COPD GOLD 2023 update (慢性阻塞性肺病治療指引2023更新）

COPD治療黃金指引於2023年做出些以下重大的改變outline：

新增疾病預防概念：

PRISm (preserved ratio impaired spirometry)

FEV1/FEV ≥ 0.7 post bronchodilation, but impaired spirometry (FEV1 < 80% of reference, after bronchodilation).➡️ reduced lung function but do not meet the spirometry definition of COPD.

發表 Precursor概念，是疾病預防的新曙光，即病人若分類為Pre-COPD or PRISm （氣道狹窄高風險族群），即可及早介入預防惡化，進行risk reduction programs 。

• smoking cessation 
• pneumococcal + flu vaccine

治療指引改變：

以往的ABCD評估工具改成「ABE Assessment Tool」。把CD合併為E (exacerbation)。

減少ICS inhaler在COPD使用的角色。因為會增加pneumonia risk。只有在eosinophil count of ≥300 cells/μL時，才有類固醇吸入的角色。

COPD GOLD Guideline 2023「更新」的重點內容：

(內容整理自：The Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report, link)

A new definition of COPD has been proposed: 

慢性阻塞性肺疾病（COPD）是一種異質性肺部疾病，其特點是由於氣道（bronchitis, bronchiolitis）和/或肺泡（肺氣腫）的異常引起的慢性呼吸道症狀（呼吸困難，咳嗽，咳痰），為持續性、漸進式的氣道阻塞。

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction. 

Causes and risk factors

• COPD 是基因 (Gene)-環境 (Environment) 相互作用在個體 (GETomics) 一輩子 (lifeTime) 的結果，可能會損害肺部和/或改變其正常發育/衰老過程。
• COPD 的主要是暴露在吸煙、空氣中有害的微粒與污染。其他因素如個體肺部發育異常或肺部加速老化(aging)也有影響。
• 目前為止，確定與COPD 最有關（儘管罕見）的基因遺傳危險因子是SERPINA1 基因突變導致的α-1 antitrypsin deficiency。 許多其他遺傳變異也與肺功能下降和 COPD 風險相關，但目前研究的case不多。

Diagnostic Criteria

診斷標準：FEV1/FVC < 0.7 post-bronchodilation

• 2023年GOLD指引引進新Precursor概念，為疾病預防的新曙光，即病人若分類為Pre-COPD or PRISm （氣道狹窄高風險族群），即可及早介入預防惡化。（risk reduciton風險移除、疫苗計劃等）

「Pre-COPD （慢性肺阻塞前期）」：有些人可能有呼吸道症狀和/或肺部結構性病變（例如肺氣腫）和/或生理異常（包括低正常 FEV1、 gas trapping, hyperinflation、lung diffusing capacity and/or rapid FEV1 decline）但無氣流阻塞（FEV1/FVC≥ 0.7 post-bronchodilation）。 

「PRISm (Preserved Ratio Impaired Spirometry)」FEV1/FVC比例正常但spirometry異常。 

• COPD疫苗建議：

▲People with COPD should receive all recommended vaccinations in line with the relevant local guidelines

Assessment

Severity of airflow obstruction: 用FEV1/FVC來衡量阻塞/受限的嚴重程度。

▲In the presence of FEV1/FVC ratio < 0.7 the assessment of airflow limitation severity in COPD (note that this may be different from severity of the disease) is based on the post-bronchodilator value of FEV1 (% reference). The specific spirometric cut points are proposed for purposes of simplicity (COPD GOLD 2023)

用mMRC來衡量症狀多寡：

▲Dyspnea questionnaire: the modified Medical Research Council (mMRC) dyspnea scale

GOLD治療評估工具指引

GOLD 2023更新為ABE assessment tool，針對個別化的 symptoms and exacerbation risk 的評估。有別於以往的ABCD assessment tool，能更有效的判別疾病惡化，減少因評估症狀多寡而延誤惡化風險。

Group C&D被濃縮成E，意指：exacerbation-prone patients。

The GOLD 2023 Report also offers proposed clinical guidance, in the absence of high-quality clinical trial evidence, on initial pharmacologic management of COPD. The proposal is based on individual assessment of symptoms and exacerbation risk following use of the ABE Assessment Tool, a revised version of the ABCD Assessment Tool that recognizes the clinical relevance of exacerbations independent of symptom level.

Exacerbation 的定義為呼吸困難and/or 有痰的咳嗽持續<14天且有惡化跡象。有些 COPD exacerbate 的病人會PE or HF or ischemic heart disease. 所以screening of those 共病症很重要。

COPD pharmacotherapeutic strategy 更新

1. Group A: LABA (or LAMA)
2. Group B: LABA/LAMA，建議使用二合一吸入劑(fixed combination)。
3. Group E: LABA/LAMA，不常規使用ICS，只有在blood eosinophil> 300，才考慮LABA/LAMA/ICS。

🔺ICS/LABA在initial treatment治療COPD已經沒有角色了，剩下triple therapy(Eosinophil>300時用)。

ICS + LABA has been removed from the initial treatment algorithm and the follow-up treatment algorithms for both dyspnea and exacerbations. However, it is recommended that ICS + LABA is an option for those patients with stable disease who are currently receiving this therapy combination. Escalation to other therapies should be considered for patients who have further exacerbations or major symptoms. ICS + LABA may also be appropriate for those patients in areas with limited access to triple therapy. Other recommendations within the initial and follow-up treatment algorithms remain unchanged.

Triple therapy is also recommended as a follow-up treatment in patients with (1) blood eosinophils of ≥100 cells/μL who continue to exacerbate while receiving LABA + LAMA and (2) in patients with blood eosinophils ≥300 cells/μL who continue to exacerbate while receiving monotherapy. (3) Patients receiving ICS + LABA who continue to experience exacerbations are also recommended to be escalated to triple therapy.

COPD治療用藥

▲ (A) Consolidated representation of the updated GOLD treatment algorithms, as interpreted by the authors. (B) Initial Pharmacological Treatment and Follow-up Pharmacological Treatment algorithms as presented in the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease report 2023

Bronchodilators: 

• Increase FEV1 and/or change other spirometric variables
• Formoterol and salmeterol are twice-daily LABAs that significantly improve FEV1 and lung volumes, dyspnea, health status, exacerbation rate and number of hospitalizations, but have no effect on mortality or rate of decline of lung function. 
• Indacaterol is a once daily LABA that improves breathlessness, health status and exacerbation rate. Some patients experience cough following the inhalation of indacaterol. 
• Oladaterol and vilanterol are additional once daily LABAs that improve lung function and symptoms.
• ADR: tachycardia, hypokalemia (尤其並用thiazide diuretics時), oxygen consumption can be increased under resting conditionsin patients with chronic heart failure. Mild falls in partial pressure of oxygen (PaO2) can occur after administration of both SABAs and LABAs but the clinical significance of these changes is uncertain. Despite prior concerns related to the use of beta2- agonists in the management of asthma, no association between beta2-agonist use and loss of lung function or increased mortality has been reported in COPD.

Antimuscarinic drugs: 

• Block the bronchoconstrictor effects of acetylcholine on M3 muscarinic receptors expressed in airway smooth muscle.
• Short-acting antimuscarinics (SAMAs), namely ipratropium and oxitropium, also block the inhibitory neuronal receptor M2, which potentially can cause vagally induced bronchoconstriction. 所以當吸入ipratropium 時，可先使用SABA，再吸SAMA。
• Long-acting muscarinic antagonists (LAMAs), such as tiotropium, aclidinium, glycopyrronium bromide (also known as glycopyrrolate) and umeclidinium have prolonged binding to M3 muscarinic receptors, with faster dissociation from M2 muscarinic receptors, thus prolonging the duration of bronchodilator effect.
• A systematic review of randomized controlled trials concluded that ipratropium, a SAMA, alone provided small benefits over SABA in terms of lung function, health status and requirement for oral steroids.  
• Among LAMAs, some are administered once a day (tiotropium and umeclidinium), others twice a day (aclidinium), and some are approved for once daily dosing in some countries and twice daily dosing in others (glycopyrrolate). 
• LAMA treatments improve symptoms, including cough and sputum and health status. They also improve the effectiveness of pulmonary rehabilitation and reduce exacerbations and related hospitalizations. Clinical trials have shown a greater effect on exacerbation rates for LAMA treatment (tiotropium) versus LABA treatment.
• ADR: dryness of mouth, occasional urinary symptoms, An unexpected small increase in cardiovascular events in COPD patients regularly treated with ipratropium bromide has been reported. In a large, long-term clinical trial in COPD patients, tiotropium added to other standard therapies had no effect on cardiovascular risk. Although there were some initial concerns regarding the safety of tiotropium delivery via the Respimat®  inhaler, the findings of a large trial observed no difference in mortality or exacerbation rates when comparing tiotropium in a dry-powder inhaler and the Respimat® inhaler. There are less safety data available for the other LAMAs, but the rate of anti-cholinergic side effects for drugs in this class appears to be low and generally similar.

Methylxanthines

• Controversy remains about the exact effects of xanthine derivatives. They may act as non-selective phosphodiesterase inhibitors, but have also been reported to have a range of non-bronchodilator actions, the significance of which is disputed. Data on duration of action for conventional, or even slow-release, xanthine preparations are lacking in COPD.
• Aware of Drug interactions!!!
• LABA單用比較xanthine類+LABA併用，更可以增加FEV1，改善氣道狹窄。
• 但xanthine 類與類固醇併用，對於改善exacerbation無幫助。
• There is evidence for a modest bronchodilator effect compared with placebo in stable COPD. Addition of theophylline to salmeterol produces a greater improvement in FEV1 and breathlessness than salmeterol alone. Earlier studies reported contradictory evidence regarding the effect of low-dose theophylline on exacerbation rates. A study that investigated the effectiveness of adding low-dose theophylline to ICS in COPD patients at increased risk of exacerbation showed no difference compared with placebo in the number of COPD exacerbations over a one-year period. A large placebo-controlled trial showed no effect of oral theophylline alone or in combination with prednisolone 5 mg daily on exacerbations of severe COPD.
• ADR: atrial and ventricular arrhythmias (which can prove fatal), grand mal convulsions (which can occur irrespective of prior epileptic history). Other side effects include headaches, insomnia, nausea, and heartburn, and these may occur within the therapeutic range of serum levels of theophylline.

▲COPD常見吸入劑

▲COPD治療選擇建議

Anti-inflammatory agents

▲ To date, exacerbations (e.g., exacerbation rate, patients with at least one exacerbation, time-to-first exacerbation) represent the main clinically relevant end-point used for efficacy assessment of drugs with anti-inflammatory effects.

Inhaled corticosteroids (ICS) 

Preliminary generalconsiderations:

In vitro evidence suggests that COPD-associated inflammation has limited responsiveness to corticosteroids. Moreover, some drugs including beta2-agonists, theophylline or macrolides may partially facilitatecorticosteroid sensitivity in COPD. The clinical relevance of this effect has not yet been fully established. In vivo data suggest that the dose-response relationships and long-term (> 3 years) safety of ICS in people with COPD are unclear and require further investigation. Because the effects of ICS in COPD can be modulated by the concomitant use of long-acting bronchodilators, these two therapeutic options are discussed separately. Both current and ex-smokers with COPD benefit from ICS use in terms of lung function and exacerbation rates, although the magnitude of the effect is lower in heavy or current smokers compared to light or ex-smokers.

Efficacy of ICS (alone)

Most studies have foundthat regular treatment with ICS alone does not modify the long-term decline of FEV1 nor mortality in people with COPD.

ICS in combination with long-acting bronchodilator therapy

在中度至重度COPD和有exacerbation風險病人，使用ICS＋LABA比單用ICS or 單用 LABA對於肺功能進步和降低exacerbation效果較好。臨床試驗發現在ICS+LABA吸入劑使用是，無法有效地改善死亡率。(In patients with moderate to very severe COPD and exacerbations, an ICS combined with a LABA is moreeffective than either component alone in improving lung function, health status and reducing exacerbations. Clinical trials powered on all-cause mortality as the primary outcome failed to demonstrate a statistically significant effect of combination therapy on survival.)

Blood eosinophil count

• A number of studies have shown that blood eosinophil counts predict the magnitude of the effect of ICS (added on top of regular maintenance bronchodilator treatment) in preventing future exacerbations. There is a continuous relationship between blood eosinophil counts and ICS effects; no and/or small effects are observed at lower eosinophil counts, with incrementally increasing effects observed at higher eosinophil counts. Data modeling indicates that ICS containing regimens have little or no effect at a blood eosinophil count < 100 cells/μL, therefore this threshold can be used to identify patients with a low likelihood of treatment benefit with ICS. In addition, lower blood and sputum eosinophils are associated with greater presence of proteobacteria, notably haemophilus, and increased bacterial infections and pneumonia. Lower blood eosinophil counts therefore may identify individuals with microbiome profiles associated with increased risk of clinical worsenings due to pathogenic bacterial species. The threshold of a blood eosinophil count ≥ 300 cells/μL identifies the top of the continuous relationship between eosinophils and ICS, and can be used to identify patients with the greatest likelihood of treatment benefit with ICS.
• ADR: oral candidiasis, hoarse voice, skin bruising and lung infection. Patients at higher risk of pneumonia include those who currently smoke, are aged ≥ 55 years, have a history of prior exacerbations or pneumonia, a body mass index (BMI) < 25 kg/m2, a poor MRC dyspnea grade and/or severe airflow obstruction. Independent of ICS use, there is evidence that a blood eosinophil count < 2% increases the risk of developing pneumonia. In studies of patients with moderate COPD, ICS by itself or in combination with a LABA did not increase the risk of pneumonia.

Oral glucocorticoids

• 短期使用口服類固醇可以降低急性發作的治療失敗率，但長期使用無角色。
• Oral glucocorticoids have numerous side effects, including steroid myopathy which cancontribute to muscle weakness, decreased functionality, and respiratory failure in people with very severe COPD. Systemic glucocorticoids for treating acute exacerbations in hospitalized patients, or during emergency department visits, have been shown to reduce the rate of treatment failure, the rate of relapse and to improve lung function and breathlessness. Conversely, prospective studies on the long-term effects of oral glucocorticoids in stable COPD are limited. Therefore, while oral glucocorticoids play a role in the acute management of exacerbations, they have no role in the chronic daily treatment in COPD because of a lack of benefit balanced against a high rate of systemic complications.

Systemic corticosteroids 

在急性exacerbation時，給予注射或口服類固醇，可以改善肺功能FEV1，需氧量及減少住院天數。但一般使用不超過五天。

▲Association of Inhaled Corticosteroids With All-Cause Mortality Risk in Patients With COPD- A Meta-analysis of 60 Randomized Controlled Trials.

▲Trial簡介。Chen, H. et al. (2023) “Association of inhaled corticosteroids with all-cause mortality risk in patients with COPD,” Chest, 163(1), pp. 100–114. (link)

Phosphodiesterase-4 (PDE4) inhibitors

• The principal action of PDE4 inhibitors is to reduce inflammation by inhibiting the breakdown of intracellular cyclic AMP. Roflumilast is a once daily oral medication with no direct bronchodilator activity. Roflumilast reduces moderate and severe exacerbations treated with systemic corticosteroids in patients with chronic bronchitis, severe to very severe COPD, and a history of exacerbations. The effects on lung function are also seen when roflumilast is added to long-acting bronchodilators, and in patients who are not controlled on fixed-dose LABA+ICS combinations. The beneficial effects of roflumilast have been reported to be greater in patients with a prior history of hospitalization for an acute exacerbation. There has been no study directly comparing roflumilast with an inhaled corticosteroid.
• ADR: diarrhea, nausea, reduced appetite, weight loss, abdominal pain, sleep disturbance, and headache.

 

Antibiotics

• In older studies prophylactic, continuous use of antibiotics had no effect on the frequency of exacerbations in COPD and a study that examined the efficacy of chemoprophylaxis undertaken in winter months over a period of 5 years concluded that there was no benefit. Later studies have shown that regular use of some antibiotics may reduce exacerbation rate.
• Azithromycin (250 mg/day or 500 mg three times per week) or erythromycin (250mg two times per day) for one year in patients prone to exacerbations reduced the risk of exacerbations compared to usual care. Azithromycin use was associated with an increased incidence of bacterial resistance, prolongation of QTc interval, and impaired hearing tests. A post-hoc analysis suggests lesser benefit in active smokers. There are no data showing the efficacy or safety of chronic azithromycin treatment to prevent COPD exacerbations beyond one-year of treatment.
• Pulse therapy with moxifloxacin (400 mg/day for 5 days every 8 weeks) in patients with chronic bronchitis and frequent exacerbationshad no beneficial effect on the exacerbation rate overall.

Mucolytic (mucokinetics, mucoregulators) and antioxidant agents (N-acetylcysteine, carbocysteine, erdosteine)

In COPD patients not receiving ICS, regular treatment with mucolytics such as carbocysteineand N-acetylcysteine (NAC) may reduce exacerbations and modestly improve health status. In contrast, it has been shown that erdosteine may have a significant effect on (mild) exacerbations irrespective of concurrent treatment with ICS. Due to the heterogeneity of studied populations, treatment dosing and concomitant treatments, currently available data do not allow precise identification of the potential target population for antioxidant agents in COPD.

▲ Pharmacological and non-pharmacological therapy should be adjusted as necessary (see below) and further reviews undertaken

非藥物治療方法：

▲ non-pharmacological measures

處理共病症：

• 建議吸菸導致的COPD病人每年做一次低劑量電腦斷層(Low dose CT scan)以確保及早發現肺癌。非吸菸患者不建議每年做CT。
• 胃食道逆流會增加exacerbation的風險。
• 定期審視有無骨質疏鬆及憂鬱/焦慮。

延伸閱讀：

1. GOLD 2023 Update: Implications for Clinical Practice (link)
2. Are We Missing the Opportunity to Disseminate GOLD Recommendations Through AECOPD Discharge Letters? (link)
3. Risk Factors of Readmission Within 90 Days for Chronic Obstructive Pulmonary Disease Patients with Frailty and Construction of an Early Warning Mode (link)

First released: March.2023 

1st Update April.2023 2nd Update May 2023