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Background: Gefapixant is a P2X3 receptor antagonist for treatment of refractory (RCC) and unexplained chronic cough (UCC). The aim of this study was to evaluate 12 weeks of gefapixant compared with placebo after 12 weeks of treatment for RCC/UCC. Methods: We conducted a 12-week, Phase 2b, randomized, double-blind, placebo-controlled study in RCC or UCC (>1 year) patients (no radiographic chest abnormality; ≥40 mm on the Cough Severity Visual Analog Scale [VAS]) recruited from 44 secondary/tertiary care sites in UK and US (clinicaltrials.gov: NCT02612610, status closed). Patients were randomized to placebo or gefapixant (7·5 mg twice daily [BID], 20 mg BID, or 50 mg BID). The primary endpoint was placebo-adjusted change from baseline in Awake Cough Frequency (coughs/hour) after 12 weeks analysed by intention-to-treat analysis. Adverse events (AE) were monitored and safety was evaluated in all patients receiving ≥1 dose of study drug. Findings: Between December 2015 and July 2016 253 patients were randomized to placebo (n=63), gefapixant 7·5 mg (n=64), 20 mg (n=63), or 50 mg (n=63). Mean (SD) age was 60 (10·0) years and 76% of patients were women. At 12 weeks, Geometric Mean Awake Cough Frequency was 18·2, 14·5, 12·0, 11·3 coughs/hr with placebo and gefapixant 7·5 mg, 20 mg, and 50 mg, respectively; percent change vs. placebo (95% CI) was -37% (-53·3,-14·9) with gefapixant 50 mg (p=0·003), -22·2% (-42,4·3) with 20 mg (p=0·093), and -22·0% (-41·8,4·6) with 7·5 mg (p=0·097). Dysgeusia was the most common AE, occurring in 5%, 10%, 33%, and 48% of placebo and gefapixant 7·5-mg, 20-mg, and 50-mg patients, respectively. Interpretation: Targeting P2X3 with gefapixant at a dose of 50 mg BID significantly reduces cough frequency in patients with RCC and UCC after 12 weeks of treatment compared with placebo. Gefapixant was generally well tolerated with dysgeusia being the most frequent AE.

Shan-Shan Su,1,* Sheng-Nan Zhang,1,* Jun-Ru Ye,1 Ling-Na Xu,1 Peng-Cheng Lin,1 Han-Yan Xu,1 Qing Wu,2 Yu-Ping Li1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People’s Republic of China; 2The Center of Laboratory and Diagnosis, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-Ping LiDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, South Baixiang, Ouhai District, Wenzhou, Zhejiang Province 325015, People’s Republic of ChinaTel/fax +86 577 5557 9273Email wzliyp@163.comBackground: Patients with high-titer anti-IFN-γ autoantibodies present disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections. Due to its rare occurrence and non-specific symptoms, this syndrome is difficult to diagnose during early disease stages. Here, we report a case with high-concentrations of serum anti-IFN-γ autoantibodies who presented with disseminated Talaromyces marneffei and NTM disease accompanied Sweet’s syndrome.Case presentation: A 62-year-old Chinese woman with no previous history was admitted to our hospital in August 2016 due to intermittent fever for 2 years, left chest wall redness, and swelling for 3 months. During hospitalization, the patient was confirmed with disseminated T. marneffei and successfully treated with antifungal therapy. In July 2017, upon second admission, Mycobacterium avium intracellular (MAC) pulmonary infection was established after positive cultures from the right lung tissue. The patient failed treatment after 1 month of anti-NTM therapy due to side effects. In May 2018, she was confirmed as having disseminated MAC disease accompanied by hand rashes, which was considered as Sweet’s syndrome. High-level anti-IFN-γ antibodies in the patient serum were detected upon comparison with normal controls (2.85-fold increase). Following anti-NTM therapy, both symptoms and pulmonary infiltration gradually improved, and joint destruction and lymphadenitis remained.Conclusions: Patients with anti-interferon-γ autoantibodies should be considered for severe, recurrent infections in adults in the absence of other known risk factors. Sweet’s syndrome is a common skin manifestation of the syndrome.Keywords: Talaromyces marneffei, Mycobacterium avium, Sweet’s syndrome, autoantibodies, interferon-gamma