] versus 8.8 percent [LMWH]) and major bleeding (5.2 [DOACs] versus 5.6 percent [LMWH]) [26]. Despite limitations such as lack of blinding, late randomization, and poor adherence rates with LMWH, these data are in keeping with previous evidence and support our suggestion for DOACs rather than LMWH in patients with cancer-associated VTE. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Direct oral anticoagulant mono- or dual therapy'.) Increased use of computed tomographic pulmonary angiography (June 2023) Recent data suggest increased use of computed tomographic pulmonary angiography (CTPA), despite the publication of several well-validated protocols targeted at avoiding its overuse for the diagnosis of pulmonary embolism (PE). A retrospective analysis of almost 9000 CTPA studies performed for suspected PE, reported an increase in CTPA use over the five-year period of the study (836 versus 1112 per 100,000 visits) [27]. More patients were diagnosed with low-risk PE and higher rates of ambulatory management were also noted. While these findings do not prove overuse of CTPA, more research is needed to determine the reasons for and potential clinical implications of its increased use. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Overview'.) OTHER PULMONARY MEDICINE Efficacy and side effects of gefapixant treatment for refractory chronic cough (September 2023) https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine/print?search=whats new respiratory&source=search_re… 9/10 10/19/23, 4:25 PM What's new in pulmonary and critical care medicine - UpToDate P2X3 inhibitors decrease sensitivity of airway sensory nerve fibers and are under investigation for the treatment of refractory chronic cough. In a recent meta-analysis of over 2000 patients receiving 45 mg twice daily of the P2X3 inhibitor gefapixant or placebo, the gefapixant group demonstrated greater reduction in 24-hour cough frequency (66 versus 50 percent) and improved cough quality of life (4- versus 3-point improvement on a 19-point scale), but nearly one-third of patients developed a taste disturbance [28]. The modest benefit compared with significant risk of adverse side effects continues to be a barrier to regulatory approval and widespread use of this agent. (See "Evaluation and treatment of subacute and chronic cough in adults", section on 'P2X3 antagonists'.) Gene candidate for refractory chronic cough in adults (May 2023) Refractory chronic cough (RCC) is defined as cough despite a complete work-up and systemic, guideline-based trials of empiric therapy. In a recent prospective case series of 68 patients with RCC who underwent genetic testing, approximately one quarter of patients carried repeat expansions in the replication factor C subunit 1 (RFC1) gene (8.8 percent monoallelic, 16.2 percent biallelic), a significantly higher carrier frequency than the expected 0.7 percent [29]. Biallelic RFC1 repeat expansions (RE-RFC1) are associated with Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome (CANVAS), a neurologic syndrome that frequently manifests with chronic cough long before onset of other neurologic sequelae. Pending confirmation in larger cohorts, these findings suggest an association between RFC1 repeat expansions and refractory chronic cough. (See "Causes and epidemiology of subacute and chronic cough in adults", section on 'Chronic refractory cough'.) Use of UpToDate is subject to the Terms of Use. 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