Common concerns in managing bronchial asthma during the COVID-19 pandemic

The use of corticosteroids and nebulised bronchodilators in bronchial asthma (BA) is a major concern during the COVID-19 pandemic. Inhaled corticosteroid (ICS) is the recommended treatment for all levels of BA severity, while oral corticosteroid (OCS) is used in severe asthma and acute exacerbation of BA (AEBA).1 Because corticosteroid is an immunosuppressant, BA patients on corticosteroid treatment are theoretically at a higher risk of contracting COVID-19 and may suffer more severe disease. Nebulisation of bronchodilators is a frequent treatment modality for patients attending an emergency department for AEBA because of a common perception that it is more effective and faster in symptom relief. However, nebulisation may cause dispersion of SARS-CoV-2 into the surrounding environment, putting other patients and 1 healthcare workers at risk. There are several issues that need to be addressed. First, AEBA precipitated by COVID-19 is difficult to distinguish from other respiratory tract infections. Second, patients may have asymptomatic COVID-19 and their AEBA may be precipitated by other causes. Third, AEBA may be the only complaint of the COVID-19 patients, who lack symptoms such as fever, headache etc. In this Letter, we address some common concerns in managing BA during the COVID-19 pandemic. First, are patients with BA more susceptible to SARS-CoV-2 infection? The prevalence of BA in COVID-19 patients in China is remarkably low (see Table). A recent study by Li et al. reported that only 0.9% of COVID-19 patients admitted to a hospital in Wuhan, China, had BA.2 Two other studies specifically looked for BA among COVID-19 patients but did not report any cases.3,4 BA was not included as a significant comorbidity reported by other studies conducted in China. In contrast, studies in the United States reported the prevalence of BA to be 17% among hospitalised COVID-19 patients and 9.1% among COVID-19 patients admitted to intensive care units, which is higher than the national average of 7.7%.5,6 Based on these data, there is no consistent evidence to suggest patients with BA are more susceptible to COVID-19. The second concern is whether BA patients suffer from severe COVID-19 if infected by SARS-CoV-2. Li et al. reported that BA is not associated with more severe disease or higher mortality in COVID-19.2 To date, no other study has reported BA patients are at higher risk of poor outcomes or have more severe exacerbation if infected by SARS-CoV-2. Since SARS-CoV-2 utilises angiotensin-converting enzyme 2 (ACE-2) as a cellular entry receptor to infect the human host, one possible explanation for the reduced susceptibility of BA patients to SARS-CoV-2 infection and to severe COVID-19 is the reduced ACE-2 gene expression in nasal and bronchial epithelial cells in patients with allergic rhinitis and atopic asthma.7 Next, should regular ICS or OCS be withheld during the COVID-19 pandemic? The Global Initiative for Asthma and the National Institute for Health and Care Excellence has recommended continuation of ICS and OCS as clinically indicated during the COVID-19 pandemic.1 Withdrawal of corticosteroids may lead to worsening of asthma control and severe AEBA. Seeking treatment at healthcare facilities for uncontrolled BA during the pandemic may predispose these patients to SARS-CoV-2 infection and further overwhelm the healthcare facility. Therefore, corticosteroids should be maintained during the pandemic to keep BA under control. There is also some evidence suggesting ICS may be beneficial in treating COVID-19. First, the combination of ICS with bronchodilator has been shown to supress coronavirus replication and cytokine production in vitro.8 Second, inhaled ciclesonide, a corticosteroid 1 commonly used to treat allergic rhinitis and BA has been shown to successfully treat three cases of COVID-19 pneumonia.9 A fourth concern is the administration of bronchodilators by nebulisers to patients with moderate-to-severe AEBA during the pandemic. Current evidence indicates that COVID-19 is transmitted by droplets, direct contact and fomites. Airborne transmission of COVID-19 from person-to-person has not been reported. However, nebulisation may promote airborne transmission of respiratory viruses, including SARS-CoV-2. Viable SARS-CoV-2 is reported in aerosols generated by jet nebuliser for up to 3 hours.10 The use of a jet nebuliser to deliver bronchodilators to a severe acute respiratory syndrome (SARS) patient was the cause of a major nosocomial SARS outbreak.11 SARS-CoV-2 has a higher binding affinity to the ACE-2 receptor than the SARS coronavirus. Therefore, it is very likely nebulisation of bronchodilators can cause aerosol transmission of COVID-19. If possible, nebulisation should be avoided. Airborne precautions should be strictly adhered to if nebulisation is unavoidable, such as in patients with life-threatening AEBA. The fifth concern is how to administer bronchodilators for moderate-to-severe AEBA during the COVID-19 pandemic. Randomised control trials (RCTs) have reported that delivery of bronchodilators using pressurised meter-dose inhalers (pMDIs) with a spacer is equally effective and safe as nebulisation in adults with non-life-threatening AEBA.12 The 2005 joint report by the American College of Chest Physician and the American College of Asthma, Allergy and Immunology concluded that there is no significant difference in terms of efficacy and adverse outcomes among patients receiving pMDIs, dry powder inhalers (DPIs), or nebulisation for AEBA.13 Therefore, either pMDI with spacer or DPI can be used to administer bronchodilators in AEBA. The former does not depend on the patient’s inspiratory effort which is frequently reduced during AEBA, making it a better option than DPI. A meta-analysis of several RCTs concludes that patients with AEBA receiving a combination of inhaled short-acting ß2-agonist (SABA) and short-acting muscarinic antagonist (SAMA) are more likely to have lung function improvement and less likely to be hospitalised compared to inhaled SABA alone.14 Based on this evidence, pMDI of SABA and SAMA with a spacer is the most appropriate treatment for adults with moderate-to-severe AEBA. Finally, the use of systemic corticosteroids to treat AEBA may raise safety concerns during the COVID-19 outbreak. Systemic corticosteroids significantly reduce hospitalisations and exacerbation relapse in adults with AEBA. To our knowledge, an adverse effect of systemic corticosteroids has only been reported in patients with severe SARS and Middle East Respiratory Syndrome (MERS), but not in patients with COVID-19. Guidelines by the WHO 1 do not recommend against the use of systemic corticosteroids in COVID-19 patients if the use is clinically indicated, such as for AEBA.15 Therefore, short courses of systemic corticosteroids can be given to patients with AEBA during the COVID-19 pandemic. In conclusion, other than avoiding nebuliser use, the management of BA during the COVID-19 pandemic is not different from the usual practice. However, more studies are needed to determine whether BA patients are more susceptible to COVID-19 or have more severe COVID-19

Development and Validation of an Attitudinal-Profiling Tool for Patients With Asthma

This study was supported and funded by Mundipharma Pte Ltd. Online survey and statistical analysis were performed by Pei-Li Teh, Rachel Howard, Tsin-Li Chua and Jie Sun of Research Partnership Pte Ltd. Medical writing support was provided by Sen-Kwan Tay of Research2Trials Clinical Solutions Pte Ltd. The authors received honoraria from Mundipharma for their participation in the REALISE Asia Working Group meetings and discussions. Prof Price has Board membership with Mundipharma; and had received consultancy and speaker fees, grants and unrestricted funding support from Mundipharma; and payment for manuscript preparation and travel/accommodations/meeting expenses from Mundipharma. Profs Liam and David-Wang are members of the Asia-Pacific Advisory Board of Mundipharma. Profs Cho and David-Wang had received speaker fees from Mundipharma in the past. Dr Neira was an employee of Mundipharma Pte Ltd, Singapore. Ms Teh is an employee of Research Partnership Pte Ltd which conducted the REALISE Asia survey for Mundipharma. Prof Cho is a member of the Editorial Board of Allergy, Asthma & Immunology.Peer reviewedPublisher PD

Acrometastasis from an epidermal-growth-factor-receptor (EGFR) mutation-positive lung adenocarcinoma

AbstractWe report the first case of epidermal-growth-factor-receptor (EGFR) mutation-positive lung adenocarcinoma with acrometastasis in a 51-year-old woman who presented with a swelling on her right hand. Magnetic resonance imaging revealed an expansile lesion at the base of the 5th metacarpal bone of her right hand with cortical erosion and patchy enhancement suggestive of a malignant transformation of a giant-cell tumor. A core needle biopsy of this lesion showed a metastatic adenocarcinoma on histopathological examination which was immunoreactive to cytokeratin (CK) 7 and thyroid transcription factor (TTF)-1 but not to CK20 suggesting a lung primary. A chest radiograph and computed tomography (CT) scan revealed a right upper lobe lung mass. Fluoro-deoxyglucose hypermetabolism was noted in the lung mass and the right 5th metacarpal bone lesion but not elsewhere on positron-emission-tomography/CT scan. Needle biopsy of the lung mass showed adenocarcinoma with histopathological and immunohistochemical features similar to that of the right 5th metacarpal bone lesion. Both the primary lung adenocarcinoma and the acrometastatic lesion were tested positive for EGFR mutation in exon 21 (L858R substitution). She underwent R0 resection of her right upper and middle lobes with systematic mediastinal lymph nodes resection and wide excision of the metacarpal metastasis followed by cytotoxic chemotherapy. A curative approach with complete resection of the primary tumor and oligometastastic site in Stage IV non-small cell lung carcinoma (NSCLC) followed by additive cytotoxic chemotherapy has not been reported to date and as such there is still no data on disease-free survival with this approach

P3. 13-15 First-Line Afatinib Dose Initiation and Adjustment in Patients with EGFR Mutant Advanced Non-Small Cell Lung Cancer

Background: The recommended starting dose of afatinib is 40mg od with 20mg, 30mg and 50mg tablets available for dose adjustment. Method: This is a retrospective observational study of starting dose, dose adjustment and optimal dose of first-line afatinib in patients withEGFR mutant advanced non-small cell lung cancer in University Malaya Medical Center from 1st December 2014 to 30th April 2018. Result: Of 22 patients on first-line afatinib, the starting dose was 40 mg od in 12 patients and 30 mg od in 10 patients (Figure 1). Among the 12 patients started on afatinib 40mg od, 4 (33.3%) did not require dose adjustment, 4 (33.3%) needed dose reduction to 30mg od, 2 (16.7%) needed dose reduction to 20mg od, and 2 (16.7%) had dose escalation to 50mg od. Among 10 patients started on afatinib 30mg od, 6 (60%) did not require dose adjustment, 1 (10%) needed dose reduction to 25mg od and 3 (30%) had dose escalation to 40mg od. Dose reduction was to reduce the cost of treatment in 1 patient and to reduce drug related side-effects in the rest. Dose escalation was exclusively to improve disease control. The overall response rate and disease control rate was 80% (8/10) and 90% (9/10) in patients who did not require dose adjustment; while the respective rates were 85.7% (6/7) and 100% (7/7) in patients who had dose reduction. The optimal dose of afatinib defined by good disease control and tolerable side-effects was 50mg od in 9.1% (2/22), 40mg od in 31.8% (7/22), 30mg od in 31.8% (7/22), 25mg od in 13.6% (3/22) and 20mg od in 13.6% (3/22) of patients. Conclusion: We suggest starting afatinib at 30mg od and adjust the dose accordingly because dose adjustment is not required in most cases on this starting dose and it is the commonest optimal dose

P3. 15-21 Real-World Experience of First-Line Afatinib Treatment in Patients with EGFR Mutant Advanced Non-Small Cell Lung Cancer.

Background: Published reports of first-line afatinib treatment efficacy, side-effects and resistance mechanism in the real-world setting are lacking. Method: A retrospective observational study of patients with EGFR mutant advanced non-small cell lung cancer (NSCLC) receiving first-line afatinib in University Malaya Medical Center from 1st December 2014 to 30th April 2018. Result: Twenty-two of 33 patients on first-line afatinib were eligible for analysis. The patients’ demographic and clinical characteristics are as shown in Table 1. The mPFS was 14.3 months, overall response rate was 86.3% (19/22) and disease control rate was 95.5% (21/22). The median time-to-treatment failure was 16.2 months. The median overall survival has not been reached but 12-month survival rate was 81.8% (18/22). A patient with exon 18 G719X and exon 20 S768I mutation had received treatment for 23.3 months without disease progression (PD). The PFS of a patient with exon 20 insertion was 9 months and of another patient with exon 18 G719X and exon 20 T790M mutations was 4.4 months. Of patients with brain metastases, the PFS of 2 patients treated with stereotactic radiosurgery (SRS) was 15.9 months and 9 months, respectively while that of a patient who had whole brain radiotherapy (WBRT) and a patient who underwent debulking surgery only was 16.5 months and 2.6 months, respectively. The incidence of side-effects was rash 90.1% (20/22), stomatitis 63.3% (14/22), paronychia 72.7% (16/22), and diarrhea 77.3% (17/22). One (4.5%) patient each had grade 3 diarrhea and cutaneous lesions. Of 17 patients with PD, 2 (11.8%) had PD in the brain. T790M mutation was detected in 62.2% (8/13) patients who underwent repeat biopsy. Conclusion: Afatinib is an effective treatment of EGFR-mutant advanced NSCLC. When combined with SRS or WBRT, afatinib conferred good PFS in patients with symptomatic brain metastases. Severe side effects are uncommon and T790M mutation was the commonest resistance mechanism

P1. 15-15 Real-world Experience with Afatinib after Failure of First-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor

Background: Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is the recommended first-line treatment for patients with advanced non-small cell lung cancer harbouring sensitizing EGFR mutations. The role of afatinib after failure of first-generation EGFR-TKIs is controversial. Method: A retrospective observational study of patients with EGFR mutant advanced NSCLC receiving second-line afatinib after failure of firstgeneration EGFR-TKI in University Malaya Medical Center from 1st December 2014 to 30th April 2018. Result: The demographic and clinical characteristics of 27 patients treated with afatinib after failure of first-generation EGFR-TKI are shown in Table 1. Twenty-three patients received gefitinib and 4 patients received erlotinib as first-line treatment. The mPFS with first-line treatment was 11.9 months. Fifteen patients had progression of disease (PD) following second-line afatinib with mPFS of 4.2 months and median time-to-treatment failure of 5.7 months. The mPFS2 conferred by first-line first-generation EGFR-TKI and second-line afatinib was 18.4 months. The overall response rate to second-line afatinib was 18.5% (5/27) while the disease control rate as 70.3% (19/27). Two patients who had PD on first-generation EGFR-TKI due to T790M mutation received second-line afatinib while waiting for compassionate access to osimertinib. Nine of the 15 patients (69.2%) with PD on afatinib underwent investigations for resistance mechanisms. Three patients had T790M mutation, one of whom had concomitant small cell lung cancer transformation. c-MET amplification was detected in another 3 patients. One patient each had EML4-ALK rearrangement and epithelial mesenchymal transition. Conclusion: Afatinib conferred a modest mPFS benefit after failure of first-generation EGFR-TKI. The mPFS of sequential treatment with first-generation EGFR-TKI followed by afatinib seems longer than the mPFS of first-line afatinib in phase 3 randomised controlled trials. Apart from T790M mutation, the resistance mechanisms to second-line afatinib in our patients are more heterogenous

Time for a new language for asthma control : Results from REALISE Asia

Acknowledgments: This study was supported and funded by Mundipharma Pte Ltd. Online survey and statistical analysis were performed by Pei-Li Teh, Rachel Howard, Tsin-Li Chua, and Jie Sun of Research Partnership Pte Ltd. Medical writing support was provided by Sen-Kwan Tay of Research2Trials Clinical Solutions Pte Ltd.Peer reviewedPublisher PD

Copd assessment test (cat) score of patients with chronic obstructive pulmonary disease based on clinical phenotypes

Background and Aims: Spanish chronic obstructive pulmonary disease (COPD) guideline classifies COPD into 4 clinical phenotypes: nonexacerbator (A), asthma-COPD overlap (B), exacerbator with emphysema (C) and exacerbator with bronchitis (D). Methods: A cross-sectional observational study of quality of life (QOL) of COPD patients utilizing COPD Assessment Test (CAT), conducted in University of Malaya Medical Center from 1 June 2017 – 31 May 2018. Results: Of 220 patients traeted for COPD, 189 patients with post bronchodilator Force Expiratory Volume in 1 second (FEV1)/Force Vital Capacity (FVC) of <0.70 were recruited. Patients’ demographic, clinical characteristics and CAT score are as shown in Table 1. Patients with COPD phenotype C and D had poorer modified medical research center (MMRC) functional status and global initiative of COPD (GOLD) class based on their FEV1. Patients with phenotype D had significantly higher total CAT score than patients with other clinical phenotypes. Other than sleep quality, patients with phenotype D had significantly higher score in every other components, notably cough severity, phlegm volume, chest tightness, breathlessness upon walking uphill, activity limitation at home, ability toleave home and energy. There was no different in terms of total and components CAT score of patients with phenotype A, B and C. Conclusion: Patients with phenotype D had significant higher CAT score, thus poorer quality of life and higher tendency of execebration. This group of patients need better medical treatment and closer monitoring

363P A randomized controlled trial of mindfulness breathing exercise in patients with advanced lung cancer

Background: Study of mindfulness breathing exercise in dyspnea reduction of patients with advanced lung cancer is lacking. Methods: This is a parallel-group, nonblinded randomized controlled trial of mindfulness breathing exercise versus placebo (best medical care alone) in patients with advanced lung cancer admitted to the respiratory unit and palliative unit of University Malaya Medical Center from 1st August 2017 to 31st March 2018. Results: A total of 34 patients were equally assigned to mindfulness breathing exercise group and control group (Table). For patients receiving mindfulness breathing exercise, 10 (58.8%) of them had reduction in modified Borg dyspnea scale (MBDS) score at 5-minutes (OR, 9.33; 95% CI, 1.80–48.38; p¼0.005) and 20-minutes (OR, 2.86; 95% CI, 0.67–12.11; p¼0.149), compared to only 3 (17.6%) and 7 (41.1%) of them in control arm at 5-minutes and 20-minutes, respectively. 5 patients (29.4%) on mindfulness breathing exercise achieved improvement in their SpO2 compare to only 2 patients (11.8%) of control arm had that at 5-minutes (OR, 3.75; 95% CI, 0.61–23.35; p¼0.209). 4 patients (23.5%) on mindfulness breathing exercise had SpO2 improvement at 20-minutes, while none in control arm had SpO2 improvement at same time. Similar number of patients had reduced respiratory rate after mindfulness breathing exercise or at control for 5-minutes [9 (52.9%) versus 10 (58.8%), (OR, 1.05; 95% CI, 0.26–4.32; p¼0.946)]. At 20-minutes, similar number of patients on mindfulness breathing exercise still had sustained reduction in respiratory rate while only 7 patients (41.1%) in control arm had similar respiratory benefit (OR, 2.14; 95% CI, 0.52–8.81; p¼0.288). Conclusions: Mindfulness breathing exercise is effective in reducing dyspnea among patients with advanced lung cancer

Epidermal growth factor receptor mutations in non- small cell lung cancers in a multiethnic Malaysian patient population

In Malaysian patients with NSCLC, the EGFR mutation rate was similar to that in other Asian populations. EGFR mutations were significantly more common in female patients and in never smokers. Never smoking status was the only independent predictor for the presence of EGFR mutations