Phase Angle and Frailty Are Important Prognostic Factors in Critically Ill Medical Patients: A Prospective Cohort Study.

OBJECTIVES: To investigate whether phase angle (PhA) measured by bioelectrical impedance analysis (BIA) and frailty are associated with the outcomes of critical illnesses. DESIGN: A single-center prospective cohort study. SETTING: Medical intensive care unit (ICU) in Seoul National University Hospital, Seoul, Republic of Korea. PARTICIPANTS: 97 patients who were admitted to the medical ICU. MEASUREMENTS: On admission, PhA was measured by BIA, and frailty was assessed by the Korean Modified Barthel Index (KMBI) scoring system. Patients were classified according to PhA and KMBI scores, and their impact on the outcomes of critical illnesses was evaluated. RESULTS: The patients' mean age was 62.4 ± 16.4 years, and 56 of the patients (57.7%) were men. Having a high PhA above 3.5 at the time of ICU admission was associated with lower in-hospital mortality (adjusted OR 0.42, p = .042), and a shorter duration of ICU stay (5.6 days vs. 9.8 days, p = .016) compared to those with a low PhA. Other indices measured by BIA were not significantly associated with outcomes of critical illnesses. Frailty (KMBI > 60) was associated with more mechanical ventilation days (2.3 days vs. 7.1 days; p = .018). CONCLUSION: Both PhA and frailty are important prognostic factors predicting the outcomes of critical illnesses. Low PhA scores were associated with increased mortality and a longer duration of ICU stay, and frailty was associated with more mechanical ventilation days.

Impact of resistance to first-line and injectable drugs on treatment outcomes in MDR-TB.

Recently, resistance to additional first-line and injectable drugs was reported to be an independent risk factor for adverse outcomes in multidrug-resistant (MDR) tuberculosis (TB) patients. The aim of the present study was to confirm these observations in MDR-TB patients without HIV infection. MDR-TB patients treated at a tertiary referral hospital in South Korea between January 1996 and December 2005 were included. The unadjusted and adjusted odds ratios of adverse treatment outcome were calculated for resistance to each drug and combination of drugs using simple or multiple logistic regressions. None of the resistance to additional first-line or injectable drugs was associated with higher odds for adverse treatment outcome in 155 MDR but nonextensively drug-resistant (non-XDR) TB patients. However, streptomycin resistance was associated with 12 times the odds for adverse treatment outcome in 42 extensively drug-resistant (XDR) TB patients. Neither combinations of first-line drugs nor those of injectable drugs were associated with increased odds for adverse treatment outcomes in non-XDR MDR-TB patients or XDR-TB patients. Only streptomycin resistance among the first-line or injectable drugs was associated with adverse treatment outcomes in extensively drug-resistant tuberculosis patients without HIV infection.

Multidrug-resistant tuberculosis over 20 years at a referral hospital in South Korea: trends and outcomes.

SETTING: A referral centre in South Korea. OBJECTIVE: To investigate trends in drug resistance, treatment modalities and outcomes, and adverse events of multidrug-resistant tuberculosis (MDR-TB) over two decades. DESIGN: MDR-TB patients treated at Seoul National Hospital University between 1996 and 2015 were divided into four 5-year cohorts according to the date of initial diagnosis. Changes in demographic characteristics, drug resistance, drugs used, treatment outcomes and adverse events over time were elucidated. RESULTS: Between 1996 and 2015, 418 patients were treated for MDR-TB: 86 patients between 1996 and 2000, 125 between 2001 and 2005, 123 between 2006 and 2010, and 84 between 2011 and 2015. The proportion of patients with positive acid-fast bacilli sputum (60.5-29.7%, P < 0.001) or cavities on chest radiographs (86.0-40.5%, P < 0.001) decreased over time. Resistance to pyrazinamide, fluoroquinolones, cycloserine and p-aminosalicylic acid decreased. Later-generation fluoroquinolones (77.9-90.5%) and linezolid (0-26.2%) became more frequently prescribed. The treatment success rate increased (45.3-88.1%, P < 0.001); neurological adverse events, including peripheral neuropathy also increased (4.7-13.1%, P = 0.027). CONCLUSION: MDR-TB patients presented with less severe disease and better resistance profiles over time in South Korea, with treatment outcomes improving continuously.

Predictors of persistent airway stenosis in patients with endobronchial tuberculosis.

SETTING: The university and municipal hospitals in Seoul, Korea. OBJECTIVE: To evaluate the predictors of persistent airway stenosis following anti-tuberculosis chemotherapy in patients with endobronchial tuberculosis (TB). DESIGN: Diagnosis of TB was confirmed by microbiology or histopathology. Bronchoscopic examinations revealed that patients had endobronchial lesions compatible with endobronchial TB. Study subjects had at least one follow-up bronchoscopy to evaluate their treatment response. Treatment response was determined by changes in the degree or extent of airway stenosis between the first and last bronchoscopic examinations. RESULTS: Sixty-seven subjects were recruited retrospectively from Seoul National University Hospital and Seoul National University Boramae Hospital. Persistent bronchostenosis occurred in 41.8% of the patients. In multivariate regression analysis, age >45 years (OR 3.65), pure or combined fibrostenotic subtype (OR 5.54) and duration from onset of chief complaint to the initiation of anti-tuberculosis chemotherapy >90 days (OR 5.98) were identified as independent predictors of persistent airway stenosis. Oral corticosteroids (prednisolone equivalent >or=30 mg/d) did not reduce the frequency of persistent airway stenosis. CONCLUSION: Early diagnosis and early administration of anti-tuberculosis chemotherapy before involvement of the deeper airways is important to prevent the development of unwanted sequelae of bronchostenosis.

Aetiologies and predictors of pulmonary cavities in South Korea.

OBJECTIVE: To identify the aetiologies of pulmonary cavities and the clinical predictors of cavities of mycobacterial origin. SETTING: A tertiary referral hospital in South Korea, where the prevalence of tuberculosis (TB) is intermediate. DESIGN: A retrospective review of clinical records and radiographic examinations of patients presenting pulmonary cavities on simple chest radiograph between January and December 2005. RESULTS: Of 131 patients enrolled with pulmonary cavities, 66 (50.4%) had cavities of mycobacterial origin. Age <50 years (P = 0.04) and largest cavity located in the upper lobes (P = 0.04) increased the likelihood that the cavities were of mycobacterial origin. Conversely, history of malignancy (P = 0.02), lesions confined to one lobe (P = 0.02) and multiple enlarged mediastinal lymph nodes (P = 0.03) suggested a non-mycobacterial cause. CONCLUSION: Mycobacterial infection accounted for half of the cavitary lesions identified in this study. In older patients with a history of malignancy, non-nodular infiltration, lesions confined to one lobe and with multiple lymphadenopathy, diseases not caused by mycobacteria should be considered.

Lack of association between COPD and transforming growth factor-beta1 (TGFB1) genetic polymorphisms in Koreans.

OBJECTIVE: Many genetic variations have been suggested as genetic risk factors for the development of chronic obstructive pulmonary disease (COPD), including single nucleotide polymorphisms in the transforming growth factor-beta1 (TGFB1) gene. We attempted to elucidate the association between TGFB1 genetic polymorphisms and COPD among Koreans. DESIGN: The genotypes of 102 male patients with COPD and 159 volunteers with similar distributions of age, sex and smoking intensity, as well as normal pulmonary function, were determined for three previously associated TGFB1 single nucleotide polymorphisms (SNPs), -10807G/A (rs2241712) and -509T/C (rs1800469), located in or near the promoter, and 29T/C (rs1982073), located in exon 1 of the TGFB1 gene. RESULTS: No significant associations between COPD and the three TGFB1 SNPs could be identified. In addition, the haplotypes composed of three TGFB1 SNPs were not associated with the presence of COPD. CONCLUSION: These results differ from previous reports involving Caucasians, and might reflect racial differences in the pathogenesis of COPD.

An adenovirus expressing mutant p27 showed more potent antitumor effects than adenovirus-p27 wild type.

The main inhibitory action of p27, a cyclin-dependent kinase inhibitor (CDKI), arises from its binding with the cyclin E/cyclin-dependent kinase 2 (Cdk2) complex that results in G(1)-S arrest. Degradation of p27 is mediated by phosphorylation of Thr-187 of p27, which follows ubiquitination. In this study, we generated two adenoviruses expressing wild-type p27 (ad-p27wt) and mutant p27 (ad-p27mt), with mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188 (ATGATC), which was produced with the belief that mutant p27 would bind cyclin E/CDK2 more stably and show more potent antitumor effects. Ad-p27wt and ad-p27mt expressed p27 proteins that were indistinguishable by anti-p27 antibody. A pulse chase experiment showed that p27mt was more resistant to degradation than p27wt. In human lung cancer cell lines, ad-p27mt showed stronger growth inhibition than ad-p27wt. Both types of ad-p27 induced G(1)-S arrest and apoptosis; however, ad-p27mt induced stronger G(1)-S arrest and apoptosis. Intratumoral injection of ad-p27mt induced partial regression of established tumors and inhibited the growth of human lung cancer xenografts more strongly than ad-p27wt. From these results, we conclude that ad-p27mt has the potential to become a novel and powerful gene therapy tool.

Impact of fluoroquinolones on the diagnosis of pulmonary tuberculosis initially treated as bacterial pneumonia.

OBJECTIVE: The excellent in vitro activity of fluoroquinolones against Mycobacterium tuberculosis has raised concerns about the delayed diagnosis of pulmonary tuberculosis (PTB) initially misdiagnosed as pneumonia. The aim of this study was to assess the effect of empiric fluoroquinolone therapy on delays in diagnosis in patients with PTB initially misdiagnosed as bacterial pneumonia. DESIGN: Patients with PTB initially treated as having community-acquired pneumonia and treated with fluoroquinolones for more than 5 consecutive days, from January 2000 to December 2004, were enrolled. As a control group, TB patients initially treated with nonfluoroquinolone antibiotics were enrolled. We reviewed the clinical data and compared treatment responses between the two groups. RESULTS: Nine patients in the fluoroquinolone group and 19 patients in the non-fluoroquinolone group were enrolled. In the fluoroquinolone group, eight patients (89%) improved clinically or radiographically, whereas only eight patients (42%) in the non-fluoroquinolone group improved (P = 0.04). The delay in initiation of anti-tuberculosis medication was longer in the fluoroquinolone group than in the non-fluoroquinolone group (43.1 - 40.0 vs. 18.7 +/- 16.9 days, P = 0.04). CONCLUSION: Delay in the initiation of anti-tuberculosis treatment is possible in patients administered fluoroquinolone and initially misdiagnosed as having bacterial pneumonia.

Oral insertion of a flexible bronchoscope is associated with less discomfort than nasal insertion for Korean patients.

OBJECTIVE: The route of bronchoscope insertion varies between centres, without a firm rationale based on well-designed studies. We therefore compared nasal and oral insertion of a flexible bronchoscope and evaluated efficacy and patient satisfaction. DESIGN: Prospective randomised study of patients who underwent flexible bronchoscopy from May to September 2003 and who were randomly assigned to nasal and oral insertion approaches. RESULTS: Clinical characteristics, factors related to the procedure and patient satisfaction were analysed. In total, 307 patients were randomly assigned to the nasal (n = 158) or oral insertion groups (n = 149). No difference in baseline characteristics was identified between the groups. Insertion by the oral route was associated with a smaller amount of lidocaine use during the procedure (P = 0.04) and less frequent insertion site bleeding (P = 0.005). Patients assigned to oral insertion reported less discomfort during anaesthesia (P = 0.01) and scope insertion (P < 0.001), as well as less dyspnoea (P = 0.04) and coughing (P = 0.03). CONCLUSION: Oral insertion of a flexible bronchoscope was associated with less discomfort for patients than nasal insertion, although the route of insertion had no significant effect on outcome.

Differential effects of adenovirus-p16 on bladder cancer cell lines can be overcome by the addition of butyrate.

High frequency of p16 alteration and high local recurrence rate of bladder cancer make this cancer an ideal target for p16 gene therapy. However, a low transduction rate of p16 via adenoviral vector causes an inconsistent result. In this study, we have tested adenovirus-p16 in several bladder cancer cell lines and investigated a way of improving the low transduction rate. Adenovirus-p16 showed a strong antitumor effect on bladder cancer cell lines (253J and T24) with strong Coxackie-adenoviral receptor (CAR) expression but little antitumor effect on bladder cancer cell lines (J82 and HT1376) with little CAR expression. In this study, we suggest a simple way of overcoming the differential effects of the adenovirus. The addition of butyrate to media was found to increase the transduction rate of adenovirus remarkably and increase the antitumor effect of adenovirus-p16 in bladder cancer cell lines with little CAR expression. Butyrate effects were related with increased CAR expression on the cell surface as well as increased transgene expression from adenoviral vector. From these observations, application of adenovirus-p16 gene therapy with butyrate can overcome the obstacle of low gene transfer and enhance the antitumor effect of adenovirus-p16 in bladder cancer.

Accuracy of the Xpert® MTB/RIF assay for the diagnosis of extra-pulmonary tuberculosis in South Korea.

SETTING: The Xpert(®) MTB/RIF assay has been endorsed by the World Health Organization for the detection of pulmonary and extra-pulmonary tuberculosis (EPTB). OBJECTIVE: To determine the accuracy of the Xpert assay in diagnosing EPTB in South Korea, a country with an intermediate TB burden. DESIGN: We retrospectively reviewed the medical records of 1429 patients in whom the Xpert assay using EPTB specimens was requested between 1 January 2011 and 31 October 2013 in a tertiary referral hospital in South Korea. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of EPTB and detection of rifampicin (RMP) resistance were calculated. RESULTS: Using culture as gold standard, the sensitivity, specificity, PPV and NPV of the assay were respectively 67.7%, 98.1%, 60% and 98.6%. Using a composite reference standard, the sensitivity, specificity, PPV and NPV were respectively 49.3%, 100%, 100% and 95.1%. The sensitivity, specificity, PPV and NPV for the detection of RMP resistance among specimens with positive results for Mycobacterium tuberculosis were respectively 80%, 100%, 100% and 97.7%. CONCLUSION: The Xpert assay showed acceptable sensitivity in certain groups and excellent specificity in diagnosing EPTB and detecting RMP resistance in an intermediate TB burden country.

Evaluation of Xpert(®) MTB/RIF assay: diagnosis and treatment outcomes in rifampicin-resistant tuberculosis.

SETTING: The Xpert(®) MTB/RIF assay is endorsed by the World Health Organization for the detection of rifampicin (RMP) resistant tuberculosis (TB). OBJECTIVE: To evaluate Xpert for its diagnostic accuracy in detecting RMP-resistant TB and its impact on treatment outcomes. DESIGN: Patients with available phenotypic drug susceptibility testing (DST) results and those in whom RMP-resistant pulmonary TB was diagnosed using Xpert were evaluated. The accuracy and turnaround time (TAT) of Xpert for determining RMP-resistant TB was calculated. The TATs for treatment between patients diagnosed with RMP-resistant TB using Xpert and those diagnosed without the assay (phenotypic DST group) were compared. RESULTS: In 321 patients, when phenotypic DST was used as the gold standard, Xpert sensitivity and specificity for RMP resistance diagnosis was respectively 100% and 98.7%; the positive and negative predictive values were respectively 86.2% and 100%. The Xpert group had a much shorter interval from initial evaluation to commencing second-line anti-tuberculosis treatment (64 vs. 2 days, P < 0.001), and negative conversion of mycobacterial cultures (197 vs. 62.5 days, P < 0.001) than the phenotypic DST group. CONCLUSION: Xpert was accurate at diagnosing RMP resistance in this setting with an intermediate TB burden and a low level of RMP resistance. Xpert might reduce disease transmission by reducing the sputum culture conversion times for patients with RMP-resistant TB.

Changes in treatment outcomes of multidrug-resistant tuberculosis.

SETTING: After several changes in treatment modalities, it is time to re-evaluate treatment outcomes of multidrug-resistant tuberculosis (MDR-TB). OBJECTIVE: To evaluate treatment outcomes, elucidate changes in outcomes over time and identify predictors of treatment success for MDR-TB. DESIGN: Patients diagnosed with MDR-TB at a tertiary referral centre in South Korea between January 2006 and December 2010 were included. Treatment modalities and outcomes were assessed. Predictors of treatment success were analysed using multiple logistic regression. The treatment modalities and outcomes of these patients were compared with those of MDR-TB patients between January 1996 and December 2005. RESULTS: Of the 123 MDR-TB patients diagnosed during the later study period, treatment was successful in 103 (83.7%). Extensive drug resistance (OR 0.31, P = 0.044) and additional resistance to fluoroquinolones (OR 0.23, P = 0.039) were inversely associated with treatment success. The treatment success rate improved from 53.5% in 1996-2000 to 68.8% in 2001-2005 and 83.7% in 2006-2010 (P < 0.001). Improved outcomes were accompanied with more frequent use of later-generation fluoroquinolones and linezolid and less frequent surgical resection. CONCLUSION: Treatment outcomes for MDR-TB improved at a tertiary referral centre in South Korea. The improvement was associated with more frequent use of later-generation fluoroquinolones and linezolid.

Genetic instability of microsatellite sequences in non-small cell lung cancers.

To evaluate the frequency and pattern of microsatellite instability in NSCLCs, we examined 36 cases of resected NSCLC. The mean age of the patients was 59.9+/-8.4 years. There were 19 cases of squamous cell carcinoma, 15 of adenocarcinoma and two of large cell carcinoma. We observed microsatellite instability at one or more loci in 13 (36%) of 36 tumors analyzed, and this instability ranged from six tumors showing instability in only a single microsatellite to three tumors that had alterations in three of four tested microsatellites. The microsatellite that showed instability most frequently in these tumors was D3S1340 (31%). Microsatellite instability was found in five (26%) of 19 squamous cell carcinomas, six (40%) of 15 adenocarcinomas, and in both large cell carcinomas tested. We found microsatellite instability in four (24%) of 17 cancers at stage I, in one (17%) of six at stage II, in eight (73%) of eleven at stage IIIa, and in neither at stage IIIb. In conclusion, microsatellite instability was noted in at least one third of non-small cell lung cancers, suggesting its possible role in cancer development.

Telomerase activity in lung cancer cell lines and tissues.

Using TRAP assay, we studied the activity of the telomerase in the lung cancer cell lines, and lung cancer and normal tissues in which expression appears to be related to the immortality of cancer cells. All the human lung cancer cell lines and the majority of human lung cancer tissues (78%) expressed telomerase activity, but this was undetectable in normal human lung tissues. Positivity for telomerase activity in lung cancer cell lines was higher than in lung cancer tissues; this result implies the expression of telomerase activity may play a crucial role in the development or progression of lung cancer, and also suggests that improved method of detection may lead to the higher positivity for telomerase activity in primary lung cancer tissues. To determine whether there is a definite causal relationship between telomerase and cancer, and to develop new anti-cancer agents which inhibit telomerase, further study is needed.

Alteration of cell growth and morphology by overexpression of transforming growth factor beta type II receptor in human lung adenocarcinoma cells.

TGF-beta is a potent inhibitory regulator of cell growth, which is transduced through interaction between type I (RI) and type II (RII) receptors that form heteromeric kinase complexes. Abnormal expression of these receptors has been identified in several human epithelial cancers and has been shown to be highly associated with resistance to TGF-beta. In this study, we investigated the expression of RI and RII in 13 human non-small cell lung cancer cell lines (NSCLCs) and demonstrated decreased or loss of RII expression in five lung cancer cell lines, but not of RI. Of these cell lines, the role of RII in NCI-H358 adenocarcinoma, which lacks RII and is insensitive to TGF-beta, was investigated by transducing this cell line with a recombinant retrovirus expressing full-length TGF-beta RII. Stably transfected cells showed significant increase in RII mRNA and protein expression. These cells responded to exogenous TGF-beta1 with suppressed proliferation in a dose-dependent manner and G1 arrest accompanied by morphological change distinct from control cells. We also investigated whether overexpression of dominant-negative RII (dnRII) in NCI-H441 adenocarcinoma, which is sensitive but expresses low levels of RII, could block signaling through the receptor complex. The overexpression of this kinase-domain-truncated RII by expressing the retroviral dnRII construct led to loss of the ability to respond to TGF-beta1 and an exhibition of uncontrolled growth. These results suggest a close association between the loss of the expression of wild-type TGF-beta RII and carcinogenesis in human lung cancer cells.

Adenovirus expressing p27(Kip1) induces growth arrest of lung cancer cell lines and suppresses the growth of established lung cancer xenografts.

p27(Kip1) (p27) is a member of the universal cyclin-dependent kinase inhibitor (CDKI) family and a putative tumor suppressor gene. In several tumors including lung cancer, decreased expression of p27 is associated with poor prognosis. These observations suggest a potential role for p27 as a new gene therapy target. In this study, we constructed adenovirus expressing human p27 (ad-p27) and investigated its antitumor effects on human lung cancer cell lines. Upon transduction of several human lung cancer cells with ad-p27, a high level of p27 expression, with a decrease in cdk2 and an increase in cyclin E were observed. These changes resulted in G1/S arrest. Transduction of human lung cancer cell lines with ad-p27 showed in vitro growth inhibition and a marked suppression of colony formation upon soft agar clonogenic assay. Direct intratumoral injection of ad-p27 induced the growth suppression of established lung tumors in nude mice. From these observations, gene therapy using ad-p27 seems to offer a potential basis for the development of new cancer gene therapy modality and a useful tool to investigate the mechanisms of cell cycle control.

Giant lymph node hyperplasia (Castleman's disease) in the chest.

We have experienced 7 cases of giant lymph node hyperplasia in the chest from 1981 to 1992. The ages of the 1 male and 6 female patients ranged from 9.9 to 40.4 years (mean age, 29.2 +/- 10.4 years). In 4 patients, a mass was discovered in routine radiographs. Focal calcification suggesting continual enlargement over a long time was noted in 1 patient. The sites of lesions were unusual in 2 patients (intercostal space and intrapulmonary fissure). All patients underwent surgical removal of the mass. Five cases had typical features of the hyaline-vascular type, and 2 cases revealed a mixture of the hyaline-vascular type and the plasma-cell type. Follow-up was available in all patients (mean follow-up, 31.9 months). In 1 patient, recurrence was observed 9 years after surgical removal. In general, giant lymph node hyperplasia can occur anywhere in the chest, grow without symptoms, and recur in spite of complete resection. Surgical resection and close follow-up are advised.

The inhibitory effect of adenovirus-mediated p16INK4a gene transfer on the proliferation of lung cancer cell line.

Abnormalities in the p16INK4a tumor suppressor gene are found in many lung cancer cell lines and primary lung cancer tissue. To examine its tumor suppressor function and potential adequacy in cancer gene replacement therapy, wild-type p16INK4a gene was inserted in an adenovirus derived gene delivery system and introduced into lung cancer cell lines (NCI-H441 and NCI-H157) that did not express p16INK4a. Western blot assay and immunocytochemistry demonstrated production of wild-type p16 protein in these cell lines. The biological function of exogenous p16 protein was confirmed by the inhibition of pRB phosphorylation. The expression of exogenous p16 protein via recombinant adenovirus significantly inhibited cancer cell growth and colony formation in vitro of NSCLC that can not express endogenous p16. The flow cytometric analysis showed these results correlated with G1 cell cycle arrest. These observations suggest the value of adenovirally-mediated p16INK4a gene replacement therapy for lung cancer.

Effect of inhalers on the development of haemoptysis in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: The association of inhaler use with haemoptysis has rarely been reported in patients with non-cystic fibrosis (CF) bronchiectasis. OBJECTIVE: To elucidate the effect of inhaler use on the development of haemoptysis in patients with non-CF bronchiectasis. METHODS: In a case-crossover study of 192 non-CF bronchiectasis patients with a history of haemoptysis and inhaler use, the risk of haemoptysis associated with the use of inhalers was elucidated. Two inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA), one long-acting muscarinic antagonist and one short-acting ß2-agonist (SABA) were evaluated. The case and control periods were defined respectively as 030 and 180210 days before haemoptysis. RESULTS: The risk of haemoptysis during the case period was 3.51 times higher than during the control period with any use of inhalers (95%CI 1.966.28). The results of clinically significant haemoptysis showed good agreement with those of total events. These associations were consistent with the sensitivity analyses. In the sub-analysis according to inhaler type, ICS/LABA and SABA were significantly associated with an increased risk of haemoptysis (aOR 2.62, 95%CI 1.255.45; aOR 2.51, 95%CI 2.235.15). CONCLUSIONS: In patients with non-CF bronchiectasis, the use of inhalers, especially including 2-agonist, was associated with an increased risk of haemoptysis.