COPD and Sleep Apnea Overlap

Etiology

Evidence exists of a bidirectional relationship between COPD and OSA.[5] Overlap syndrome can emerge in patients with COPD who later develop OSA or in those with OSA who are later diagnosed with COPD. Older age, male gender, exposure to cigarette smoke and alcohol, and reduced reported physical activity are all associated with the development of overlap syndrome.[1][6]

Cigarette smoking is a common and independent risk factor for developing COPD and OSA. Smoking accelerates the underlying disease process by inducing oxidative stress and inflammatory mediator release, thereby triggering upper airway inflammation and increasing the susceptibility to OSA.[7] Moreover, obesity, notably increased neck circumference, poses a significant risk for developing OSA. These anthropomorphic changes result in upper airway narrowing, predisposing patients to nocturnal oxygen desaturations.[8] Additional risk factors for OSA include:

• Shortening of the mandible or maxilla
• Hypothyroidism
• Acromegaly 
• Male gender
• Age 40 to 65
• Myotonic dystrophy
• Ehlers-Danlos syndrome 

COPD encompasses a spectrum of airway diseases, including emphysema, chronic bronchitis, and chronic obstructive asthma. The likelihood of developing OSA varies depending on the patient's underlying pathophysiology. Patients with emphysema classically demonstrate hyperinflated lungs and a lower BMI due to prominent dyspnea and increased work of breathing encountered in the advanced stages of COPD. Conversely, individuals with chronic bronchitis often have an elevated BMI, increasing their risk of developing OSA, particularly when adipose tissue accumulates around the neck.[7] In the developing world, occupational and environmental exposures significantly contribute to the onset and development of COPD.

Epidemiology

Despite being among the most widespread pulmonary diseases globally, there's variability in the prevalence of concurrent COPD and OSA.[9] Nevertheless, studies suggest approximately 1 in 10 individuals diagnosed with either COPD or OSA will, by chance alone, have the other disorder as well.[1] A systematic review demonstrates a 1.0% to 3.6% rate of coexistence in the general and hospital populations.[5]

As of 2019, COPD stands as the third leading cause of death globally, accounting for 3.23 million deaths. In 2017, 55% of the estimated 544.9 million individuals living with chronic respiratory disease could attribute their diagnosis to COPD.[10] The global prevalence of COPD is estimated at 10%.[11][12][13] Cigarette smoking contributes to 70% of cases in high-income countries and 30% in low- and middle-income countries, while indoor air pollution is a significant risk factor in low- and middle-income countries.

The prevalence of isolated OSA in the US is approximately 30%, affecting 1 billion people worldwide.[14] According to the Wisconsin Sleep Cohort, OSA prevalence in men and women aged 30 to 60 is 24% and 9%, respectively.[15] Rising rates of obesity contribute to the increased prevalence of OSA.[16][17]

Epidemiological data regarding the prevalence of overlap syndrome is continually evolving. A review of available literature regarding the prevalence of overlap syndrome reveals significant variations in disease rates, making it challenging to calculate the true incidence accurately. For patients with a primary diagnosis of COPD, the reported incidence of overlap syndrome varies between 2.9% and 65.9%. Among those primarily diagnosed with OSA, the incidence falls between 7.6% and 55.7%.[5] In studies focusing on patients with COPD older than 70 and those on long-term oxygen therapy, overlap syndrome incidence rates were 21.4% and 15.7%, respectively.[5]

Limitations in determining the true prevalence of overlap syndrome are:

• Differing diagnostic criteria for COPD and OSA across studies

• Lack of a standardized definition and specific diagnostic code for overlap syndrome

• Updated scoring criteria to categorize nocturnal respiratory events by the American Academy of Sleep Medicine [18][19]

• Inability to define and include additional disordered breathing-related physiologic disturbances like hypoxic burden, respiratory-related arousal, and autonomic disturbances [20][21] 

• Overlooking COPD or OSA once establishing the other diagnosis

• Study selection bias evidenced by small convenient samples or heterogeneous groups

• Results of home versus traditional overnight polysomnography

• Varying cut-offs for apnea-hypopnea index (AHI) [22] 

• Effects of long-term oxygen therapy on overnight polysomnography results

• Cost of overnight polysomnography

Pathophysiology

The underlying pathophysiology of overlap syndrome encompasses a combination of the individual effects of COPD and OSA. To comprehend the physiologic alterations involved, it is essential to recognize the typical changes during sleep. These include:

• Reduced upper airway muscle activity
• Decreased pharyngeal caliber
• Increased upper airway resistance
• Increased upper airway compliance
• Increased internal load on the respiratory system
• Changes in the ratio of the rib cage and abdominal muscle contribution to tidal volume 
  • During non-REM sleep, rib cage muscles contribute more than abdominal muscles to tidal volume
• Increased partial PaCO₂

Obstructive Sleep Apnea

OSA involves recurrent pharyngeal airway obstruction, causing hypoxia and sleep disruption.[23][24][25] During normal sleep, humans experience a diminished drive to breathe compared to wakefulness, resulting in decreased ventilatory motor output to the respiratory muscles. This decreased activity and immediate decrease in inspiratory flow are particularly evident in muscles like the tensor palatini and genioglossus that maintain upper airway patency.[26][27][28][29] Respiration becomes dependent on the level of chemoreceptor and mechanoreceptor stimuli.[5] Consequently, patients are more vulnerable to central apnea and upper airway obstruction.[2][30][31] While reduced upper airway muscle activity typically has little impact on healthy patients, it can result in upper airway narrowing for those at risk. 

Upper airway narrowing, causing turbulent airflow, is a routine finding during sleep. As the resistance in the upper airway rises, turbulent flow increases, along with a restriction in inspiratory flow. This phenomenon causes the soft palate and upper airway soft tissue to flutter. 

The narrowed upper airway and increased resistance to flow create an increased internal load on the lungs. These loads trigger an automatic respiratory effort during wakefulness to counteract their effects. However, during sleep, ventilation decreases, leading to an elevation of PaCO₂. This rise in PaCO₂ prompts ventilation to return to normal levels in healthy individuals. However, patients with COPD or other abnormal respiratory mechanics may experience worsening ventilation issues due to the increased internal load.

Repetitive respiratory events are associated with increased airway resistance and can lead to increased patient end-tidal CO2 and alternating periods of hypoventilation and hyperventilation (see Image. Airway Resistance and End-Tidal CO2). The oxidative stress caused by breathing interruptions during sleep results in sporadic reductions in airflow to the lungs and significant variations in the partial pressure of oxygen between the proximal and distal airways.[32]

In a healthy individual with ideal anatomy, maintaining normal oxygen saturation and sleep patterns is achievable even with a slightly elevated PaCO₂. Patients with a less ideal anatomy may experience inspiratory flow limitation and snore. Breathing during wakefulness and in patients who do not snore typically does not encounter flow limitation. Snoring suggests flow limitation and the risk of upper airway collapse. Patients with significant upper airway compromise may develop OSA.

For individuals with obesity, the fat deposition surrounding the pharyngeal airway can increase its susceptibility to collapse.[26] This contributes to increased neck circumference, a standard measurement to assess the risk of developing OSA. A neck circumference exceeding 16 inches in a female or 17 inches in a male is associated with an increased risk of developing OSA.[30]

Chronic Obstructive Pulmonary Disease

COPD is characterized by airflow obstruction that is minimally reversible and aberrant inflammatory responses in the lungs. It encompasses a group of overlapping diseases consisting of emphysema and chronic bronchitis, primarily involving the airways but potentially involving the lung parenchyma and vasculature, depending on the underlying condition.[31][32] The pathophysiologic changes of COPD typically have a more pronounced impact during physiological challenges such as exercise or sleep. The overall effects of the pathogenic processes include:

• Mucous hypersecretion
• Ciliary dysfunction
• Airflow obstruction
• Hyperinflation
• Gas exchange abnormalities
• Pulmonary hypertension
• Systemic effects like cachexia and polycythemia

The mechanism of respiratory function impairment can be broadly categorized into 2 main groups. Each category, including mechanical and ventilatory, represents distinct pathways contributing to respiratory dysfunction. These classifications help elucidate the diverse factors underlying respiratory impairment, aiding in diagnostic and therapeutic approaches.

Mechanical factors

Peripheral airway obstruction, destruction of pulmonary connective tissue, or a combination of both leads to alterations in the mechanical properties of the respiratory system. These structural changes set off a cascade of events that can contribute to the morbidity and chronicity of the disease.

Inflammation of the small airways due to cigarette smoke or air pollutants triggers an exaggerated response to inhaled toxins. The amplified natural protective mechanism causes tissue destruction, impairs the defense mechanisms that typically limit such destruction, and disrupts natural healing processes. Patients with COPD also have increased protease production by neutrophils, macrophages, and matrix metalloproteinases, while antiproteases like Alpha₁-antitrypsin become inactivated. This imbalance can lead to structural damage to the alveolar air sacs, resulting in emphysematous changes. Additionally, cigarette smoke and inflammatory cells release oxidants, the production of which further increases during an exacerbation of COPD. This heightened oxidant production exacerbates protease activity, mucous production, and the release of inflammatory mediators. The overall results are as follows:

• Reduction in forced expiratory volume (FEV) due to the inflammatory reaction and blockage of the airways 

• Airflow obstruction and reduced gas exchange due to tissue damage [31] 

• Air trapping from airway collapse on exhalation [31]

• Hyperinflation leading to an increase in the anterior-posterior diameter of the lower rib cage, causing depression and shortening of the diaphragm, making diaphragmatic contraction less mechanically advantageous [33]

• Increased airway resistance with chronic bronchitis due to mucous gland enlargement and mucociliary dysfunction resulting in excessive mucus production and reduced airway caliber

• Fibrosis and smooth muscle hypertrophy due to increased mucus production [34]

• Loss of elastic recoil in patients with emphysema causing diminished expiratory flow rates, air trapping, and airway collapsing [34]

• Skeletal muscle myopathy from long-term corticosteroid usage, systemic inflammatory response with oxidative damage, and persistent hypoxemia [35]

• Increased airway resistance during inspiration and expiration 

Ventilatory factors

Ventilatory control remains relatively unaffected in individuals with mild COPD. However, as COPD progresses, alterations in ventilatory motor output become more apparent, leading to significant changes in gas exchange and respiratory function during wakefulness and sleep.[36] Expected ventilatory changes include:

• Prolonged inspiratory time and reduced expiratory time exacerbate hyperinflation due to a reduced ventilatory drive, resulting in a significant decrease in tidal volume.[36] 

• Transient episodes of nocturnal hypoxemia, particularly during REM sleep, are common in patients with chronic bronchitis. These patients often experience hypoxemia and CO2 retention while awake and breathing.[37]

• Increased respiratory frequency or work of breathing due to increased airway resistance during inspiration and expiration.  

• Increased work of breathing causing increased oxygen extraction from the blood and increased carbon dioxide production. 

• A reduction in hypercapnic ventilatory response due to increased mechanical load.[38]

• Increased oxygen levels contributing to hypercarbia due to several mechanisms like reduced ventilatory responses, ventilation/perfusion (V/Q) mismatch, and the Haldane effect.[39]

Overlap Syndrome

The link between OSA and COPD is reciprocal, where exacerbation of 1 condition can exacerbate the other. Severity scales exist to categorize patients with COPD and OSA. However, the point at which these combined disorders have additive or synergistic clinical significance is uncertain.[9] 

Overlap syndrome results in more profound nocturnal oxygen desaturations than in COPD or OSA alone. Previous studies defined nocturnal oxygen desaturations as SaO2 below 88% or 90% during at least 30% of the recording time.[9][40]

Alveolar hypoventilation, decreased ventilation-perfusion matching, and reduced end-expiratory volume (ERV) are the 3 primary mechanisms contributing to nocturnal oxygen desaturations in patients with COPD.[8] This hypoxia causes the release of systemic inflammatory mediators such as C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), nuclear factor-kappa beta (NF-κB), tumor necrosis factor-alpha (TNF-α), and hypoxia-inducible factor (HIF).[8][32] Reactive oxygen species are also released, contributing to endothelial dysfunction and accelerated atherosclerosis, thereby increasing mortality and the risk of pulmonary hypertension.[8] 

Patients with overlap syndrome exhibit higher sympathetic activity and reduced parasympathetic activity measured by sympathetic and parasympathetic modulation of heart rate, compared to those with OSA or COPD alone. Moreover, research suggests that individuals with overlap syndrome have increased arterial stiffness, surpassing even patients with OSA alone, indicating another underlying mechanism for cardiac disease.[7]

The precise mechanism for developing OSA in patients with COPD remains unclear. Studies propose protective mechanisms that may contribute to the development of OSA in individuals with COPD. These mechanisms include larger end-expiratory lung volumes (EELV), which promote tracheal traction, thereby reducing airway resistance and stabilizing the upper airway.[41]  

Chronic oral steroid use and decreased exercise tolerance leading to obesity may increase the risk of OSA. The elevated pulmonary artery pressure associated with severe COPD can lead to right ventricular dysfunction and right heart failure, causing edema in the pharyngeal soft tissues and increasing the risk of OSA. Additionally, COPD is associated with generalized muscle weakness, which may contribute to higher upper airway collapse.

Obstructive sleep apnea can induce local and systemic inflammation, causing a reduction in airway lumen and potentially contributing to alveolar wall destruction. Patients with gastrointestinal reflux disease can have worsening COPD and OSA symptoms. Furthermore, allergic rhinitis is associated with sleep-disordered breathing and COPD.

History and Physical

The clinical characteristics specific to overlap syndrome often coexist with the common presentations of COPD and OSA. Typical findings include obesity, increased neck circumference, excessive daytime sleepiness, sleep disruptions, and hypertension.

Patients with COPD commonly present with sputum production, shortness of breath, cough, wheezing, forgetfulness, confusion, and disrupted sleep, likely related to sleep-disordered breathing. Conversely, patients with OSA commonly present with daytime sleepiness, loud snoring, gasping for air, nocturia, morning headache, and choking. Additionally, the patient's sleeping partner often observes snoring, which may progress to apneic episodes.

In addition to the common symptoms of the individual diseases, COPD and OSA, patients with overlap syndrome exhibit increased hypoxemia, hypercapnia, and pulmonary hypertension. Consequently, they may experience morning headaches resulting from hypercapnia, cyanosis resulting from hypoxemia, and peripheral edema resulting from cor pulmonale, which are additional possible findings associated with overlap syndrome.[7]

Evaluation

Clear guidelines do not currently exist for screening patients with COPD for OSA. However, utilizing the STOP-Bang questionnaire (SBQ), which assesses snoring, tiredness, observed apnea, blood pressure, body mass index, age, neck size, and gender in all patients with COPD, is recommended. Diagnostic testing should be considered in all patients with an intermediate-to-high risk for OSA.

Patients with an SBQ score of 0 to 2 are at low risk for moderate to severe OSA, while those scoring 5 to 8 are considered at high risk for moderate to severe OSA. Patients scoring 3 or 4 require further clinical assessment for classification. For example, a patient with a score of 3 or 4 and a BMI of 35 is at high risk for moderate to severe OSA.

Patients with COPD, pulmonary hypertension, and borderline or nocturnal hypoxemia warrant a sleep study. Current recommendations from the American Thoracic Society and European Respiratory Society suggest that individuals with mild COPD and clinical evidence of pulmonary hypertension should be evaluated with overnight testing to assess for possible OSA.[9][8]

Additional screening tools include the recently created NoSAS (neck, obesity, snoring, age, sex) questionnaire, utilized alongside objective clinical data, including anthropometrics and medical history.[7] A NoSAS score of 8 or higher indicates probable OSA. The Berlin Questionnaire also identifies patients at increased risk of suffering from sleep apnea.[42] 

Patients with overlap syndrome demonstrate higher COPD Assessment Test (CAT), Epworth Sleepiness Scale (ESS), Charlson Comorbidity Index (CCI), and SBQ scores than patients with COPD alone.[43] Notably, excessive daytime sleepiness is not a universal finding. Some patients may complain of excessive daytime fatigue, leading to inaccuracies when using questionnaires to measure excessive sleepiness.

Diagnosis

Polysomnography is the gold standard for detecting sleep disturbances. However, overnight oximetry is a valuable screening tool for identifying nocturnal hypoxia during sleep. A cyclical or sawtooth pattern on oximetry suggests OSA in patients with COPD, although confirmation is necessary with overnight polysomnography (see Image. Flow Limitation with Snoring).[8] Polysomnography establishes the diagnosis of OSA when:

• ≥5 predominantly obstructive respiratory events per hour of sleep occur accompanied by ≥1 of the following:
  • Sleepiness, fatigue, insomnia, or other symptoms leading to impaired sleep-related quality of life
  • Waking up with breath holding, gasping, or choking
  • Habitual snoring or breathing interruptions noted by a bed partner or other observer
• ≥15 predominantly obstructive respiratory events per hour of sleep

The AHI and the respiratory disturbance index (RDI) determine the severity of OSA. The AHI is calculated as the total number of apneas and hypopneas divided by the total sleep time in hours, while the RDI includes additional respiratory effort-related arousals (RERAs) ([apneas + hypopneas + RERAs] / total sleep time in hours). 

• Mild: 5 to 14 respiratory events per hour of sleep
• Moderate: 15 to 30 respiratory events per hour of sleep
• Severe: >30 respiratory events per hour of sleep

The severity of nocturnal hypoxemia is determined using the oxygen desaturation index (ODI), which quantifies the number of episodes when blood oxygen levels decrease by 3% or 4% below baseline. Elevated ODI levels are associated with the production of inflammatory markers. While the AHI determines the severity of OSA, the ODI is superior to the AHI in predicting cardiovascular risk.[44][7]

Current recommendations advise against the use of home sleep apnea testing (HSAT) in patients with severe chronic respiratory illnesses due to several limitations:

• The inability of HSAT to detect hypoventilation as a cause of hypoxemia potentially leads to inadequate oxygen treatment or inappropriate positive airway pressure (PAP) prescription.

• HSAT is often used with auto-PAP treatment, causing an unwarranted rise in expiratory positive airway pressure (EPAP). This elevation in EPAP may exacerbate hyperinflation and worsen lung function in patients with COPD.[45]

Pulmonary function testing 

Spirometry conducted before and after bronchodilator administration is necessary to establish the diagnosis of COPD. Airflow limitation that is irreversible or only partially reversible with bronchodilator treatment is considered pathognomonic for COPD. Diagnosis depends on the FEV in 1 second (FEV₁) and forced vital capacity (FVC) values. A postbronchodilator FEV₁/FVC ratio less than 0.7 is the threshold for COPD. Using the FEV in 6 seconds (FEV₆) is an acceptable alternative. The GOLD COPD classification classifies COPD severity as:

• GOLD 1 or mild disease: FEV₁ ≥80% predicted
• GOLD 2 or moderate disease: FEV₁ between 50% and 80% predicted
• GOLD 3 or severe disease: FEV₁ between 30% and 50% predicted
• GOLD 4 or very severe disease: FEV₁ <30% predicted

Patients with overlap syndrome may have a propensity for more severe lung hyperinflation, quantified by a reduced inspiratory capacity/total lung capacity (IC/TLC) ratio. Some researchers suggest that the IC/TLC ratio may be a more accurate measure of lung disease severity than FEV1. This hyperinflation could potentially contribute to deteriorating sleep quality in overlap syndrome, possibly stemming from increased work of breathing while in the recumbent position. However, this mechanism is poorly understood and requires further evaluation.[46] 

The severity of obstruction measured by the FEV1/FVC ratio corresponds with the likelihood of persistent hypoxemia.[9] Limited documentation exists regarding the differences in pulmonary function testing related to overlap syndrome and COPD alone.

Laboratory evaluation

While unnecessary for establishing a diagnosis, laboratory abnormalities associated with overlap syndrome typically arise from the pathophysiology of overlap syndrome or a consequence of comorbidities. The risk of insulin resistance, regardless of obesity, diabetes, abnormal liver enzymes, and liver fibrosis, increases with OSA. Other potential laboratory abnormalities are normochromic normocytic anemia, polycythemia, and increased serum bicarbonate levels due to chronic hypercapnia.

Consideration of a complete blood count to evaluate for anemia, thyroid stimulating hormone levels, plasma brain natriuretic peptide (BNP) or N-terminal pro-BNP concentration for heart failure, serum electrolytes, and renal function is advisable for patients presenting with new onset dyspnea or excessive fatigue. In a single-center study that evaluated the association between microalbuminuria in patients with overlap syndrome versus OSA alone, microalbuminuria was more prevalent in patients with overlap syndrome. However, after adjusting for confounding variables such as diabetes and increased body mass index, both independent risk factors for microalbuminuria, researchers concluded that overlap syndrome is not an independent risk factor.[47] 

Radiographic 

Typical radiographic findings are:

• Lung hyperinflation
• Diaphragmatic flattening
• Increase in anterior-posterior diameter
• Bronchial wall thickening is associated with chronic bronchitis [31]

Treatment / Management

Overlap syndrome has a higher rate of morbidity and mortality than either condition alone. Therefore, concurrent management of both disorders is imperative to achieve optimal nocturnal oxygen saturation, prevent multiple arousals, and improve quality of life. 

Lifestyle Modifications and Exercise

• Structured exercise programs and pulmonary rehabilitation improve AHI, daytime sleepiness, and overall sleep quality. Particularly in COPD patients, structured exercise regimens improve skeletal muscle atrophy.[8]

• Pulmonary rehabilitation improves mood index, dyspnea scores, and quality of life while reducing the frequency of hospitalization.

• Weight loss has well-documented benefits for patients with OSA and obesity. Conversely, cachexia increases mortality in patients with advanced COPD. A clear distinction exists between therapeutic goal-directed weight loss and cachexia as part of the pathologic process in end-stage COPD.[8][9]

• Healthcare professionals must counsel all patients on smoking cessation. Smoking cessation reduces morbidity and mortality associated with overlap syndrome.

Supplemental Oxygen

Supplemental oxygen is a cornerstone in managing COPD by improving daytime and nocturnal hypoxemia and reducing mortality risk in affected patients. However, while oxygen supplementation mitigates nocturnal oxygen desaturations, it is ineffective in diminishing obstructive events in managing OSA. 

• Supplemental nocturnal oxygen is necessary when considerable nocturnal oxygen desaturations continue after the patient's medication regimen is optimized. Supplemental oxygen does not appear to be related to an increased risk of hypercapnia in these patients.[7]

• Earlier studies on nocturnal supplemental oxygen in apnea-prone patients with COPD reveal increased premature ventricular contractions. Patients with known coronary artery disease or left ventricular dysfunction should receive oxygen cautiously. Thus, oxygen therapy alone is not recommended to treat overlap syndrome.[9][48]

• In the recent International Nocturnal Oxygen (INOX) trial, nocturnal supplemental oxygen did not reduce mortality or delay the progression of long-term oxygen therapy in patients with COPD with nocturnal hypoxemia.[45][49]
(A1)

• Studies suggest that the effects of nasal high-flow air on a nocturnal gas exchange may be superior to oxygen supplementation.[7]

• Researchers in a relatively small study containing 40 patients older than 65 compared nasal high-flow oxygen treatment (NHF-OT) to conventional O2 treatment. Nasal high-flow oxygen therapy improved the severity of OSA, with nearly half of the patients having an AHI of <5 events/hour.[50]

Pharmacologic Therapies

Treatment regimens for patients with COPD are determined by the severity of symptoms and the risk of future exacerbations. Maintenance therapy typically involves the use of inhaled bronchodilators, usually long-acting beta-agonists and muscarinic antagonists, either alone or in combination, with the potential addition of inhaled glucocorticoids. All patients with COPD should have access to a short-acting bronchodilator. Generally, the preferred choice is a short-acting beta-agonist (SABA) to avoid combining a short-acting muscarinic agent (SAMA) with a long-acting muscarinic agent. Patients treated with long-acting beta-agonists alone or who use only short-acting therapy should use a combination of SABA-SAMA for rescue therapy due to the superior bronchodilator response compared to either agent alone. Patients with COPD should also receive pneumococcal, influenza, pertussis, COVID-19, and respiratory syncytial virus vaccinations.

• Mean nocturnal oxygen saturation improves approximately 2% to 3% after treatment with inhaled long-acting beta-agonist and anticholinergic medications compared to a placebo alone. Neither medication affects sleep quality.[7]

• Theophylline reduces nocturnal hypoxemia and benefits patients with OSA by reducing the AHI. Stimulation of the central respiratory drive is the likely mechanism of action and may be more beneficial in central sleep apnea. Side effects, however, limit the use of this medication.[51] 
(A1)

• Patients with a history of COPD exacerbations benefit from inhaled corticosteroids. The efficacy of inhaled corticosteroids for overlap syndrome is under debate. A study shows improved AHI, nocturnal hypoxemia, daytime PaCO2, and lung function by decreasing inflammation. Unfortunately, other studies demonstrate that inhaled corticosteroids may increase myopathy risk, worsening upper airway collapsibility.[45]
(B3)

• Respiratory stimulants such as acetazolamide improve oxygenation in patients with predominantly central sleep apnea, but the clinical benefit is not evident.[52]  Additionally, worsening respiratory acidosis limits the use of these medications.[45]
(B3)

Positive Airway Pressure and Noninvasive Ventilation 

The most appropriate and well-established therapeutic option for COPD-OSA overlap is PAP therapy, which has demonstrated efficacy in eliminating respiratory events, flow limitation, and snoring, (see Image. Polygraph Study of Patient on CPAP). Studies show that patients with hypoxemia, COPD, and concomitant OSA who undergo PAP treatment exhibit an increased survival rate than those who decline PAP therapy.[7] 

Likewise, patients undergoing PAP therapy experience fewer hospitalizations and emergency room visits from any cause, a lower rate of severe acute COPD exacerbations, and lower healthcare costs.[53] PAP therapy also decreases proinflammatory markers such as CRP and TNF-α, which are involved in developing and exacerbating cardiovascular disease.[45] (B3)

When selecting the type of PAP therapy for patients with COPD, it is essential to consider the underlying etiology of their condition. Patients with emphysema may experience increased sleep-related hypoventilation due to the downward displacement of the diaphragm and accessory muscle paralysis during REM sleep. These patients benefit from continuous positive airway pressure (CPAP) or EPAP to nullify patients' auto-positive end-expiratory pressure (PEEP) or the positive pressure that will remain in the airways at the end of the respiratory cycle. This therapy also supports ventilation and reduces muscle fatigue. Titrating CPAP is crucial, as studies indicate that if the applied PEEP exceeds auto-PEEP, it may increase expiratory load, dampen ventilation, and worsen lung function.

Some authors advocate using bilevel positive airway pressure (BPAP) in chronic bronchitis as it supports ventilation.[45] However, the superiority of BPAP over other forms of PAP therapy has not been conclusively demonstrated to date.[54](A1)

Recent studies evaluated the role of high-intensity noninvasive ventilation (NIV), particularly in patients with COPD and chronic hypercapnic respiratory failure.[55] This strategy utilizes high inspiratory positive airway pressure (IPAP) settings and a backup respiratory rate to elevate minute ventilation and normalize the PaCO2 or achieve a 20% decrease in CO2 levels.[56]. When titrated appropriately, this technique can potentially enhance these patients' survival outcomes.[57] (A1)

The titration of high-intensively NIV in stable patients with COPD-OSA and chronic hypercapnic respiratory failure requires an IPAP of 15 to 20 cm H2O. The EPAP level is determined based on the opening pressure identified during the PAP titration portion of the sleep study. If this information is unavailable, the EPAP setting can be empirically determined using the 10% rule based on the patient's body weight. For example, for a patient weighing 70 kg, the EPAP setting would be 7 cm H2O.[55]

Differential Diagnosis

COPD-OSA overlap syndrome may present similarly to other overlapping respiratory diseases, such as the coexistence of asthma and COPD.[55] To distinguish between these pathologies, pulmonary function testing and evaluation of symptomatology consistent with asthma are essential. Additionally, the absence of symptoms suggestive of OSA can aid in differentiation. 

The differential diagnoses for COPD include:

• Chronic obstructive asthma without risk factors for COPD
• Central airway obstruction
• Chronic bronchitis with normal spirometry
• Bronchiectasis
• Heart failure
• Tuberculosis
• Constrictive bronchiolitis
• Diffuse panbronchiolitis
• Lymphangioleiomyomatosis

The differential diagnoses for obstructive sleep apnea alone include:

• Nocturnal asthma
• Pulmonary edema
• Idiopathic hypersomnia
• Chronic insufficient sleep
• Nocturnal panic attacks
• Nonobstructive alveolar hypoventilation
• Obesity-hypoventilation syndrome or Pickwickian syndrome
• Periodic limb movement disorder
• Simple snoring [58][59][60] 

Pertinent Studies and Ongoing Trials

Multiple trials are ongoing to evaluate treatment strategies for overlap syndrome, focusing on the distinct phenotypic variations of COPD. One randomized controlled trial is investigating whether early diagnosis and initiation of PAP therapy in hospitalized patients can reduce 30-day readmission rates. Another clinical trial is comparing CPAP versus BPAP therapy in managing overlap syndrome. These trials hold promise in elucidating the optimal treatment approach for patients with overlap syndrome and potentially enhancing clinical outcomes.[45]

Prognosis

Overlap syndrome presents an increased risk of morbidity and mortality compared to either COPD or OSA alone. Patients affected by this syndrome face an elevated likelihood of cardiovascular morbidity, hospitalization due to COPD exacerbations, and increased all-cause mortality.[61] 

Treatment of OSA with CPAP has been shown to significantly reduce the risk of death and cardiovascular events independent of age, gender, BMI, and preexisting cardiovascular comorbidities. Additionally, strategies such as smoking cessation, long-term oxygen therapy, noninvasive ventilation, and pharmacologic interventions play crucial roles in mitigating the morbidity and mortality associated with COPD.

Complications

As assessed by the St. George's Respiratory Questionnaire, patients with overlap syndrome report a worse quality of life than those with COPD alone.[9]

Complications associated with overlap syndrome include the following:

• Hypertension
• Coronary artery disease 
• Myocardial infarction
• Peripheral arterial disease
• Heart failure
• Hyperlipidemia
• New-onset atrial fibrillation
• Pulmonary hypertension
• COPD exacerbations
• Bronchiectasis
• Motor vehicle collisions
• Impaired executive function
• Increased medical costs [41][61][5]

Improper treatment strategies in overlap syndrome may lead to reduced ventilation, deterioration of lung function, and poor adherence to therapy, ultimately impacting clinical outcomes. Research indicates that patients with emphysema exhibit lower adherence rates to CPAP therapy compared to other phenotypic variants, resulting in inadequate treatment and worsened clinical outcomes.[45] Moreover, bronchiectasis, associated with more severe nocturnal oxygen desaturations and increased sleep time spent with SpO2 below 90%, occurs more frequently in individuals with overlap syndrome.[5] This association underscores the significance of disease severity, particularly COPD severity, in shaping the clinical outcomes of overlap syndrome.[62]

Complications associated with COPD include the following:

• Cachexia
• Skeletal muscle wasting and disuse atrophy
• Normochromic normocytic anemic
• Secondary polycythemia
• Osteoporosis
• Depression and anxiety

Complications noted with OSA include:

• Motor vehicle collisions
• Stroke
• Insulin resistance
• Diabetes
• Nonalcoholic fatty liver disease [63]
• Sexual dysfunction [64]
• Possibly gout and venous thromboembolism