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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 2  |  Page : 162-170

Management of chronic obstructive pulmonary disease: Insights into patient profile – Use of inhaled corticosteroids/long-acting β2-Agonists or long-acting β2-agonists/long-acting muscarinic antagonists


1 Department of Respiratory Medicine, Max Hospital, Gurgaon, Haryana, India
2 Department of Pulmonologist, Allergy Asthma Center, Kolkata, West Bengal, India
3 Department of Pulmonologist, Fortis Hospital, Noida, Uttar Pradesh, India

Date of Submission18-Nov-2019
Date of Decision25-Nov-2019
Date of Acceptance25-Apr-2020
Date of Web Publication07-Jul-2020

Correspondence Address:
Dr. Nevin Kishore
Max Hospital, Gurgaon, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijrc.ijrc_56_19

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  Abstract 


The noncommunicable chronic obstructive pulmonary disease (COPD) ranks among the top five leading causes of death worldwide. It is a preventable chronic disease that has become a major public health concern globally, as well as in India. To improve the pharmacotherapeutic management of COPD and to increase awareness about the prevalence of the disease, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has updated recommendations for the disease, based on the current clinical evidence. The present GOLD guideline endorses inhaled corticosteroids (ICS) combined with long-acting β2-agonists (LABA) for a subgroup of patients. The article is an attempt to clearly define patient profiles that stand to benefit from ICS/LABA, LABA/long-acting muscarinic antagonists (LAMA), and ICS/LABA/LAMA combination therapy based on current clinical evidence. The discussion is presented under the following headings: (i) disease burden worldwide, as well as in India; (ii) clinical symptoms and diagnosis of disease; (iii) risk factors leading to the development of disease; (iv) pharmacotherapeutic agents for COPD; (v) current updated recommendations from GOLD guidelines; (vi) subgroup of patients who can benefit from various combinations of therapeutic agents; and (vii) comparative analysis of clinical studies on various GOLD guideline-suggested combination therapies.

Keywords: Bronchodilators, chronic obstructive lung disease, eosinophil count, exacerbations, inhaled corticosteroids, long-acting muscarinic antagonists, long-acting β2-agonists, smoking


How to cite this article:
Kishore N, Moitra S, Sircar M. Management of chronic obstructive pulmonary disease: Insights into patient profile – Use of inhaled corticosteroids/long-acting β2-Agonists or long-acting β2-agonists/long-acting muscarinic antagonists. Indian J Respir Care 2020;9:162-70

How to cite this URL:
Kishore N, Moitra S, Sircar M. Management of chronic obstructive pulmonary disease: Insights into patient profile – Use of inhaled corticosteroids/long-acting β2-Agonists or long-acting β2-agonists/long-acting muscarinic antagonists. Indian J Respir Care [serial online] 2020 [cited 2020 Aug 3];9:162-70. Available from: http://www.ijrc.in/text.asp?2020/9/2/162/289093




  Introduction Top


Chronic obstructive pulmonary disease (COPD) is a preventable disease characterized by pulmonary symptoms and airflow limitations that may or may not be accompanied by alveolar abnormalities.[1] The airflow limitation is the result of either airway obstruction or parenchymal destruction, which evolves over time, at different rates, through exposure to pollutant and noxious gases.[1],[2] The disease is one of the most common causes of death and disability worldwide, after ischemic heart and cerebrovascular disease in both men and women.[3] Environmental factors such as tobacco smoking and air pollution coupled with genetic factors and physical inactivity lead to disease progression.[1],[2],[4] The Global Initiative for Chronic Obstructive Lung Disease (GOLD), in order to streamline the pharmacotherapeutic management of the disease, provides recent updates based on clinical evidence. The treatment and management of the COPD involve the use of agents such as short- and long-acting beta-2 (β2)-agonists and anticholinergics, inhaled corticosteroid (ICS), and combinations of these agents. However, variations in clinical response to combination therapy are documented among different patients, necessitating further exploration of distinct patient profiles that respond well to certain combinations of therapeutic agents.[1] Based on literature evidence, this article aims to clearly establish the patients who will respond well to long-acting β2-agonists/long-acting muscarinic antagonists (LABA/LAMA) and ICS/LAMA combination therapy for COPD.

For this review article, PubMed served as the primary electronic literature search engine. The international guidelines and report available from GOLD were also consulted. The search was performed using the following key terms: (i) disease burden worldwide, as well as in India; (ii) clinical symptoms and diagnosis of disease; (iii) risk factors leading to development of disease; (iv) pharmacotherapy for COPD; (v) current recommendations from GOLD guidelines for management of COPD; (vi) subgroup of patients who benefit from various combinations of therapeutic agents; and (vii) comparative analysis of clinical studies of various GOLD guideline-suggested combination therapy (ICS/LABA, LABA/LAMA, and ICS/LABA/LAMA). The available literature and evidence were collated from 2000 to 2018.


  Prevalence and Burden of Disease Top


The global prevalence rate of COPD is close to 10% in the adult population aged above 40 years.[4] It is estimated that by 2030, COPD will emerge as the third leading cause of mortality globally. India has not remained untouched by the increased burden of noncommunicable disease, due to urbanization, industrialization, rapid socioeconomic development, and changing lifestyles. Of the total mortality contributed by the noncommunicable diseases, COPD accounts for seven percent of the total deaths.[1] India contributes among the highest rate of death due to COPD globally, and the estimated age-standardized death rate per 100,000 for both men and women was found to be more than 65.[5] Multiple surveys and epidemiological studies conducted in various parts of India have revealed a vast variation in the prevalence of COPD, which ranges from 2% to 22% among men and from 1.2% to 19% in women.[6] The incidence of COPD in urban and rural areas, based on population-based data collected from 1996 to 2016 by the National Commission on Macroeconomics and Health of India, is depicted in [Figure 1]; it shows a rising trend in the incidence in both regions.[7]
Figure 1: Number of COPD patients in rural and urban area in India between 1996 and 2016[7]

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Apart from the associated mortality, the disease puts a massive economic burden on the health-care system and affects the quality of life of patients.[7]


  Risk Factors, Pathogenesis, and Clinical Manifestations Top


An interplay of various factors leads to the development of COPD. Tobacco consumption in the form of cigarette, beedi, or hookah smoking in India is strongly related to the development of COPD and lung cancer.[5] Passive smoking contributes to a decline in lung function in young children. Continuous exposure to passive smoke during adulthood further increases the risk of developing COPD.[4] Nonsmoking women in rural areas are at a high risk of developing the disease, due to air pollution associated with the burning of dry fuel in poorly ventilated households.[7] A genetic mutation in the SERPINA 1 gene results in a severe alpha 1-antitrypsin deficiency that has been clinically proven to be a cause of COPD in young individuals.[4]

Smoking or other factors trigger the natural inflammatory response in the lungs. However, in COPD patients, this inflammatory response is modified by increased oxidative stress and increased activity of proteinases. The disease is characterized by chronic bronchitis and emphysema.[2] Several mechanisms have been suggested for the development of COPD. Oxidative stress, proteinase–antiproteinase hypothesis, inflammatory cells, mediator involvement, and interstitial fibrosis have all been implicated in the development of COPD.[1],[4]

The clinical manifestations of the above-stated mechanism lead to changes in the small peripheral airway, pulmonary parenchyma, central airway, and pulmonary vasculature. As a consequence of the narrowing of the peripheral airway, there is a sharp decline in forced expiratory volume in one second (FEV1). In addition, airway limitation impairs the contractility of pulmonary muscles; the severity of airway limitation is stratified based on the FEV1/forced vital capacity (FVC) ratio values after bronchodilation. The aim of the diagnosis is not restricted to assessing only the severity of airway limitation but also to determine the patient's current status of health and the threat of any exacerbations in the future. Exacerbations refer to a worsening of respiratory symptoms that further requires therapeutic intervention. These are complex events triggered by viral or bacterial infections and air pollutants. Assessing the history of frequent exacerbations, i.e., two or more exacerbations annually, is crucial, as exacerbations have a significant correlation with the risk of death, hospitalization, and poor prognosis of the disease.[1],[4] The mortality rate related to increased exacerbations is more than 50% after 5 years of hospitalization.[8] To measure health status impairment in COPD, a modified British Medical Research Council-graded questionnaire is used; the multi-item COPD assessment test is used and breathlessness is also assessed.[1]

For individualizing therapy, all the above assessments [Figure 2] are taken into consideration. A comprehensive approach facilitates the selection of a precise treatment regimen.[1]
Figure 2: Diagnosis and combined severity assessment of COPD as per GOLD guidelines 2018.[1] Airway limitation is based on FEV1 values after bronchodilation and in patients with FEV1/FVC ratio <0.70. COPD assessment test assesses the health status of the patient. Modified British Medical Research Council assesses breathlessness. 0–1 exacerbation implies not leading to hospital admission. >2 or >1 exacerbation leads to hospital admission. COPD: Chronic obstructive pulmonary disease, FEV1: Forced expiratory volume in 1 second, FVC: Forced vital capacity

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  Pharmacotherapeutic Options Top


Disease treatment aims to relieve symptoms, as well as to reduce the frequency and severity of exacerbations. Treatment further targets a reduction in disease progression and death, with improvement in the quality of life of the patient.[9] Various agents used in the management of COPD, along with their mechanisms of action, are presented in [Table 1].[9],[10]
Table 1: Pharmacological agents for chronic obstructive pulmonary disease management[9],[10]

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  Global Initiative for Chronic Obstructive Lung Disease-2018 Guidelines: Current Recommendations and Further Insights Top


As per the combined assessment of severity of airflow limitation (graded from 1 to 4), along with the clinical symptom burden and the risk of exacerbations, the patients are grouped from A to D.[11] According to the recent GOLD guideline, the management of COPD starts with the cessation of smoking. Recommendations for pharmacotherapeutic agents, based on the current GOLD guidelines, are presented in [Table 2].[1]
Table 2: Pharmacotherapeutic recommendations of Global Initiative for Chronic Obstructive Lung Disease guidelines
2018[1]


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The guidelines emphasize a comprehensive approach, focusing on an individualized therapeutic regimen for patients, by dividing patients into different categories based on exacerbations and clinical symptoms. However, further insights are needed, as the current categorization of patients has limitations with respect to predicting the risk of mortality across the demarcated categories.[12] As stated earlier, exacerbations are a complex series of events of different etiologies and severities. The current recommendations take into account only the history of exacerbations, in the form of the number of past events. However, further focus is required on the severity and underlying etiology of the exacerbations, to pave the way for the adoption of a more individualized approach to treatment.[13] The guidelines recommend triple therapy with LABA/LAMA/ICS for group D patients with persistent exacerbations, which requires using two inhalers, thereby jeopardizing compliance. Patient compliance must also be taken into consideration while planning treatment.[1],[11]

Considering that COPD is multifarious, intragroup variability must be further explored, along with due consideration given to comorbid conditions in the patient.

The guidelines propose a sequential method in case combination of LAMA/LABA is required after the failure of monotherapy with LAMA or LABA in group B patients. However, the fundamental question of evidentiary proof stills looms on selection of initiation therapy between LABA or LAMA. Hence, the guidelines need to go beyond traditional clinical symptoms, to address the multifarious nature of COPD.[1],[14]


  Patient Profiles in Chronic Obstructive Pulmonary Disease: Response to Different Treatment Options Top


The current GOLD guidelines have made an attempt to classify patients in a holistic manner; however, further subgrouping or phenotyping of patients is critical to achieving more effective and precise treatment. Considering the disease is highly heterogeneous in nature, it becomes further important to take into account intersubject variability, to make the treatment regimen more personalized.[15] The various subgroups of COPD patient, and the indicated treatments for these subgroups, are presented in [Figure 3].[15],[16]
Figure 3: Various subgroups of COPD patients and indicated therapy.[15],[16] COPD: Chronic obstructive pulmonary disease, BMI: Body mass index, FEV1: Forced expiratory volume in 1 second, LABA: Long-acting beta-agonist, LAMA: Long-acting muscarinic antagonist, ICS: Inhaled corticosteroid

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A combination of two different therapeutic agents offers the advantage of an increased degree of bronchodilation and a reduced adverse-event profile.[1]


  Long-Acting β2-Agonists/long-Acting Muscarinic Antagonists Dual Therapy: Benefitted Phenotype and Comparative Evidence Top


Patients with reduced lung function (decreased FEV1) and showing fewer exacerbations are benefitted more by an intensive LABA/LAMA combination than by LABA/ICS combination.[1] The ILLUMINATE trial demonstrated the superiority of bronchodilation by LABA/LAMA compared with LABA/ICS in patients with a nonexacerbating COPD profile. The enrolled patients had postbronchodilator FEV1 values of 40%–80% and had moderate COPD severity.[17] Further, results from the LANTERN study supported the above findings. The LABA/LAMA combination was proved to offer a statistically significant improvement in FEV1, trough FVC, peak FEV1, and peak FVC, as well as being associated with a good safety profile. Further, a post hoc analysis revealed a reduction in the rate of moderate or severe exacerbations in the subgroups of patients with and without a previous history of exacerbations.[18] A meta-analysis was conducted by Horita et al. including 11 studies among moderate-to-severe COPD patients with no recent history of exacerbations. The pooled data revealed LAMA/LABA therapy to be associated with fewer exacerbations, a greater improvement in lung function (FEV1), a lower risk of pneumonia, and more frequent improvement in the quality of life, as assessed by an increase on the St. George's Respiratory Questionnaire (>4 units).[19] Summarized presentation of the evidence for LABA and LAMA dual therapy is represented in [Table 3].
Table 3: Brief summary of key long-acting β2-agonists/long-acting muscarinic antagonists trials

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  Long-Acting β2-Agonists/inhaled Corticosteroids Dual Therapy: Benefitted Phenotypes and Comparative Evidence Top


The current GOLD recommendations have laid the foundation for further evaluating the effectiveness of LABA/ICS over LABA/LAMA combination, as they acknowledge the subcategory of patients in whom ICS and LABA therapy stands out.[1] Group C and D COPD patients are at a higher risk of developing exacerbations. The Inhaled Steroids in Obstructive Lung Disease in Europe study revealed a clinical improvement with monotherapy using fluticasone, an ICS. Moderate-to-severe COPD patients receiving ICS in the trial showed a 25% reduction in the exacerbation rate, compared to placebo. In addition, ICS therapy improved the health status of the patients: health status improved over time, from 15 to 24 months.[20] When ICS is combined with LABA, which has been proven to improve lung function and control symptoms, patients stand to reap multiple benefits. The same was proved by a randomized controlled trial conducted by Calverley et al. in which enrolled patients were administered budesonide and formoterol either alone or in combination and placebo for a year. Combination therapy showed an improvement in posttreatment FEV1 versus baseline. In addition, the combination offered patients the benefits of a clinically significant improvement in health status and a reduction in the daily symptoms of the disease. Patients on budesonide/formoterol combination had a prolonged time to flrst exacerbation (254 days) compared to other treatment groups in the study.[21] The observational, population-based registry trial (PATHOS study) with a follow-up duration of 11 years elaborated the long-term benefits of budesonide/formoterol combination over the fluticasone/salmeterol combination. The results from the two cohorts (2734 COPD patients) of the study revealed the annual rate of COPD-related hospitalizations of 0.15 versus 0.21 for patients on fluticasone/salmeterol combination. The exacerbation rate per patient-year was significantly less for budesonide/formoterol group when compared to fluticasone/salmeterol combination.[22] A similar trend of fewer exacerbation for budesonide/formoterol was observed in another observational retrospective analysis conducted by Perrone et al. The study utilized the data of patients from the Italian health unit databases and included patients with at least one prescription of a fluticasone/salmeterol or budesonide/formoterol combination.[23] A 1-year population-based cohort study conducted by Blais et al. further established the advantage of the budesonide/formoterol combination in reducing the economic burden as results revealed the use of combination to be associated with reduction in number, as well as frequency of emergency room visits and hospitalizations for COPD patients. The results showed a rate of hospitalization per patient-year to be 0.11 for the budesonide/formoterol compared to 0.21 for the fluticasone/salmeterol combination along with less occurrence of exacerbation.[24]

The Towards a Revolution in COPD Health (TORCH) trial offered insights into clinically relevant survival benefits offered by LABA/ICS. The multicenter randomized double-blind study enrolled moderate-to-severe COPD patients with a prebronchodilator FEV1 of <60%. Patients received LABA and ICS combination, LABA monotherapy, ICS monotherapy, or matching placebo for 3 years. The results revealed a significant reduction in exacerbations and hospitalization with LABA/ICS combination. Health status and lung function, as assessed by spirometry, were also found to significantly better for ICS/LABA combination; in addition, ICS/LABA combination was associated with a reduction in the risk of cardiovascular mortality.[25]

Similar clinically relevant survival benefits with ICS/LABA combination were reported in the Study to Understand Mortality and Morbidity trial, which demonstrated a 12% relative reduction in all-cause mortality for the ICS/LABA combination. Patients with moderate COPD were enrolled, and the fluticasone and vilanterol combination was analyzed. The percentage reduction in moderate and severe exacerbations was found to be statistically significant for patients receiving ICS/LABA combination, compared to placebo.[26]

A detailed meta-analysis conducted by Nannini et al. compared ICS/LABA and LABA in COPD patients. A total of 14 randomized controlled trials were included, and the analysis revealed ICS/LABA to be more effective than LABA for improving the health-related quality of life of patients. A reduced risk of exacerbations over a year was found for the ICS and LABA combination.[27] Pathophysiological features for the frequent exacerbator subgroup of patients are airway inflammation along with higher susceptibility to viral infection. Observations from the above-discussed trials are indicative of the fact that the subgroup of patients with frequent exacerbations will benefit more from the use of ICS.

Category D patients and patients with asthma-COPD overlap have the pathophysiological feature of increased blood eosinophil counts. A post hoc analysis of the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management trial revealed that patients with higher blood eosinophil counts are more likely to have exacerbations when ICS treatment is withdrawn. The analysis was conducted in severe-to-very severe COPD patients with a history of exacerbations. The study was the first of its kind to investigate and further confirm the association between high eosinophil count, exacerbations, and ICS. Patients aged 40 years and above with predicted FEV1<50%, FVC <70% and at least one documented exacerbation in the past year were included in the study. A statistically significant increase in annual exacerbation rate was observed among patients in whom ICS was withdrawn, compared to patients continued on ICS therapy.[28] Various trials report potential risk of pneumonia with ICS/LABA combination therapy.[29],[30],[31] Long-term observational comparative cohort-based study showed a reduced risk of pneumonia event and death associated with pneumonia with the budesonide/formoterol when compared to fluticasone/salmeterol therapy. The trial showed a 76% increase in risk of mortality related to pneumonia with the use of fluticasone/salmeterol when compared to budesonide/formoterol.[32] However, a real-world study conducted in 7394 patients in the United States demonstrated no difference in COPD-related exacerbations or pneumonia events between the two combination treatment groups for patients who were new to ICS/LABA treatment.[33] Indirect comparison involving eight salmeterol/fluticasone and four budesonide/formoterol clinical studies revealed budesonide/formoterol combination to be associated with fewer pneumonia events compared to salmeterol/fluticasone in COPD. However, it is pertinent to mention that the TORCH trial which evaluated salmeterol/fluticasone combination had a major impact on the overall findings of this indirect comparative analysis. The other limitations to this analysis were heterogeneity in the length and the dosing of the various combinations given in the included trials and the lack of predefined diagnostic standards for pneumonia in these studies.[34] Hence, in the light of limited direct comparative data for two combinations, the risk–benefit ratio should be carefully assessed to achieve best clinical benefits with respect to rate of exacerbations in severe COPD patients.[32],[33] Summarized presentation of the evidence for LABA and ICS dual therapy is represented in [Table 4].
Table 4: Brief summary of long-acting β2-agonists/inhaled corticosteroids trials

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  Long-Acting β2-Agonists/inhaled Corticosteroids/long-Acting Muscarinic Antagonists Triple Therapy: Benefitted Phenotype and Comparative Evidence Top


Patients with severe COPD who develop exacerbations even after ICS/LABA therapy are recommended triple combination therapy with the addition of LAMA.[1] A double-blind randomized study conducted by Vestbo et al. compared the triple combination of ICS (beclomethasone dipropionate), LABA (formoterol fumarate), and LAMA (glycopyrronium) with LAMA (tiotropium). The results revealed a reduction in moderate and severe exacerbations with triple therapy, compared with LAMA, along with an improvement in predose FEV1. Furthermore, triple therapy reduced hyperinflation and the need for additional rescue medications.[35]

The Lung Function and Quality of Life Assessment in COPD with Closed Triple Therapy (FULFIL) supported the beneficial effects of triple therapy (fluticasone/umeclidinium and vilanterol), compared to ICS/LABA therapy. The study revealed triple therapy to significantly improve lung function, compared with ICS/LABA, over a 24-and 52-week period. Moderate and severe exacerbation rate also reduced significantly (35%) with the use of triple therapy versus ICS/LABA combination.[36]

A multicentric randomized double-blind trial conducted by Welte et al. highlighted the benefits of the use of budesonide/formoterol along with tiotropium (triple therapy) in the management of patients with COPD. Patients received either the tiotropium added with budesonide/formoterol or matched placebo. Over a period of 12 weeks, the triple therapy was associated with a signiflcant increase in predose FEV1 by 6% and a postdose by 11% when compared to patients receiving only tiotropium. The patients on triple therapy experienced less severe exacerbations had decreased hospitalization visits (65%) when compared to alone tiotropium group. In addition, the triple therapy patients had improved morning lung function and symptoms, thereby facilitating patients to perform morning activities in an efficient manner.[37] Data from the studies suggest the clinical value of triple therapy in patients with advanced or severe patients. However, further clinical data from studies with comparison of triple therapy with LABA/LAMA are required to establish the benefits offered by triple therapy in advanced or severe patients.


  Conclusion and Future Prospects Top


A holistic, individualized approach for the management of COPD is required, giving full consideration to the heterogeneous and complex nature of COPD. For achieving the same, it is necessary to evaluate the shortcomings of the current GOLD guidelines. A one-size-fits-all approach cannot be implemented for COPD management; distinct phenotypic patient categorization is the need of the hour. Present clinical data indicate that ICS/LABA combination is beneficial in patients with frequent exacerbations, high eosinophil counts, and asthma/COPD overlap. In patients with severe and very severe COPD, triple therapy (ICS/LABA/LAMA) is indicated, although further research is needed in this regard. Patient profiling will not only help in achieving optimal treatment response but will also aid in reducing frequent exacerbations and the overuse of nonindicated drugs.

To strengthen our discussion on the need for establishing distinct patient profiles in COPD, we suggest conducting real-world trials in patients with different phenotypes, aiming at head-to-head comparisons between various combination therapies suggested for COPD treatment. This will aid physicians in robust decision-making regarding treatment of COPD.

Acknowledgment

The authors thank AstraZeneca Pharma India Ltd for providing medical writing assistance in the development of this manuscript, in collaboration with BioQuest Solutions Pvt Ltd, Bangalore.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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Introduction
Prevalence and B...
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Global Initiativ...
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Long-Acting ^...
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