Definitions

Relationship Between Various Obstructive Lung Diseases

• Key Points
  • Classical Obstructive Lung Diseases, Such as Chronic Obstructive Pulmonary Disease and Asthma, May or May Not Demonstrate Obstruction
  • Obstruction (with Wheezing, etc) Can Also Be Variably Present in Other Airway and Lung Diseases

---

Epidemiology

Prevalence

• COPD is the 3rd Leading Cause of Death in the US (2009 Data)
  • COPD Accounted for 133,965 Deaths in 2009
• 2011 Data: approximately 12.7 million adults in the US had COPD
  • Approximately 24 Million US Adults Have Evidence of Impaired Lung Function: suggests that COPD is underdiagnosed

Cost

• COPD-Related Health Care Utilization (2009 Data)
  • 8 Million Office Visits
  • 1.5 Million Emergency Department Visits
  • 715,000 Hospitalizations
• Costs Due to COPD
  • Approximately $49.9 billion: $29.5 billion in direct health-care expenditures, $8.0 billion in indirect morbidity costs, and $12.4 billion in indirect mortality costs
• COPD Exacerbations Account for Most of the Morbidity, Mortality, and Costs Associated with COPD
  • COPD Exacerbations Cause Frequent Hospital Admissions/Relapses/Readmissions, Contribute to Death During Hospitalization or Shortly Thereafter, Significantly Decrease Quality of Life, Expend Financial Resources, and Accelerate a Progressive Decline in Pulmonary Function

Undiagnosis/Overdiagnosis

• xxxxx
• Undiagnosed and ‘overdiagnosed’ COPD using postbronchodilator spirometry in primary healthcare settings: a systematic review and meta-analysis. BMJ Open Respir Res. 2023 Apr;10(1):e001478. doi: 10.1136/bmjresp-2022-001478 [MEDLINE]
  • Background: Despite chronic obstructive pulmonary disease (COPD) being a major global cause of mortality and hospitalisation, it is often undiagnosed or inaccurately diagnosed in clinical settings
  • Objective: To systematically synthesise all peer-reviewed papers from primary healthcare settings that have reported data on: (1) undiagnosed COPD, that is, patients with respiratory symptoms and postbronchodilator airflow obstruction consistent with COPD, without a formal clinician’s diagnosis of COPD either documented in health records or reported by patients and (2) ‘overdiagnosed COPD’, that is, clinician’s diagnosis without postbronchodilator airflow obstruction
  • Methods: Studies investigating these diagnostic metrics in patients from primary healthcare clinics (according to predefined inclusion/exclusion criteria) were sourced from Medline and Embase and assessed for bias (Johanna Briggs Institute tools for prevalence studies and case series). Meta-analyses of studies of adequate sample size used random effect modelling stratified by risk factor categories
  • Results: Of 26 eligible articles, 21 cross-sectional studies investigated 3959 cases of spirometry-defined COPD (with or without symptoms), and 5 peer-reviewed COPD case series investigated 7381 patients. The prevalence of spirometry-confirmed COPD without a diagnosis documented in their health records was 14%-26% in studies of symptomatic smokers (N=3). 1 in 4 patients taking inhaled therapies (25% (95% CI 22% to 28%), N=2) and 1 in 6 smokers irrespective of symptoms (16% (95% CI 14% to 18%), N=6) fulfilled diagnostic spirometry criteria but did not report receiving a COPD-related diagnosis. In an adequately powered series of COPD cases documented in primary healthcare records (N=4), only between 50% and 75% of subjects had any airflow obstruction on postbronchodilator spirometry performed by study researchers, therefore, COPD was clinically ‘overdiagnosed’ in 25%-50% of subjects
  • Discussion: Although data were heterogeneous and of modest quality, undiagnosed COPD was common in primary healthcare, especially for symptomatic smokers and patients treated with inhaled therapies. In contrast, frequent COPD ‘overdiagnosis’ may represent treatment of asthma/reversible component or another medical diagnosis.

Association with Cardiovascular Disease

• xxx
• Association between chronic obstructive pulmonary disease and cardiovascular disease in adults aged 40 years and above: Data from NHANES 2013-2018. BMC Pulm Med. Published online August 31, 2023. doi:10.1186/s12890-023-02606-1 [MEDLINE]
  • Background: Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are two major age-related diseases prevalent in the elderly. However, it is unclear whether there is a higher prevalence of one or more CVDs in COPD patients compared to those without COPD, and the magnitude of this increased prevalence
  • Methods: This population-based cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2013-2018 among American adults aged 40 years and above. Multivariable logistic regression models (including unadjusted model, minimally adjusted model, and fully adjusted model) were conducted to investigate the association between COPD and the prevalence of one or more CVDs, including coronary heart disease, heart failure, angina pectoris, heart attack, diabetes, and stroke
  • Results: This study included 11,425 participants, consisting of 661 participants with COPD and 10,764 participants without COPD. COPD patients had a significantly higher prevalence of CVD than those without COPD (59.6% vs. 28.4%). After adjusting for covariates, COPD was significantly associated with the prevalence of one CVD (OR = 2.2, 95% CI = 1.6-3.0, p < 0.001), two or more CVDs (OR = 3.3, 95% CI = 2.2-5.0, p < 0.001), and three or more CVDs (OR = 4.3, 95% CI = 2.9-6.5, p < 0.001)
  • Conclusions: Patients with COPD have a higher prevalence of one or more CVDs compared with those without COPD. Our findings highlight the importance of CVD prevention and management in patients with COPD.

Risk Factors for Chronic Obstructive Pulmonary Disease (COPD)

Tobacco Use (see Tobacco

• xxxx
• Low smoking exposure and development and prognosis of COPD over four decades: A population-based cohort study. Eur Respir J. Published online July 26, 2024. doi:10.1183/13993003.00314-2024 [MEDLINE]
  • Background: A diagnosis of COPD is mainly considered in individuals with >10 pack-years of smoking. We tested the hypothesis that low smoking exposure, below the critical threshold of 10 pack-years, increases risk of COPD and leads to poor prognosis
  • Methods: We followed non-obstructed adult smokers from the Copenhagen City Heart Study for COPD, defined as a forced expiratory volume in 1 s (FEV1)/forced vital capacity <0.70 and FEV1 <80% predicted, and for related clinical outcomes. First, we followed individuals for 5 years according to baseline smoking for risk of developing COPD, and thereafter for up to four decades for severe exacerbations and death
  • Results: In 6098 non-obstructed smokers, 1781 (29%) developed COPD after 5 years of follow-up: 23% of individuals with <10 pack-years of smoking at baseline, 26% of those with 10-19.9 pack-years, 30% of those with 20-39.9 pack-years and 39% of those with ≥40 pack-years. During four decades of follow-up, we recorded 620 exacerbations and 5573 deaths. Compared to individuals without COPD with <10 pack‑years of smoking, multivariable adjusted hazard ratios (HRs) for exacerbations were 1.94 (95% CI 1.36-2.76) in those without COPD and ≥10 pack-years, 2.83 (95% CI 1.72-4.66) in those with COPD and <10 pack-years, 4.34 (95% CI 2.93-6.43) in those with COPD and 10-19.9 pack-years, 4.39 (95% CI 2.98-6.46) in those with COPD and 20-39.9 pack-years and 4.98 (95% CI 3.11-7.97) in those with COPD and ≥40 pack-years. Corresponding HRs for all-cause mortality were 1.20 (95% CI 1.10-1.32), 1.31 (95% CI 1.13-1.53), 1.59 (95% CI 1.40-1.79), 1.81 (95% CI 1.62-2.03) and 1.81 (95% CI 1.55-2.10)
  • Conclusion: Low smoking exposure below the critical threshold of 10 pack-years increases risk of COPD in middle-aged adults within 5 years, and these individuals have increased risk of severe exacerbation and early death over four decades.

Environmental Pollutants

• Indoor Air Pollution: biomass cooking and heating in poorly-ventilated structures are important risk factors for COPD
• Outdoor Air Pollution: probably a small contributor, in comparison to tobacco smoke
• Short-term air pollution exposure and exacerbation events in mild to moderate COPD: a case-crossover study within the CanCOLD cohort. Thorax. 2023 May 5;thorax-2022-219619. doi: 10.1136/thorax-2022-219619 [MEDLINE]
  • Background: Infections are considered as leading causes of acute exacerbations of chronic obstructive pulmonary disease (COPD). Non-infectious risk factors such as short-term air pollution exposure may play a clinically important role. We sought to estimate the relationship between short-term air pollutant exposure and exacerbations in Canadian adults living with mild to moderate COPD
  • Methods: In this case-crossover study, exacerbations (‘symptom based’: ≥48 hours of dyspnoea/sputum volume/purulence; ‘event based’: ‘symptom based’ plus requiring antibiotics/corticosteroids or healthcare use) were collected prospectively from 449 participants with spirometry-confirmed COPD within the Canadian Cohort Obstructive Lung Disease. Daily nitrogen dioxide (NO2), fine particulate matter (PM2.5), ground-level ozone (O3), composite of NO2 and O3 (Ox), mean temperature and relative humidity estimates were obtained from national databases. Time-stratified sampling of hazard and control periods on day ‘0’ (day-of-event) and Lags (‘-1’ to ‘-6’) were compared by fitting generalised estimating equation models. All data were dichotomised into ‘warm’ (May-October) and ‘cool’ (November-April) seasons. ORs and 95% CIs were estimated per IQR increase in pollutant concentrations
  • Results: Increased warm season ambient concentration of NO2 was associated with symptom-based exacerbations on Lag-3 (1.14 (1.01 to 1.29), per IQR), and increased cool season ambient PM2.5 was associated with symptom-based exacerbations on Lag-1 (1.11 (1.03 to 1.20), per IQR). There was a negative association between warm season ambient O3 and symptom-based events on Lag-3 (0.73 (0.52 to 1.00), per IQR)
  • Conclusions: Short-term ambient NO2 and PM2.5 exposure were associated with increased odds of exacerbations in Canadians with mild to moderate COPD, further heightening the awareness of non-infectious triggers of COPD exacerbations.

Alpha-1 Antitrypsin Deficiency (see Alpha-1 Antitrypsin Deficiency)

• xxx

Asthma/Bronchial Hyperreactivity (see Asthma)

• Epidemiology: may be risk factors for COPD

Dust (Organic and Inorganic)

• xxx

Genetic Factors

• Alpha-1 Antitrypsin
• Matrix Metalloproteinase 12 (MMP12)

Infection

• Epidemiology: unclear risk factor for COPD
  • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
    • HIV Infection Accelerates the Onset of Smoking-Related Emphysema (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
    • In a Population-Based Study Using Ontario’s Health Administration Database of Patients Diagnosed with COPD Between 1996-2015, the Rate of COPD was Higher in HIV-Positive Patients, as Compared to HIV-Negative Patients (10.4 vs 9.0 Cases Per 1000 Person-Years; Standardized Incidence ratio 1.16, 95% Confidence Interval 1.10 to 1.21; Adjusted Rate Ratio 1.34, 95% CI 1.27 to 1.41) (CMAJ Open, 2020) [MEDLINE]
      • In a Sensitivity Analysis, Smoking Explained the Observed Differences in COPD Incidence

Inflammatory Bowel Disease (IBD) (see Inflammatory Bowel Disease): chronic bronchitis is associated with UC

• xxx

Positive Family History of COPD (Chest, 2011) [MEDLINE]

• xxxxx

Poverty

• Clearly a risk factor for COPD, but exact contributors are unclearB

Toxins/Chemicals

• Chronic Hydrocarbon Inhalant Abuse (see Hydrocarbons, [[Hydrocarbons]]): associated with panacinar emphysema

---

Physiology

Mechanisms of Airflow Limitation in COPD (GOLD; Global Strategy for Diagnosis, Management, and Prevention of COPD 2016) [LINK]

• Small Airways Disease
• Airway Inflammation
• Airway Fibrosis
  • Luminal Plugs Increase Airway Resistance
• Decrease of Lung Elastic Recoil
• Loss of Alveolar Attachments
• Parenchymal Destruction

Dynamic Compression

Background

• During Forced Expiration, Airway Diameter is Determined by Multiple Factors
  • Inherent Size of the Airway
    • Inherent Size of the Airway Depends on the Level of the Airway in Tracheobronchial Tree, the Airway Smooth Muscle Tone (Which Becomes Relevant During Bronchospasm), and the Amount of Secretions in the Airway
  • Amount of Radial Traction Exerted by Surrounding Lung Tissue on the Airway Wall
  • Balance Between the Intrapleural Pressure and the Intra-Airway Pressure
    • During Forced Expiration, the Intrapleural Pressure is Strongly Positive
    • “Equal Pressure Point”: point at which the intrapleural pressure = intra-airway pressure
      • The Level at Which the Equal Pressure Point Occurs Depends on Lung Volume: it is dynamic
      • At Low Lung Volumes, the Elastic Recoil of the Lung is Lesser, Resulting in an Equal Pressure Point Which is Farther From the Mouth
      • At High Lung Volumes, the Elastic Recoil of the Lung is Greater, Resulting in Equal Pressure Point Which is Closer to the Mouth
      • Pursed Lip Breathing Acts to Move the Equal Pressure Point Toward the Mouth
    • Dynamic Compression Occurs When the Intrapleural Pressure Exceeds the Intra-Airway Pressure During Expiration

Dynamic Compression in Normal Subjects

• The Phenomenon of Dynamic Compression Limits Maximum Expiratory Flow in a Lung Volume-Dependent Manner in Normal Subjects
  • In Normal Subjects, There is a Point at Which the Subject Can No Longer Increase Their Expiratory Flow Rate, Despite Increasing Effort: this point of airflow limitation is due to a critical narrowing of the airways caused by dynamic compression

Dynamic Compression in Chronic Obstructive Pulmonary Disease

• Dynamic Compression is Exaggerated in Patients with COPD Due to Multiple Factors
  • Loss of Elastic Recoil of the Lung
  • Loss of Radial Traction on Airways Due to Destruction of Lung Tissue
  • Decreased Small Airway Diameter Due to Bronchospasm and Mucous Hypersecretion

Dynamic Compression in Other Disease States

• Effect of Respiratory Muscle Weakness on Dynamic Compression
  • Weak Expiratory Muscles Does Not Exaggerate Dynamic Compression Because Maximum Expiratory Flow is Independent of Effort (Even in Normal Subjects) and Depends on Lung Volume

Airway Resistance

• During a Severe COPD Exacerbation, the Airways Behave Like a Starling Resistor (Chest, 1989) [MEDLINE]
  • Ohmic Resistor (i.e. One Which Follows Ohm’s Law):
    • With an Ohmic Resistor, if Extrinsic PEEP is Decreased, the Peak Airway Pressure (PIP) Would Be Expected to Decrease by a Similar Amount: this is one would expect with normal lungs
  • Starling Resistor: flow rate in the airways is not dependent on the amount extrinsic PEEP applied
    • Example Using a “Waterfall” Analogy: the flow rate of a waterfall is not impacted by the level of the pool of water below (of course, until the pool of water rises to the level of the waterfall)
    • With a Starling Resistor, When Extrinsic PEEP is Decreased, the Peak Airway Pressure (PIP) Does Not Decrease by a Similar Amount: this is due to the fact that flow is determined by upstream events only

Chronic Bronchitis: chronic or recurrent secretion of mucus into bronchial tree

• Mucus originates from submucosal mucus glands (major source) and goblet cells (minor source)
• Mucus gland are enlarged, due to hyperplasia (major source of enlargement) and hypertrophy (minor source of enlargement)
• Reid Index: quantifies mucus gland size, defined as ratio of thickness of bronchial mucus glands: thickness of bronchial wall (measured from BM to inner cartilage)
  • Normal Reid Index: 0.35
  • Chronic Bronchitis Reid Index: 0.51
• Volume Proportion of Mucus Glands: also used to quantify the mucus gland size
• Other pathologic changes: goblet cell metaplasia of surface epithelium, chronic inflammation (mononuclear cells, neutrophils), smooth muscle hyperplasia

Emphysema: defined by NHLBI workshop as condition of the lung characterized by abnormal permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, and without obvious fibrosis

• Destruction : non-uniformity in respiratory airspace enlargement so that the orderly appearance of the acinus and its components is disturbed or lost
• Degree of emphysema is the most important correlate of airflow obstruction in cigarette smokers with moderate or severe COPD

Classification of Emphysema

• Proximal Acinar (Centrilobular): most common/primary feature is enlargement of respiratory bronchioles
  • Typical COPD (Upper Lung Zones: Sup/Post UL and Sup Seg-LL): due to tobacco abuse (see xxxx, [[xxxx]])
  • Simple Coal Worker’s Pneumoconiosis (Upper Lung Zones: Sup/Post UL and Sup Seg-LL): due to occupational coal dust exposure
• Panacinar (Panlobular)
• Widespread (Most Severe in Lower Zones)——————————————————————————-Alpha1-Antitrypsin Deficiency (Homo PiZ, Homo PiS, and PiSZ)
• Lower Zones——————————————————————————————————————–Centrilobular Emphysema and COPD, IVDA
• Lower Zones (In Anterior Margins)—————————————————————————————–Variant of Aging (in 7th-9th Decades)
• Unilateral Swyer-James Syndrome—————————————————————————————–(Associated with Bronchiolar Obstruction)
• Distal Acinar (Paraseptal): least common form/only rarely associated with clinical airflow obstruction
  • Upper Zones (In Anterior and Posterior Margins)————————————————————————Spontaneous Pneumothorax

Small Airways Disease

• Small Airways Disesase defined by Macklem [Ann Int Med, 1971] as patient with clinical features of chronic obstructive airways disease without evidence of emphysema or chronic bronchitis
• Pathology: non-specific pattern of peribronchiolar inflammation with varying concentric peribronciolar fibrosis/thickening of walls of terminal and respiratory bronchioles
• There is a correlation between small airway wall thickness and the degree of emphysema

Pulmonary Hypertension

• pulmonary HTN due to COPD (Chronic Bronchitis > Emphysema)/ Cystic Fibrosis/ Bronchiectasis
• Anatomic lung blood vessel distortion/ pulmonary vascular destruction/ hypercapnia and hypoxia-induced vasoconstriction/ increased blood viscosity due to polycythemia
• PA pressure usually increases with exercise
• PA pressure usually decreases (but not to normal) with oxygen therapy

Respiratory Mechanics in COPD

• Hyperinflation with Flattened Diaphragms
  • Increases diaphragmatic muscle tension -> increased impedance to diaphragmatic blood flow
  • Flattening results in compromised inspiratory force generation
  • Horizontal orientation of diaphragm (and loss of zone of apposition between chest wall and diaphragm) -> results in diaphragmatic force vector on rib cage becoming more inward, rather than cephalad
    • Hoover Sign: paradoxic inward inspiratory movement of lower lateral rib cage
• Recruitment of Accessory Muscles: increases oxygen consumption
• Development of Auto-PEEP: due to airway obstruction (with increased airway resistance)
  • Results in inspiratory pressure load that diaphragm must overcome with each inspiration
• Association between systemic immune-inflammation index and chronic obstructive pulmonary disease: A population-based study. BMC Pulm Med. Published online August 10, 2023. doi:10.1186/s12890-023-02583-5 [MEDLINE]
  • Background: The Systemic Immune-Inflammation Index (SII) is a quantitative measurement of the systemic immune-inflammatory response in the human body. The SII has been shown to have prognostic value in various clinical settings, including critical illness, sepsis, and cancer. Its role in chronic obstructive pulmonary disease (COPD) remains unclear and requires further investigation
  • Methods: We analyzed demographic data from 16,636 participants in the National Health and Nutrition Examination Survey. Logistic regression analysis was performed to assess the correlation between COPD, lung function, chronic respiratory symptoms and SII. We used Cox proportional hazards (PH) model to analyze the relationship between SII and mortality in COPD patients and healthy individuals. We used propensity score matching (PSM) method to match the COPD population with similar baseline levels with the normal population to further analyze the correlation between SII and COPD
  • Results: We recruited 16,636 participants, ages 40 and above, for the study. A multivariable logistic regression analysis revealed that a higher SII level was independently associated with an elevated likelihood of COPD (Odds Ratio (OR) = 1.449; 95% Confidence Interval (CI): 1.252-1.676, P < 0.0001) after controlling for all other factors. Results of subgroup analysis showed a significant positive correlation between SII and COPD in different age groups, gender, Body Mass Index, smoking status, and those with a history of hypertension. The SII index had positive correlation with COPD after PSM (OR = 1.673; 95%CI: 1.443-1.938). After full adjustment, an increase in the SII is associated with a higher all-cause mortality rate. The hazard ratio (HR) with a 95% CI in the general population, COPD patients, and healthy individuals are 1.161 (1.088, 1.239), 1.282 (1.060, 1.550), and 1.129 (1.055, 1.207), respectively
  • Conclusions: Higher SII levels are linked to higher prevalence of COPD. COPD patients with a higher SII levels have a higher risk of all-cause mortality. Additional large-scale, long-term studies are necessary to confirm these results.

---

Pathology

• Marked lymphocytic infiltration of adventitia

---

Diagnosis

Complete Blood Count (CBC) (see Complete Blood Count)

• Polycythemia: in COPD patients with daytime and/or nocturnal hypoxemia

Arterial Blood Gas (ABG) (see Arterial Blood Gas)

• Hypoxemia (with elevated A-a gradient in most cases, although 1991 study suggests that gradient may normalize in severe COPD with increasing hypercapnia due to shifted oxyHb dissociation curve and V/Q mismatching)
• Hypercapnia does not usually occur until FEV1 is <1.3 L

Sputum Culture (see Sputum Culture)

• Exacerbations are most commonly associated with Moraxella Catarrhalis/H Flu/Pneumococci
• By protected brush, sputum C/S is positive for organisms in 25% of stable COPD patients (and in 52% of acute COPD exacerbation cases: in these, 24% of this group had >104 organisms per ml)

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests)

• Obstructive Pattern
  • Decreased FEV1
    • FEV1 Correlates Poorly with Health-Related Quality of Life
  • Normal FVC
  • Decreased FEV1/FVC Ratio
• Bronchodilator Responsiveness (Defined as Increase in FEV1 and/or FVC ≥12% of Control and ≥200 mL)
  • Bronchodilator Responsiveness is Observed in <50% of COPD Patients
• Total Lung Capacity (TLC)
  • Disparity Between TLC Measured by Body Plethysmography (Higher) and Helium Dilution (Lower) Suggests a Non-Communicating Gas Space (Bulla)
  • The Rare Bulla Which Communicates with the Airways (as Demonstrated by a Lesser Disparity of the TLC Between Body Plethysmography and Helium Dilution) Will Contribute More to Dead Space Ventilation, Resulting in Worsening Dyspnea
• Functional Residual Capacity (FRC)
• Residual Volume (RV)
  • Increased RV/TLC Ratio (Indicative of Gas Trapping): may be found
• DLCO: decreased
• Recommendations (GOLD; Global Strategy for Diagnosis, Management, and Prevention of COPD, 2016 [LINK]
  • Post-Bronchodilator FEV1/FVC Ratio <70% Should Be Used as a Diagnostic Criterion for COPD
    • This Criterion Will Result in More Frequent Diagnosis of COPD in the Elderly and Less Frequent Diagnosis in Adults <45 y/o (As Compared to Using Lower Limit of Normal Cutoffs for FEV1 of FVC): especially with milder disease
    • Lower Limit of Normal Cutoff Values are Highly Dependent on Valid Reference Equations Using Post-Bronchodilator FEV1 Values: however, neither longitudinal studies validating the use of the lower limit of normal nor studies using reference equations in populations where smoking is not the major cause of COPD are available
  • Grading of Severity of Airflow Obstruction (In Patient with FEV1/FVC Ratio <70%)
    • GOLD 1 (Mild): FEV1 ≥80% Predicted
    • GOLD 2 (Moderate): FEV1 50-80% Predicted
    • GOLD 3 (Severe): FEV1 30-50% Predicted
    • GOLD 4 (Very Severe): FEV1 <30% Predicted
• Application of the ERS/ATS spirometry standards and race-neutral equations in the COPDGene study. Am J Respir Crit Care Med. Published online April 12, 2024. doi:10.1164/rccm.202311-2145OC [MEDLINE]
  • Rationale: The European Respiratory Society (ERS) and the American Thoracic Society (ATS) recommend using z-scores, and the ATS has recommended using Global Lung Initiative (GLI)- “Global” race-neutral reference equations for spirometry interpretation. However, these recommendations have been variably implemented and the impact has not been widely assessed, both in clinical and research settings
  • Objectives: We evaluated the ERS/ATS airflow obstruction severity classification
  • Methods: In the COPDGene Study (n = 10,108), airflow obstruction has been defined as a forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ratio <0.70, with spirometry severity graded from class 1 to 4 based on race-specific percent predicted (pp) FEV1 cut-points as recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). We compared the GOLD approach, using NHANES III race-specific equations, to the application of GLI-Global equations using the ERS/ATS definition of airflow obstruction as FEV1/FVC ratio < lower limit of normal (LLN) and z-FEV1 cut-points of -1.645, -2.5, and -4 (“zGLI Global”). We tested the four-tier severity scheme for association with COPD outcomes
  • Measurements and main results: The lowest agreement between ERS/ATS with zGLI Global and the GOLD classification was observed in individuals with milder disease (56.9% and 42.5% in GOLD 1 and 2) and race was a major determinant of redistribution. After adjustment for relevant covariates, zGLI Global distinguished all-cause mortality risk between normal spirometry and the first grade of COPD (Hazard Ratio 1.23, 95% CI 1.04-1.44, p=0.014), and showed a linear increase in exacerbation rates with increasing disease severity, in comparison to GOLD
  • Conclusions: The zGLI Global severity classification outperformed GOLD in the discrimination of survival, exacerbations, and imaging characteristics.
• Longitudinal changes in maximal forced inspiratory flow and clinical outcomes in COPD patients. Chest. Published online August 14, 2024. doi:10.1016/j.chest.2024.07.162 [MEDLINE]
  • Background: COPD primarily impairs expiratory flow due to progressive airflow obstruction and reduced lung elasticity. Increasing evidence underlines the importance of inspiratory flow as a biomarker for selecting inhaler devices and providing ancillary aerodynamic information
  • Research question: Does the longitudinal changes in maximum forced inspiratory flow (FIFmax) influence acute exacerbations and lung function decline in patients with COPD?
  • Study design and methods: This longitudinal study evaluated FIFmax in patients with COPD over a 7-year period from 2004 to 2020. Eligible patients were categorized into 2 groups based on FIFmax trajectory: the increased FIFmax group and the decreased FIFmax group. The study assessed the annual rate of acute exacerbations and the annual decline rate of FEV1. Subgroup analyses were conducted based on treatment status, with a focus on inhaled therapy and inhaler device usage
  • Results: Among the eligible 956 patients with COPD, 56.5% belonged to the increased FIFmax group. After propensity score matching, the increased FIFmax group experienced lower rates of severe exacerbations (0.16 per year vs 0.25 per year, P = .017) and a slower decline in FEV1 (0 [interquartile range, -51 to 71] mL/y vs -43 [interquartile range, -119 to 6] mL/y; P < .001) compared with the decreased FIFmax group. These associations were particularly prominent in patients using specific inhaler therapies such as dry powder inhalers
  • Interpretation
    • This study showed that the longitudinal changes in FIFmax are associated with clinical outcomes in patients with COPD
    • Patients with increased FIFmax experienced a lower rate of severe exacerbations and a slower decline in lung function
    • These findings suggest the potential benefits of optimizing inspiratory flow in COPD management, although further studies are needed to confirm these observations due to potential confounding factors

6-Minute Walk Test (6MWT) (see 6-Minute Walk Test)

• Indications
  • xxxx
• Clinical Efficacy
  • ECLIPSE Trial (2013) [MEDLINE]
    • 6MWT with a 30 m (98.4 ft) Decline in 6MWT Distance in the First Year was Associated with an Increased Risk for Mortality in the Subsequent 2 yrs
    • 6MWT Had No Significant Association with Frequency of Hospitalization Due to COPD Exacerbation
    • 6MWT Had a Weak Associations with Decline in FEV1
    • 6MWT Had a Weak Association with Decline in St George’s Respiratory Questionnaire (SGRQ) Criteria

Cardiopulmonary Exercise Test (see Cardiopulmonary Exercise Test)

• xxxx

Bronchoscopy (see Bronchoscopy)

Bronchoalveolar Lavage (BAL)

• xxx

Chest X-Ray (CXR) (see Chest X-Ray)

• Findings
  • Hyperinflation with Flattened Diaphragms
  • Enlarged Pulmonary Arteries: right PA >16mm
  • Enlarged Right Ventricle with Loss of Retrosternal Air Space
  • Enlarged Superior Vena Cava and Azygous Vein
  • “Pruned Tree” Pulmonary Vasculature

Chest Computed Tomography (CT) (see Chest Computed Tomography)

Findings

• Emphysematous Changes
• xxxx

Clinical Data

• Cohort Study Examining the Predictive Value of Emphysematous Changes on Chest CT (Ann Int Med, 2014) [MEDLINE]
  • Presence of Emphysematous Changes on CT Imaging in Patients without Spirometrically-Defined COPD were Linearly Associated with Increased All-Cause Mortality
    • Even after adjusting for confounding variables, such as cardiovascular risk factors and FEV1
  • The Association was of the Greatest Magnitude Among Smokers
• Study of the Impact Centrilobular vs Paraseptal Emphysema on the Longitudinal Changes in Diffusing Capacity and Mortality in Chronic Obstructive Pulmonary Disease (COPD) (Chest, 2023) [MEDLINE]
  • This pooled analysis included 399 patients with COPD from two prospective Observational COPD Cohorts
  • Centrilobular Emphysema and Paraseptal Emphysema were visually assessed on CT scan according to the Fleischner Society statement
  • The diffusing capacity and transfer coefficient of the lung for carbon monoxide (Dlco and KCO) and FEV1 were evaluated at least annually over a 5-year Period
  • Mortality was recorded over 10 years
  • Longitudinal changes in FEV1, Dlco, and KCO and mortality were compared between mild or less severe and moderate or more severe Centrilobular Emphysema and between present and absent Paraseptal Emphysema in each Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage
  • Results
    • The Dlco and KCO decline was weakly associated with FEV1 and greater in GOLD stage 3 or above than in GOLD stages 1 and 2\
    • Furthermore, moderate or more severe CLE, but not present PSE, was associated with steeper declines in Dlco for GOLD stages 1 and 3 or higher and KCO for all GOLD stages independent of age, sex, height, and smoking history
    • The moderate or more severe CLE, but not present PSE, was associated with additional FEV1 decline and higher 10-year mortality among patients with GOLD stage 3 or higher
  • Conclusions
    • A CT scan finding of moderate or more severe CLE, but not PSE, was associated with a subsequent accelerated impairment in diffusing capacity and higher long-term mortality in severe GOLD stage among patients with COPD

High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography)

Findings

• Emphysematous Changes

Electrocardiogram (EKG) (see Electrocardiogram)

• RVH Strain Pattern
  • Epidemiology: seen in 57-60% of COPD patients with cor pulmonale
  • Features: ST-Segment Depression and T-Wave Inversion in the Leads Corresponding to the Right Ventricle
    • Right Precordial Leads: V1-V3 (and often V4)
    • Inferior Leads: II/III/AVF (most pronounced in III, as this is the most rightward-facing lead)
• Right Ventricular Hypertrophy (RVH)
  • Epidemiology
    • Observed in 2-27% of all COPD patients
    • Observed in 28-75% of patients with COPD + cor pulmonale
• Right Axis Deviation >90 Degrees
  • Epidemiology
    • Observed in 46-85% of all COPD patients
    • Observed in 18-79% of patients with COPD + cor pulmonale
  • Features
    • Usually present in association with RVH
    • May be seen without RVH in cases of pure emphysema with associated hyperinflation (RV swings more anteriorly and LV swings more posteriorly)
• P-Pulmonale: may be seen
• S1S2S3 Pattern
  • Epidemiology: least sensitive but most specific pattern for COPD (observed in 2-5% of all COPD patients)
    • Unrelated to COPD disease severity
  • Features: distinct S waves in I/II/III
• Left Axis Deviation
  • Epidemiology: seen in 2-10% of all COPD patients
  • Features: usually in the range of -80 to -120°, as opposed to the -30 to -60° typically seen in LAD associated with LV disease
• Right Bundle Branch Block (RBBB)
  • Epidemiology: seen in 2% of all COPD patients

Ventilation/Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan)

• Indications
  • May Be Useful to Exclude Acute Pulmonary Embolism, CTEPH, etc in Select Cases

Pulmonary Artery Angiogram (see Pulmonary Artery Angiogram)

• Indications
  • May Be Useful to Exclude CTEPH in Select Cases

Echocardiogram (see Echocardiogram)

• Bubble Study: useful to exclue intracardiac shunt (due to VSD, ASD, etc)*
• Evaluation for Pulmonary Hypertension
  • RV Enlargement
  • Tricuspid Regurgitation

Swan-Ganz Catheter (Pulmonary Artery Catheter) (see Swan-Ganz Catheter)

• RA: normal (at rest)
• RV-SYS: elevated (with normal RV-EDP)
• PA-SYS: mild-moderately ele-vated (PA-SYS usually <30-50 mm Hg in COPD)
• PA-DIA: usually elevated
• PA-Mean: mild-moderately elevated
• PCWP: normal (reflects normal LA and LV-EDP)
• CO: normal at rest (does not rise appropriately with exercise)

Cardiac Catheterization (see Cardiac Catheterization)

• Indications
  • May Be Useful to Exclude Intracardiac Shunt, Coronary Artery Disease, etc

---

Clinical Manifestations

General Comments

Clinical Indicators Which May Signal the Presence of Chronic Obstructive Pulmonary Disease (COPD) (GOLD; Global Strategy for Diagnosis, Management, and Prevention of COPD, 2016) [LINK]

• Dyspnea (see Dyspnea)
  • Progressive
  • Characteristically Worse with Exercise
  • Persistent*
• Chronic Cough (see Cough)
  • May Be Intermittent
  • May Be Dry
• Chronic Sputum Production
  • Any Pattern
• History of Exposures
  • Tobacco Smoke (see Tobacco)
  • Smoke from Home Cooking and Heating Fuels
  • Occupational Dusts and Exposures
• Family History of COPD

Cardiovascular Manifestations

Cardiac Arrhythmias

• Epidemiology
  • COPD is Associated with Increased Cardiovascular Morbidity and Mortality
• Physiology
  • May Be Related to Hypoxemia (Especially During REM Sleep) or to Other Factors
• Clinical
  • Atrial Fibrillation (AF) (see Atrial Fibrillation)
  • Multifocal Atrial Tachycardia (MAT) (see Multifocal Atrial Tachycardia)
  • Ventricular Tachycardia (VT) (see Ventricular Tachycardia)
• Clinical Data
  • Even After Adjusting for Age/Gender/Tobacco Use/Obesity/Hypertension/CAD/Heart Failure/Diabetes Mellitus/Anemia/Cancer/CKD/Rate or Rhythm Control Medications, COPD was a Significant Risk Factor for Atrial Fibrillation/Flutter, and Non-Sustained/Sustained Ventricular Tachycardia (Am J Cardiol, 2014) [MEDLINE]

Increased Risk of Acute Myocardial Infarction (see Coronary Artery Disease)

• Epidemiology
  • COPD is Associated with an Increased Risk for Cardiovascular Disease, Stroke, and Diabetes Mellitus (Thorax, 2010) [MEDLINE]
    • After Adjusting for Sex/Smoking Status/Age, the Greatest Risk for Arteriovascular Events was Observed in the Youngest Age Group
    • Hazard Ratio for Acute MI was 10.34 (95% CI 3.28 to 32.60; p<0.001) in the Youngest Age Group, as Compared to the Oldest Age Group
• Sex-specific and age-specific incidence of ischaemic heart disease, atrial fibrillation and heart failure in community patients with chronic obstructive pulmonary disease. BMJ Open Respir Res. 2022 Dec;9(1):e001307. doi: 10.1136/bmjresp-2022-001307 [MEDLINE]
  • Objective: To estimate the incidence of ischaemic heart disease, atrial fibrillation and heart failure in community patients with or without chronic obstructive pulmonary disease (COPD)
  • Methods: For this population-based study, we used primary care data of the Julius General Practitioners’ Network. Eligible participants were aged 40-80 years old and contributed data between January 2014 and February 2019. Participants were divided into groups according to COPD status and were followed up for new ischaemic heart disease, atrial fibrillation and/or heart failure. Age-specific and sex-specific incidence and incidence rate ratios were calculated for patients with and without COPD
  • Results: Mean follow-up was 3.9 years, 6223 patients were included in the COPD group, and 137 028 individuals in the background group without COPD. Incidence rates of all three heart diseases increased with age and were higher in males, independent of presence of COPD. Incidence rate ratios for patients with COPD, adjusted for age and sex, were 1.69 (95% CI 1.49 to 1.92) for ischaemic heart disease, 1.56 (95% CI 1.38 to 1.77) for atrial fibrillation and 2.96 (95% CI 2.58 to 3.40) for heart failure
  • Conclusion: The incidence of all major cardiovascular diseases is higher in patients with COPD, with the highest incidence rate ratio observed for heart failure.
• Impaired Spirometry and COPD Increase the Risk of Cardiovascular Disease: A Canadian Cohort Study. Chest. 2023 Sep;164(3):637-649. doi: 10.1016/j.chest.2023.02.045 [MEDLINE]
  • Background: Individuals with COPD and preserved ratio impaired spirometry (PRISm) findings in clinical settings have an increased risk of cardiovascular disease (CVD)
  • Research question: Do individuals with mild to moderate or worse COPD and PRISm findings in community settings have a higher prevalence and incidence of CVD compared with individuals with normal spirometry findings? Can CVD risk scores be improved when impaired spirometry is added?
  • Study design and methods: The analysis was embedded in the Canadian Cohort Obstructive Lung Disease (CanCOLD). Prevalence of CVD (ischemic heart disease [IHD] and heart failure [HF]) and their incidence over 6.3 years were compared between groups with impaired and normal spirometry findings using logistic regression and Cox models, respectively, adjusting for covariables. Discrimination of the pooled cohort equations (PCE) and Framingham risk score (FRS) in predicting CVD were assessed with and without impaired spirometry
  • Results: Participants (n = 1,561) included 726 people with normal spirometry findings and 835 people with impaired spirometry findings (COPD Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1 disease, n = 408; GOLD stage ≥ 2, n = 331; PRISm findings, n = 96). Rates of undiagnosed COPD were 84% in GOLD stage 1 and 58% in GOLD stage ≥ 2 groups. Prevalence of CVD (IHD or HF) was significantly higher among individuals with impaired spirometry findings and COPD compared with those with normal spirometry findings, with ORs of 1.66 (95% CI, 1.13-2.43; P = .01∗) (∗ indicates statistical significane with P < .05) and 1.55 (95% CI, 1.04-2.31; P = .033∗), respectively. Prevalence of CVD was significantly higher in participants having PRISm findings and COPD GOLD stage ≥ 2, but not GOLD stage 1. CVD incidence was significantly higher, with hazard ratios of 2.07 (95% CI, 1.10-3.91; P = .024∗) for the impaired spirometry group and 2.09 (95% CI, 1.10-3.98; P = .024∗) for the COPD group compared to individuals with normal spirometry findings. The difference was significantly higher among individuals with COPD GOLD stage ≥ 2, but not GOLD stage 1. The discrimination for predicting CVD was low and limited when impaired spirometry findings were added to either risk score
  • Interpretation: Individuals with impaired spirometry findings, especially those with moderate or worse COPD and PRISm findings, have increased comorbid CVD compared with their peers with normal spirometry findings, and having COPD increases the risk of CVD developing
• Differential Association of COPD Subtypes With Cardiovascular Events and COPD Exacerbations. Chest. 2024 Dec;166(6):1360-1370. doi: 10.1016/j.chest.2024.07.148 [MEDLINE]
  • Background: The coronary artery calcium score (CACS) and ratio of the pulmonary artery to aorta diameters (PA:A ratio) measured from chest CT scans have been established as predictors of cardiovascular events and COPD exacerbations, respectively. However, little is known about the reciprocal relationship between these predictors and outcomes. Furthermore, the prognostic implications of COPD subtypes on clinical outcomes remain insufficiently characterized
  • Research question: How can these two chest CT scan-derived parameters predict subsequent cardiovascular events and COPD exacerbations in different COPD subtypes?
  • Study design and methods: Using COPDGene study data, we assessed prospective cardiovascular disease (CVD) and COPD exacerbation risk in participants with COPD (Global Initiative for Chronic Obstructive Lung Disease spirometric grades 2-4), focusing on CACS and PA:A ratio at study enrollment, with logistic regression models. These outcomes were analyzed in three COPD subtypes: 1,042 participants with non-emphysema-predominant COPD (NEPD; low attenuation area at -950 Hounsfield units [LAA-950] < 5%), 1,324 participants with emphysema-predominant COPD (EPD; LAA-950 ≥ 10%), and 465 participants with intermediate emphysema COPD (IE; 5% ≤ LAA-950 < 10%)
  • Results: Our study indicated significantly higher overall risk for cardiovascular events in participants with higher CACS (≥ median; OR, 1.61; 95% CI, 1.30-2.00) and increased COPD exacerbations in those with higher PA:A ratios (≥ 1; OR, 1.80; 95% CI, 1.46-2.23). Notably, participants with NEPD showed a stronger association between these indicators and clinical events compared to EPD (with CACS/CVD, NEPD vs EPD: OR, 2.02 vs 1.41; with PA:A ratio/COPD exacerbation, NEPD vs EPD: OR, 2.50 vs 1.65); the difference in ORs between COPD subtypes was statistically significant for CACS/CVD
  • Interpretation: Two chest CT scan parameters, CACS and PA:A ratio, hold distinct predictive values for cardiovascular events and COPD exacerbations that are influenced by specific COPD subtypes.

Neurologic Manifestations

Anxiety/Depression (see Anxiety, [[Anxiety]] and Depression)

• Epidemiology
  • Anxiety/Depression Occur with Higher Prevalence in COPD than in Other Chronic Diseases (Chest, 2008) [MEDLINE]
    • Prevalence of Anxiety in COPD: 10-33%
    • Prevalence of Depression in COPD: 10-40%
  • Untreated/Undetected Anxiety and Depression May Increase Physical Disability, Morbidity, and Health Care Utilization (Chest, 2008) [MEDLINE]

Circadian Rhythm Disruption

• Epidemiology
  • XXX
• Association of rest-activity circadian rhythm with chronic respiratory diseases, a cross-section survey from NHANES 2011-2014. Respir Med. 2023 Feb 6;209:107147. doi: 10.1016/j.rmed.2023.107147 [MEDLINE]
  • A total of 7412 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 were included in this study. The rest-activity circadian rhythm indices were calculated using accelerometer data and were divided into quartiles to perform logistic regression.
  • Results: Participants in the highest quartile of Relative amplitude (RA) had a lower prevalence of emphysema, chronic bronchitis and asthma, compared to those in the lowest quartile. Participants in the highest quartile of Intradaily variability (IV) was associated with a higher prevalence of emphysema relative to those in the lowest quartile. Compared to those in the lowest quartile, participants in the highest quartile of the average activity of the most active continuous 10-h period (M10) had a lower prevalence of emphysema. Additionally, compared to those in the lowest quartile of the average activity of the least active continuous 5-h period (L5) and L5 start time, participants in the highest quartile had a higher prevalence of asthma.
  • Conclusions: This study demonstrated that in general US adult population, disrupted rest-activity circadian rhythm was associated with a higher prevalence of chronic respiratory diseases

Increased Risk of Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident)

• Epidemiology:
  • COPD is Associated with an Increased Risk for Cardiovascular Disease, Stroke, and Diabetes Mellitus (Thorax, 2010) [MEDLINE]
    • After Adjusting for Sex/Smoking Status/Age, the Greatest Risk for Arteriovascular Events was Observed in the Youngest Age Group
    • Hazard Ratio for Stroke was 3.44 (95% CI 0.85 to 13.84; p<0.001) in the Youngest Age Group, as Compared to the Oldest Age Group

Neuropsychiatric Consequences of Hypoxemia

• Epidemiology
  • Frequency correlates with the degree of hypoxemia

Pulmonary Manifestations

General Clinical Features

• Accessory Muscle Use
• Chest Tightness
• Chronic Productive Cough (see Cough)
  • Clinical Definition of Chronic Bronchitis: sputum production for ≥3 months in the last 2 consecutive years (in the absence of any other conditions that may explain it)
  • Clinical
    • Cough-Related Rib Fractures
    • Post-Tussive Syncope (see Syncope)
  • Clinical Data
    • Study of Chronic Productive Cough in Smokers with Early COPD (COPD, 2014) [MEDLINE]: used Lung Health Study data
      • Combination of Cough with Sputum was Associated with Increased Mortality Rate in Mild-Moderate COPD (After Adjustment for Age, Gender, Race, Smoking Status at Year 5, Pack-Years Smoked, Randomization Group, and Baseline FEV1)
• Dyspnea (see Dyspnea)
  • Epidemiology: common
• Hoover Sign (see Hoover Sign, [[Hoover Sign]]): paradoxic inward inspiratory movement of lower lateral rib cage
• Hypoxemia (see Hypoxemia)
  • Cyanosis (see Cyanosis)
• Tachypnea (see Tachypnea)
• Wheezing (see Wheezing)

Nocturnal Hypoxemia

• Epidemiology
  • Approximately 30% of COPD Who are Not Hypoxemic While Awake Manifest Nocturnal Hypoxemia (Chest, 1987) [MEDLINE] (Am Rev Respir Dis, 1992) [MEDLINE]
• Nocturnal Hypoxemia
  • Generally closely related to need for daytime oxygen: occurs in 27% of COPD patients with awake pO2 >60 mm Hg
  • Normal subjects demonstrate small increases in pCO2 and small decreases in pO2 during sleep: these are accentuated in COPD patients
  • Nocturnal desaturations in COPD are most marked in REM (probably due to decreased alveolar ventilation, inhibited respiratory muscles, decreased VT, decreased FRC with worsened V/Q mismatching during REM): typically worse in later REM periods
  • Predictors of Nocturnal Hypoxemia in COPD
    • Daytime pCO2 >45 mmg Hg
    • Daytime pO2 <65 mm Hg

Chronic Hypoventilation (see Chronic Hypoventilation)

• CO2 retention in patients with COPD typically occurs when the FEV1 falls below 1L
  • However, not all COPD patients with FEV1 <1L develop hypercapnia (due to multifactorial variability)
• Etiology of Acute Worsening of Pre-Existing Hypercapnia in COPD:
  • Acute Pulmonary Embolism (PE)
  • Pneumonia/Acute Bronchitis
  • CHF
  • Sedatives: such as antihistamines, benzodiazepines, etc.
    • Zolpidem (which is an imidazopyridine) does not cause significant respiratory depression
• Mechanisms of Supplemental O2 Administration Worsening Pre-Existing Hypercapnia in COPD:
  • Worsened V/Q Mismatch (Primary Etiology)
    • Release of hypoxic vasoconstriction -> increase in blood flow to poorly ventilated lung segments -> increase in dead space and decrease in effective alveolar ventilation
  • Release of Hypoxic Drive
    • Decrease in VT + RR occurs transiently (usually for 15 min) and then increases back to pre-supplemental O2 baseline
  • Haldane Effect
    • Administration of oxygen causes concurrent decrease in the CO2 carrying capacity of the hemoglobin molecule -> resulting in a slight increase in pCO2

[Aubier M, Murciano D, Milic-Emili J, et al. Effects of the administration of O2 on the ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis 1980; 122:747-754 Agusti A, Carrera M, Barbe F, et al. Oxygen therapy during exacerbations of chronic obstructive pulmonary disease. Eur Respir J 1999; 14:934-939 Murciano D, Armengaud M, Cramer P, et al. Acute effects of zolpidem, triazolam, flunitrazepam on arterial blood gases and control of breathing in severe COPD. Eur Respir J 1993; 6:625-629]

• Hypercapnia and lung function parameters in chronic obstructive pulmonary disease. BMC Pulm Med. 2024 Jul 16;24(1):345. doi: 10.1186/s12890-024-03151-1 [MEDLINE]
  • Background
    • In advanced chronic obstructive pulmonary disease (COPD), hypercapnia may occur due to severe bronchial obstruction with lung hyperinflation
    • Non-invasive ventilation (NIV) provides the standard of care intended to achieve physiological PCO2 levels, thereby reducing overall mortality
    • The present study aimed to evaluate pulmonary function parameters derived from spirometry (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1]), body plethysmography (residual volume [RV], total lung capacity [TLC]), and lung diffusion capacity for carbon monoxide (single-breath method [DCO-SB], alveolar-volume corrected values [DCO-VA]) as predictors of chronic hypercapnia in patients with advanced COPD
  • Methods
    • This monocentric, retrospective observational study included 423 COPD patients
    • Receiver operating characteristic (ROC) curve analysis and cross-validation were used to assess lung function parameters’ diagnostic accuracy for predicting chronic hypercapnia, with the resulting performance expressed as area under the ROC curve (AUROC)
    • We performed univariable and multivariable binary logistic regression analysis to determine if these parameters were independently associated with chronic hypercapnia, with probabilities reported as odds ratios [OR] with 95% confidence intervals [95%CI]
  • Results: FVC% (AUROC 0.77 [95%CI 0.72-0.81], P < 0.01) and FEV1% (AURIC 0.75 [95%CI 0.70-0.79], P < 0.01) exhibited reasonable accuracy in the prediction of chronic hypercapnia, whereas lung diffusion capacity performed poorly (AUROC 0.64 [95%CI 0.58-0.71] for DCO-SB%, P < 0.01)
  • FVC% (OR 0.95 [95%CI 0.93-0.97], P < 0.01) and FEV1% (OR 0.97 [95%CI 0.94-0.99], P = 0.029) were the only parameters associated independently with chronic hypercapnia in logistic regression analysis. FVC and FEV1 thresholds that best separated hypercapnic from normocapnic subjects reached 56% and 33% of predicted values
  • Conclusions
    • Routinely collected pulmonary function parameters, particularly FVC% and FEV1%, may predict chronic hypercapnia during COPD progression

Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea)

• Epidemiology
  • Occurs in 10-15% of COPD patients

Pulmonary Hypertension/Cor Pulmonale (see Pulmonary Hypertension)

• Epidemiology
  • In a Retrospective Study of 998 COPD Patients Who Underwent Swan-Ganz Catheterization, Only 1% had Severe Pulmonary Hypertension (PAP-Mean >40 mm Hg) (Am J Respir Crit Care Med, 2005) [MEDLINE]
  • Study of the Prevalence of Pulmonary Hypertension in Advanced COPD Patients Referred for Lung Volume Reduction or Lung Transplant (Chest, 2005) [MEDLINE]
    • Pulmonary Hypertension (PA-Mean >25 mm Hg) was Present in 50.2% of Patients
    • Pulmonary Hypertension was Moderate (PA-Mean: 35-45 mm Hg) in 9.8% of Patients
    • Pulmonary Hypertension was Severe (PA-Mean: >45 mm Hg) in 3.7% of Patients
  • Study of Severe Pulmonary Hypertension in Patients with COPD (Chest, 2022) [MEDLINE]
    • In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity
    • The contribution of severe PH and severe airflow limitation to impaired survival is comparable
• Physiology
  • Due to chronic hypoxemia
• Clinical
  • Symptoms of Right-Sided Congestive Heart Failure (Pulmonary Edema, etc) (see Congestive Heart Failure): variable
  • Absence of Kussmaul Sign (see Kussmaul Sign)
• Prognosis
  • PA >20 mm Hg Correlated with Poorer Survival in COPD (mean PAP 25-35 mm Hg) (Thorax, 1981) [MEDLINE]
  • PA-Mean Pressure >45 mm Hg Has a Significantly Worse 5–yr Survival (<10% vs >90%) in COPD (Scand J Respir Dis Suppl, 1971) [MEDLINE]
• Severe Pulmonary Hypertension in COPD: Impact on Survival and Diagnostic Approach. Chest. 2022 Jul;162(1):202-212. doi: 10.1016/j.chest.2022.01.031 [MEDLINE]
  • Background: Severe pulmonary hypertension (PH) is prognostically highly relevant in patients with COPD. The criteria for severe PH have been defined based on hemodynamic thresholds in right heart catheterization
  • Research question: Can noninvasive clinical tools predict severe PH in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease?
  • Study design and methods: We retrospectively analyzed all consecutive patients with COPD with suspected PH undergoing in-depth clinical evaluation, including right heart catheterization, in our PH clinic between 2005 and 2018. Clinical variables potentially indicative of severe PH or death were analyzed using univariate and stepwise multivariate logistic regression and Cox regression analysis adjusted for age and sex
  • Results: We included 142 patients with median FEV1 of 55.0% predicted (interquartile range [IQR], 42.4%-69.4% predicted) and mean pulmonary arterial pressure of 35 mm Hg (IQR, 27-43 mm Hg). A multivariate model combining echocardiographic systolic pulmonary arterial pressure of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values (both 94%). After correction for age and sex, both airflow limitation (P = .002; Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-2 vs stage 3: hazard ratio [HR], 1.56 [95% CI, 0.90-2.71]; GOLD stages 1-2 vs stage 4: HR, 3.45 [95% CI, 1.75-6.79]) and PH severity (P = .012; HR, 1.85 [95% CI, 1.15-2.99]) remained associated independently with survival. The combination of GOLD stages 3 and 4 airflow limitation and severe PH showed the poorest survival (HR for death, 3.26 [95% CI, 1.62-6.57; P = .001] vs GOLD stages 1-2 combined with nonsevere PH)
  • Interpretation: In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable.
• Burden of pulmonary hypertension due to chronic obstructive pulmonary disease: Analysis of exacerbations and healthcare resource utilization in the United States. Respir Med. 2023 Sep 18:219:107412. doi: 10.1016/j.rmed.2023.107412 [MEDLINE]
  • Background: The burden of pulmonary hypertension (PH) among patients with chronic obstructive pulmonary disease (COPD) is not well understood. The present retrospective cohort study aimed to quantify the clinical and economic burden of PH in patients with COPD
  • Methods: Adults with COPD were retrospectively identified in the Optum® Clinformatics® Data Mart between July 1, 2016 and June 30, 2021. Those diagnosed with PH were assigned to the PH-COPD cohort and those without a diagnosis of PH were assigned to the COPD cohort. Outcomes, including the number of visits for exacerbations and all-cause and COPD-related healthcare resource utilization (HCRU) and costs per patient per month (PPPM), were compared between cohorts. Baseline and study outcomes were analyzed descriptively. For significance testing, continuous variables were analyzed using Student’s t-tests and categorical variables were analyzed using Chi-square tests
  • Results: A total of 1627 patients with PH-COPD were matched 1:1 to COPD patients without PH. A greater percentage of PH-COPD patients experienced COPD exacerbations vs. the COPD cohort (p < 0.001) and the PH-COPD cohort had more total (p < 0.001) and severe exacerbation-related visits PPPM (p < 0.001). All-cause and COPD-related HCRU PPPM estimates were higher among the PH-COPD cohort vs. the COPD cohort (p < 0.01). Total all-cause (p < 0.001) and COPD-related costs (p < 0.001) were higher among PH-COPD patients than COPD patients
  • Conclusions: Patients with PH-COPD had higher rates of severe exacerbations, hospitalizations, and costs compared to COPD patients without PH, underscoring the need for targeted therapies to prevent and manage PH in patients with COPD.

Other Manifestations

• Anorexia (see Anorexia)
  • Epidemiology: common
• Cachexia: occurs in 20% of COPD outpatients, in 35% of pulm rehab candidates, and in 70% of COPD patients with acute respiratory failure
  • Muscle wasting in COPD is associated with systemic inflammation (with low anabolic hormone levels and catabolism), rather than simple starvation and nutritional imbalance
  • Cachexia iis associated with greater duration of mechanical ventilation after LVRS, lower exercise capacity, lower muscle strength, greater need for mechanical ventilation in acute exacerbation, impaired health status, increased rate of ealr nonelective readmission after an exacerbation, increased duration of ventilation post-lung transplant, increased hospital admission rates (in those on home oxygen), and worse survival rate
• Fatigue (see Fatigue)
  • Epidemiology: common

Specific Clinical Features of Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation

• Epidemiology
  • The Best Predictor of Having Frequent COPD Exacerbations (≥2 Exacerbations Per Year) is a Prior History of COPD Exacerbations
  • Approximately 66% of All COPD Exacerbations are Due to Respiratory Infection or Air Pollution and 33% Have No Identifiable Etiology
  • Rate of COPD Exacerbations is Related to the GOLD Spirometric Class (GOLD; Global Strategy for Diagnosis, Management, and Prevention of COPD, 2016) [LINK]
    • GOLD 1 (Mild, FEV1 ≥80% Predicted): unknown annual exacerbation rate
    • GOLD 2 (Moderate, FEV1 50-80% Predicted): 0.7-0.9 annual exacerbation rate
    • GOLD 3 (Severe, FEV1 30-50% Predicted): 1.1-1.3 annual exacerbation rate
    • GOLD 4 (Very Severe, FEV1 <30% Predicted): 1.2-2.0 annual exacerbation rate
  • XXXX
• Low human beta-defensin-2 levels in the sputum of COPD patients are associated with the risk of exacerbations. BMC Pulm Med. 2023 Mar 31;23(1):106. doi: 10.1186/s12890-023-02364-0 [MEDLINE]
  • Rationale: Chronic obstructive pulmonary disease (COPD) is a complicated chronic inflammatory disease. It is important to investigate the characteristics of acute exacerbation of COPD to develop new therapeutic strategies.
  • Objective: This study aimed to determine the relationship between the human beta-defensin-2 (hBD-2) levels and aggravation of COPD.
  • Methods: We detected the sputum hBD-2 level of 254 patients from Guangzhou, China, for 2 years. The study participants were categorized into the COPD group (n = 203, GOLD 0-4) and the control group (n = 51, 40-79 years old). At baseline, 12th month, and 24th month, we detected the sputum hBD-2 level and levels of cytokines, such as CXCL10, CXCL11, and IFN
  • Results: At baseline, there were no significant differences in the sputum and serum hBD-2 levels between the patients and the controls. However, the sputum hBD-2 levels of patients who had at least one symptom aggravation over the next 2 years were significantly lower than those of patients without any exacerbations (1130.9 ± 858.4 pg/mL vs. 2103.7 ± 1294.2 pg/mL, respectively; p = 0.001). Nevertheless, there were no statistically significant differences in the sputum hBD-2 levels between patients (no aggravation history) and controls (2084.9 ± 1317.6 pg/mL vs. 2152.5 ± 1251.6 pg/mL, respectively; p = 0.626). We used a logistic regression model to assess the relationship between aggravation and sputum hBD-2 levels. Interestingly, we found that low hBD-2 level (< 1000 pg/mL) was significantly associated with exacerbations. Specifically, patients with low hBD-2 levels were more likely to experience exacerbations in the next 12 months (0.333 vs. 0.117; p = 0.001). Moreover, we compared the hBD-2 levels between controls and patients with GOLD 3-4 and found that participants with bacteria (+) and/or viruses (+) had an association between hBD-2 level and disease severity (p = 0.02)
  • Conclusion: Patients at risk of exacerbations are more likely to have lower sputum hBD-2 levels. These results have important implications for future therapies for COPD.
• Differential Association of COPD Subtypes With Cardiovascular Events and COPD Exacerbations. Chest. 2024 Dec;166(6):1360-1370. doi: 10.1016/j.chest.2024.07.148 [MEDLINE]
  • Background: The coronary artery calcium score (CACS) and ratio of the pulmonary artery to aorta diameters (PA:A ratio) measured from chest CT scans have been established as predictors of cardiovascular events and COPD exacerbations, respectively. However, little is known about the reciprocal relationship between these predictors and outcomes. Furthermore, the prognostic implications of COPD subtypes on clinical outcomes remain insufficiently characterized
  • Research question: How can these two chest CT scan-derived parameters predict subsequent cardiovascular events and COPD exacerbations in different COPD subtypes?
  • Study design and methods: Using COPDGene study data, we assessed prospective cardiovascular disease (CVD) and COPD exacerbation risk in participants with COPD (Global Initiative for Chronic Obstructive Lung Disease spirometric grades 2-4), focusing on CACS and PA:A ratio at study enrollment, with logistic regression models. These outcomes were analyzed in three COPD subtypes: 1,042 participants with non-emphysema-predominant COPD (NEPD; low attenuation area at -950 Hounsfield units [LAA-950] < 5%), 1,324 participants with emphysema-predominant COPD (EPD; LAA-950 ≥ 10%), and 465 participants with intermediate emphysema COPD (IE; 5% ≤ LAA-950 < 10%)
  • Results: Our study indicated significantly higher overall risk for cardiovascular events in participants with higher CACS (≥ median; OR, 1.61; 95% CI, 1.30-2.00) and increased COPD exacerbations in those with higher PA:A ratios (≥ 1; OR, 1.80; 95% CI, 1.46-2.23). Notably, participants with NEPD showed a stronger association between these indicators and clinical events compared to EPD (with CACS/CVD, NEPD vs EPD: OR, 2.02 vs 1.41; with PA:A ratio/COPD exacerbation, NEPD vs EPD: OR, 2.50 vs 1.65); the difference in ORs between COPD subtypes was statistically significant for CACS/CVD
  • Interpretation: Two chest CT scan parameters, CACS and PA:A ratio, hold distinct predictive values for cardiovascular events and COPD exacerbations that are influenced by specific COPD subtypes.
• Microbiology: clinical features cannot reliably distinguish bacterial from viral episodes (although presence of sputum neutrophilia more likely suggests a bacterial etiology)
  • Most Common Bacterial Etiologies: non-typable Moraxella, H Flu, and Pneumococci
  • Mycoplasma is rarely isolated
  • Chlamydia pneumoniae is uncommonly isolated (5-10% of outpt cases and 18% of mechanically ventilated cases)
  • Gram-Negative Rod (Pseudomonas, Stenotrophomonas, and PCN-Resistant Pneumococcus) are isolated 30% of the time in patients with the most severe exacerbations (those that require mechanical ventilation)
• Clinical
  • Acute Respiratory Failure (see Respiratory Failure)
  • Elevated Serum Troponin (see Serum Troponin)
• Prognosis
  • Hospitalization for COPD Exacerbation is Associated with a Poor Prognosis and Increased Mortality Rate

Acute Respiratory Failure (see Respiratory Failure)

• Epidemiology
  • COPD exacerbation is the most common cause of acute ventilatory failure in US adults
  • Approximately 33% of COPD exacerbations admitted to an acute care hospital develop acute ventilatory failure: risk is highest in those with FEV1 <50% pred
• Clinical
  • Acute Hypoxemic Respiratory Failure
  • Acute Hypercapnic/Ventilatory Failure
• Treatment
  • xxxx

---

Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)

• Recommendations (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • Vaccination
    • 23-Valent Pneumococcal Vaccination is Recommended, Although There is No Evidence that it Decreases COPD Exacerbation Rate (Grade 2C Recommendation)
    • Annual Influenza Vaccination is Recommended to Decrease the COPD Exacerbation Rate (Grade 1B Recommendation)
  • Smoking Cessation is Recommended to Decrease the COPD Exacerbation Rate (Grade 2C Recommendation) (see Tobacco)
  • Pulmonary Rehabilitation (see Pulmonary Rehabilitation)
    • In Moderate-Very Severe COPD with a Recent Exacerbation (Within 4 wks), Pulmonary Rehabilitation is Recommended to Decrease the COPD Exacerbation Rate (Grade 1C Recommendation)
    • In Moderate-Very Severe COPD with an Exacerbation >4 wks Ago, Pulmonary Rehabilitation is Not Recommended to Decrease the COPD Exacerbation Rate (Grade 2B Recommendation)
  • Education, Case Management, and Action Plan
    • Education Alone is Not Recommended to Decrease the COPD Exacerbation Rate (Ungraded Recommendation)
    • Case Management Alone is Not Recommended to Decrease the COPD Exacerbation Rate (Ungraded Recommendation)
    • In Patients with a History of Prior or Recent Exacerbations, Education and Case Management (with Access to a Healthcare Provider at Least Monthly) is Recommended to Decrease the Severe COPD Exacerbation Rate (as Assessed by the Hospitalization Rate) (Grade 1C Recommendation)
    • In Patients with Moderate-Severe COPD, Education with an Action Plan (But Without Case Management) is Not Recommended to Decrease the Severe COPD Exacerbation Rate (as Assessed by a Decrease in Emergency Department Visits or Hospitalizations Over a 12 mo Period) (Grade 2C Recommendation)
    • Education with a Written Action Plan and Case Management is Recommended for the Prevention of Severe Acute COPD Exacerbations (as Assessed by a Decrease in Emergency Department Visits or Hospitalizations) (Grade 2B)
  • Telemonitoring
    • Telemonitoring (as Compared to Usual Care) is Not Recommended to Decrease the COPD Exacerbation Rate (as Assessed by Decreases in Emergency Room Visits, Exacerbations, or Hospitalizations Over a 12 mo Period (Grade 2C Recommendation)
  • Inhaled Maintenance Therapy
    • In Moderate-Severe COPD, Long-Acting β2-Agonists (as Compared to Placebo) are Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1B (Grade 1B Recommendation)
    • In Moderate-Severe COPD, Long-Acting Muscarinic Antagonists (as Compared to Placebo) are Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1A Recommendation)
    • In Moderate-Severe COPD, Long-Acting Muscarinic Antagonists (as Compared to Long-Acting β2-Agonists) are Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1C Recommendation)
    • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist Monotherapy (as Compared to Short-Acting β2-Agonist Monotherapy) is Recommended to Prevent Mild-Moderate Acute COPD Exacerbations (Grade 2C Recommendation)
    • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist + Short-Acting β2-Agonist Combination Therapy (as Compared to Short-Acting β2-Agonist Monotherapy) is Recommended to Prevent Moderate Acute COPD Exacerbations (Grade 2B Recommendation)
    • In Moderate-Severe COPD, Long-Acting β2-Agonist Monotherapy (as Compared to Short-Acting Muscarinic Antagonist Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 2C Recommendation)
    • In Moderate-Severe COPD, Long-Acting Muscarinic Antagonist Monotherapy (as Compared to Short-Acting Muscarinic Antagonist Monotherapy) is Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1A Recommendation)
    • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Combination Therapy (as Compared to Long-Acting β2-Agonist Monotherapy) is Recommended to Prevent Mild-Moderate Acute COPD Exacerbations (Grade 2C Recommendation)
    • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Placebo) is Recommended to Prevent Acute COPD Exacerbations (Grade 1B Recommendation)
    • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Long-Acting β2-Agonist Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation)
    • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Inhaled Corticosteroid Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 1B Recommendation)
    • In Stable COPD, Long-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Combination Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation): both are equally effective
    • In Stable COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation): both are equally effective
    • In Stable COPD, Inhaled Corticosteroid + Long-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Triple Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 2C Recommendation): both are equally effective
  • Macrolides (Azithromycin, etc) (see Macrolides)
    • In Moderate-Severe COPD with History of ≥1 Moderate-Severe COPD Exacerbations in Prior Year Despite Optimal Maintenance Inhaler Therapy, Long-Term Macrolide is Recommended to Decrease the COPD Exacerbation Rate (Grade 2A Recommendation)
  • Systemic Corticosteroids (see Corticosteroids)
    • For Patients with Acute COPD Exacerbation in Inpatient/Outpatient Setting, Systemic Corticosteroids (Orally or Intravenously) are Recommended to Prevent Hospitalization for Subsequent Acute COPD Exacerbation in the the Next 30 Days Following the Initial Exacerbation (Grade 2B Recommendation)
    • For Patients with Acute COPD Exacerbation in Inpatient/Outpatient Setting, Systemic Corticosteroids (Orally or Intravenously) are Not Recommended For the Sole Purpose of Preventing Hospitalization for Subsequent Acute COPD Exacerbation Beyond the First 30 Days Following the Initial Exacerbation (Grade 1A Recommendation)
  • Roflumilast (Daliresp) (see Roflumilast)
    • In Moderate-Severe COPD with Chronic Bronchitis and a History of ≥1 COPD Exacerbation in the Prior Year, Roflumilast is Recommended to Decrease the COPD Exacerbation Rate (Grade 2A Recommendation)
  • Theophylline (see Theophylline)
    • In Stable COPD, Oral Slow-Release Theophylline BID is Recommended to Decrease the COPD Exacerbation Rate (Grade 2B Recommendation)
  • N-Acetylcysteine (Mucomyst) (see N-Acetylcysteine)
    • In Moderate-Severe COPD and a History of ≥2 COPD Exacerbations in the Prior 2 Years, Oral N-Acetylcysteine is Recommended to Decrease the COPD Exacerbation Rate (Grade 2B Recommendation)
  • Carbocysteine (see Carbocysteine)
    • In Stable Outpatient COPD with Continued Acute COPD Exacerbations Despite Maximal Therapy, Oral Carbocysteine Can Be Used to Decrease the COPD Exacerbation Rate (Ungraded Consensus-Based Statement)
  • Statins (see HMG-CoA Reductase Inhibitors)
    • In Moderate-Severe COPD at Risk for Exacerbation, Statins are Not Recommended to Decrease the COPD Exacerbation Rate (Grade 1B Recommendation)

---

Treatment

General

• Treatment intensity level as a proxy for severity of chronic obstructive pulmonary disease: a risk stratification tool. Respir Med. Published online July 31, 2024. doi:10.1016/j.rmed.2024.107742 [MEDLINE]
  • Background: Increasing severity of chronic obstructive pulmonary disease (COPD) is associated with increasing risk of poor outcomes. Using health registry data, we aimed to assess the association between treatment intensity levels (TIL), as a proxy for underlying COPD severity, and long-term outcomes
  • Methods: Using Danish nationwide registries, we identified patients diagnosed with COPD during 2001-2016, who were alive at index date of 1 January 2017. We stratified patients into exclusive TILs from least to most severe: no use, short term therapy, mono-, dual-, triple therapy, oral corticosteroid (OCS), and long-term oxygen treatment (LTOT). Survival analyses were used to assess 5-year outcomes by TIL
  • Results: We identified 53,803 patients with COPD in the study period (median age: 72 years [inter quartile range, 64-80], 48 % male). The three most severe TILs were associated with a significant incremental increase in all-cause mortality with an adjusted hazard ratio (aHR) for triple therapy, OCS and LTOT of 1.44 (95 % CI: 1.38-1.51), 1.67 (95 % CI: 1.59-1.75), and 2.91 (95 % CI: 2.76-3.07) compared with those receiving no therapy as reference. The same pattern was evident for the composite outcome of 5-year mortality or COPD-related hospitalization with an aHR for triple therapy, OCS and LTOT of 2.30 (95 % CI: 2.22-2.38), 2.85 (95 % CI: 2.74-2.96), and 4.00 (95 % CI: 3.81-4.20), respectively
  • Conclusion: Increasing TILs were associated with increasing five-year mortality and risk of COPD-related hospitalization. TILs may be used as a proxy for underlying COPD severity in epidemiological studies.

Avoidance of Tobacco Exposure (see Tobacco)

• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • Smoking Cessation is Recommended to Decrease the COPD Exacerbation Rate (Grade 2C Recommendation)

Influenza Vaccination (see Influenza Virus)

• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • Annual Influenza Vaccination is Recommended to Decrease the COPD Exacerbation Rate (Grade 1B Recommendation)

Pneumococcal Vaccination (see Streptococcus Pneumoniae)

• Clinical Efficacy
  • Systematic Review of Pneumococcal Vaccination in COPD (Cochrane Database Syst Rev, 2010) [MEDLINE]
    • Polyvalent Pneumococcal Vaccine Had No Impact on Any Outcome in COPD: outcomes studied included risk of pneumonia, COPD exacerbation rate, risk of hospital admission, risk of emergency department visits, all-cause mortality, or death from a cardiorespiratory cause
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • 23-Valent Pneumococcal Vaccination is Recommended, Although There is No Evidence that it Decreases COPD Exacerbation Rate (Grade 2C Recommendation)

Pulmonary Rehabilitation (see Pulmonary Rehabilitation)

• Clinical Efficacy-General
  • Systematic Review of Pulmonary Rehabilitation Following COPD Exacerbation (Cochrane Database Syst Rev, 2011) [MEDLINE]
    • Pulmonary Rehabilitation Following COPD Exacerbation Decreased Hospital Admissions and Mortality Rate
    • Pulmonary Rehabilitation Following COPD Exacerbation Improved Health-Related Quality of Life
    • Pulmonary Rehabilitation Following COPD Exacerbation Improved Exercise Capacity with No Adverse Events Reported
  • Study of Effects of Depression on the Completion of Pulmonary Rehabilitation (Respir Med, 2014) [MEDLINE]
    • Lower Prevalence of Depressed Mood was a Predictor for Completion of Pulmonary Rehabilitation
    • Lower Prevalence of Depressed Mood was a Predictor for Completion of Pulmonary Rehabilitation in Females, But Not in Males
    • Greater 6MWT Distance was also an Independent Predictor for Completion of Pulmonary Rehabilitation in Females
  • Study of Pulmonary Rehabilitation on Dyspnea in COPD (BMJ Open Respir Res, 2022) [MEDLINE]
    • Individualized Home-Based Pulmonary Rehabilitation (8 wks) Improved Both Physical and Affective Components of Dyspnea (at Short-Term and Long-Term)
• Clinical Efficacy-Prevention of Hospitalization for COPD Exacerbation
  • Systematic Review and Meta-Analysis of Pulmonary Rehab in the Prevention of Hospitalization for COPD Exacerbation (Chest, 2016) [MEDLINE]; n = 18 studies
    • Pulmonary Rehab Did Not Decrease the Rate of Hospitalization for COPD Exacerbation: likely due to the heterogeneous nature of patients included in observational studies and the varying standard of pulmonary rehab programs

Cost-effectiveness of pulmonary rehabilitation among US adults with chronic obstructive pulmonary disease. JAMA Netw Open. 2022;5(6):e2218189. doi:10.1001/jamanetworkopen.2022.18189

• Recommendation (Joint ACCP/AACVPR Evidence-Based Pulmonary Rehabilitation Guidelines, 2007) (Chest, 2007) [MEDLINE]
  • A Program of Exercise Training of the Muscles of Ambulation is Recommended as a Mandatory Component of Pulmonary Rehabilitation for COPD (Grade 1A Recommendation)
  • Pulmonary Rehabilitation Improves the Dyspnea in COPD (Grade 1A Recommendation)
  • Pulmonary Rehabilitation Improves Health-Related Quality of Life in COPD (Grade 1A Recommendation)
  • Pulmonary Rehabilitation Decreases the Number of Hospital Days and Other Measures of Health Care Utilization in COPD (Grade 2B Recommendation)
  • Pulmonary Rehabilitation is Cost-Effective in COPD (Grade 2C Recommendation)
  • Insufficient Evidence to Determine Whether Pulmonary Rehabilitation Improves Survival in COPD (No Recommendation)
  • There are Psychosocial Benefits from Comprehensive Pulmonary Rehabilitation Programs in COPD (Grade 2B Recommendation)
  • Six-Twelve Weeks of Pulmonary Rehabilitation Produces Benefits in Several Outcomes Which Decline Gradually Over 12-18 mo (Grade 1A Recommendation)
    • Some Benefits (Such as Health-Related Quality of Life) Remain Above Control Levels at 12-18 mo (Grade 1C Recommendation)
  • Longer Pulmonary Rehabilitation Programs (Beyond 12 wks) Produce Greater Sustained Benefits than Shorter Programs (Grade 2C Recommendation)
  • Maintenance Strategies Following Pulmonary Rehabilitation Have a Modest Effect on Long-Term Outcomes (Grade 2C Recommendation)
  • Lower Extremity Exercise Training at Higher Exercise Intensity Produces Greater Physiologic Benefits than Lower Intensity Training in COPD (Grade 1B Recommendation)
  • Both Low-Intensity and High-Intensity Exercise Training Produce Clinical Benefits for COPD (Grade 1A Recommendation)
  • Addition of a Strength-Training Component to a Program of Pulmonary Rehabilitation Increases Muscle Strength and Muscle Mass (Grade 1A Recommendation)
  • Current Evidence Does Not Support the Routine Use of Anabolic Agents in Pulmonary Rehabilitation for COPD (Grade 2C Recommendation)
  • Unsupported Endurance Training of the Upper Extremities is Beneficial in COPD and Should Be Included in Pulmonary Rehabilitation Programs (Grade 1A Recommendation)
  • Current Evidence Does Not Support the Routine Use of Inspiratory Muscle Training as an Essential Component of Pulmonary Rehabilitation (Grade 1B Recommendation)
  • Education (Information on Collaborative Self-Management and the Prevention/Treatment of Exacerbations) Should Be an Integral Component of Pulmonary Rehabilitation (Grade 1B Recommendation)
  • Minimal Evidence to Support the Benefits of Psychosocial Interventions as a Single Therapeutic Modality (Grade 2C Recommendation)
    • Although No Recommendation is Provided, Since Evidence is Lacking, Current Practice and Expert Opinion Support the Inclusion of Psychosocial Interventions as a Component of Comprehensive Pulmonary Rehabilitation Programs for COPD
  • Supplemental Oxygen Should Be Used During Rehabilitative Exercise Training in Patients with Severe Exercise-Induced Hypoxemia (Grade 1C Recommendation)
  • Supplemental Oxygen During High-Intensity Exercise Programs in Patients without Exercise-Induced Hypoxemia May Improve Gains in Exercise Endurance (Grade 2C Recommendation)
  • As an Adjunct to Exercise Training in Selected Patients with Severe COPD, Noninvasive Ventilation Produces Modest Additional Improvements in Exercise Performance (Grade 2B Recommendation)
  • Insufficient Evidence to Support the Routine Use of Nutritional Supplementation in the Pulmonary Rehabilitation in COPD (No Recommendation)
  • Pulmonary Rehabilitation is Beneficial for Patients with Some Chronic Respiratory Diseases Other than COPD (Grade 1B Recommendation)
    
    • Although No Recommendation is Provided Since Evidence is Lacking, the Current Practice and Expert Opinion Suggest that Pulmonary Rehabilitation for Patients with Chronic Respiratory Diseases Other than COPD Should Be Modified to Include Treatment Strategies Specific to Individual Diseases and Patients, in Addition to Treatment Strategies Common to Both COPD and Non-COPD Patients
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Moderate-Very Severe COPD with a Recent Exacerbation (Within 4 wks), Pulmonary Rehabilitation is Recommended to Decrease the COPD Exacerbation Rate (Grade 1C Recommendation)
  • In Moderate-Very Severe COPD with an Exacerbation >4 wks Ago, Pulmonary Rehabilitation is Not Recommended to Decrease the COPD Exacerbation Rate (Grade 2B Recommendation)

Telehealthcare/Telemonitoring

• Clinical Efficacy
  • Systematic Review of Telehealthcare in COPD (Cochrane Database Syst Rev, 2011) [MEDLINE]
    • Telehealthcare in COPD Had a Possible Impact on the Quality of Life and the Number Emergency Department/Hospital Visits: however, further study is required
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • Telemonitoring (as Compared to Usual Care) is Not Recommended to Decrease the COPD Exacerbation Rate (as Assessed by Decreases in Emergency Room Visits, Exacerbations, or Hospitalizations Over a 12 mo Period (Grade 2C Recommendation)

High Altitude (see High Altitude)

• XXXXX
• The effect of chronic altitude exposure on COPD outcomes in the SPIROMICS cohort. Am J Respir Crit Care Med. Published online March 20, 2024. doi:10.1164/rccm.202310-1965OC [MEDLINE]
  • Rationale: Individuals with COPD have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen
  • Objectives: Does residence at higher-altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, or mortality?
  • Methods: From the SPIROMICS cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n= 1,367) versus above 4,000 ft (1,219 m) elevation (n= 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes
  • Measurements and main results: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6MWD (-32.3 m, (-55.7 to -28.6)). There were no differences in patient-reported outcomes as defined by symptoms (CAT, mMRC), or health status (SGRQ). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (IRR 0.65, (0.46 to 0.90)). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (HR 1.25, (1.0 to 1.55)); however, this association was no longer significant when accounting for air pollution
  • Conclusions
    • Chronic altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status
    • Additionally, chronic high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry
• High altitudes and partial pressure of arterial oxygen in patients with chronic obstructive pulmonary disease – A systematic review and meta-analysis. Pulmonology. 2024 Jul 18:S2531-0437(24)00095-3. doi: 10.1016/j.pulmoe.2024.06.002 [MEDLINE]
  • Importance: Prior study in healthy subjects has shown a reduction of partial pressure of arterial oxygen (PaO2) by -1.60 kPa/kilometre of altitude gain. However, the association of altitude-related change in PaO2 and altitude-related adverse health effects (ARAHE) in patients with chronic obstructive pulmonary disease (COPD) remain unknown
  • Objective: To provide an effect size estimate for the decline in PaO2 with each kilometre of altitude gain and to identify ARAHE in relation to altitude in patients with COPD. www.crd.york.ac.uk/prospero: CRD42020217938
  • Data sources: A systematic search of PubMed and Embase was performed from inception to May 30, 2023
  • Study selection: Peer-reviewed and prospective studies in patients with COPD staying at altitudes >1500 m providing arterial blood gases within the first 3 days at the target altitude
  • Data extraction and synthesis: Aggregate data (AD) on study characteristics were extracted, and individual patient data (IPD) were requested. Estimates were pooled using random-effects meta-analysis
  • Main outcome and measures: Relative risk estimates and 95 % confidence intervals for the association between PaO2 and altitude in patients with COPD
  • Results: Thirteen studies were included in the AD analysis, of which 6 studies (222 patients, 45.2 % female) provided IPD, thus were included in the quantitative analysis. The estimated effect size of PaO2 was -0.84 kPa [95 %CI, -0.92 to -0.76] per 1000 m of altitude gain (I2=65.0 %, P < 0.001). In multivariable regression analysis, COPD severity, baseline PaO2, age and time spent at altitude were predictors for PaO2 at altitude. Overall, 37.8 % of COPD patients experienced an ARAHE, whereas older age, female sex, COPD severity, baseline PaO2, and target altitude were predictors for the occurrence of ARAHE (area under ROC curve: 0.9275, P < 0.001)
  • Conclusions and relevance: This meta-analysis, providing altitude-related decrease in PaO2 and risk of ARAHE in patients with COPD ascending to altitudes >1500 m, revealed a lower altitude-related decrease in PaO2 in COPD patients compared with healthy. However, these findings might improve patient care and facilitate decisions about initiating preventive measures against hypoxaemia and ARAHE in patients with COPD planning an altitude sojourn or intercontinental flight, i.e. supplemental oxygen or acetazolamide.

Oxygen (see Oxygen)

Epidemiology

• Long-Term Oxygen Therapy is Used in 1 Million Patients Per Year in the US Via Medicare and Accounts for a Cost of >$2 Billion Per Year (Am J Respir Crit Care Med, 2006) [MEDLINE]: cost appears to be increasing at 13% per year
• Indications: pO2 <55 or pO2 <59 + cor pulmonale or polycythemia
• Physiology: flow is highest during the early part of inspiration (this is when most of the oxygen is delivered to the alveoli)
• Daytime O2: prevents polycythemia/variably decreases PA pressure acutely but, long-term prevents increases in PA pressure/improves survival (when used for at >18 hrs per day, per data from NOTT Trial)/increases exercise endurance/decreases dyspnea
• Nocturnal O2: blunts increases in PA pressures that occur with nocturnal desaturations/inhibits development of polycythemia/prolongs survival
  • Nocturnal use alone does not significantly prevent the development of pulmonary hypertension
• Prognostic Factors in COPD Patients on Chronic O2 (Chailleux; Chest, 1996):
  • Good Prognosis: stable pCO2 >55 (but rising pCO2 portends poor prognosis, represents progressing cor pulmonale)
  • Poor Prognosis: older age/male gender/lower BMI/lower pO2/lower FEV1 (as %pred)
• NOTT Trial: data suggested that 45% of those discharged with oxygen (for pO2 <55) no longer required oxygen when assessed later (1 month) after discharge, therefore reevaluation is necessary
• Transtracheal O2 Delivery: results in decreased oxygen requirements (due to more efficient delivery), decreased work of breathing (possibly due to wash out of anatomic dead space with less CO2 reinspired and possiblt less demanding pattern of breathing), decreased sleep apneas/hypopneas (possibly due to oxygen delivery even during obstructive events or increased mean airway pressure), and decreased dyspnea (unclear if it affects the rate of COPD exacerbations)
• Impact of Oxygen Therapy in COPD with Chronic Hypercapnia: excessive oxygen therapy in the setting of chronic hypercapnia may result in worsened CO2 retention and respiratory failure
  • Excess oxygen may blunt the hypoxic ventilatory drive and/or increase physiologic dead space (due to oxygen-induced bronchodilation in poorly-perfused areas of the lung)

Clinical Efficacy

• Multicenter Nocturnal Oxygen Therapy Trial (NOTT) in Chronic Obstructive Pulmonary Disease Patients with Hypoxemia (Ann Intern Med, 1980) [MEDLINE]: n = 203 followed for ≥12 mos (mean: 19.3 mos)
  • In Hypoxemic Chronic Obstructive Pulmonary Disease, Continuous Oxygen Therapy (Used at Least 18 hrs Per Day) Had Lower Mortality than Nocturnal Oxygen Therapy: nocturnal oxygen therapy group had 1.94x higher mortality than the continuous oxygen therapy group
    • Benefit was Most Significant in Patients with Chronic Hypercapnia
  • NOTT and MRC Trials Only Included Patients with More Severe Hypoxemia (pO2 ≤60 mm Hg), as Opposed to Other Trials Which Did Not Demonstrate a Benefit of Long-Term Oxygen Therapy, Which Also Included Less Severely Hypoxemic Patients (pO2 <69 mm Hg) (Am J Respir Crit Care Med, 2006) [MEDLINE]: indicates that COPD patients with less severe hypoxemia may not benefit from long-term oxygen therapy
• Medical Research Council (MRC) Trial of Oxygen Therapy in Chronic Obstructive Pulmonary Disease Patients with Severe Hypoxemia, Hypercapnia, and a History of Heart Failure (Lancet, 1981) [MEDLINE]: n = 87
  • Oxygen Therapy (Used at Least 15 hrs Per Day) Improved the Mortality Rate
  • NOTT and MRC Trials Only Included Patients with More Severe Hypoxemia (pO2 ≤60 mm Hg), as Opposed to Other Trials Which Did Not Demonstrate a Benefit of Long-Term Oxygen Therapy, Which Also Included Less Severely Hypoxemic Patients (pO2 <69 mm Hg) (Am J Respir Crit Care Med, 2006) [MEDLINE]: indicates that COPD patients with less severe hypoxemia may not benefit from long-term oxygen therapy
• Home oxygen for moderate hypoxaemia in chronic obstructive pulmonary disease: a systematic review and meta-analysis. Lancet Respir Med. 2022 Jul 8;S2213-2600(22)00179-5. doi: 10.1016/S2213-2600(22)00179-5 [MEDLINE]
  • Background: Long-term oxygen therapy (LTOT) improves survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxaemia. However, the best method of management of moderate hypoxaemia not qualifying for LTOT (including isolated nocturnal desaturation) is uncertain. We examined the effect of home oxygen (either LTOT or nocturnal oxygen therapy) on overall survival in patients with COPD and moderate hypoxaemia
  • Methods: In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, CINHAL, and Web of Science from database inception to Jan 13, 2022, for parallel-group randomised trials of long-term or nocturnal oxygen in patients with COPD and moderate daytime hypoxaemia or isolated nocturnal desaturation, or both. Control groups received usual care or ambient air through sham concentrators (placebo) throughout the study period. The primary outcome of interest was 3-year mortality. Crossover trials and trials of oxygen in severe hypoxaemia were excluded. Two reviewers applied inclusion and exclusion criteria to titles and abstracts and screened the full-text articles and reference lists of relevant studies. Aggregate data were extracted manually in duplicate using structured data collection forms. Methodological quality was assessed using the Cochrane Risk of Bias tool. Random-effects meta-analysis was used to pool individual studies. We considered the minimal clinically important difference for home oxygen to be a relative risk reduction in mortality at 3-year follow-up of 30-40%. The meta-analysis is registered on PROSPERO, CRD42021225372
  • Findings: We identified 2192 studies and screened 1447 after removal of duplicates, of which 161 were subjected to full-text screening, and six were identified as being eligible for inclusion. These six randomised trials were published between 1992 and 2020 and the quality of evidence was high. In the primary meta-analysis (five trials; 1002 patients), we found the effect of home oxygen in reducing 3-year mortality to be small or absent (relative risk 0·91 [95% CI 0·72-1·16]; τ2 = 0·00), hence the lower limit of the 95% CI did not meet the prespecified minimal clinically important difference
  • Interpretation: The results of our meta-analysis suggest that home oxygen probably makes little or no difference to 3-year mortality in patients with COPD and moderate hypoxaemia. The data do not support the widespread use of home oxygen in this patient population.
• Breathlessness and exercise performance to predict mortality in long-term oxygen therapy – The population-based DISCOVERY study. Respir Med. 2023 Jun 5;216:107306. doi: 10.1016/j.rmed.2023.107306 [MEDLINE]
  • Background: Patients with chronic respiratory failure treated with long-term oxygen therapy (LTOT) often have severe breathlessness, impaired exercise performance, and high but variable mortality that is difficult to predict. We aimed to evaluate breathlessness and exercise performance upon starting LTOT as predictors of overall and short-term mortality
  • Methods: This was a longitudinal, population-based study of patients who initiated LTOT between 2015 and 2018 in Sweden. Breathlessness was measured using the Dyspnea Exertion Scale, and exercise performance using the 30s-Sit-To-Stand test. Associations with overall and three-month mortality were analyzed using Cox-regression. Subgroup analyses were performed for patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) respectively. The predictive capacity of models was assessed using a C-statistic
  • Results: A total of 441 patients (57.6% female, aged 75.4 ± 8.3 years) were analyzed, of whom 141 (32%) died during a median follow-up of 260 (IQR 75-460) days. Both breathlessness and exercise performance were independently associated with overall mortality in the crude models, but only exercise performance remained independently associated with overall mortality when models were adjusted for other predictors, when short-term mortality was analyzed, or when breathlessness and exercise capacity were analyzed concurrently. The multivariable model including exercise performance but not breathlessness provided a relatively high predictive capacity for overall mortality, C-statistic 0.756 (95% CI 0.702-0.810). Similar results were seen in the COPD and ILD subgroups
  • Conclusion: Exercise performance as measured by the 30s-STS may be useful to identify patients with higher mortality on LTOT for optimized management and follow-up.

Recommendations (Canadian Thoracic Society Guidelines for the Management of Dyspnea in COPD) (Can Respir J, 2011) [MEDLINE]

• Continuous Oxygen Therapy for Hypoxemic Patients Decreases the Mortality Rate and May Decrease Dyspnea in Advanced COPD (Grade 2B Recommendation) (see Oxygen)
  • No Evidence to Support the Routine Use of Supplemental Oxygen to Decrease Dyspnea in Normoxemic Patients with Advanced COPD
  • There is Little Benefit from Supplemental Oxygen on Quality of Life in Patients with Advanced COPD

Medication Compliance

• Adherence and persistence to once-daily single-inhaler versus multiple-inhaler triple therapy among patients with chronic obstructive pulmonary disease in the USA: a real-world study. Respiratory Medicine. Published online March 18, 2022. doi:10.1016/j.rmed.2022.106807 [MEDLINE]
  • Background: Triple therapy comprising an inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2 agonist (ICS/LAMA/LABA) is recommended for chronic obstructive pulmonary disease (COPD) patients at risk of exacerbation. Multiple-inhaler triple therapy (MITT) is associated with poor adherence and persistence; however, these outcomes have not been evaluated for single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI)
  • Methods: This retrospective analysis of the IQVIA PharMetrics Plus claims database identified patients with COPD initiating triple therapy between 18 September 2017 and 30 June 2019. The first date of single-inhaler FF/UMEC/VI dispensing, or first day of overlapping ICS, LAMA, and LABA medications for MITT users, defined the index date. Patients were ≥40 years, had ≥12 months of continuous insurance coverage pre-index (baseline) and ≥6 months’ coverage post-index; those with MITT during baseline were excluded. Inverse probability weighting was used to balance baseline characteristics. Adherence was assessed using proportion of days covered (PDC) and was evaluated using linear and log-binomial models. Persistence (non-persistence identified as >30-day gap between fills) was evaluated using Cox models
  • Results: 9942 patients (FF/UMEC/VI: 2782; MITT: 7160) were included. Adherence was significantly higher for FF/UMEC/VI versus MITT users (mean PDC, 0.66 vs. 0.48; p < 0.001), and FF/UMEC/VI users were twice as likely to be adherent (PDC ≥0.8) than MITT users (46.5% vs. 22.3%; risk ratio [95% CI]: 2.08 [1.85-2.30]; p < 0.001). After 12 months, significantly more FF/UMEC/VI users persisted on therapy than MITT users (35.7% vs. 13.9%; hazard ratio [95% CI]: 1.91 [1.81-2.01]; p < 0.001)
  • Conclusions: COPD patients initiating single-inhaler FF/UMEC/VI had significantly improved adherence and persistence compared with MITT.

Dual Therapy vs Triple Therapy

• xxxx
• Clinical and economic outcomes in patients with chronic obstructive pulmonary disease initiating maintenance therapy with tiotropium bromide/olodaterol or fluticasone furoate/umeclidinium/vilanterol. J Manag Care Spec Pharm. 2023 May 3;1-16. doi: 10.18553/jmcp.2023.22373 [MEDLINE]
  • BACKGROUND
    • Clinical practice guidelines recommend dual long-acting muscarinic antagonists (LAMAs)/long-acting β2agonists (LABAs) as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD) and dyspnea or exercise intolerance
    • Escalation to triple therapy (TT) (LAMA/LABA/inhaled corticosteroid) is conditionally recommended for patients with continued exacerbations on dual LAMA/ LABA therapy. Despite this guidance, TT use is widespread across COPD severities, which could impact clinical and economic outcomes
  • OBJECTIVE
    • To compare COPD exacerbations, pneumonia events, and disease-related and all-cause health care resource utilization and costs (in 2020 US dollars) in patients initiating fixed-dose combinations of either LAMA/ LABA (tiotropium/olodaterol [TIO + OLO]) or TT (fluticasone furoate/umeclidinium/vilanterol [FF + UMEC + VI])
  • METHODS
    • This retrospective observational study of administrative claims included patients with COPD aged 40 years or older initiating TIO + OLO or FF + UMEC + VI from June 2015 to November 2019. TIO + OLO and FF + UMEC + VI cohorts in the overall and maintenance-naive populations were 1:1 propensity score matched on baseline demographics, comorbidities, COPD medications, health care resource utilization, and costs
    • Multivariable regression compared clinical and economic outcomes up to 12 months in FF + UMEC + VI vs TIO + OLO postmatched cohorts
  • RESULTS
    • After matching, there were 5,658 and 3,025 pairs in the overall and maintenance-naive populations, respectively. In the overall population, the risk of any (moderate or severe) exacerbation was 7% lower in FF + UMEC + VI vs TIO + OLO initiators (adjusted hazard ratio [aHR] = 0.93; 95% CI = 0.86-1.0; P = 0.047)
    • There was no difference in the adjusted risk of any exacerbation in the maintenance-naive population (aHR = 0.99; 95% CI = 0.88-1.10). Pneumonia risk was not statistically different between cohorts in the overall (aHR = 1.12; 95% CI = 0.98-1.27) and maintenance-naive (aHR = 1.13; 95% CI = 0.95-1.36) populations
    • COPD- and/or pneumonia-related adjusted total annualized costs (95% CI) were significantly greater for FF + UMEC + VI vs TIO + OLO in the overall ($17,633 [16,661-18,604] vs $14,558 [13,709-15,407]; P < 0.001; differences [% of relative increase] = $3,075 [21.1%]) and maintenancenaive ($19,032 [17,466-20,598] vs $15,004 [13,786-16,223]; P < 0.001; $4,028 [26.8%]) populations, with significantly higher pharmacy costs with FF + UMEC + VI (overall: $6,567 [6,503-6,632] vs $4,729 [4,676-4,783]; P < 0.001; $1,838 [38.9%]; maintenance-naive: $6,642 [6,560-6,724] vs $4,750 [4,676-4,825]; P < 0.001; $1,892 [39.8%])
  • CONCLUSIONS
    • A lower risk of exacerbation was observed with FF + UMEC + VI vs TIO + OLO in the overall population but not among the maintenance-naive population
    • Patients with COPD initiating TIO + OLO had lower annualized costs than FF + UMEC + VI initiators in the overall and maintenance-naive populations
    • Thus, in the maintenance-naive population, initiation with dual LAMA/LABA therapy per practice guidelines can improve real-world economic outcomes

Short-Acting β2-Adrenergic Receptor Agonists (SABA) (see β2-Adrenergic Receptor Agonists)

• Agents
  • Albuterol (Salbutamol, Ventolin) (see Albuterol)
  • Levalbuterol (Xopenex) (see Levalbuterol)
  • Pirbuterol (Maxair) (see Pirbuterol)
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist Monotherapy (as Compared to Short-Acting β2-Agonist Monotherapy) is Recommended to Prevent Mild-Moderate Acute COPD Exacerbations (Grade 2C Recommendation)
  • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist + Short-Acting β2-Agonist Combination Therapy (as Compared to Short-Acting β2-Agonist Monotherapy) is Recommended to Prevent Moderate Acute COPD Exacerbations (Grade 2B Recommendation)

Long-Acting ß2-Adrenergic Agonists (LABA) (see β2-Adrenergic Receptor Agonists)

• Long-Acting ß2-Adrenergic Agonists (LABA) Agents
  • Arformoterol (Brovana, Erdotin) (see Arformoterol)
  • Bambuterol (Bambec, Oxeol) (see Bambuterol)
  • Clenbuterol (Spiropent, Ventipulmin, Dilaterol, Spiropent) (see Clenbuterol)
  • Formoterol (Foradil, Oxeze, Oxis, Atock, Atimos, Perforomist) (see Formoterol)
    • Formoterol + Budesonide (Symbicort) (see Formoterol + Budesonide)
  • Olodaterol (Striverdi Respimat) (see Olodaterol)
    • Olodaterol + Tiotropium (Stiolto Respimat) (see Olodaterol-Tiotropium)
  • Salmeterol (Serevent) (see Salmeterol)
    • Salmeterol + Fluticasone (Advair) (see Salmeterol + Fluticasone)
• Ultra Long-Acting ß2-Adrenergic Agonists (Ultra LABA) Agents
  • Indacaterol (Arcapta) (see Indacaterol)
  • Olodaterol (Striverdi Respimat) (see Olodaterol)
    • Olodaterol + Tiotropium (Stiolto Respimat) (see Olodaterol-Tiotropium)
  • Vilanterol(see Vilanterol)
    • Vilanterol + Fluticasone (Breo Ellipta) (see Vilanterol + Fluticasone)
    • Vilanterol + Umeclidinium (Anoro Ellipta) (see Vilanterol + Umeclidinium)
• Clinical Efficacy
  • OPTIMO Trial (Respir Res, 2014) [MEDLINE]
    • Withdrawal of Inhaled Corticosteroids in COPD Patients at Low Risk for Exacerbation is Safe, Provided that Patients are Left on Maintenance LABA Therapy
  • Systematic Review of LABA Monotherapy vs LAMA Monotherapy vs LABA + LAMA Combination Therapy in COPD (Cochrane Database Syst Rev, 2015) [MEDLINE]
    • Combination LABA + LAMA Therapy Resulted in a Small Improvement in Health-Related Quality of Life in COPD, as Compared to LABA Monotherapy or LAMA Monotherapy
    • Adding Tiotropium to LABA Decreased the COPD Exacerbation Rate
    • Interestingly, Adding LABA to Tiotropium Did Not Decrease the COPD Exacerbation Rate
    • Adding LABA to Tiotropium Did Not Decrease the Hospital Admission or Mortality Rate: although there may be insufficient data
  • xxxx
• Comparative Effectiveness and Safety of Generic Versus Brand-Name Fluticasone-Salmeterol to Treat Chronic Obstructive Pulmonary Disease. Ann Intern Med. 2023 Aug;176(8):1047-1056. doi: 10.7326/M23-0615 [MEDLINE]
  • Background: In 2019, the U.S. Food and Drug Administration (FDA) approved the first generic maintenance inhaler for asthma and chronic obstructive pulmonary disease (COPD). The inhaler, Wixela Inhub (fluticasone-salmeterol; Viatris), is a substitutable version of the dry powder inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline). When approving complex generic products like inhalers, the FDA applies a special “weight-of-evidence” approach. In this case, manufacturers were required to perform a randomized controlled trial in patients with asthma but not COPD, although the product received approval for both indications
  • Objective: To compare the effectiveness and safety of generic (Wixela Inhub) and brand-name (Advair Diskus) fluticasone-salmeterol among patients with COPD treated in routine care
  • Design: A 1:1 propensity score-matched cohort study
  • Setting: A large, longitudinal health care database
  • Patients: Adults older than 40 years with a diagnosis of COPD
  • Measurements: Incidence of first moderate or severe COPD exacerbation (effectiveness outcome) and incidence of first pneumonia hospitalization (safety outcome) in the 365 days after cohort entry
  • Results: Among 45 369 patients (27 305 Advair Diskus users and 18 064 Wixela Inhub users), 10 012 matched pairs were identified for the primary analysis. Compared with Advair Diskus use, Wixela Inhub use was associated with a nearly identical incidence of first moderate or severe COPD exacerbation (hazard ratio [HR], 0.97 [95% CI, 0.90 to 1.04]) and first pneumonia hospitalization (HR, 0.99 [CI, 0.86 to 1.15])
  • Limitations: Follow-up times were short, reflecting real-world clinical practice. The possibility of residual confounding cannot be completely excluded
  • Conclusion: Use of generic and brand-name fluticasone-salmeterol was associated with similar outcomes among patients with COPD treated in routine practice.
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Moderate-Severe COPD, Long-Acting β2-Agonists (as Compared to Placebo) are Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1B (Grade 1B Recommendation)
  • In Moderate-Severe COPD, Long-Acting Muscarinic Antagonists (as Compared to Long-Acting β2-Agonists) are Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1C Recommendation)
  • In Moderate-Severe COPD, Long-Acting β2-Agonist Monotherapy (as Compared to Short-Acting Muscarinic Antagonist Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 2C Recommendation)
  • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Combination Therapy (as Compared to Long-Acting β2-Agonist Monotherapy) is Recommended to Prevent Mild-Moderate Acute COPD Exacerbations (Grade 2C Recommendation)
  • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Placebo) is Recommended to Prevent Acute COPD Exacerbations (Grade 1B Recommendation)
  • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Long-Acting β2-Agonist Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation)
  • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Inhaled Corticosteroid Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 1B Recommendation)
  • In Stable COPD, Long-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Combination Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation): both are equally effective
  • In Stable COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation): both are equally effective
  • In Stable COPD, Inhaled Corticosteroid + Long-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Triple Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 2C Recommendation): both are equally effective

Anticholinergic (Muscarinic Antagonist) Agents (see Muscarinic Antagonists)

• Short-Acting Muscarinic Antagonists
  • Ipratropium Bromide (Atrovent) (see Ipratropium Bromide)
• Long-Acting Muscarinic Antagonists
  • Aclidinium (Tudorza Pressair) (see Aclidinium)
  • Glycopyrronium Bromide (see Glycopyrronium Bromide)
  • Tiotropium (Spiriva) (see Tiotropium) [MEDLINE]: antagonist at airway M2 and M3 muscarinic receptors
  • Umeclidinium (Incruse) (see Umeclidinium)
    • Vilanterol + Umeclidinium (Anoro Ellipta) (see Vilanterol-Umeclidinium)
• Clinical Efficacy
  • Systematic Review of LABA Monotherapy vs LAMA Monotherapy vs LABA + LAMA Combination Therapy in COPD (Cochrane Database Syst Rev, 2015) [MEDLINE]
    • Combination LABA + LAMA Therapy Resulted in a Small Improvement in Health-Related Quality of Life in COPD, as Compared to LABA Monotherapy or LAMA Monotherapy
    • Adding Tiotropium to LABA Decreased the COPD Exacerbation Rate
    • Interestingly, Adding LABA to Tiotropium Did Not Decrease the COPD Exacerbation Rate
    • Adding LABA to Tiotropium Did Not Decrease the Hospital Admission or Mortality Rate: although there may be insufficient data
  • xxx
  • Randomized ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol vs Glycopyrrolate/Formoterol or Budesonide/Formoterol (NEJM, 2020) [MEDLINE]
    • Triple Therapy with Twice Daily Budesonide (at Either the 160 μg or 320 μg dose), Glycopyrrolate, and Formoterol Resulted in a Lower Rate of Moderate or Severe COPD Exacerbations than Glycopyrrolate/Formoterol or Budesonide/Formoterol
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Moderate-Severe COPD, Long-Acting Muscarinic Antagonists (as Compared to Placebo) are Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1A Recommendation)
  • In Moderate-Severe COPD, Long-Acting Muscarinic Antagonists (as Compared to Long-Acting β2-Agonists) are Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1C Recommendation)
  • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist Monotherapy (as Compared to Short-Acting β2-Agonist Monotherapy) is Recommended to Prevent Mild-Moderate Acute COPD Exacerbations (Grade 2C Recommendation)
  • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist + Short-Acting β2-Agonist Combination Therapy (as Compared to Short-Acting β2-Agonist Monotherapy) is Recommended to Prevent Moderate Acute COPD Exacerbations (Grade 2B Recommendation)
  • In Moderate-Severe COPD, Long-Acting β2-Agonist Monotherapy (as Compared to Short-Acting Muscarinic Antagonist Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 2C Recommendation)
  • In Moderate-Severe COPD, Long-Acting Muscarinic Antagonist Monotherapy (as Compared to Short-Acting Muscarinic Antagonist Monotherapy) is Recommended to Prevent Moderate-Severe Acute COPD Exacerbations (Grade 1A Recommendation)
  • In Moderate-Severe COPD, Short-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Combination Therapy (as Compared to Long-Acting β2-Agonist Monotherapy) is Recommended to Prevent Mild-Moderate Acute COPD Exacerbations (Grade 2C Recommendation)
  • In Stable COPD, Long-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Combination Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation): both are equally effective
  • In Stable COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation): both are equally effective
  • In Stable COPD, Inhaled Corticosteroid + Long-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Triple Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 2C Recommendation): both are equally effective

HMG-CoA Reductase Inhibitors (Statins) (see HMG-CoA Reductase Inhibitors)

• Clinical Efficacy
  • Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) Trial (NEJM, 2014) [MEDLINE]: randomized, controlled trial of simvastatin (40 mg daily) versus placebo -> primary outcome: annual exacerbation rate
    • Simvastatin Had No Effect on the COPD Exacerbation Rate, Time to First Exacerbation, or Cardiac Events
  • Danish Study of Impact of Statins on the COPD Exacerbation Rate (Thorax, 2015) [MEDLINE]: Copenhagen General Population Study (2003-2008)
    • Statins Decreased the COPD Exacerbation Rate in General Population, Although This was Not Demonstrated in the Most Severe COPD Patients without Cardiovascular Comorbidity: suggesting that statins may decrease the risk of exacerbations only in patients with coexisting cardiovascular disease
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Moderate-Severe COPD at Risk for Exacerbation, Statins are Not Recommended to Decrease the COPD Exacerbation Rate (Grade 1B Recommendation)

Inhaled Corticosteroids (see Corticosteroids)

• Clinical Efficacy-Exacerbation Rate in COPD
  • ISOLDE Trial in Moderate-Severe COPD (Br Med J, 2000) [MEDLINE]
    • Fluticasone Decreased the COPD Exacerbation rate, Increased FEV1 Slightly, and Resulted in a Slower Decline in Health Status
  • Torch Trial Data. Trial of Salmeterol and Fluticasone in COPD (NEJM, 2007) [MEDLINE]
    • Salmeterol and Fluticasone Did Not Impact the Mortality Rate, But Decreased the COPD Exacerbation Tate
    • Salmeterol and Fluticasone Increased the Pneumonia Rate in COPD
  • Systematic Review of Combination Corticosteroid + LABA Inhaler in COPD (2013) [MEDLINE]
    • Combination Corticosteroid + LABA Inhaler Decreased the Exacerbation Rate and Decreased All-Cause Mortality (Although Latter Finding was Due Primarily to the TORCH Trial)
    • Combination Corticosteroid + LABA Inhaler Increased the Pneumonia Rate (But Without an Increase in Exacerbations, Hospitalizations, or Deaths)
    • Inadequate data to determine superiority of one combination over another
  • Randomized ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol vs Glycopyrrolate/Formoterol or Budesonide/Formoterol (NEJM, 2020) [MEDLINE]
    • Triple Therapy with Twice Daily Budesonide (at Either the 160 μg or 320 μg dose), Glycopyrrolate, and Formoterol Resulted in a Lower Rate of Moderate or Severe COPD Exacerbations than Glycopyrrolate/Formoterol or Budesonide/Formoterol
• Clinical Efficacy-Mortality Rate Large Meta-Analysis of Inhaled Corticosteroid Maintenance Therapy in COPD (Chest, 2022) [MEDLINE]: n = 103,034 (from 60 randomized controlled trials) Inhaled therapy containing ICSs (Peto OR, 0.90; 95% CI, 0.84-0.97), especially triple therapy (Peto OR, 0.73; 95% CI, 0.59-0.91), was associated with a reduction in the cause-death risk among COPD patients when compared to inhaled therapy without ICSs. Subgroup analyses revealed that treatment duration ＞6 mos (Peto OR, 0.90; 95% CI, 0.83-0.97), medium-dose (Peto OR, 0.71; 95% CI, 0.56-0.91)/low-dose ICSs (Peto OR, 0.88; 95% CI, 0.79-0.97), and budesonide (Peto OR, 0.75; 95% CI, 0.59-0.94) were involved in this association Predictors of This Association Eosinophil Count ≥200/μL or Eosinophil Percentage ≥2%: eosinophil counts ≥200/μL (Peto OR, 0.58; 95% CI, 0.36-0.95) was the strongest predictor Documented History of ≥2 Moderate-Severe Exacerbations in the Previous Year GOLD Stage III-IV Age ＜65 y/o BMI ≥25
• Inhaled Corticosteroids Versus Placebo for Stable Chronic Obstructive Pulmonary Disease: A Review. Clin Exp Allergy. 2024 Jun 12. doi: 10.1111/cea.14521 [MEDLINE]
  • Cochrane systematic review included 36 placebo-controlled trials, involving 23,139 participants and aimed to evaluate the ben- efits and harms of using ICS as monotherapy when compared to placebo in people with stable COPD
  • This systematic review updates the evidence base for ICS monotherapy with newly published trials to aid the ongoing assessment of their role for people with COPD
  • Use of ICS alone for COPD likely results in a reduction in exacerbation rates of clinical relevance, probably results in a reduction in the rate of decline of FEV1 of uncertain clinical relevance and likely results in a small improvement in health-related quality of life not meeting the threshold for a minimally clinically import- ant difference
  • These potential benefits should be weighed up against adverse events (likely to increase local oropharyngeal adverse effects and may increase the risk of pneumonia) and probably no reduction in mortality
  • Though not recommended as monotherapy, the probable benefits of ICS highlighted in this review support their continued consideration in combination with long-acting bronchodilators
  • Future research and evidence syntheses should be focused in that area.
• Clinical Efficacy-Risk of Pneumonia in Chronic Obstructive Pulmonary Disease (COPD)
  • TORCH Study (Eur Respir J, 2009) [MEDLINE]
    • Inhaled Corticosteroids Increased the Risk of Pneumonia in COPD
  • XXXX
• Inhaled Corticosteroids in Patients with Chronic Obstructive Pulmonary Disease and Risk of Acquiring Streptococcus pneumoniae Infection. A Multiregional Epidemiological Study. Int J Chron Obstruct Pulmon Dis. 2023 Mar 21;18:373-384. doi: 10.2147/COPD.S386518. eCollection 2023 [MEDLINE]
  • Background: Inhaled corticosteroids (ICS) are associated with an increased risk of clinical pneumonia among patients with chronic obstructive pulmonary disease (COPD). It is unknown whether the risk of microbiologically verified pneumonia such as pneumococcal pneumonia is increased in ICS users.
  • Methods: The study population consists of all COPD patients followed in outpatient clinics in eastern Denmark during 2010-2017. ICS use was categorized into four categories based on accumulated use. A Cox proportional hazard regression model was used adjusting for age, body mass index, sex, airflow limitation, use of oral corticosteroids, smoking, and year of cohort entry. A propensity score matched analysis was performed for sensitivity analyses.
  • Findings: A total of 21,438 patients were included. Five hundred and eighty-two (2.6%) patients acquired a positive lower airway tract sample with S. pneumoniae during follow-up. In the multivariable analysis ICS-use was associated with a dose-dependent risk of S. pneumoniae as follows: low ICS dose: HR 1.11, 95% CI 0.84 to 1.45, p = 0.5; moderate ICS dose: HR 1.47, 95% CI 1.13 to 1.90, p = 0.004; high ICS dose: HR 1.77, 95% CI 1.38 to 2.29, p < 0.0001, compared to no ICS use. Sensitivity analyses confirmed these results.
  • Interpretation: Use of ICS in patients with severe COPD was associated with an increased and dose-dependent risk of acquiring S. pneumoniae, but only for moderate and high dose. Caution should be taken when administering high dose of ICS to patients with COPD. Low dose of ICS seemed not to carry this risk.
• The impact of inhaled corticosteroids on the prognosis of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2023 May 2;18:733-743. doi: 10.2147/COPD.S388367. eCollection 2023 [MEDLINE]
  • Background: A comprehensive analysis of the effects of inhaled corticosteroids (ICS) on COPD in a real-world setting is required due to safety concerns regarding ICS in COPD. This study aimed to explore the impact of ICS on the prognosis of Asian COPD patients in the real-life world
  • Methods: We examined 978 COPD patients registered in the Korean National Health and Nutrition Examination Survey (KNHANES) database and with their data linked to Health Insurance and Review Assessment (HIRA) data. The outcome measures were ascertained by HIRA from January 1, 2009, to December 31, 2012. This study enrolled two arms; ICS users (N = 85, mean age = 66.7 ± 8.9 years) and non-ICS users (N = 893, mean age = 63.7 ± 9.7 years)
  • Results: Compared to the non-ICS users, the ICS users had a higher rate of pneumonia, tuberculosis, and acute exacerbations (P<0.05). Hospitalization due to respiratory causes was also higher among ICS users (P<0.05). Multivariate analysis showed that acute exacerbation was independently associated with the development of pneumonia (P<0.05), whereas ICS therapy had a tendency to be associated with pneumonia. Another multivariate analysis demonstrated that old age, FEV1, ICS therapy, and pneumonia were independently associated with the occurrence of acute exacerbation (P<0.05). The concomitant pneumonia (HR = 3.353, P = 0.004) was independently associated with higher mortality (P<0.05)
  • Conclusion: Our data demonstrated that the ICS users had a higher rate of pneumonia and tuberculosis and the concomitant pneumonia was independently associated with higher mortality, highlighting the importance of cautious and targeted administration of ICS in COPD
• Inhalation devices and inhaled corticosteroids particle size influence on severe pneumonia in patients with chronic obstructive pulmonary disease: a nationwide cohort study. BMJ Open Respir Res. 2023;10(1):e001814. doi:10.1136/bmjresp-2023-001814 [MEDLINE]
  • Background: Inhaled corticosteroids (ICSs) are associated with an increased risk of pneumonia among patients with chronic obstructive pulmonary disease (COPD). The introduction of extrafine particle ICS has aimed to improve the distribution of medicine in the airways by altering deposition within the lungs, potentially affecting efficacy and side effects. It remains unclear if extrafine particle ICS administration alters the risk of pneumonia compared with standard particle size ICS
  • Methods: An observational cohort study including all Danish COPD outpatients receiving ICS from 2010 to 2017. The primary outcome was pneumonia hospitalisation in the different ICS particle dosing regimens. The primary analysis was an adjusted Cox proportional hazards model. For sensitivity analysis, a subgroup analysis of patients receiving spray devices was done. Further, we created a propensity score matched cohort, in which we matched for the same covariates as adjusted for in the main analysis
  • Results: A total of 35 691 patients were included of whom 1471 received extrafine particle ICS. Among these patients, 4657 were hospitalised due to pneumonia. Patients with COPD receiving extrafine particle ICS had a lower risk of hospitalisation due to pneumonia compared with patients receiving standard particle size ICS in our primary analysis (HR 0.75; 95% CI 0.63 to 0.89; p=0.002), subgroup analysis (HR 0.54; 95% CI 0.45 to 0.65; p<0.0001) and the propensity-matched population (HR 0.72; 95% CI 0.60 to 0.87; p=0.0006)
  • Interpretation: The use of extrafine particle ICS administration was associated with a lower risk of pneumonia hospitalisation in patients with COPD compared with those who received standard size treatment.
• Clinical factors linked to the type of respiratory medication in COPD: Results from the COSYCONET cohort. Ther Adv Respir Dis. January-December 2023;17:17534666231208584. doi:10.1177/17534666231208584 [MEDLINE]
  • Background: The use of maintenance medication in patients with chronic obstructive pulmonary disease (COPD) in real life is known to deviate from recommendations in guidelines, which are largely based on randomized controlled trials and selected populations
  • Objectives: We used the COSYCONET (COPD and Systemic Consequences – Comorbidities Network) cohort to analyze factors linked to the use of COPD drugs under non-interventional circumstances
  • Design: COSYCONET is an ongoing, multi-center, non-interventional cohort of patients with COPD
  • Methods: Patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 0-4 participating in visits 1-5 were included. Data covered the period from 2010 to 2018. Generalized linear models were used to examine the relation of COPD characteristics to different types of respiratory medication
  • Results: A total of 1043 patients were included. The duration of observation was 4.5 years. Use of respiratory medication depended on GOLD grades 0-4 and groups A-D. Long-acting muscarinic antagonist therapy increased over time, and was associated with low carbon monoxide (CO) diffusing capacity, while inhaled corticosteroid (ICS) use decreased. Active smoking was associated with less maintenance therapy in general, and female sex with less ICS use. From the eight items of the COPD Assessment Test, only hill and stair climbing were consistently linked to treatment
  • Conclusion: Using data from a large, close to real-life observational cohort, we identified factors linked to the use of various types of respiratory COPD medication. Overall, use was consistent with GOLD recommendations. Beyond this, we identified other correlates of medication use that may help us to understand and improve therapy decisions in clinical practice.
• Clinical Efficacy-Risk of Parapneumonic Effusion in Association with Pneumonia (in Both Asthma and COPD)
  • Spanish Study of the Effect of Prior Inhaled Corticosteroids (in Both Asthma and COPD) on the Risk of Developing Parapneumonic Effusion in Association with Pneumonia (Am J Respir Crit Care Med, 2013) [MEDLINE]
    • Prior Use of Inhaled Corticosteroids Decreased the Risk of Parapneumonic Effusion in Association with Pneumonia
    • Prior Use of Inhaled Corticosteroids was Associated with Higher Pleural pH, Higher Pleural Glucose, Lower Pleural Protein, and Lower Pleural LDH
• Clinical Efficacy-Withdrawal of Inhaled Corticosteroids
  • OPTIMO Trial (Respir Res, 2014) [MEDLINE]
    • Withdrawal of Inhaled Corticosteroids in COPD Patients at Low Risk for Exacerbation is Safe, Provided that Patients are Left on Maintenance LABA Therapy
  • WISDOM Trial Examining Withdrawal of Inhaled Corticosteroids in Severe Stable COPD Which is Managed with Tiotropium and Salmeterol (NEJM, 2014) [MEDLINE]
    • Withdrawal of Inhaled Corticosteroids (in COPD Patients on Tiotropium and Salmeterol) Had No Effect on Risk of Moderate-Severe Exacerbations or Dyspnea, But Led to a Minimal Decrease in FEV1 (38 mL)
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Placebo) is Recommended to Prevent Acute COPD Exacerbations (Grade 1B Recommendation)
  • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Long-Acting β2-Agonist Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation)
  • In Stable Moderate-Very Severe COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy (as Compared to Inhaled Corticosteroid Monotherapy) is Recommended to Prevent Acute COPD Exacerbations (Grade 1B Recommendation)
  • In Stable COPD, Inhaled Corticosteroid + Long-Acting β2-Agonist Combination Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 1C Recommendation): both are equally effective
  • In Stable COPD, Inhaled Corticosteroid + Long-Acting Muscarinic Antagonist + Long-Acting β2-Agonist Triple Therapy or Long-Acting Muscarinic Antagonist Monotherapy are Both Recommended to Prevent Acute COPD Exacerbations (Grade 2C Recommendation): both are equally effective

Systemic Corticosteroids (see Corticosteroids)

• Agents
  • Prednisone (see Prednisone)
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • For Patients with Acute COPD Exacerbation in Inpatient/Outpatient Setting, Systemic Corticosteroids (Orally or Intravenously) are Recommended to Prevent Hospitalization for Subsequent Acute COPD Exacerbation in the the Next 30 Days Following the Initial Exacerbation (Grade 2B Recommendation)
  • For Patients with Acute COPD Exacerbation in Inpatient/Outpatient Setting, Systemic Corticosteroids (Orally or Intravenously) are Not Recommended For the Sole Purpose of Preventing Hospitalization for Subsequent Acute COPD Exacerbation Beyond the First 30 Days Following the Initial Exacerbation (Grade 1A Recommendation)

Secretion Clearance

Rationale

• xxxx

Mucolytics

• Agents
  • Carbocysteine (see Carbocysteine)
  • N-Acetylcysteine: cleaves disulfide bonds which cross-link glycoproteins in mucus -> results in decreased mucus viscosity, facilitating airway mucus clearance
• Clinical Efficacy
  • Systematic Review of Mucolytics in Outpatients with Chronic Bronchitis or Chronic Obstructive Pulmonary Disease (Cochrane Database Syst Rev, 2019) [MEDLINE]
    • In participants with chronic bronchitis or COPD, we are moderately confident that treatment with mucolytics leads to a small reduction in the likelihood of having an acute exacerbation, in days of disability per month and possibly hospitalisations, but is not associated with an increase in adverse events
    • There appears to be limited impact on lung function or health-related quality of life
    • Results are too imprecise to be certain whether or not there is an effect on mortality
    • Our confidence in the results is reduced by high levels of heterogeneity in many of the outcomes and the fact that effects on exacerbations shown in early trials were larger than those reported by more recent studies
    • This may be a result of greater risk of selection or publication bias in earlier trials, thus benefits of treatment may not be as great as was suggested by previous evidence
  • Chinese PANTHEON N-Acetylcysteine Trial (Lancet Respir Med, 2014) [MEDLINE]: prospective, randomized, double-blind, placebo-controlled trial of N-Acetylcysteine performed in China, n = 1006 -> primary endpoint was the annual COPD exacerbation rate
    • In Moderate-Severe COPD, Long-Term Use of N-Acetylcysteine (600 mg PO BID) Decreased the Number of Exacerbations (Especially in the Moderate Disease Subgroup)
    • N-Acetylcysteine Probably Exerts its Effect Via a Mucolytic Action: other potential mechanisms, such as the generation or neutralization of reactive species (with a potential anti-inflammatory effect), are less supported by the available data
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Moderate-Severe COPD and a History of ≥2 COPD Exacerbations in the Prior 2 Years, Oral N-Acetylcysteine is Recommended to Decrease the COPD Exacerbation Rate (Grade 2B Recommendation)
  • In Stable Outpatient COPD with Continued Acute COPD Exacerbations Despite Maximal Therapy, Oral Carbocysteine Can Be Used to Decrease the COPD Exacerbation Rate (Ungraded Consensus-Based Statement)
• Mucolytics for acute exacerbations of chronic obstructive pulmonary disease: a meta-analysis. Eur Respir Rev. 2023 Jan 25;32(167):220141. doi: 10.1183/16000617.0141-2022. Print 2023 Mar 31 [MEDLINE]
  • This meta-analysis explored the safety and effectiveness of mucolytics as an add-on treatment for chronic obstructive pulmonary disease (COPD) exacerbations
  • Based on a pre-registered protocol and following Cochrane methods, we systematically searched for relevant randomised or quasi-randomised controlled trials (RCTs)
  • We used the Risk of Bias v2 tool for appraising the studies and performed random-effect meta-analyses when appropriate
  • We assessed certainty of evidence using GRADE
  • This meta-analysis included 24 RCTs involving 2192 patients with COPD exacerbations, entailing at least some concerns of methodological bias. We demonstrated with moderate certainty that mucolytics increase the rate of treatment success (relative risk 1.37, 95% CI 1.08-1.73, n=383), while they also exert benefits on overall symptom scores (standardised mean difference 0.86, 95% CI 0.63-1.09, n=316), presence of cough at follow-up (relative risk 1.93, 95% CI 1.15-3.23) and ease of expectoration (relative risk 2.94, 95% CI 1.68-5.12)
  • Furthermore, low or very low certainty evidence suggests mucolytics may also reduce future risk of exacerbations and improve health-related quality of life, but do not impact on breathlessness, length of hospital stay, indication for higher level of care or serious adverse events. Overall, mucolytics could be considered for COPD exacerbation management
  • These findings should be validated in further, rigorous RCTs.
• The effect of nebulized N-acetylcysteine on the phlegm of chronic obstructive pulmonary disease: the NEWEST study. BMC Pulm Med. Published online September 2, 2024. doi:10.1186/s12890-024-03243-y [MEDLINE]
  • Background: Phlegm is prevalent symptom in patients with chronic obstructive pulmonary disease (COPD). Few studies have investigated the effectiveness of N-acetylcysteine (NAC) nebulizer therapy in COPD patients. We evaluated the effect of nebulized NAC on the improvement of phlegm symptom in COPD patients
  • Methods: This was a 12-week, prospective, single-arm, open-label, phase IV multi-center trial (NCT05102305, Registration Date: 20-October-2021). We enrolled patients aged ≥ 40 years with post bronchodilator forced expiratory volume in one second/forced vital capacity (FEV1/FVC) < 0.7 and COPD assessment test (CAT) phlegm score ≥ 2; the patients were current or ex-smoker with smoking pack-years ≥ 10. The primary endpoint was to determine the change in CAT phlegm score at 12 weeks compared to the baseline. Patients were assessed at baseline, 4, 8, and 12 weeks of treatment using the CAT score
  • Results: In total, 100 COPD patients were enrolled from 10 hospitals. The mean age of the patients was 71.42 ± 8.20 years, with 19.78% being current-smokers and 80.22% being ex-smokers. The mean smoking pack-years was 40.32 ± 35.18. The mean FVC, FEV1, and FEV1/FVC were 3.94 L (75.44%), 2.22 L (58.50%), and 0.53, respectively. The CAT phlegm score at baseline was 3.47 ± 1.06, whereas after 12 weeks of nebulized NAC it significantly decreased to 2.62 ± 1.30 (p < 0.01). More than half (53.5%) of the patients expressed satisfaction with the effects of nebulized NAC therapy. Adverse events occurred in 8 (8.0%) patients. Notably, no serious adverse drug reactions were reported
  • Conclusion: In this study, we have established the effectiveness and safety of nebulized NAC over 12 weeks

Oscillatory Positive Expiratory Pressure Therapy (see Oscillatory Positive Expiratory Pressure)

• Brands
  • Acapella
  • Aerobika
• Clinical Efficacy
  • O-COPD Randomized Trial of Positive Expiratory Pressure Therapy in Chronic Obstructive Pulmonary Disease (Thorax, 2022) [MEDLINE]
    • n = 122 (61/61 Oscillatory Positive Expiratory Pressure Therapy/Control) were recruited (103 completed the study: 55/48 Oscillatory Positive Expiratory Pressure Therapy/Control)
      • 40% female
      • 17% smokers
      • FEV1 38 (25-56)% Predicted
      • Age 62±10 y/o
    • Use of Oscillatory Positive Expiratory Pressure was Associated with Improvement in Leicester Cough Questionnaire, as Compared to Control; Median 1.03 (95% CI: 0.71 to 2.10; p = 0.03), Functional Assessment of Chronic Illness Therapy Score 4.68 (95% CI: 1.34 to 8.02; p<0.001), and EuroQol-5 Dimensions Score 4.00 (95% CI: 0.49 to 19.75; p=0.04)
    • There was Also an Improvement in Cough Frequency -60 (-43 to -95) Coughs/24 hours (p<0.001), But No Statistically Significant Effect on Sleep Disturbance was Identified
    • Regular Use of an Acapella Device Improves Symptoms and Quality of life in COPD Patients Who Produce Sputum Daily or Most Days

Azithromycin (Zithromax) (see Azithromycin)

• Pharmacology: macrolide antibiotic (see Macrolides)
• Administration: 250 mg PO qday x 1 year
• Adverse Effects
  • Hearing Loss (see Hearing Loss): with azithromycin x 1 year, hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, p = 0.04) (NEJM, 2011) [MEDLINE]
  • Drug-Induced Pulmonary Eosinophilia (see Drug-Induced Pulmonary Eosinophilia)
  • Increased General Cardiovascular Risk
  • Increased Risk of Acute Myocardial Infarction (MI) (see Coronary Artery Disease)
  • Risk of Q-T Prolongation with Definite Association with Torsade (see Torsade)
• Clinical Efficacy
  • COPD Clinical Research Network Daily Azithromycin Trial (NEJM, 2011) [MEDLINE]: randomized, placebo-controlled trial (n = 1577) with daily azithromycin (250 mg PO) x 1 year
    • Exclusion Criteria: asthma, a resting HR >100 beats, prolonged QTc >450 msec, use of medications that prolong the QTc or are associated with torsades (with the exception of amiodarone), and hearing impairment
    • Azithromycin Decreased the COPD Exacerbation Rate (1.48 vs 1.83 Per Year)
    • Azithromycin Improved QOL
    • Azithromycin Decreased Colonization with Selected Respiratory Pathogens (But Increased Colonization with Macrolide-Resistant Organisms)
    • Azithromycin Resulted in a Small Increase in Hearing Decrements (25% vs. 20%, p = 0.04)
    • No Clear Impact on Microbial Resistance Patterns
  • Predictors of COPD Exacerbation Reduction in Response to Daily Azithromycin Therapy (Am J Resp Crit Care Med, 2014) [MEDLINE]
    • Azithromycin is Most Effective in Preventing COPD Exacerbations in Patients Requiring Both Antibiotic and Corticosteroid Treatment
    • Variables Which Did Not Affect Azithromycin Efficacy: sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy
    • Variables Associated with Increased Azithromycin Efficacy: older age, milder Global Initiative for Chronic Obstructive Lung Disease stage
    • Variables Associated with Decreased Azithromycin Efficacy: current tobacco abuse
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Moderate-Severe COPD with History of ≥1 Moderate-Severe COPD Exacerbations in Prior Year Despite Optimal Maintenance Inhaler Therapy, Long-Term Macrolide is Recommended to Decrease the COPD Exacerbation Rate (Grade 2A Recommendation)

Dupilumab (XXXX) (see Dupilumab)

Clinical Efficacy

• xxx
• BOREAS Trial. Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts. N Engl J Med. 2023 Jul 20;389(3):205-214. doi: 10.1056/NEJMoa2303951 [MEDLINE]
  • Background: In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation
  • Methods: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV1) and in the scores on the St. George’s Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms)
  • Results: A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P = 0.002). The E-RS-COPD score at week 52 had improved by an LS mean of -2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P = 0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups
  • Conclusions: Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo
• Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. N Engl J Med. 2024 May 20. doi: 10.1056/NEJMoa2401304 [MEDLINE]
  • Background: Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear
  • Methods: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) at weeks 12 and 52 and in the St. George’s Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52
  • Results: A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchiodilator FEV1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab
  • Conclusions: In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo.

Theophylline (see Theophylline)

Pharmacology

• xxxx

Clinical Efficacy

• Benefit of Theophylline in COPD is Unclear (Chest, 2001) [MEDLINE]

Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]

• In Stable COPD, Oral Slow-Release Theophylline BID is Recommended to Decrease the COPD Exacerbation Rate (Grade 2B Recommendation)

Roflumilast (Daliresp, Daxas) (see Roflumilast)

• Contraindications
  • Concomitant Theophylline Use (see Theophylline)
  • Depression (see Depression): roflumilast should be used with caution in the setting of depression
• Pharmacology: phosphodiesterase type 4 inhibitor (PDE4 Inhibitor) (see Phosphodiesterase Type 4 Inhibitors)
  • Anti-Inflammatory Effect
• Administration: 500 ug PO qday
• Adverse Effects
  • Anorexia (see Anorexia)
  • Back Pain (see Back Pain)
  • Diarrhea (see Diarrhea)
  • Insomnia (see Insomnia)
  • Nausea (see Nausea and Vomiting)
  • Weight Loss (see Weight Loss)
• Clinical Efficacy
  • Cardiovascular Safety of Roflumilast in COPD (Chest, 2013) [MEDLINE]
    • Roflumilast Decreased the Rates of Non-Fatal Acute MI and Non-Fatal Stroke
  • REACT Trial in Patients with Severe COPD and Chronic Bronchitis Who are at Risk of Frequent and Severe Exacerbations Despite Inhaled Corticosteroids/LABA/Tiotropium (Lancet, 2015) [MEDLINE]
    • Roflumilast Decreased Exacerbations and Hospital Admissions
• Recommendation (American College of Chest Physicians/Canadian Thoracic Society Guidelines on the Prevention of COPD Exacerbations, 2015) (Chest, 2015) [MEDLINE]
  • In Moderate-Severe COPD with Chronic Bronchitis and a History of ≥1 COPD Exacerbation in the Prior Year, Roflumilast is Recommended to Decrease the COPD Exacerbation Rate (Grade 2A Recommendation)

Mepolizumab (XXXXXXXX) (see Mepolizumab)

Clinical Efficacy

• METREX and METREO Trials of Mepolizumab in Eosinophilic COPD (NEJM, 2017) [MEDLINE]
  • Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype
  • This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations
• MATINEE Trial of Mepolizumab in Chronic Obstructive Pulmonary Disease
  • GSK announces positive results from phase III trial of Nucala (mepolizumab) in COPD. News release. GSK. September 6, 2024 [LINK]

Opioids (see Opioids)

Indications

• Refractory Dyspnea (see Dyspnea)

Clinical Efficacy

• Trial of Opiates in Advanced COPD (CMAJ Open, 2013) [MEDLINE]
  • Opioids Were a Helpful and Acceptable Intervention for Improving Dyspnea and Health-Related Quality of Life in Advanced COPD
  • Adverse Effects were Minimal

Recommendations (Canadian Thoracic Society Guidelines for the Management of Dyspnea in COPD) (Can Respir J, 2011)* [MEDLINE]

• Oral (But Not Nebulized) Opiates are Recommended for the Treatment of refractory Dyspnea in Advanced COPD (Grade 2C Recommendation)

Metoprolol (see Metoprolol)

Clinical Efficacy

• BLOCK-COPD Trial of Metoprolol for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) (NEJM, 2019) [MEDLINE]: n = 532
  • Methods
    • Mean (± SD) Age of the Patients was 65.0 ± 7.8 y/o
    • Mean Forced Expiratory Volume in 1 Second (FEV1) was 41.1 ± 16.3% of the Predicted Value
    • Trial was Stopped Early Because of Futility with Respect to the PrimaryEnd Point and Safety Concerns
  • Results
    • No Significant Between-Group Difference in the Median Time Until the First Exacerbation, Which was 202 Days in the Metoprolol Group and 222 Days in the Placebo Group (Hazard Ratio for Metoprolol vs Placebo 1.05; 95% CI: 0.84-1.32; P = 0.66)
    • Metoprolol was Associated with an Increased Risk of Exacerbation Leading to Hospitalization (Hazard Ratio 1.91; 95% CI: 1.29-2.83)
    • Frequency of Side Effects that were Possibly Related to Metoprolol was Similar in the Two Groups, as was the Overall Rate of Non-Respiratory Serious Adverse Events
    • During the Treatment Period, There were 11 Deaths in the Metoprolol Group and 5 in the Placebo Group
  • Conclusions
    • Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group
    • Hospitalization for exacerbation was more common among the patients treated with metoprolol

Bronchoscopic Lung Volume Reduction

Endobronchial Valve Therapy

• Product: Zephyr endobronchial valve (Emphasys Medical/Pulmonyx)
• Technique: duckbill valve mechanism placed unilaterally via bronchoscopy
• Clinical Efficacy
  • Modest Improvement in Symptoms/Lung Function After Zephyr Placement: best candidates are probably those with intact inter lobar fissures and no collateral ventilation
    • Exclusion Criteria: FEV1 <20% pred, hypercapnia, pulmonary hypertension, DLCO <25% pred
  • Endobronchial Valve (Zephyr) for Emphysema Palliation Trial (VENT) Trial (NEJM, 2010) [MEDLINE]: randomized multi-center trial of endobronchial valves in heterogeneous emphysema (n = 321)
    • At 90 Days
      • Increased Rate of COPD Exacerbation (Requiring Hospitalization) and Hemoptysis
    • At 6 mo
      • Modest Improvement in FEV1 and 6MWT Distance, with a Non-Statistically-Significant Increase in Mortality (2.8% vs 0% in Control Group, p = 0.19)
    • At 12 mo
      • Valve Group Had 4.2% Pneumonia Rate in the Target Lobe, Bit No Change in Complication Rates or Mortality
  • Retrospective Analysis from Multicenter Registry
  • Dutch STELVIO Trial of Endobronchial Valves (from Pulmonyx) in Patients without Interlobar Collateral Ventilation (NEJM, 2015) [MEDLINE]
    • At 6 mo, Endobronchial Valves Improved PFT’s and 6MWT Distance in Patients Without Interlobar Collateral Ventilation (As Assessed by Complete Fissure on HRCT)
    • Adverse Event Rate was Higher (with 1 Death in the Valve Group)

Intrabronchial Valve Therapy

• Product: Spiration implantable Intrabronchial Valve (Spiration)
• Technique: umbrella-shaped nitinol frame with synthetic polymer cover placed through flexible bronchoscope
• Sustained clinical benefits of spiration valve system in severe emphysema patients: 24-month follow-up of EMPROVE. Ann Am Thorac Soc. 2023 Nov 10. doi: 10.1513/AnnalsATS.202306-520OC [MEDLINE]
  • Rationale: Follow-up of emphysema patients treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and controls with a longer follow-up
  • Objective: To assess the durability of the Spiration® Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period
  • Methods: EMPROVE, a multicenter, randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed
  • Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment vs. control group. Similarly, significant improvements were maintained in several QOL measures, including St. George’s Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council Dyspnea Scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute COPD exacerbation rates in the SVS treatment and control groups were 13.7% (14/102) and 15.6% (7/45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1/102) and 0.0% (0/45), respectively
  • Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months, while maintaining an acceptable safety profile.

Nitinol Coil Therapy

• Technique spring-like device delivered via bronchoscope
• Clinical Efficacy
  • French REVOLENS Trial of Nitinol Coils (JAMA, 2016) [MEDLINE]
    • Approximately 66% of Trial Patients Had Homogenous Emphysema (Generally Considered to Be Not Amenable to Surgery or Endobronchial Valve Placement)
    • Compared to Usual Care, Bronchoscopic Treatment with Nitinol Coils Resulted in Improved Exercise Capacity with High Short-Term Costs: incremental cost-effectiveness ratio was $782,598 per additional quality-adjusted life-year

Biologic Lung Volume Reduction Therapy

• Technique: application of sealant/remodeling system to collapse areas of emphysematous lung

Thermal Airway Ablation Therapy

• Technique: steam vapor applied to segmental airways

Airway Bypass Procedure

• Technique: extra-anatomic bronchial fenestration is used to decompress areas of emphysema (stent placed through bronchial wall into an area with severe emphysema decompresses the emphysematous area)

Bronchoscopic Vapor Ablation Lung Volume Reduction

• Technique
  • Bronchoscopic application of thermal vapor ablation
• Clinical Efficacy
  • STEP-UP Trial of Bronchoscopic Vapor Ablation Lung Volume Reduction in Emphysema (Lancet Respir Med, 2016) [MEDLINE]
    • Vapor Ablation of More Diseased Lung Segments (with Preservation of Less Diseased Segments) Improved Lung Function (FEV1) and Quality of Life at 6 mo
    • Acceptable Safety Profile: most common serious adverse event was COPD exacerbation, one death was reported in treatment group

Lung Volume Reduction

Indications

• Maximal Exercise Tolerance <50W

Technique

• Lung Volume Reduction Surgery (LVRS)
  • Operative Mortality: <10% (in experienced centers)
• Bronchoscopic Lung Volume Reduction
  • XXXX

Current Criteria for Ideal Candidates for LVRS

• General Comments
  • 50% of these candidates demonstrate significant improvement in lung function post-operatively
• Predominantly Upper Lobe Disease
• Absence of Significant Pulmonary Hypertension
• Absence of Hypercapnia
• FEV1 >20% Pred with DLCO >20% Pred

Clinical Efficacy

• Improved Mortality
• Improved Symptoms
• Improved Lung Function/Functional Status
• Improved BMI (Am J Respir Crit Care Med, 2012) [MEDLINE]: especially in COPD patients who had prior low BMI
  • The Improvement in BMI is Associated with Improvements in Lung Function, Exercise Capacity, Respiratory Muscle Strength, and Ventilatory Efficiency
• Study of Bronchoscopic Lung Volume Reduction with Coils/Endobronchial Valves (Respir Med, 2022) [MEDLINE]: n = 1,471
  • A total of 531 patients (35%) died during follow-up and the median survival time of the total population was 2694 days (95% confidence interval(CI) 2462-2926) which is approximately 7.4 years
  • The median survival time of patients who were treated with BLVR was significantly longer compared to patients who were not treated with bronchoscopic lung volume reduction (3133 days versus 2503 days, p < 0.001), and bronchoscopic lung volume reduction was found to be an independent predictor of survival when adjusting for other survival-influencing factors such as age, gender or severity of disease
  • Bronchoscopically reducing lung volume in patients with severe hyperinflation may lead to a survival benefit for a population with a severely reduced life expectancy
• Sustained clinical benefits of Spiration Valve System in patients with severe emphysema: 24-Month follow-up of EMPROVE. Ann Am Thorac Soc. February 2024;21(2):251-260. doi:10.1513/AnnalsATS.202306-520OC [MEDLINE]
  • Rationale: Follow-up of patients with emphysema treated with endobronchial valves is limited to 3-12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives: To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period
  • Methods: EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed
  • Results: A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George’s Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively
  • Conclusions: SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile.

Bullectomy

Criteria for Ideal Candidates for Bullectomy

• Bulla is >1/3 of Hemithorax
  • The rare bulla which communicates with airways (as determined by disparity between body box and helium dilution TLC) is more likely to lead to improvement with bullectomy (as it contributes more to dead space ventilation, worsening dyspnea)
• Absence of Generalized Emphysematous Changes in Remaining Lung: the best test for this is a inspiratory/expiratory chest CT scan
  • Presence of generalized emphysema predicts poor results
• FEV1 Around 50% Predicted: most benefit in this group
  • Those with higher FEV1 generally have few symptoms (with little room for improvement)
  • Those with lower FEV1 generally have generalized emphysema

Post-Operative Outcome from Bullectomy

• Prediction of Post-Op Outcomes: bronchography, exercise testing, and quantitative V/Q scanning do not predict post-operative outcome from bullectomy
• Post-Op Outcomes
  • Most patients without severe emphysema show improved FEV1 and FVC post-operatively
  • DLCO is improved, if the compressed lung is better perfused
  • Post-op ventilatory capacity and oxygen consumption (at anaerobic threshold and maximal exercise) are both improved

Noninvasive Positive Pressure Ventilation (NIPPV)

• German/Austrian Randomized Trial of NIPPV in Stable Hypercapnic COPD (2014) [MEDLINE]
  • Study: randomized German/Austrian trial of NIPPV (n = 195 from 36 centers)
    • NIPPV was used for at least 6 hrs per day (preferably during sleep)
    • NIPPV was provided using ventilator set to pressure support mode with a backup rate, or alternately assisted ventilation (if high backup rates were not tolerated)
    • NIPPV was targted to decrease pCO2 by at least 20%
  • Main Findings: addition of long-term NIPPV to standard COPD treatment improved survival of patients with hypercapnic, stable COPD when the NIPPV is targeted to significantly reduce hypercapnia (1-year mortality was 12% in the NIPPV group vs 33% in the control group; hazard ratio 0.24 (95% CI 0.11-0.49; p=0.0004)
• Systematic Review and Meta-Analysis of Home Noninvasive Positive Pressure Ventilation in Patients with Hypercapnic Chronic Obstructive Pulmonary Disease (JAMA, 2020) [MEDLINE]: 21 RCT’s and 12 observational studies (n = 51, 085
  • Study Population
    • Mean Age was 65.7 +/- 2.1 y/o (SD)
    • Sex: 43% female were included
    • 434 Deaths
    • 27 Patients Who Underwent Intubation
  • BPAP compared with no device was significantly associated with lower risk of mortality (22.31% vs 28.57%; risk difference [RD], -5.53% [95% CI, -10.29% to -0.76%]; odds ratio [OR], 0.66 [95% CI, 0.51-0.87]; P = .003; 13 studies; 1423 patients; strength of evidence [SOE], moderate), fewer patients with all-cause hospital admissions (39.74% vs 75.00%; RD, -35.26% [95% CI, -49.39% to -21.12%]; OR, 0.22 [95% CI, 0.11-0.43]; P < .001; 1 study; 166 patients; SOE, low), and lower need for intubation (5.34% vs 14.71%; RD, -8.02% [95% CI, -14.77% to -1.28%]; OR, 0.34 [95% CI, 0.14-0.83]; P = .02; 3 studies; 267 patients; SOE, moderate)
  There was no significant difference in the total number of all-cause hospital admissions (rate ratio, 0.91 [95% CI, 0.71-1.17]; P = .47; 5 studies; 326 patients; SOE, low) or quality of life (standardized mean difference, 0.16 [95% CI, -0.06 to 0.39]; P = .15; 9 studies; 833 patients; SOE, insufficient) Noninvasive HMV use compared with no device was significantly associated with fewer all-cause hospital admissions (rate ratio, 0.50 [95% CI, 0.35-0.71]; P < .001; 1 study; 93 patients; SOE, low), but not mortality (21.84% vs 34.09%; RD, -11.99% [95% CI, -24.77% to 0.79%]; OR, 0.56 [95% CI, 0.29-1.08]; P = .49; 2 studies; 175 patients; SOE, insufficient) There was no statistically significant difference in the total number of adverse events in patients using NIPPV compared with no device (0.18 vs 0.17 per patient; P = .84; 6 studies; 414 patients).

CONCLUSIONS AND RELEVANCE:

• In this meta-analysis of patients with COPD and hypercapnia, home BPAP, compared with no device, was associated with lower risk of mortality, all-cause hospital admission, and intubation, but no significant difference in quality of life
• Noninvasive HMV, compared with no device, was significantly associated with lower risk of hospital admission, but there was no significant difference in mortality risk
• However, the evidence was low to moderate in quality, the evidence on quality of life was insufficient, and the analyses for some outcomes were based on small numbers of studies.

Nutritional Management

• Despite prevalence of cachexia in COPD, there is no evidence that enhanced nutrition improves body wieght, lung function, exercise capacity, or survival

Management of Dyspnea (in Advanced COPD) (see Dyspnea)

• Recommendations (Canadian Thoracic Society Guidelines for the Management of Dyspnea in COPD) (Can Respir J, 2011) [MEDLINE]
  • Anxiolytics/Antidepressants are Not Routinely Recommended for the Management of Dyspnea in Advanced COPD (Grade 2B Recommendation)
  • Oral (But Not Nebulized) Opiates are Recommended for the Treatment of refractory Dyspnea in Advanced COPD (Grade 2C Recommendation)
  • Neuromuscular Electrical Muscle Stimulation (NMES) and Chest Wall Vibration are Recommended to Decrease Dyspnea in Advanced COPD
  • Walking Aids are Recommended for Appropriate Patients to Decrease Dyspnea in Advanced COPD (Grade 2B Recommendation)
  • Pursed-Lip Breathing is Recommended to Decrease Dyspnea in Advanced COPD (Grade 2B Recommendation)
  • Insufficient Evidence to Recommend the Routine Use of Acupuncture, Acupressure, Distractive Auditory Stimuli (Music), Relaxation, Handheld Fans, Counseling and Support Programs, or Psychotherapy to Decrease Dyspnea in Advanced COPD
  • Continuous Oxygen Therapy for Hypoxemic Patients Decreases the Mortality Rate and May Decrease Dyspnea in Advanced COPD (Grade 2B Recommendation) (see Oxygen)
    • No Evidence to Support the Routine Use of Supplemental Oxygen to Decrease Dyspnea in Normoxemic Patients with Advanced COPD
    • There is Little Benefit from Supplemental Oxygen on Quality of Life in Patients with Advanced COPD

Treatment of Concomitant Metabolic Alkalosis (see Metabolic Alkalosis)

Clinical Efficacy

• Trial of Acetazolamide to Treat Metabolic Alkalosis in the Setting of Obesity Hypoventilation Syndrome (Respir Care, 2010) [MEDLINE]
  • Acetazolamide Decreased Serum Bicarbonate and Increased Carbon Dioxide Responsiveness
• Systematic Review of Acetazolamide in the Treatment of Metabolic Alkalosis Complicating Chronic Hypercapnic Respiratory Failure in Chronic Obstructive Pulmonary Disease or Obesity Hypoventilation Syndrome (Thorax, 2023) [MEDLINE]: n = 504 (4 studies) (99% of patients in study had chronic obstructive pulmonary disease; 50% of trials recruited patients requiring mechanical ventilation)
  • Rationale
    • Metabolic Alkalosis May Lead to Respiratory Inhibition and Increase the Need for Ventilatory Support (or Prolong Ventilator Weaning) for Patients with Chronic Respiratory Disease
    • Acetazolamide Can Decrease Alkalemia and May Decrease Respiratory Depression
  • Primary Outcome
    • Mortality Rate
  • Risk of Bias: low-some risk
  • There was No Statistically Significant Difference with Acetazolamide with Respect to Mortality Rate (Relative Risk 0.98; 95% CI: 0.28 to 3.46); p = 0.95; 490 Subjects; Three Studies; GRADE: Low Certainty) or Duration of Ventilatory Support (Mean Difference -0.8 days; 95% CI -7.2 to 5.6; p = 0.36; 427 Subjects; Two Studies; GRADE: Low Certainty)
  • Clinically Significant Benefits or Harms are Unable to Be Excluded, and Larger Trials are Required

Management of Pulmonary Hypertension (see Pulmonary Hypertension)

• Calcium Channel Blockers (see Calcium Channel Blockers): Nifedipine decreases exercise PA pressure and CO (effects last up to 9 weeks but symptoms are unchanged)
  • Verapamil is not an effective pulmonary vasodilator in COPD
• Prazosin (see Prazosin): decreases PA pressure and increases CO in COPD (effects last for 8 weeks but cause a decrease in pO2 and worsened dyspnea)

Treatment of Polycythemia (see Polycythemia)

• If patient is polycythemic, treatment decreases PA pressure, decreases PVR, and increases RV-EF

Scuba Diving with Chronic Obstructive Pulmonary Disease

• Contraindicated: due to risk of pneumothorax

End of Life Care

• xxx
• Differences in Health Care and Palliative Care Use at the End of Life: A Comparison Study Among Lung Cancer, COPD, and Idiopathic Pulmonary Fibrosis. Chest. 2024 Dec;166(6):1487-1496. doi: 10.1016/j.chest.2024.08.018 [MEDLINE]
  • Background: Patients with lung cancer, idiopathic pulmonary fibrosis (IPF), and COPD have high symptom burden, poor quality of life, and high health care use at the end of life. Although proactive integration of palliative care in lung cancer can improve outcomes, it is unclear whether similar practices have been adopted in COPD and IPF care
  • Research question: Do patients with COPD and IPF have different patterns of health care and palliative care use at the end of life compared with patients with lung cancer?
  • Study design and methods: We retrospectively identified deceased patients with lung cancer, COPD, or IPF with ≥ 1 outpatient visit at the University of California, San Francisco, in the last 6 months of life. We compared outpatient palliative care and opioid prescriptions, inpatient palliative care, hospitalizations, intensive care use, and in-hospital death in the last 6 months of life between each group. We used multivariable logistic regression to calculate adjusted ORs (aORs) of each outcome, with lung cancer as the reference group
  • Results: Among 1,819 patients, patients with COPD and IPF were more likely to be male and older at the time of death compared with patients with lung cancer. Compared with patients with lung cancer, patients with COPD and IPF showed a lower adjusted odds (P < .001) of receiving outpatient palliative care (COPD: aOR, 0.26 [95% CI, 0.19-0.36]; IPF: aOR, 0.48 [95% CI, 0.32-0.70]), outpatient opioid prescription (COPD: aOR, 0.50 [95% CI, 0.40-0.63]; IPF: aOR, 0.40 [95% CI, 0.29-0.54]), and a higher odds of end-of-life ICU use (COPD: aOR, 2.88 [95% CI, 2.11-3.93]; IPF: aOR, 4.15 [95% CI, 2.66-6.49]). Patients with IPF showed higher odds of receiving inpatient palliative care (aOR: 2.02 [95% CI, 1.30-3.13]; P = .002) Interpretation: This study showed that patients with COPD and IPF are less likely to receive outpatient palliative care and opioid prescriptions and are more likely to use end-of-life intensive care than patients with lung cancer. Further research should explore health system barriers contributing to differences in care patterns to optimize quality of life and to align with patient goals of care.

---

Treatment of Chronic Obstructive Pulmonary Disease Exacerbation

Prediction of Hypercapnic Respiratory Failure

Clinical Efficacy

• xxx
• A Diagnostic Nomogram for Predicting Hypercapnic Respiratory Failure in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis. 2024 May 18:19:1079-1091. doi: 10.2147/COPD.S454558. eCollection 2024 [MEDLINE]
  • Purpose: To develop and validate a nomogram for assessing the risk of developing hypercapnic respiratory failure (HRF) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD)
  • Patients and methods: From January 2019 to August 2023, a total of 334 AECOPD patients were enrolled in this research. We employed the Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate logistic regression to determine independent predictors and develop a nomogram. This nomogram was appraised by the area under the receiver operating characteristic curve (AUC), calibration curve, Hosmer-Lemeshow goodness-of-fit test (HL test), decision curve analysis (DCA), and clinical impact curve (CIC). The enhanced bootstrap method was used for internal validation
  • Results: Sex, prognostic nutritional index (PNI), hematocrit (HCT), and activities of daily living (ADL) were independent predictors of HRF in AECOPD patients. The developed nomogram based on the above predictors showed good performance. The AUCs for the training, internal, and external validation cohorts were 0.841, 0.884, and 0.852, respectively. The calibration curves and HL test showed excellent concordance. The DCA and CIC showed excellent clinical usefulness. Finally, a dynamic nomogram was developed (https://a18895635453.shinyapps.io/dynnomapp/)
  • Conclusion: This nomogram based on sex, PNI, HCT, and ADL demonstrated high accuracy and clinical value in predicting HRF. It is a less expensive and more accessible approach to assess the risk of developing HRF in AECOPD patients, which is more suitable for primary hospitals, especially in developing countries with high COPD-related morbidity and mortality.

Oxygen (see Oxygen)

• Oxygen Therapy: judicious oxygen therapy is crucial
  • Excessive oxygen therapy in COPD exacerbation in the setting of chronic hypercapnia may result in worsened CO2 retention and respiratory failure
    • Excess oxygen may blunt the hypoxic ventilatory drive and/or increase physiologic dead space (due to oxygen-induced bronchodilation in poorly-perfused areas of the lung)

Bronchodilators

• Short-Acting β2-Adrenergic Receptor Agonists (SABA) (see β2-Adrenergic Receptor Agonists): standard treatment
• Long-Acting β2-Adrenergic Receptor Agonists (LABA) (see β2-Adrenergic Receptor Agonists): standard treatment
• Short-Acting Anticholinergics (see Muscarinic Antagonists): standard treatment
  • Ipratropium Bromide (Atrovent) (see Ipratropium Bromide)
• Long-Acting Anticholinergics (see Muscarinic Antagonists)
  • Tiotropium (Spiriva) (see Tiotropium) [MEDLINE]

Corticosteroids (see Corticosteroids)

• Considered a standard treatment for COPD exacerbation
• Clinical Efficacy
  • Swiss REDUCE Trial Examining Duration of Systemic Corticosteroids in the Treatment of Acute COPD Exacerbation (JAMA, 2013) [MEDLINE]
    • Five Day Treatment with Systemic Corticosteroids was Non-Inferior (in Terms of Re-Exacerbation Rates within 6 mo), as Compared to 14 Day Systemic Corticosteroid Treatment
    • No Difference in Time to Death
    • No Difference in the Combined End Point of Exacerbation, Death, or Both
    • No Difference in Recovery of Lung Function
    • No Difference in Treatment-Associated Adverse Reactions (Hyperglycemia, Hypertension)
  • Systematic Review of Different Durations of Corticosteroid Therapy in Acute COPD Exacberation (Cochrane Database Syst Rev, 2014) [MEDLINE]
    • Five Days of Oral Corticosteroids is Likely to Be Sufficient for the Treatment of Adults with Acute COPD Exacerbation

Antibiotics

XXXXX

• Indications for antibiotics in chronic bronchitis include sputum purulence, increased sputum volume, and increased dyspnea
• Antibiotics have been shown to decrease days of illness, symptoms, and increase flow rates (benefit of antibiotics is greatest when all 3 are present, of lesser benefit when only 2 are present, and of no benefit when only 1 is present)
• Microbiologic Coverage in Simple Chronic Bronchitis (<65 y/o, <4 exacerbations per year): cover Moraxella/H Flu/Pneumococci/possibly atypicals
• Microbiologic Coverage in Complicated Chronic Bronchitis (>65 y/o, >4 exacerbations per year, FEV1 <50% pred, presence of underlying comorbid condition, COPD for >10 years): cover above organisms + GNR

Clinical Guidelines for Short-Course Antibiotics in Common Infections (Annals of Internal Medicine, 2021) [MEDLINE]

• Clinicians should limit antibiotic treatment duration to 5 days when managing patients with COPD exacerbations and acute uncomplicated bronchitis who have clinical signs of a bacterial infection (presence of increased sputum purulence in addition to increased dyspnea, and/or Increased Sputum Volume)

Mucolytics (see xxxx)

Clinical Efficacy

• xxx
• Mucolytics for acute exacerbations of chronic obstructive pulmonary disease: a meta-analysis. Eur Respir Rev. 2023 Jan 25;32(167):220141. doi: 10.1183/16000617.0141-2022. Print 2023 Mar 31 [MEDLINE]
  • This meta-analysis explored the safety and effectiveness of mucolytics as an add-on treatment for chronic obstructive pulmonary disease (COPD) exacerbations
  • Based on a pre-registered protocol and following Cochrane methods, we systematically searched for relevant randomised or quasi-randomised controlled trials (RCTs)
  • We used the Risk of Bias v2 tool for appraising the studies and performed random-effect meta-analyses when appropriate
  • We assessed certainty of evidence using GRADE
  • This meta-analysis included 24 RCTs involving 2192 patients with COPD exacerbations, entailing at least some concerns of methodological bias. We demonstrated with moderate certainty that mucolytics increase the rate of treatment success (relative risk 1.37, 95% CI 1.08-1.73, n=383), while they also exert benefits on overall symptom scores (standardised mean difference 0.86, 95% CI 0.63-1.09, n=316), presence of cough at follow-up (relative risk 1.93, 95% CI 1.15-3.23) and ease of expectoration (relative risk 2.94, 95% CI 1.68-5.12)
  • Furthermore, low or very low certainty evidence suggests mucolytics may also reduce future risk of exacerbations and improve health-related quality of life, but do not impact on breathlessness, length of hospital stay, indication for higher level of care or serious adverse events. Overall, mucolytics could be considered for COPD exacerbation management
  • These findings should be validated in further, rigorous RCTs.

Oxygen (see Oxygen)

• xxxx
• High-flow nasal cannula may prolong the length of hospital stay in patients with hypercapnic acute COPD exacerbation. Respir Med. Published online November 11, 2023. doi:10.1016/j.rmed.2023.107465 [MEDLINE]
  • Background: High-flow nasal cannula (HFNC) is increasingly used in patients with acute exacerbation of COPD (AECOPD). We aimed to confirm whether the baseline bicarbonate is an independent predictor of outcomes in patients with hypercapnic AECOPD receiving HFNC
  • Methods: This was a secondary analysis of a multicentre randomised trial that enrolled 330 patients with non-acidotic hypercapnic AECOPD supported by HFNC or conventional oxygen treatment (COT). We compared the length of stay (LOS) in hospital and the rate of non-invasive positive pressure ventilation (NPPV) use according to baseline bicarbonate levels using the log-rank test or Cox proportional hazard model
  • Results: In the high bicarbonate subgroup (n = 165, bicarbonate 35.0[33.3-37.9] mmol/L, partial pressure of arterial carbon dioxide [PaCO2] 56.8[52.0-62.8] mmHg), patients supported by HFNC had a remarkably prolonged LOS in hospital when compared to COT (HR 1.59[1.16-2.17], p = 0.004), whereas patients in the low bicarbonate subgroup (n = 165, bicarbonate 28.8[27.0-30.4] mmol/L, PaCO2 48.0[46.0-50.0] mmHg) had a comparable LOS in hospital regardless of respiratory support modalities. The rate of NPPV use in patients with high baseline bicarbonate level was significantly higher than that in patients with low baseline bicarbonate level (19.4 % vs. 3.0 %, p < 0.0001). Patients with high bicarbonate level in HFNC group had a lower rate of NPPV use compared to COT group (15.4 % vs. 23.0 %, p = 0.217)
  • Conclusions
    • Among patients with non-acidotic hypercapnic AECOPD with high baseline bicarbonate level, HFNC is significantly associated with a prolonged LOS in hospital, which may be due to the reduced escalation of NPPV treatment

Noninvasive Positive-Pressure Ventilation (NIPPV) (see Noninvasive Positive-Pressure Ventilation)

• History : first used to treat COPD excerbation in the early 1990’s
• Mechanisms
  • CPAP decreases auto-PEEP during COPD exacerbation -> decreases inspiratory load and work of breathing
  • Pressure support decreases work of breathing in COPD
  • Combined CPAP + pressure support (NIPPV) decreases transdiaphragmatic pressure more than each alone
• Clinical Efficacy in COPD Exacerbation
  • NIPPV decreases pCO2, heart rate, respiratory rate, and dyspnea within the first hour of treatment
  • NIPPV decreases encephalopathy scores
    • The presence of hypercapneic encephalopathy or coma in COPD exacerbation is not a contraindication to NIPPV
  • NIPPV decreases intubation rate from 75% -> 25% of cases
  • NIPPV decreases mortality rate from 30% -> 10% of cases
    • Mortality rate may not be decreased in the subset of patients with pH <7.30 (at least in patients treated on general medical wards, outside of the ICU): this study suggested that patients with moore severe COPD exacerbation might have better outcomes if treated in the ICU, suggesting the importance of appropriate monitoring of NIPPV [MEDLINE]
    • Decreased mortality rate may not be observed with the USE of NIPPV in milder COPD exacerbations [MEDLINE]
    • Decreases mortality rate in the setting COPD exacerbation with concomitant pneumonia [MEDLINE]
  • NIPPV decreases complication rates and hospital length of stay

Clinical Efficacy of NIPPV

• NIPPV Decreased pCO2, Heart Rate, Respiratory Rate, and Dyspnea within the First Hour of Treatment
• NIPPV Decreased Encephalopathy Scores
  • The Presence of Hypercapnic Encephalopathy or Coma in COPD Exacerbation is Not a Contraindication to NIPPV
• NIPPV Decreased Complication Rates and Hospital Length of Stay
• NIPPV Decreased Intubation Rate from 75% -> 25%
• NIPPV Decreased Mortality Rate from 30% -> 10%
  • Decreased Mortality Rate May Not Be Observed with the Use of NIPPV in Milder COPD Exacerbations (Eur Resir J, 1996) [MEDLINE]
  • NIPPV decreased mortality rate in the setting COPD exacerbation with concomitant pneumonia (Am J Respir Crit Care MED, 1999) [MEDLINE]
  • Mortality rate may not be decreased in the subset of patients with pH <7.30 (at least in patients treated on general medical wards, outside of the ICU): this study suggested that patients with moore severe COPD exacerbation might have better outcomes if treated in the ICU, suggesting the importance of appropriate monitoring of NIPPV (Lancet, 2000) [MEDLINE]
• Systematic Review and Meta-Analysis of Trials Using NIPPV for Prevention or Treatment of Acute Respiratory Failure or as a Tool to Facilitate Early Extubation (Crit Care Med, 2015) [MEDLINE]: n = 78 trials
  • Overall (in All Populations), NIPPV Decreased the Mortality Rate (at Longest F/U) with Relative Risk 0.73 (95% CI: 0.66–0.81) (p<0.001): number needed to treat = 19
  • Chronic Obstructive Pulmonary Disease (COPD) Exacerbation (see Chronic Obstructive Pulmonary Disease)
    • NIPPV Decreased Mortality Rate (at Longest F/U) with Relative Risk 0.56 (95% CI: 0.42-0.74) (p<0.001)

Clinical Efficacy of Combination of HELIOX + NIPPV

• HELIOX + NIPPV Decreased Airway Resistance and More Rapidly Improved Gas Exchange in COPD Exacerbation (Am J Respir Crit Care MED, 2000) [MEDLINE]
• HELIOX + NIPPV Had No Benefit (in Terms of Intubation Rate, Mortality Rate, or Hospital Length of Stay) over NIPPV Alone in Randomized, Prospective Trial in COPD Exacerbation (Crit Care Med, 2003) [MEDLINE]

Clinical Efficacy

• UK Randomized Trial of Home Noninvasive Ventilation Following COPD Exacerbation (JAMA, 2017)[MEDLINE]: n = 166
  • Exclusion Criteria: obesity (BMI >35), obstructive sleep apnea syndrome, or other cause of respiratory failure
  • In COPD Patients with Persistent Hypercapnia Following an Acute COPD Exacerbation, Adding Home Noninvasive Ventilation to Home Oxygen Therapy Prolonged the Time to Hospital Readmission or Death within 12 Months
    • The 12-Month Risk of Readmission or Death was 63.4% in the Home Oxygen Plus Home Noninvasive Ventilation Group vs 80.4% in the Home Oxygen Alone Group (Absolute Risk Reduction of 17.0%; 95% CI, 0.1%-34.0%)

Recommendations (ERS/ATS Clinical Practice Guidelines for Noninvasive Ventilation for Respiratory Failure, 2017) (Eur Respir J, 2017) [MEDLINE]

• Background
  • Bilevel NIPPV May Theoretically Be Considered in Acute COPD Exacerbation in the Following Clinical Settings
    • Prevention of Acute Respiratory Acidosis in the Presence of COPD Exacerbation with Chronically Compensated Hypercapnia (with Normal pH)
    • Prevention of Endotracheal Intubation/Invasive Mechanical Ventilation in the Setting of COPD Exacerbation with Respiratory Failure and Mild-Moderate Acidemia
    • As an Alternative to Endotracheal Intubation/Invasive Mechanical Ventilation in the Setting of COPD Exacerbation with Respiratory Failure and Severe Acidemia
    • As the Only Method of Ventilatory Support in the Setting of COPD Exacerbation with Respiratory Failure in Patients Who are Not Candidates for or Decline Invasive Mechanical Ventilation
• Bilevel NIPPV is Not Recommended as a Preventative Treatment in COPD Exacerbation with Hypercapnia without Acidemia (i.e. Chronic Hypercapnia with Metabolic Compensation) (Conditional Recommendation, Low Certainty of Evidence)
• Bilevel NIPPV is Recommended for COPD Exacerbation and Acute/Acute on Chronic Hypoxemic, Hypercapnic Respiratory Failure and Acidemia (pH ≤7.35) (Strong Recommendation, High Certainty of Evidence)
  • Bilevel NIPPV Should Be Considered with pH ≤7.35, pCO2 >45 mmHg, and Respiratory Rate >20–24 Despite Standard Medical Therapy
  • There is No Lower Limit of pH Below Which a Trial of NIPPV is Contraindicated
    • However, the Lower the pH, the Greater the Risk of Failure, Suggesting that the Patient Be Closely Monitored with Rapid Access to Endotracheal Intubation/Invasive Mechanical Ventilation (Should the Need Arise)
• A Trial of Bilevel NIPPV is Recommended in COPD Exacerbation and Acute/Acute on Chronic Respiratory Failure Who May Require Endotracheal Intubation/Invasive Mechanical Ventilation, Unless the Patient is Immediately Deteriorating (Strong Recommendation, Moderate Certainty of Evidence)

Mechanical Ventilation (see Mechanical Ventilation)

• Indications: respiratory failure unresponsive to NIPPV (or if patient is not a candidate for NIPPV) Clinical Efficacy-Heliox with Invasive Ventilation
• Small Prospective Trial of Heliox in Mechanically Ventilated COPD Patients (Crit Care Med, 2000 [MEDLINE]: n = 23
  • In Mechanically-Ventilated COPD Patients with Auto-PEEP (5+/-2.7 cm H2O vs 9+/-2.5 cm H2O), Heliox Decreased Trapped Lung Volume, Auto-PEEP, Peak Inspiratory Pressure (25+/-6 cm H2O vs 30+/-5 cm H2O), and Mean Airway Pressure, as Compared to Usual Care
  • In Mechanically-Ventilated COPD Patients with Auto-PEEP, Heliox Did Not Impact Hemodynamics or Arterial Blood Gases

Treatments with No Demonstrated Clinical Benefit in Acute COPD Exacerbation

• Extracorporeal Carbon Dioxide Removal (ECCO2R) (see Extracorporeal Carbon Dioxide Removal)
  • Trial of Extracorporeal Carbon Dioxide Removal (as Add-On Therapy to Noninvasive Positive-Pressure Ventilation) in the Treatment of COPD Exacerbation with Hypercapnic Respiratory Failure (Ann Intensive Care, 2022) [MEDLINE]: n = 18
    • As Compared to Noninvasive Positive-Pressure Ventilation (NIPPV) Alone, Noninvasive Ventilation and ECCO2R Resulted in Increased ICU and Hospital Length of Stay with No Difference in 90-Day Mortality or Functional Outcomes
• Intravenous Magnesium Sulfate (see Magnesium Sulfate)
  • Systematic Review of Magnesium Sulfate in Acute COPD Exacerbation (Ann Thorac Med, 2014) [MEDLINE]: trials were cited as poor -> further study is required
    • Intravenous Magnesium Sulfate: did not have an immediate bronchodilatory effect, but potentiates the bronchodilatory effect of inhaled beta-2 agonists
    • Nebulized Magnesium Sulfate: no benefit (in terms of FEV1 or need for hospital admission), as compared to salbutamol alone
    • Combined Intravenous and Nebulized Magnesium Sulfate: no benefit in terms of hospital admission/intubation/death, as compared to nebulized ipratropium bromide (but the nebulized ipratropium bromide group had a better bronchodilator effect and improvement in arterial blood gas parameters)
• Nebulized Magnesium Sulfate (see Magnesium Sulfate)
  • Australian New Zealand Clinical Trials Registry Study of Nebulized Magnesium Sulfate Added to Salbutamol in Acute COPD Exacerbation (Thorax, 2013) [MEDLINE]: no benefit (in terms of FEV1 or need for hospital admission), as compared to salbutamol alone
  • Systematic Review of Magnesium Sulfate in Acute COPD Exacerbation (Ann Thorac Med, 2014) [MEDLINE]: trials were cited as poor -> further study is required
    • Intravenous Magnesium Sulfate: did not have an immediate bronchodilatory effect, but potentiates the bronchodilatory effect of inhaled β2 agonists
    • Nebulized Magnesium Sulfate: no benefit (in terms of FEV1 or need for hospital admission), as compared to salbutamol alone
    • Combined Intravenous and Nebulized Magnesium Sulfate: no benefit in terms of hospital admission/intubation/death, as compared to nebulized ipratropium bromide (but the nebulized ipratropium bromide group had a better bronchodilator effect and improvement in arterial blood gas parameters)
• Combined Intravenous and Nebulized Magnesium Sulfate (see Magnesium Sulfate)
  • Systematic Review of Magnesium Sulfate in Acute COPD Exacerbation (Ann Thorac Med, 2014) [MEDLINE]: trials were cited as poor -> further study is required
    • Intravenous Magnesium Sulfate: did not have an immediate bronchodilatory effect, but potentiates the bronchodilatory effect of inhaled beta-2 agonists
    • Nebulized Magnesium Sulfate: no benefit (in terms of FEV1 or need for hospital admission), as compared to salbutamol alone
    • Combined Intravenous and Nebulized Magnesium Sulfate: no benefit in terms of hospital admission/intubation/death, as compared to nebulized ipratropium bromide (but the nebulized ipratropium bromide group had a better bronchodilator effect and improvement in arterial blood gas parameters)

---

Prognosis

Mortality Rate is Related to the GOLD Spirometric Class (GOLD; Global Strategy for Diagnosis, Management, and Prevention of COPD, 2016) [LINK]

• GOLD 1 (Mild, FEV1 ≥80% Predicted): 3-yr mortality rate is unknown
• GOLD 2 (Moderate, FEV1 50-80% Predicted): 3-yr mortality rate is 11%
• GOLD 3 (Severe, FEV1 30-50% Predicted): 3-yr mortality rate is 15%
• GOLD 4 (Very Severe, FEV1 <30% Predicted): 3-yr mortality rate is 24%
• Longitudinal changes in maximal forced inspiratory flow and clinical outcomes in COPD patients. Chest. Published online August 14, 2024. doi:10.1016/j.chest.2024.07.162 [MEDLINE]
  • Background: COPD primarily impairs expiratory flow due to progressive airflow obstruction and reduced lung elasticity. Increasing evidence underlines the importance of inspiratory flow as a biomarker for selecting inhaler devices and providing ancillary aerodynamic information
  • Research question: Does the longitudinal changes in maximum forced inspiratory flow (FIFmax) influence acute exacerbations and lung function decline in patients with COPD?
  • Study design and methods: This longitudinal study evaluated FIFmax in patients with COPD over a 7-year period from 2004 to 2020. Eligible patients were categorized into 2 groups based on FIFmax trajectory: the increased FIFmax group and the decreased FIFmax group. The study assessed the annual rate of acute exacerbations and the annual decline rate of FEV1. Subgroup analyses were conducted based on treatment status, with a focus on inhaled therapy and inhaler device usage
  • Results: Among the eligible 956 patients with COPD, 56.5% belonged to the increased FIFmax group. After propensity score matching, the increased FIFmax group experienced lower rates of severe exacerbations (0.16 per year vs 0.25 per year, P = .017) and a slower decline in FEV1 (0 [interquartile range, -51 to 71] mL/y vs -43 [interquartile range, -119 to 6] mL/y; P < .001) compared with the decreased FIFmax group. These associations were particularly prominent in patients using specific inhaler therapies such as dry powder inhalers
  • Interpretation
    • This study showed that the longitudinal changes in FIFmax are associated with clinical outcomes in patients with COPD
    • Patients with increased FIFmax experienced a lower rate of severe exacerbations and a slower decline in lung function
    • These findings suggest the potential benefits of optimizing inspiratory flow in COPD management, although further studies are needed to confirm these observations due to potential confounding factors

Predictors of Mortality in Chronic Obstructive Pulmonary Disease

BODE Index

• BMI: low BMI
• Obstruction: degree of airway obstruction by PFT’s
• Dyspnea
  • Medical Research Council (MRC) Dyspnea Scale
    • Grades 1 and 2 = mild disability, while grades 3-5 = moderate to severe disability
      
      • Grade 1) I only get breathless with strenuous exercise
      • Grade 2) I get short of breath when hurrying on the level or walking up a slight hill
      • Grade 3) I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking on my own pace on the level
      • Grade 4) I stop for breath after walking about 100 yards or after a few minutes on the level
      • Grade 5) I am too breathless to leave the house or I am breathless when dressing or undressing
• Exercise Capacity: poor exercise capacity (as assessed by clinical symptoms or 6-minute walk test)

Prediction of COPD Mortality with 6-Minute Walk Test (see 6-Minute Walk Test)

• ECLIPSE Trial (2013) [MEDLINE]
  • 6MWT with a 30 m (98.4 ft) Decline in 6MWT Distance in the First Year was Associated with an Increased Risk for Mortality in the Subsequent 2 yrs
  • 6MWT Had No Significant Association with Frequency of Hospitalization Due to COPD Exacerbation
  • 6MWT Had a Weak Associations with Decline in FEV1
  • 6MWT Had a Weak Association with Decline in St George’s Respiratory Questionnaire (SGRQ) Criteria

Emphysematous Changes Noted on Chest CT Predict All-Cause Mortality (see Chest Computed Tomography)

• Cohort Study Examining the Predictive Value of Emphysematous Changes on Chest CT (Ann Int Med, 2014) [MEDLINE]
  • Presence of Emphysematous Changes on CT Imaging in Patients without Spirometrically-Defined COPD were Linearly Associated with Increased All-Cause Mortality: even after adjusting for confounding variables, such as cardiovascular risk factors and FEV1
  • The Association was of the Greatest Magnitude Among Smokers

Frailty

• xxx
• Prevalence and clinical impact of frailty in COPD: a systematic review and meta-analysis. BMC Pulm Med. 2023;23(1):164. doi:10.1186/s12890-023-02454-z [MEDLINE]
  • Background: Frailty has been increasingly identified as a risk factor of adverse outcomes in chronic obstructive pulmonary disease (COPD). The prevalence and impact of frailty on health outcomes in people with COPD require clarification
  • Methods: PubMed, Embase, The Cochrane Library and Web of Science (January 1, 2002, to July 1, 2022) were comprehensively searched to identify studies related to frailty and COPD. Comparisons were made between people who did and did not have frailty for pulmonary function, dyspnea severity, 6-minute walking distance, activities of daily life, and mortality
  • Results: Twenty studies (9 cross-sectional, 10 cohort studies,1 clinical trial) from Europe (9), Asia (6), and North and South America (4), Oceania (1) involving 11, 620 participants were included. The prevalence of frailty was 32.07% (95% confidence interval (CI) 26.64-37.49) with a range of 6.43-71.70% based on the frailty tool used. People with frailty had lower predicted forced expiratory volume in the first second (mean difference – 5.06%; 95%CI -6.70 to -3.42%), shorter 6-minute walking distance (mean difference – 90.23 m; 95%CI -124.70 to -55.76), poorer activities of daily life (standardized mean difference – 0.99; 95%CI -1.35 to -0.62), higher CAT(COPD Assessment Test) score(mean difference 6.2; 95%CI 4.43 to 7.96) and mMRC (modified Medical Research Council) grade (mean difference 0.93; 95%CI 0.85 to 1.02) compared with those who did not (P < 0.001 for all). Meta-analysis showed that frailty was associated with an increased risk of long-term all-cause mortality (HR 1.68; 95% CI 1.37-2.05; I2 = 0%, P < 0.001)
  • Conclusion: Frailty is prevalent in people with COPD and linked with negative clinical outcomes including pulmonary function, dyspnea severity, exercise capacity, quality of life and mortality.

Systemic Inflammation

• xx
• Association between systemic immune-inflammation index and chronic obstructive pulmonary disease: A population-based study. BMC Pulm Med. Published online August 10, 2023. doi:10.1186/s12890-023-02583-5 [MEDLINE]
  • Background: The Systemic Immune-Inflammation Index (SII) is a quantitative measurement of the systemic immune-inflammatory response in the human body. The SII has been shown to have prognostic value in various clinical settings, including critical illness, sepsis, and cancer. Its role in chronic obstructive pulmonary disease (COPD) remains unclear and requires further investigation
  • Methods: We analyzed demographic data from 16,636 participants in the National Health and Nutrition Examination Survey. Logistic regression analysis was performed to assess the correlation between COPD, lung function, chronic respiratory symptoms and SII. We used Cox proportional hazards (PH) model to analyze the relationship between SII and mortality in COPD patients and healthy individuals. We used propensity score matching (PSM) method to match the COPD population with similar baseline levels with the normal population to further analyze the correlation between SII and COPD
  • Results: We recruited 16,636 participants, ages 40 and above, for the study. A multivariable logistic regression analysis revealed that a higher SII level was independently associated with an elevated likelihood of COPD (Odds Ratio (OR) = 1.449; 95% Confidence Interval (CI): 1.252-1.676, P < 0.0001) after controlling for all other factors. Results of subgroup analysis showed a significant positive correlation between SII and COPD in different age groups, gender, Body Mass Index, smoking status, and those with a history of hypertension. The SII index had positive correlation with COPD after PSM (OR = 1.673; 95%CI: 1.443-1.938). After full adjustment, an increase in the SII is associated with a higher all-cause mortality rate. The hazard ratio (HR) with a 95% CI in the general population, COPD patients, and healthy individuals are 1.161 (1.088, 1.239), 1.282 (1.060, 1.550), and 1.129 (1.055, 1.207), respectively
  • Conclusions: Higher SII levels are linked to higher prevalence of COPD. COPD patients with a higher SII levels have a higher risk of all-cause mortality. Additional large-scale, long-term studies are necessary to confirm these results.

Mortality After Hospital Admission

• Research Letter Studying the Mortality Rate in COPD Following Hospitalization for Pneumonia vs Acute Exacerbation (Eur Respir J, 2022) [MEDLINE]
  • In patients with chronic obstructive pulmonary disease (COPD), the 30-day risk of death was higher after hospitalization for pneumonia than after hospitalization for a severe COPD exacerbation
• Characteristics, treatments, in-hospital and long-term outcomes among inpatients with acute exacerbation of chronic obstructive pulmonary disease in China: sex differences in a large cohort study. BMC Pulm Med. 2024;24(1):125. doi:10.1186/s12890-024-02948-4 [MEDLINE]
  • Background: Data related to the characteristics, treatments and clinical outcomes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients in China are limited, and sex differences are still a neglected topic
  • Methods: The patients hospitalized for AECOPD were prospectively enrolled from ten medical centers in China between September 2017 and July 2021. Patients from some centers received follow-up for 3 years. Data regarding the characteristics, treatments and in-hospital and long-term clinical outcomes from male and female AECOPD patients included in the cohort were analyzed and compared
  • Results: In total, 14,007 patients with AECOPD were included in the study, and 11,020 (78.7%) were males. Compared with males, female patients were older (74.02 ± 10.79 vs. 71.86 ± 10.23 years, P < 0.001), and had more comorbidities (2.22 ± 1.64 vs. 1.73 ± 1.56, P < 0.001), a higher frequency of altered mental status (5.0% vs. 2.9%, P < 0.001), lower diastolic blood pressure (78.04 ± 12.96 vs. 79.04 ± 12.47 mmHg, P < 0.001). In addition, there were also significant sex differences in a range of laboratory and radiographic findings. Females were more likely to receive antibiotics, high levels of respiratory support and ICU admission than males. The in-hospital and 3-year mortality were not significantly different between males and females (1.4% vs. 1.5%, P = 0.711; 35.3% vs. 31.4%, P = 0.058), while female smokers with AECOPD had higher in-hospital mortality than male smokers (3.3% vs. 1.2%, P = 0.002) and male smokers exhibited a trend toward higher 3-year mortality compared to female smokers (40.7% vs. 33.1%, P = 0.146)
  • Conclusions
    • In AECOPD inpatients, females and males had similar in-hospital and long-term survival despite some sex differences in clinical characteristics and treatments, but female smokers had significantly worse in-hospital outcomes than male smokers

Impact of Obesity (see Obesity)

• Increased Risk of Morbidity/Mortality in the Setting of Chronic Obstructive Pulmonary Disease (COPD)
• Obesity Is Associated With Increased Morbidity in Moderate to Severe COPD. Chest. 2017 Jan;151(1):68-77. doi: 10.1016/j.chest.2016.08.1432 [MEDLINE]
  • Background: Obesity is prevalent in the United States; however, the impact of obesity on COPD morbidity is unclear. We hypothesized that obesity is associated with worse outcomes in COPD
  • Methods: We examined 3,631 participants from the multicenter prospective cohort study Genetic Epidemiology of COPD (COPDGene) who had spirometry-confirmed COPD, a postbronchodilator FEV1 < 80% predicted, and a BMI ≥ 18.5 kg/m2. We conducted logistic and linear regression analyses to determine the association between COPD outcomes and obesity class, adjusting for relevant confounders. The referent for obesity classes included normal/overweight individuals (BMI range, 18.5-29.9 kg/m2)
  • Results: Overall, 35% of participants were obese, with 21% class I (BMI range, 30-34.9 kg/m2), 9% class II (BMI range, 35-39.9 kg/m2), and 5% class III (BMI ≥ 40 kg/m2). The number of comorbidities increased with increasing obesity class (P < .001). Increasing obesity class was independently associated with worse respiratory-specific and general quality of life (QOL) (St. George’s Respiratory Questionnaire score and Short Form-36 score version 2, respectively), reduced 6-min walk distance (6MWD), increased dyspnea (Modified Medical Research Council score ≥ 2), and greater odds of severe acute exacerbation of COPD (AECOPD). The associations between obesity and worse outcomes were independent of the presence of comorbidities, except in the case of SF-36 and severe exacerbations
  • Conclusions: Obesity is prevalent among individuals with COPD and associated with worse COPD-related outcomes, ranging from QOL and dyspnea to 6MWD and severe AECOPD. These associations were strengthened when obesity was analyzed as a dose-dependent response. Obesity in patients with COPD may contribute to a worse COPD-related course.

---

References

General

• Role of hypoxia in the pulmonary hypertension of chronic bronchitis and emphysema. Scand J Respir Dis Suppl. 1971;77:61 [MEDLINE]
• Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax 1981;36:752–8 [MEDLINE]
• Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(7):581-586
• The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005-1012.
• Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest 2005;127:1531–6 [MEDLINE]
• Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:189–94 [MEDLINE]
• The modified BODE index: validation with mortality in COPD. Eur Respir J. 2008;32(5):1269-1274
• Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest. 2008 Oct;134(4 Suppl):43S-56S. doi: 10.1378/chest.08-0342 [MEDLINE]
• Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease Updated 2008. Available at: https://www.goldcopd.org/Guidelineitem.asp?l1=2&l2=1&intId=2003. Accessed December 15, 2009
• Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax. 2010;65(11):956–962 [MEDLINE]
• Family History Is a Risk Factor for COPD. Chest 2011; 140 (2): 343-350 [MEDLINE]
• ECLIPSE Trial. Six-minute-walk test in chronic obstructive pulmonary disease: minimal clinically important difference for death or hospitalization. Am J Respir Crit Care Med 2013;187:382-386 [MEDLINE]
• Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095-2128 [MEDLINE]
• Association between emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: A cohort study. Ann Intern Med 2014;161:863-873 [MEDLINE]
• Chronic productive cough is associated with death in smokers with early COPD. COPD. 2014 Aug;11(4):451-8. doi: 10.3109/15412555.2013.837870. Epub 2013 Oct 15 [MEDLINE]
• Relation of chronic obstructive pulmonary disease to atrial and ventricular arrhythmias. Am J Cardiol. 2014 Jul 15;114(2):272-7 [MEDLINE]
• Global Initiative for Chronic Obstructive Lung Disease (GOLD); Global Strategy for Diagnosis, Management, and Prevention of COPD, 2016 [LINK]

Epidemiology

• Incidence of chronic obstructive pulmonary disease in people with HIV in Ontario, 1996-2015: a retrospective population-based cohort study. CMAJ Open. 2020 Feb 18;8(1):E83-E89. doi: 10.9778/cmajo.20190028 [MEDLINE]

Diagnosis

• Stronger associations of centrilobular than paraseptal emphysema with longitudinal changes in diffusing capacity and mortality in COPD. Chest. Published online January 31, 2023. doi:10.1016/j.chest.2023.01.034 [MEDLINE]

Clinical Manifestations

Neurologic Manifestations

• Association of rest-activity circadian rhythm with chronic respiratory diseases, a cross-section survey from NHANES 2011-2014. Respir Med. 2023 Feb 6;209:107147. doi: 10.1016/j.rmed.2023.107147 [MEDLINE]

Pulmonary Manifestations

Nocturnal Hypoxemia

• Nocturnal oxyhemoglobin desaturation in COPD patients with arterial oxygen tensions above 60 mm Hg. Chest. 1987;92(4):604 [MEDLINE]
• A double-blind trial of nocturnal supplemental oxygen for sleep desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mm Hg. Am Rev Respir Dis. 1992;145(5):1070 [MEDLINE]

Pulmonary Hypertension (see xxxx)

• Severe pulmonary hypertension in COPD – impact on survival and diagnostic approach. CHEST. Published online January 2, 2022. doi: 10.1016/j.chest.2022.01.031 [MEDLINE]

Treatment

General

• Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001;119:1661-1670 [MEDLINE]
• Ipratropium bromide versus long-acting beta-2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006 Jul 19;3:CD006101 Telehealthcare for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD007718. doi: 10.1002/14651858.CD007718.pub2 [MEDLINE]
• Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease. The REDUCE Randomized Clinical Trial. JAMA. 2013 Jun 5;309(21):2223-31. doi: 10.1001/jama.2013.5023 [MEDLINE]
• Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015 Apr;147(4):894-942. doi: 10.1378/chest.14-1676 [MEDLINE]

Vaccination

• Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD001390. doi: 10.1002/14651858.CD001390.pub3 [MEDLINE]

Pulmonary Rehabilitation (see Pulmonary Rehabilitation)

• Out-patient rehabilitation improves activities of daily living, quality of life and exercise tolerance in chronic obstructive pulmonary disease. Eur Respir J. 1997;10(12):2801-2806
• Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines. Chest. 2007;131(5 Suppl):4S-42S [MEDLINE]
• Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. A Cochrane systematic review. Eura Medicophys. 2007;43(4):475-485
• Optimizing pulmonary rehabilitation in chronic obstructive pulmonary disease–practical issues: a Canadian Thoracic Society Clinical Practice Guideline. Can Respir J. 2010 Jul-Aug;17(4):159-68 [MEDLINE]
• Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD005305. doi: 10.1002/14651858.CD005305.pub3 [MEDLINE]
• British Thoracic Society guideline on pulmonary rehabilitation in adults. Thorax. 2013 Sep;68 Suppl 2:ii1-30. doi: 10.1136/thoraxjnl-2013-203808 [MEDLINE]
• Depressed mood predicts pulmonary rehabilitation completion among women, but not men. Respir Med. 2014 Jul;108(7):1007-13. doi: 10.1016/j.rmed.2014.04.010. Epub 2014 Apr 26 [MEDLINE]
• Pulmonary Rehabilitation as a Mechanism to Reduce Hospitalizations for Acute Exacerbations of COPD: A Systematic Review and Meta-Analysis. Chest. 2016 Oct;150(4):837-859. doi: 10.1016/j.chest.2016.05.038. Epub 2016 Aug 3 [MEDLINE]
• Physical and affective components of dyspnoea are improved by pulmonary rehabilitation in COPD. BMJ Open Respir Res. 2022 Jan;9(1):e001160. doi: 10.1136/bmjresp-2021-001160 [MEDLINE]

Oxygen (see Oxygen)

• Long-term results of continuous oxygen therapy at sea level. Chest. 1975;68(4):486 [MEDLINE]
• Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93(3):391 [MEDLINE]
• Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet. 1981;1(8222):681 [MEDLINE]
• Psychologic effects of continuous and nocturnal oxygen therapy in hypoxemic chronic obstructive pulmonary disease. Arch Intern Med. 1983;143(10):1941 [MEDLINE]
• Evolution of physiological variables in patients with chronic obstructive pulmonary disease before and during long-term oxygen therapy. Respiration. 1991;58(3-4):126 [MEDLINE]
• Psychological status of COPD patients before and after one year of long-term oxygen therapy. Monaldi Arch Chest Dis. 1996;51(1):7 [MEDLINE]
• Long-term home care programmes may reduce hospital admissions in COPD with chronic hypercapnia. Eur Respir J. 1996;9(8):1605 [MEDLINE]
• Does long-term oxygen therapy affect quality of life in patients with chronic obstructive pulmonary disease and severe hypoxaemia? Eur Respir J. 1996;9(11):2335 [MEDLINE]
• Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia. Thorax. 1997;52(8):674 [MEDLINE]
• A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J. 1999;14(5):1002 [MEDLINE]
• Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients. Eur Respir J. 2001;18(1):77 [MEDLINE]
• Enhancement of exercise performance in COPD patients by hyperoxia: a call for research. Chest. 2002;122(5):1830 [MEDLINE]
• Does long-term oxygen therapy reduce hospitalisation in hypoxaemic chronic obstructive pulmonary disease? Eur Respir J. 2002;20(1):38 [MEDLINE]
• Long-term oxygen therapy improves health-related quality of life. Respir Med. 2004;98(4):285 [MEDLINE]
• Long-term oxygen therapy stops the natural decline of endurance in COPD patients with reversible hypercapnia. Respiration. 2004;71(4):342 [MEDLINE]
• Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for future research: an NHLBI workshop report. Am J Respir Crit Care Med. 2006;174(4):373 [MEDLINE]
• Short burst oxygen therapy after activities of daily living in the home in chronic obstructive pulmonary disease. Thorax. 2007;62(8):702 [MEDLINE]
• Effect of oxygen on health quality of life in patients with chronic obstructive pulmonary disease with transient exertional hypoxemia. Am J Respir Crit Care Med. 2007;176(4):343 [MEDLINE]
• Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ. 2010;341:c5462 [MEDLINE]
• Oxygen therapy for patients with COPD: current evidence and the long-term oxygen treatment trial. Chest. 2010;138(1):179 [MEDLINE]
• LOTT Trial. A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation. N Engl J Med. 2016;375(17):1617 [MEDLINE]

Long-Acting β2-Agonists (LABA)

• Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;11:CD003794 [MEDLINE]
• Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015 Oct 22;(10):CD008989. doi: 10.1002/14651858.CD008989.pub3 [MEDLINE]

Long-Acting Muscarinic Antagonists (LAMA)

• Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Jul 11;7:CD009285. doi: 10.1002/14651858.CD009285.pub2 [MEDLINE]
• Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015 Oct 22;(10):CD008989. doi: 10.1002/14651858.CD008989.pub3 [MEDLINE]

Inhaled Corticosteroids (see Corticosteroids)

• Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297-303 [MEDLINE]
• Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775-89 [MEDLINE]
• Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD. 2009;6(5):320-329
• Safety and efficacy of combined long-acting beta-agonists and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic review. Chest. 2009;136(4):1029-1038
• Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009; 34(3):641-647 [MEDLINE]
• Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;11:CD003794 [MEDLINE]
• Influence of previous use of inhaled corticoids on the development of pleural effusion in community-acquired pneumonia. Am J Respir Crit Care Med. 2013;187(11):1241 [MEDLINE]
• WISDOM Investigators. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014;371:1285-1294 [MEDLINE]
• Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation: a real-life study on the appropriateness of treatment in moderate COPD patients (OPTIMO). Respir Res. 2014 Jul 8;15:77. doi: 10.1186/1465-9921-15-77 [MEDLINE]
• ETHOS Trial. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD. N Engl J Med 2020; 383:35-48 [MEDLINE]
• Association of Inhaled Corticosteroids With All-cause Death Risk in COPD Patients: A Meta-analysis of Sixty Randomized Controlled Trials. Chest. 2022 Jul 31;S0012-3692(22)01345-9. doi: 10.1016/j.chest.2022.07.015 [MEDLINE]

Secretion Clearance

• Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Aug 15;8:CD001287 [MEDLINE]
• Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014 Mar;2(3):187-94 [MEDLINE]
• Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;5:CD001287 [MEDLINE]
• Oscillatory positive expiratory pressure therapy in COPD (O-COPD): a randomised controlled trial. Thorax. 2022 Aug 10;thoraxjnl-2022-219077. doi: 10.1136/thorax-2022-219077 [MEDLINE]

Macrolides (see Macrolides)

• Azithromycin for Prevention of Exacerbations of COPD. NEJM 2011; 365(8): 689-698 [MEDLINE]
• Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med 2014;189:1503-1508 [MEDLINE]

Statins (see HMG-CoA Reductase Inhibitors)

• Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006;47:2554-2560 [MEDLINE]
• Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006;47:2554-2560 [MEDLINE]
• STATCOPE Trial. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014 Jun 5;370(23):2201-10. doi: 10.1056/NEJMoa1403086. Epub 2014 May 18 [MEDLINE]
• Statin use and exacerbations in individuals with chronic obstructive pulmonary disease. Thorax. 2015 Jan;70(1):33-40 [MEDLINE]

Roflumilast (see Roflumilast)

• Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013; 144(3):758–765 [MEDLINE]
• Benefits and harms of roflumilast in moderate to severe COPD. Thorax. 2014 Jul;69(7):616-22 [MEDLINE]
• Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015 Mar 7;385(9971):857-66. doi: 10.1016/S0140-6736(14)62410-7. Epub 2015 Feb 13 [MEDLINE]
• Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2016 Jan 6;11:81-90. doi: 10.2147/COPD.S89849. eCollection 2016 [MEDLINE]

Mepolizumab (XXXXXXXXXXX) (see Mepolizumab)

• METREX and METREO Trials. Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017 Oct 26;377(17):1613-1629. doi: 10.1056/NEJMoa1708208 [MEDLINE]

Opiates (see Opiates)

• Opioid therapy for refractory dyspnea in patients with advanced chronic obstructive pulmonary disease: patients’ experiences and outcomes. CMAJ Open. 2013 Jan 24;1(1):E27-36. doi: 10.9778/cmajo.20120031. eCollection 2013 [MEDLINE]
• Managing dyspnea in patients with advanced chronic obstructive pulmonary disease: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2011 Mar-Apr;18(2):69-78 [MEDLINE]

Endobronchial Valves/Coils

• Bronchoscopic lung volume reduction for end-stage emphysema: report on the first 98 patients. Chest 2006;129:518-526 [MEDLINE]
• VENT Study Research Group. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med 2010;363(13):1233-1244 [MEDLINE]
• Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation (STELVIO). N Engl J Med 2015; 373:2325-2335December 10, 2015DOI: 10.1056/NEJMoa1507807 [MEDLINE]
• Lung Volume Reduction Coil Treatment vs Usual Care in Patients With Severe Emphysema: The REVOLENS Randomized Clinical Trial. JAMA. 2016 Jan;315(2):175-84 [MEDLINE]

Lung Volume Reduction

• Weight gain after lung reduction surgery is related to improved lung function and ventilatory efficiency. Am J Respir Crit Care Med 2012;186:1109-1116 [MEDLINE]
• Segmental volume reduction using thermal vapour ablation in patients with severe emphysema: 6-month results of the multicentre, parallel-group, open-label, randomised controlled STEP-UP trial. Lancet Respir Med. 2016 Mar;4(3):185-93. doi: 10.1016/S2213-2600(16)00045-X. Epub 2016 Feb 16 [MEDLINE]
• Lung volume reduction for emphysema. Lancet Respir Med. 2016 Sep 29. pii: S2213-2600(16)30221-1. doi: 10.1016/S2213-2600(16)30221-1 [MEDLINE]
• Survival in COPD patients treated with bronchoscopic lung volume reduction. Respir Med. 2022 Mar 16;196:106825. doi: 10.1016/j.rmed.2022.106825 [MEDLINE]

Ventilation-Based Treatment

• Noninvasive ventilatory support does not facilitate recovery from acute respiratory failure in chronic obstructive pulmonary disease. Eur Respir J. 1996 Jun;9(6):1240-5 [MEDLINE]
• Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized evaluation of noninvasive ventilation. Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 1):1585-91 [MEDLINE]
• Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet. 2000 Jun 3;355(9219):1931-5 [MEDLINE]
• Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ. 2003 Jan 25;326(7382):185 [MEDLINE]
• Which patients with acute exacerbation of chronic obstructive pulmonary disease benefit from noninvasive positive-pressure ventilation? A systematic review of the literature. Ann Intern Med. 2003 Jun 3;138(11):861-70 [MEDLINE]
• Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive pulmonary disease: a prospective, multicentre, randomised, controlled clinical trial. Lancet Respir Med. 2014 Sep;2(9):698-705. doi: 10.1016/S2213-2600(14)70153-5 [MEDLINE]
• Association of Home Noninvasive Positive Pressure Ventilation With Clinical Outcomes in Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis. JAMA. 2020 Feb 4;323(5):455-465. doi: 10.1001/jama.2019.22343 [MEDLINE]

Treatment of Metabolic Alkalosis (see Metabolic Alkalosis)

• Acetazolamide for metabolic alkalosis complicating respiratory failure with chronic obstructive pulmonary disease or obesity hypoventilation syndrome: a systematic review. Thorax. 2023 May 22;thorax-2023-219988. doi: 10.1136/thorax-2023-219988 [MEDLINE]

Treatment of Acute Chronic Obstructive Pulmonary Disease Exacerbation

• PEEP, auto-PEEP, and waterfalls. Chest. 1989 Sep;96(3):449-51 [MEDLINE]
• Effects of helium-oxygen on intrinsic positive end-expiratory pressure in intubated and mechanically ventilated patients with severe chronic obstructive pulmonary disease. Crit Care Med. 2000;28(8):2721-2728 [MEDLINE]
• Dynamic hyperinflation and auto-positive end-expiratory pressure: lessons learned over 30 years. Am J Respir Crit Care Med. 2011;184:756–762 [MEDLINE]
• Different durations of corticosteroid therapy for exacerbations of COPD. Cochrane Database Syst Rev 2011;(10) CD00697 [MEDLINE]
• Short-term vs conventional glucocorticoid therapy in acute exacerbations of COPD: The REDUCE randomized clinical trial. JAMA 2013; 309: 2233-2231 [MEDLINE]
• Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial. Thorax. 2013 Apr;68(4):338-43. doi: 10.1136/thoraxjnl-2012-202225. Epub 2013 Jan 7 [MEDLINE]
• Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014 Dec 10;12:CD006897. doi: 10.1002/14651858.CD006897.pub3 [MEDLINE]
• Magnesium for acute exacerbation of chronic obstructive pulmonary disease: A systematic review of randomised trials. Ann Thorac Med. 2014 Apr;9(2):77-80. doi: 10.4103/1817-1737.128844 [MEDLINE]
• Effect of Home Noninvasive Ventilation With Oxygen Therapy vs Oxygen Therapy Alone on Hospital Readmission or Death After an Acute COPD Exacerbation: A Randomized Clinical Trial. JAMA. 2017 Jun 6;317(21):2177-2186. doi: 10.1001/jama.2017.4451 [MEDLINE]
• Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J. 2017 Aug 31;50(2). pii: 1602426. doi: 10.1183/13993003.02426-2016 [MEDLINE]
• Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021 Apr 6. doi: 10.7326/M20-7355 [MEDLINE]
• A randomised controlled trial of non-invasive ventilation compared with extracorporeal carbon dioxide removal for acute hypercapnic exacerbations of chronic obstructive pulmonary disease. Ann Intensive Care. 2022 Apr 21;12(1):36. doi: 10.1186/s13613-022-01006-8 [MEDLINE]

Prognosis

• Mortality after admission with pneumonia is higher than after admission with an exacerbation of COPD. Eur Respir J. 2022 Mar 10;2102899. doi: 10.1183/13993003.02899-2021 [MEDLINE]