Sumita B. Khatri, MD, MS

Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley & Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley &amp; Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

Many patients who have obstructive lung disease, ie, chronic obstructive pulmonary disease (COPD) or asthma, also have obstructive sleep apnea (OSA), and vice versa.

The combination of COPD and OSA was first described almost 30 years ago by Flenley, who called it “overlap syndrome.”¹ At that time, he recommended that a sleep study be considered in all obese patients with COPD who snore and in those who have frequent headaches after starting oxygen therapy. In the latter group, he doubted that nocturnal oxygen was the correct treatment. He also believed that the outcomes in patients with overlap syndrome were worse than those in patients with COPD or OSA alone. These opinions remain largely valid today.

We now also recognize the combination of asthma and OSA (alternative overlap syndrome) and collectively call both combinations obstructive lung disease-obstructive sleep apnea (OLDOSA) syndrome.² Interestingly, these relationships are likely bidirectional, with one condition aggravating or predisposing to the other.

Knowing that a patient has one of these overlap syndromes, one can initiate continuous positive airway pressure (CPAP) therapy, which can improve clinical outcomes.^3–6  Therefore, when evaluating a patient with asthma or COPD, one should consider OSA using a validated questionnaire and, if the findings suggest the diagnosis, polysomnography. Conversely, it is prudent to look for comorbid obstructive lung disease in patients with OSA, as interactions between upper and lower airway dysfunction may lead to distinctly different treatment and outcomes.

Here, we briefly review asthma and COPD, explore shared risk factors for sleep-disordered breathing and obstructive lung diseases, describe potential pathophysiologic mechanisms explaining these associations, and highlight the importance of recognizing and individually treating the overlaps of OSA and COPD or asthma.

COPD AND ASTHMA ARE VERY COMMON

About 10% of the US population have COPD,⁷ a preventable and treatable disease mainly caused by smoking, and a leading cause of sickness and death worldwide.^8,9

About 10% of the US population have COPD, and 8% have asthma

About 8% of Americans have asthma,⁷ which has become one of the most common chronic conditions in the Western world, affecting about 1 in 7 children and about 1 in 12 adults. The World Health Organization estimates that 235 million people suffer from asthma worldwide, and by 2025 this number is projected to rise to 400 million.^10,11

The prevalence of these conditions in a particular population depends on the frequency of risk factors and associated morbidities, including OSA. These factors may allow asthma or COPD to arise earlier or have more severe manifestations.^8,12

Asthma and COPD: Similarities and differences

Asthma and COPD share several features. Both are inflammatory airway conditions triggered or perpetuated by allergens, viral infection, tobacco smoke, products of biomass or fossil fuel combustion, and other substances. In both diseases, airflow is “obstructed” or limited, with a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC). Symptoms can also be similar, with dyspnea, cough, wheezing, and chest tightness being the most frequent complaints. The similarities support the theory proposed by Orie et al¹³ (the “Dutch hypothesis”) that asthma and COPD may actually be manifestations of the same disease.

But there are also differences. COPD is strongly linked to cigarette smoking and has at least three phenotypes:

• Chronic bronchitis, defined clinically by cough and sputum production for more than 3 months per year for 2 consecutive years
• Emphysema, characterized anatomically by loss of lung parenchyma, as seen on tomographic imaging or examination of pathologic specimens
• A mixed form with bronchitic and emphysematous features, which is likely the most common.

Particularly in emphysematous COPD, smoking predisposes patients to gas-exchange abnormalities and low diffusing capacity for carbon monoxide.

In asthma, symptoms may be more episodic, the age of onset is often younger, and atopy is common, especially in allergic asthma. These episodic symptoms may correlate temporally with measurable airflow reversibility (≥ 12% and ≥ 200 mL improvement in FVC or in FEV₁ after bronchodilator challenge).

However, the current taxonomy does not unequivocally divide obstructive lung diseases into asthma and COPD, and major features such as airway hyperresponsiveness, airflow reversibility, neutrophilic or CD8 lymphocytic airway inflammation, and lower concentration of nitric oxide in the exhaled air may be present in different phenotypes of both conditions (Table 1).

AIRFLOW IN OBSTRUCTIVE LUNG DISEASES AND DURING SLEEP

Normal airflow involves a complex interplay between airway resistance and elastic recoil of the entire respiratory system, including the airways, the lung parenchyma, and the chest wall (Figure 1).

In asthma and COPD, resistance to airflow is increased, predominantly in the upper airways (nasal passages, pharynx, and larynx) and in the first three or four subdivisions of the tracheobronchial tree. The problem is worse during exhalation, when elastic recoil of the lung parenchyma and chest wall also increases airway resistance, reduces airway caliber, and possibly even constricts the bronchi. This last effect may occur either due to mass loading of the bronchial smooth muscles or to large intrathoracic transmural pressure shifts that may increase extravasation of fluid in the bronchial walls, especially with higher vascular permeability in inflammatory conditions.

Furthermore, interactions between the airway and parenchyma and between the upper and lower airways, as well as radial and axial coupling of these anatomic and functional components, contribute to complex interplay between airway resistance and parenchymal-chest wall elastic energy—stretch or recoil.

The muscles of the upper and lower airway may not work together due to the loss of normal lung parenchyma (as in emphysema) or to the acute inflammation in the small airways and adjacent parenchyma (as in severe asthma exacerbations). This loss of coordination makes the upper airway more collapsible, a feature of OSA.

Additionally, obesity, gastroesophageal reflux, disease chronic rhinitis, nasal polyposis, and acute exacerbations of chronic systemic inflammation all contribute to more complex interactions between obstructive lung diseases and OSA.⁶

Sleep affects breathing, particularly in patients with respiratory comorbidities, and sleep-disordered breathing causes daytime symptoms and worsens quality of life.^1,13–15 During sleep, respiratory centers become less sensitive to oxygen and carbon dioxide; breathing becomes more irregular, especially during rapid eye movement (REM) sleep; the chest wall moves less, so that the tidal volume and functional residual capacity are lower; sighs, yawns, and deep breaths become limited; and serum carbon dioxide concentration may rise.

OBSTRUCTIVE SLEEP APNEA

The prevalence of OSA, a form of sleep-disordered breathing characterized by limitation of inspiratory and (to a lesser degree) expiratory flow, has increased significantly in recent years, in parallel with the prevalence of its major risk factor, obesity.

OSA is generally defined as an apnea-hypopnea index of 5 or higher, ie, five or more episodes of apnea or hypopnea per hour.

Based on Ioachimescu OC, Teodorescu M. Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome. Respirology 2013; 18:421–431; with permission from John Wiley &amp; Sons, Inc.

OSA syndrome, ie, an apnea-hypopnea index of 5 or higher and excessive daytime sleepiness (defined by an Epworth Sleepiness Scale score > 10) was found in the initial analysis of the Wisconsin Sleep cohort in 1993 to be present in about 2% of women and 4% of men.¹⁶ A more recent longitudinal analysis showed a significant increase—for example, in people 50 to 70 years old the prevalence was up to 17.6% in men and 7.5% in women.¹⁷

Upper airway resistance syndrome, a milder form of sleep-disordered breathing, is now included under the diagnosis of OSA, as its pathophysiology is not significantly different.¹⁸

In the next section, we discuss what happens when OSA overlaps with COPD (overlap syndrome) and with asthma (“alternative overlap syndrome”)^2,8 (Figure 2).

OSA AND COPD (OVERLAP SYNDROME)

Flenley¹ hypothesized that patients with COPD in whom supplemental oxygen worsened hypercapnia may also have OSA and called this association overlap syndrome.

How common is overlap syndrome?

Since both COPD and OSA are prevalent conditions, overlap syndrome may also be common.

The reported prevalence of overlap syndrome varies widely, depending on the population studied and the methods used. In various studies, COPD was present in 9% to 56% of patients with OSA,^19–23 and OSA was found in 5% to 85% of patients with COPD.^24–27

Based on the prevalence of COPD in the general population (about 10%¹²) and that of sleep-disordered breathing (about 5% to 10%¹⁷), the expected prevalence of overlap syndrome in people over age 40 may be 0.5% to 1%.²⁸ In a more inclusive estimate with “subclinical” forms of overlap syndrome—ie, OSA defined as an apnea-hypopnea index of 5 or more (about 25% of the population¹⁷) and COPD Global initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (16.8% in the National Health and Nutrition Education Survey¹²)—the expected prevalence of overlap is around 4%. Some studies found a higher prevalence of COPD in OSA patients than in the general population,^21,29 while others did not.^22,28,30 The studies differed in how they defined sleep-disordered breathing.

Larger studies are needed to better assess the true prevalence of sleep-disordered breathing in COPD. They should use more sensitive measures of airflow and standardized definitions of sleep-disordered breathing and should include patients with more severe COPD.

Fatigue and insomnia are common in COPD

At near-maximal ventilatory capacity, even a mild increase in upper airway resistance increases the work of breathing

Fatigue is strongly correlated with declining lung function, low exercise tolerance, and impaired quality of life in COPD.³¹ Factors that contribute to fatigue include dyspnea, depression, and impaired sleep.³² Some suggest that at least half of COPD patients have sleep complaints such as insomnia, sleep disruption, or sleep fragmentation.³³ Insomnia, difficulty falling asleep, and early morning awakenings are the most common complaints (30%–70% of patients) and are associated with daytime fatigue.³⁴ Conversely, comorbid OSA can contribute to fatigue and maintenance-type insomnia (ie, difficulty staying asleep and returning to sleep).

Multiple mechanisms of hypoxemia in overlap syndrome

Oxygenation abnormalities and increased work of breathing contribute to the pathophysiology of overlap syndrome. In patients with COPD, oxygenation during wakefulness is a strong predictor of gas exchange during sleep.³⁵ Further, patients with overlap syndrome tend to have more severe hypoxia during sleep than patients with isolated COPD or OSA at rest or during exercise.³⁶

In overlap syndrome, hypoxemia is the result of several mechanisms:

• Loss of upper airway muscle tone from intermittent episodes of obstructive apnea and hypopnea leads to upper airway collapse during sleep, particularly during REM sleep, increasing the severity of OSA.³⁷
• Reductions in functional residual capacity from lying in the recumbent position and during REM sleep render patients with COPD more vulnerable, as compensatory use of accessory muscles to maintain near-normal ventilation in a hyperinflated state becomes impaired.³⁷
• Alterations in pulmonary ventilation-perfusion matching may lead to altered carbon dioxide homeostasis and impaired oxygenation in patients with emphysema.
• Circadian variation in lower airway caliber may also be observed, in parallel with the bronchoconstriction caused by increased nocturnal vagotonia.
• Hypercapnia (Paco₂ ≥ 45 mm Hg) may lead to overall reduced responsiveness of respiratory muscles and to a blunted response of respiratory centers to low oxygen and high carbon dioxide levels.³⁸ Thus, hypercapnia is a better predictor of the severity of nocturnal hypoxemia than hypoxemia developing during exercise.³⁹

In a person who is at near-maximal ventilatory capacity, even a mild increase in upper airway resistance (as seen with snoring, upper airway resistance syndrome, or OSA) increases the work of breathing. This phenomenon can lead to early arousals even before significant oxyhemoglobin desaturation occurs.

Normally, inspiratory flow limitation is counteracted by increasing inspiratory time to maintain ventilation. Patients with COPD may not be able to do this, however, as they need more time to breathe out due to narrowing of their lower airways.⁴⁰ The inability to compensate for upper airway resistance, similar to the increased work of breathing seen with exercise, may lead to early arousals and increased sleep fragmentation.

Consequences of overlap syndrome

Patients with overlap syndrome appear to have higher morbidity and mortality rates than those with COPD or sleep-disordered breathing alone.

Cor pulmonale. Nighttime hypoxia is more severe and persistent in overlap syndrome than with COPD or OSA alone. This may contribute to more significant pulmonary hypertension and to the development of cor pulmonale, in which the right ventricle is altered in structure (eg, hypertrophied, dilated) or reduced in function, or both, from severe pulmonary hypertension.

In contrast to right ventricular failure due to disorders of the left heart, cor pulmonale is a result of diseases of the vasculature (eg, idiopathic pulmonary arterial hypertension), lung parenchyma (eg, COPD), upper airway (eg, OSA), or chest wall (eg, severe kyphoscoliosis). COPD is the most common cause of cor pulmonale in the United States, accounting for up to 30% of cases of cor pulmonale.^41–45 In OSA, cor pulmonale is seen in up to 20% of cases,⁴³ while in overlap syndrome cor pulmonale is encountered even more often (ie, in up to 80%); these patients have a dismal 5-year survival rate of about 30%.⁴⁶

Obesity hypoventilation syndrome is characterized by obesity (body mass index ≥ 30 kg/m²) and daytime hypercapnia (Paco₂ ≥ 45 mm Hg) that cannot be fully attributed to an underlying cardiopulmonary or neurologic condition.¹⁸ Hypercapnia worsens during sleep (especially during REM sleep) and is often associated with severe arterial oxygen desaturation. Up to 90% of patients with obesity hypoventilation syndrome have comorbid OSA, and the rest generally have sleep-related hypoventilation, particularly during REM sleep.

Overlap syndrome with cor pulmonale typically has a poor prognosis; one study found a 5-year survival rate of 30%

In patients with obesity hypoventilation syndrome, daytime hypercapnia may improve or even normalize with adequate positive airway pressure treatment and sustained adherence to treatment.¹⁸ Many patients with obesity hypoventilation syndrome respond to CPAP or bilevel positive airway pressure (BPAP), with improvement in daytime Paco₂. However, normalization of daytime Paco₂ occurs only in a subgroup of patients. In contrast, treatment with oxygen therapy alone may worsen hypercapnia.

Oxygen therapy for pure COPD, but maybe not for overlap syndrome

Continuous oxygen therapy reduces mortality in COPD,^47,48 but the duration and severity of hypoxemia that warrant oxygen therapy are less clear. Oxygen therapy in hypoxemic patients has been shown to improve sleep quality and reduce arousals.⁴⁹

Indications for oxygen treatment of nocturnal hypoxemia are generally based on Medicare guidelines:

• At least 5 minutes of sleep with peripheral oxygen saturation ≤ 88% or Pao₂ ≤ 55 mm Hg, or
• A decrease in Pao₂ of more than 10 mm Hg or in peripheral oxygen saturation of more than 5% for at least 5 minutes of sleep and associated with signs or symptoms reasonably attributable to hypoxemia (group I criteria), or
• At least 5 minutes of sleep with peripheral oxygen saturation ≥ 89% or Pao₂ 56 to 59 mm Hg and pedal edema, pulmonary hypertension, cor pulmonale, or erythrocytosis (group II criteria).⁵⁰

Approximately 47% of COPD patients who are hypoxemic during the day spend about 30% of sleep time with an oxygen saturation less than 90%, even while on continuous oxygen therapy.⁵¹ Current recommendations for nocturnal oxygen therapy are to increase the oxygen concentration by 1 L/minute above the baseline oxygen flow rate needed to maintain an oxygen saturation higher than 90% during resting wakefulness, using a nasal cannula or face mask.⁵²

Caveat. In overlap syndrome, supplemental oxygen may prolong the duration of apnea episodes and worsen hypercapnia.

Positive airway pressure for OSA

Positive airway pressure therapy improves cardiovascular outcomes in OSA.⁵³ Several studies^54–58 compared the effectiveness of CPAP vs BPAP as initial therapy for OSA but did not provide enough evidence to favor one over the other in this setting. Similarly, the results are mixed for the use of fixed or auto-adjusting BPAP as salvage therapy in patients who cannot tolerate CPAP.^59–61

In overlap syndrome, CPAP or BPAP with or without supplemental oxygen has been investigated in several studies.^26,62–65 In general, the mortality rate of COPD patients who require oxygen therapy is quite high.^47,66 In hypoxemic COPD patients with moderate to severe sleep-disordered breathing, the 5-year survival rate was 71% in those treated with CPAP plus oxygen, vs 26% in those on oxygen alone, independent of baseline postbronchodilator FEV₁.⁶⁷

There is no specific FEV₁ cutoff for prescribing CPAP. In general, daytime hypercapnia and nocturnal hypoxemia despite supplemental oxygen therapy are indications for BPAP therapy, regardless of the presence of OSA. Whether noninvasive nocturnal ventilation for COPD patients who do not have OSA improves long-term COPD outcomes is not entirely clear.^65,68,69

Adding nocturnal BPAP in spontaneous timed mode to pulmonary rehabilitation for severe hypercapnic COPD was found to improve quality of life, mood, dyspnea, gas exchange, and decline in lung function.⁷⁰ Other studies noted that COPD patients hospitalized with respiratory failure who were randomized to noninvasive nocturnal ventilation plus oxygen therapy as opposed to oxygen alone experienced improvement in health-related quality of life and reduction in intensive-care-unit length of stay but no difference in mortality or subsequent hospitalizations.⁶⁹ In stable hypercapnic COPD patients without OSA, there is no clear evidence that nocturnal noninvasive ventilation lessens the risk of death despite improved daytime gas exchange,^71,72 but additional long-term studies are needed.

Lung volume reduction surgery, a procedure indicated for highly selected patients with severe COPD, has been shown to reduce hyperinflation, improve nocturnal hypoxemia, and improve total sleep time and sleep efficiency in patients without sleep-disordered breathing.⁷³ More studies are needed to determine if reduction in lung hyperinflation has an impact on the occurrence of OSA and on morbidity related to sleep-disordered breathing.

Benefit of CPAP in overlap syndrome

In a nonrandomized study, Marin et al⁶² found that overlap syndrome is associated with an increased risk of death and hospitalization due to COPD exacerbations. CPAP therapy was associated with improved survival rates and decreased hospitalization rates in these patients.

Stanchina et al,⁷⁴ in a post hoc analysis of an observational cohort, assessed the outcomes of 227 patients with overlap syndrome. Greater use of CPAP was found to be associated with lower mortality rates.

Jaoude et al⁷⁵ found that hypercapnic patients with overlap syndrome who were adherent to CPAP therapy had a lower mortality rate than nonadherent hypercapnic patients (P = .04). In a multivariate analysis, the comorbidity index was the only independent predictor of mortality in normocapnic patients with overlap syndrome, while CPAP adherence was associated with improved survival.

Lastly, patients with overlap syndrome tend to need more healthcare and accrue higher medical costs than patients with COPD alone. An analysis of a state Medicaid database that included COPD patients showed that beneficiaries with overlap syndrome spent at least $4,000 more in medical expenditures than beneficiaries with “lone” COPD.²⁴

In conclusion, CPAP is the first line of therapy for overlap syndrome, while daytime hypercapnia or nocturnal hypoxemia despite supplemental oxygen therapy are indications for nocturnal BPAP therapy, regardless of whether patients have OSA.

OSA AND ASTHMA (ALTERNATIVE OVERLAP SYNDROME)

Epidemiology and clinical features

The coexistence of asthma and OSA can begin in childhood and continue throughout adult life. A higher prevalence of lifetime asthma and OSA has been noted in children of racial and ethnic minorities, children of lower socioeconomic status, and those with atopy.⁷⁶

In a pediatric asthma clinic, it was noted that 12 months into structured asthma management and optimization, children with sleep-disordered breathing were nearly four times more likely to have severe asthma at follow-up, even after adjusting for obesity, race, and gender.⁷⁷

In adult patients with OSA, the prevalence of asthma is about 35%.⁷⁸ Conversely, people with asthma are at higher risk of OSA. High risk of OSA was more prevalent in a group of patients with asthma than in a general medical clinic population (39.5% vs 27.2%, P < .05).⁷⁹

Analysis of a large prospective cohort found that asthma was a risk factor for new-onset OSA. The incidence of OSA over 4 years in patients with self-reported asthma was 27%, compared with 16% without asthma. The relative risk adjusted for risk factors such as body mass index, age, and gender was 1.39 (95% confidence interval [CI] 15%–19%).⁸⁰

Patients with asthma who are at high risk of OSA are more likely to have worse daytime and nighttime asthma symptoms. Interestingly, patients who are diagnosed with OSA and treated with CPAP seem to have better asthma control.

Patients with asthma who are more likely to have OSA are women (odds ratio [OR] 2.1), have greater asthma severity (OR 1.6), have gastroesophageal reflux disease (OR 2.7), and use inhaled corticosteroids (OR 4.0).⁸¹ These associations are different than the traditional, population-wide risk factors for OSA, such as male sex, excess body weight, and nocturnal nasal congestion.⁸²

OSA also worsens asthma control. Teodorescu et al¹⁵ found that severe asthma was more frequent in older asthma patients (ages 60–75, prevalence 49%) than in younger patients (ages 18–59, 39%). Older adults with OSA were seven times as likely to have severe asthma (OR 6.6), whereas young adults with sleep apnea were only three times as likely (OR 2.6).

In a group of patients with difficult-to-treat asthma, OSA was significantly associated with frequent exacerbations (OR 3.4), an association similar in magnitude to that of psychological conditions (OR 10.8), severe sinus disease (OR 3.7), recurrent respiratory tract infections (OR 6.9), and gastroesophageal reflux disease (OR 4.9).⁸³ More than half of the patients had at least three of these comorbid conditions.

Sleep quality can greatly affect asthma control, and its importance is often underestimated. Patients with severe asthma have worse sleep quality than patients with milder asthma or nonasthmatic patients, even after excluding patients with a high risk of OSA, patients on CPAP therapy, and patients with a history of gastroesophageal reflux disease. Furthermore, regardless of asthma severity, sleep quality is a significant predictor of asthma-related quality of life, even after accounting for body mass index, daytime sleepiness, and gastroesophageal reflux disease.⁸⁴

Pathophysiology of alternative overlap syndrome

Sleep significantly affects respiratory pathophysiology in asthma. The underlying mechanisms include physical and mechanical stressors, neurohormonal changes, hypoxia, confounding medical conditions, and local and systemic inflammatory changes.

Patients with nocturnal asthma experience more pronounced obstruction when sleep-deprived, suggesting that sleep loss may contribute to worsening airflow limitation.¹⁴ Although changes in pulmonary mechanics and lung volumes may also have a role, volume-dependent airway narrowing does not appear to account for all observed nocturnal increases in airway resistance. Intrathoracic blood pooling may also contribute to nocturnal bronchoconstriction through stimulation of pulmonary C fibers and increased bronchial wall edema, a mechanism that may be similar to the “cardiac asthma” seen in left ventricular dysfunction.

Early studies of sleep-disordered breathing demonstrated that patients with asthma were breathing more irregularly (with hypopnea, apnea, and hyperpnea) in REM sleep than those without asthma.⁸⁵ Interestingly, REM-related hypoxia has also been noted in children with asthma.⁸⁶ This may be related to the increased cholinergic outflow that occurs during REM sleep, which in turn modulates the caliber and reactivity of the lower airways.

In overlap syndrome, oxygen may prolong the duration of apnea episodes and worsen hypercapnia

Physical changes such as upper airway collapse and reduced pharyngeal cross-sectional area may cause further mechanical strain.⁸⁷ This can further propagate airway inflammation, alter airway mucosal muscle fibers, and stimulate neural reflexes, thereby increasing cholinergic tone and bronchoconstriction. Furthermore, heightened negative intrathoracic pressure during obstructive episodes can increase nocturnal pulmonary blood pooling.¹⁴ Hypoxia itself can augment airway hyperresponsiveness via vagal pathways or carotid body receptors, increasing reactive oxygen species and inflammatory mediators. Local inflammation can “spill over” into systemic inflammatory changes, while alterations in airway inflammatory markers in asthma seem to follow a circadian rhythm, in parallel with the nocturnal worsening of the asthma symptoms.⁸⁸ Finally, altered sleep may be related to other comorbid conditions, such as gastroesophageal reflux disease, insomnia, and restless leg syndrome.

Management and outcomes of alternative overlap syndrome

Despite optimization of asthma management, OSA can still significantly affect asthma control and symptoms.⁸⁴

Interestingly, medications that reduce airway inflammation (eg, corticosteroids) may promote OSA. This occurrence cannot be fully explained by an increase in body mass, as more respiratory disturbances occur during sleep with continuous corticosteroid treatment even without increases in body mass index.⁸⁷ Therefore, these associations may be related to upper airway myopathy caused by the treatment, a small pharynx, facial dysmorphisms, or fat deposition.⁸⁹

Does CPAP improve asthma?

OSA is often unrecognized in patients with asthma, and treating it can have an impact on asthma symptoms.

CPAP therapy has not been shown to significantly change airway responsiveness or lung function, but it has been noted to significantly improve both OSA-related and asthma-related quality of life and reduce the use of rescue bronchodilators.^3,90 CPAP has demonstrated improvement of quality of life that positively correlated with body weight and apnea-hypopnea index at baseline, suggesting that asthmatic patients with greater obesity or worse OSA may benefit most from aggressive management.⁹⁰

However, CPAP should be used only if the patient has confirmed OSA. Empiric use of CPAP without a diagnosis of OSA was poorly tolerated and failed to improve asthma symptoms or lung function.⁹¹ More importantly, using CPAP in a patient who does not have OSA may contribute to further sleep disruption.⁹¹

Second-line treatments such as mandibular advancing devices and airway or bariatric surgery have not yet been studied in alternative overlap syndrome.

A multidimensional assessment of asthma

The Western world is experiencing an epidemic of obesity and of asthma. Obesity contributes to the pathogenesis of OSA by altering the anatomy and collapsibility of the upper airway, affecting ventilatory control and increasing respiratory workload. Another paradigm, supported by some evidence, is that OSA itself may contribute to the development of obesity. Both OSA and obesity lead to activation of inflammatory biologic cascades, which are likely the pathogenic mechanisms for their cardiovascular and metabolic consequences. As such, early recognition of OSA is important, as effective treatments are available.

In some patients, obesity may cause asthma, as obesity precedes the onset of asthma in a significant proportion of patients, and bariatric surgery for morbid obesity may resolve asthma. The obese asthma phenotype seems to include chronic rhinosinusitis, gastroesophageal reflux disease, poorer asthma control, limited responsiveness to corticosteroids, and even different sets of biomarkers (eg, neutrophilic airway inflammation). A cohort of obese patients with poor asthma control demonstrated significant improvement in asthma symptoms, quality of life, and airway reactivity after weight loss from bariatric surgery.⁹²

To improve our knowledge about airway disease phenotypes and endotypes and their response to therapy, we propose taking a multidimensional, structured assessment of all patients with asthma, using a schema we call “ABCD-3P-PQRST” (Table 2).

The purpose of using this type of system in clinics and research is to capture the multi­dimensionality of the disease and better develop future individualized therapeutic strategies by employing the latest advances in systems biology and computational methods such as cluster and principal component analysis.

Multidimensional assessments addressing airway problems such as asthma, COPD, OSA, other comorbidities and risk factors, and personalized management plans will need to be the basis of future therapeutic interventions. Increased attention to the complications of asthma and obstructive airway and lung diseases in our patients is imperative, specifically to develop effective systems of care, appropriate clinical guidelines, and research studies that lead to improved health outcomes.

Asthma now has a new treatment, but it isn’t for everybody. Called bronchial thermoplasty, it is reserved for patients whose asthma is severe and refractory, as it involves three sessions of bronchoscopy, each lasting up to 1 hour, during which the smooth muscle layer is methodically ablated from the airway using radiofrequency energy.^1,2

See related editorial

The US Food and Drug Administration (FDA) has approved bronchial thermoplasty,³ and although it does not cure asthma or completely eliminate its symptoms, patients with severe asthma that was not well controlled with medical therapy who underwent this procedure in clinical trials subsequently had fewer symptoms, enjoyed better quality of life, and needed less intensive health care (such as emergency room visits) than patients who did not undergo the procedure.^4–6

Here, we present an overview of the pathophysiology of severe refractory asthma and the clinical trials of bronchial thermoplasty, its current protocols, and the status of this new treatment.

WHAT IS SEVERE REFRACTORY ASTHMA?

Asthma is a chronic inflammatory condition of the airways characterized by episodic symptoms of breathlessness, cough, and wheezing, which can wax and wane over time. Approximately 8.2% of the general population is affected.⁷

Our understanding of the pathophysiology of asthma has improved over the past 20 years, and with the publication of clinical guidelines from the National Asthma Education and Prevention Program in 1991,⁸ 1997,⁹ and 2002,¹⁰ outcomes have improved. Most people with asthma can control their symptoms if they adhere to anti-inflammatory therapies and avoid triggers. Yet 5% to 10% of asthma patients have severe refractory disease, and asthma accounts for nearly half a million hospitalizations every year.¹¹

The latest guidelines, published in 2007, emphasize the importance of assessing the severity of asthma, including the patient’s impairment (symptoms and limitations) and risk (likelihood of exacerbations).¹²

Workshop consensus definition of severe refractory asthma

A consensus group convened by the American Thoracic Society¹³ defined asthma as severe and refractory if the patient meets at least one of the following major criteria:

• Takes oral corticosteroids continuously or nearly continuously (> 50% of year)
• Takes high-dose inhaled corticosteroids.

In addition, the patient must meet at least two minor criteria, ie:

• Takes a controller medication such as a long-acting beta-agonist, theophylline, or a leukotriene antagonist every day
• Takes a short-acting beta agonist every day or nearly every day
• Has persistent airway obstruction, ie, a forced expiratory volume in 1 second (FEV₁) less than 80% of predicted, or a peak expiratory flow that has a diurnal variability greater than 20%
• Has one or more urgent care visits for asthma per year
• Needs three or more oral corticosteroid “bursts” per year
• Has prompt deterioration when the dose of oral or inhaled corticosteroid is reduced by 25% or less
• Has had a near-fatal asthma event in the past.

Compared with people with mild asthma, people who have severe refractory asthma tend to be older, have fewer allergies, and make more use of intensive and urgent health care.¹⁴

Asthma is due to both inflammation and bronchoconstriction

The pathophysiology of asthma involves both chronic airway inflammation and bronchoconstriction, the latter characterized by a greater response to methacholine. Histologic findings include excessive mucus secretion, epithelial cell injury, and smooth muscle hypertrophy. These changes can lead to persistent airflow obstruction that can be difficult to control with medical therapies.¹²

Bronchoconstriction can be reversed temporarily with bronchodilators, but no longlasting therapy to reduce it has been available until now. Bronchial thermoplasty targets this gap in asthma management.

STUDIES OF BRONCHIAL THERMOPLASTY

Radiofrequency ablation has been used to treat other medical conditions such as lung cancer and cardiac arrhythmias.^15,16 Its use to treat asthma by eradicating smooth muscle cells from the airway wall began with studies in animals.¹ Later, studies were done in people without asthma,² then in patients with mild to moderate asthma,¹⁷ and finally in patients with moderate to severe refractory asthma.^4–6

These studies helped clarify which type of patients would be appropriate candidates and the outcomes to be anticipated, including adverse events.

Early studies

Danek et al,¹ in a study in nonasthmatic dogs, found that thermoplasty at 65°C or 75°C (149°F or 167°F) attenuated the airway’s response to methacholine up to 3 years after treatment. As early as 1 week after treatment, airway smooth muscle was seen to be degenerating or absent, and the effect was inversely proportional to airway responsiveness.

Adverse effects of the procedure were cough, inflammatory edema of the airway wall, retained mucus, and blanching of the airway wall at the site of catheter contact. Three years later, there was no evidence of smooth muscle regeneration.

Miller et al² next performed a feasibility study in eight patients, mean age 58 ± 8.3 years, who were scheduled to undergo lung resection for lung cancer. Five to 20 days before surgery, the investigators performed thermoplasty at 55°C or 65°C (131°F or 149°F) in three to nine sites per patient, 1 cm from known tumors but within areas to be resected. There were no significant adverse events such as hemoptysis, respiratory infections, or excess bronchial irritation.

Cox et al¹⁷ performed the first study of bronchial thermoplasty in patients with mild to moderate asthma. This was a prospective observational study in 16 patients who were younger than the patients in the previous study, with an average age of 30 years (range 24–58). They were given prednisone 30 or 50 mg the day before the procedure and on the day of the procedure. Three treatments were done, 3 weeks apart. The right middle lobe was not treated because the bronchus leading to it is relatively long and narrow, raising concern about damaging it.¹⁸

Results. The most frequent side effects were symptoms of airway irritation such as cough, dyspnea, wheezing, and bronchospasm. The mean time to onset was less than 1.7 days, and the mean time to resolution was 4.6 days after the most recent procedure. None of the patients needed to be hospitalized in the immediate postprocedure period.

In the 2 years after the procedure, there were 312 adverse events, mainly mild. Three (1%) of the adverse events were reported as severe, but they were deemed not related to the procedure. Yearly computed tomographic scans of the chest showed no structural changes such as bronchiectasis in the parenchyma or bronchial wall.

The FEV₁ was higher at 12 weeks and at 1 year after thermoplasty than at baseline but was not significantly different from baseline at 2 years.

At baseline, the patients reported that 50% of their days were symptom-free; this increased to 73% at 12 weeks (P = .015).

In addition, airway hyperresponsiveness decreased significantly, and the effect persisted over 2 years. The provocative concentration of methacholine that caused a 20% reduction in FEV₁ (the PC₂₀) was:

• 0.92 mg/mL at baseline (95% confidence interval 0.42–1.99)
• 4.75 mg/mL at 12 weeks (2.51–8.85)
• 5.45 mg/mL at 1 year (1.54–19.32)
• 3.40 mg/mL at 2 years (1.35–8.52).

Limitations of this study include the relatively small number of patients enrolled and their relatively stable asthma.

The AIR trial: A randomized trial in moderate or persistent asthma

The first large multicenter trial of bronchial thermoplasty, the Asthma Intervention Research (AIR) trial,⁴ was prospective and randomized but not blinded. The aim was to determine whether bronchial thermoplasty would improve asthma control after long-acting beta agonists were discontinued.

Patients could be enrolled if they were 18 to 65 years old, had moderate or persistent asthma, and needed to take an inhaled corticosteroid (beclomethasone [Qvar] 200 μg or more or an equivalent drug) and a long-acting beta agonist (salmeterol [Serevent] 100 μg or more or an equivalent drug) every day. They also needed to have FEV₁ values of 60% to 85% of predicted and airway reactivity (PC₂₀ < 8 mg/mL), and their asthma had to have been stable for 6 weeks.

At baseline, the long-acting beta agonist was withdrawn temporarily; the final criterion for entry was that their asthma had to become worse when this was done.

Then, 112 patients were randomized to receive either bronchial thermoplasty with medical care (inhaled corticosteroids and long-acting beta agonists) or usual care, ie, medical therapy alone. Treatments were done in three sessions over 9 weeks, followed by attempts to discontinue their long-acting beta agonists at 3, 6, and 9 months after the procedure without exacerbations.

An exacerbation was defined as at least one of the following for 2 consecutive days: a reduction of peak flow by 20% of baseline average, the need for more than three additional puffs of rescue inhaler, or nocturnal awakenings caused by asthma symptoms. The patients kept a daily diary of their symptoms and rescue inhaler use, and they completed the Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ).

Results. The number of mild (but not severe) exacerbations per week was significantly lower at 3 and 12 months than at baseline in the thermoplasty group, with 10 fewer mild exacerbations per patient per year, but was unchanged in the control group. There were significantly greater improvements in morning peak flow at 3, 6, and 12 months from baseline in the treatment group than in the usual-care group. Rescue medication use was also significantly less at 3 and 12 months. Symptom scores, AQLQ scores, and ACQ scores were all significantly better than at baseline as well.

Not surprisingly, in this cohort with unstable asthma, there were 407 adverse events in the treatment group and 106 adverse events in the control group. Most of these occurred within 1 day and resolved within 7 days after the procedure. There were more hospitalizations in the treatment group as well, for reasons that included exacerbations of asthma, collapse of the left lower lobe, and pleurisy.⁴

Therefore, this trial found that thermoplasty improved asthma symptoms within 3 months and that the effect lasted 1 year, with an encouraging reduction in the number of mild exacerbations. However, it was not blinded, and there is a strong placebo effect in asthma. Needed was a randomized trial in which the control group would undergo a sham treatment.

The RISA trial: A randomized trial in severe asthma

The Research in Severe Asthma (RISA) trial⁵ included patients with more severe asthma than those in the AIR trial. Entry criteria were:

• Taking high doses of an inhaled corticosteroid (> 750 μg of fluticasone or its equivalent per day)
• Taking prednisone (≤ 30 mg/day)
• An FEV₁ of at least 50% of predicted without a bronchodilator
• A positive methacholine test.

Seventeen patients were randomized to undergo bronchial thermoplasty, and another 17 were randomized to receive medical treatment.

After a 2-week run-in period, the thermoplasty patients underwent three treatments, performed 3 weeks apart. For the next 16 weeks, the corticosteroid doses were kept stable in both groups, followed by a 14-week corticosteroid-weaning phase and then a 16-week reduced-corticosteroid phase. During this time, attempts were made to decrease the oral or inhaled corticosteroid doses according to a protocol (eg, a 20%–25% reduction every 2–4 weeks) unless there were mild exacerbations lasting more than 7 days.

Results. There were more adverse events in the thermoplasty group than in the medical management group in the treatment period, including seven hospitalizations for exacerbations of asthma and a partial collapse of the left lower lobe. There were no significant differences in adverse events between groups in the posttreatment period (up to 6 weeks after the last treatment). Forty-nine percent of the events were mild in each group; 10% of the events were severe in the thermoplasty group vs 4% in the control group.

During the steroid-stable phase, patients in the thermoplasty group used rescue inhalers significantly less than those in the control group, and their prebronchodilator FEV₁ and AQLQ and ACQ scores were better. The differences in rescue inhaler use and questionnaire scores remained significant at 1 year.

Comment. As expected, serious adverse events occurred more often in patients with severe asthma in the treatment group than in the control group. However, 1 year after the procedure, the adverse-event rates were similar in the treatment and control groups, suggesting that this procedure can be safely performed in similar patient populations. Although there was significant potential for a placebo effect, these patients with severe persistent asthma showed significant improvement in clinical measures of asthma compared with the control group.

The latest trial of this new therapy in severe asthma was the AIR2 trial.⁶ A major difference in its design compared with the earlier ones was that the control group underwent sham thermoplasty, allowing the trial to be truly double-blinded. (The bronchoscopy team knew which patients got which treatment, but the patients and the study physicians following them did not).

The primary outcome was the change in AQLQ score from baseline at 6, 9, and 12 months. Secondary outcomes included absolute changes in the asthma control scores, symptom scores, peak flows, rescue medication use, and FEV₁.

The randomized groups (196 patients in the thermoplasty group and 101 in the sham treatment group) were well matched, and more than 80% in each group met the American Thoracic Society criteria for severe refractory asthma.

On the AQLQ, a change of more than 0.5 is considered clinically meaningful. Interestingly, there was a significant and clinically meaningful improvement in AQLQ in 64% of the sham treatment group, highlighting the placebo effect in asthma treatment.¹⁹ However, a larger proportion (79%) of the treated group had a clinically meaningful improvement on the AQLQ than in the sham treatment group.

Adverse events occurred in both groups; however, during the treatment phase, 16 patients in the bronchial thermoplasty group needed to be hospitalized for respiratory symptoms including worsening asthma, atelectasis, lower respiratory tract infections, decreased FEV₁, and an aspirated tooth. One episode of hemoptysis required bronchial artery embolization. In contrast, only two patients in the sham treatment group needed hospitalization.

Therefore, this trial showed that patients with severe asthma treated with bronchial thermoplasty had a long-term improvement in quality of life and needed less health care.⁶

Translating these trials into practice

To summarize, these clinical trials showed that bronchial thermoplasty was feasible, was relatively safe, and produced better clinical outcomes in patients with severe asthma when medical therapies did not control their symptoms.

In practice, patient selection is likely to be important. A key question will be, Does the patient truly have severe refractory asthma, or is the patient not taking his or her medication? Adherence to therapy should be evaluated.

In addition, patients need to be observed and monitored closely during and after the treatment period, as airway complications and asthma exacerbations can occur up to 6 weeks after the last procedure. About 80% of all study patients had multiple symptoms of asthma and other symptoms in the treatment period. Rarely did these symptoms result in hospitalization, but they were more common in the treatment group in the AIR2 trial.

Long-term studies have evaluated the duration of effect and the safety of bronchial thermoplasty, and outcomes appear favorable.^20,21

WHY DOES IT WORK?

The role of airway smooth muscle in asthma is yet to be fully elucidated. The trials outlined here showed that although asthma is a disease of the airways, including the small airways, treatment of airways 3 mm or larger improves asthma symptoms, quality of life, and health care utilization.⁶ Thus, the role of airway smooth muscle in asthma and as a target of therapy has not previously been fully realized.²¹

Early investigations into the mechanisms of airflow obstruction and airway resistance found that 75% of postnasal resistance occurs in the first six to eight generations (ie, branchings) of the airways, indicating that larger airways are involved.²² (The number of generations varies depending on the size of the person but it typically is 10 to 12.) Findings from the study in dogs introduced the idea that smooth muscle alterations contributed to the changes in airway resistance, and that subtle changes in airway smooth muscle could clinically benefit asthma patients.¹

The speculated purpose of the airway smooth muscle layer is to support the airway, allow gas exchange, propel mucus for clearance, defend the airway, enhance cough, and promote lymphatic flow. However, the airway smooth muscle layer may also be vestigial. In asthma, airway smooth muscle adds to bronchoconstriction and hyperresponsiveness, and has a role in mediating inflammation and airway remodeling.²¹ No definitive studies have shown that eliminating airway smooth muscle greatly inhibits normal airway function.¹⁸

What exactly does thermoplasty do to the smooth muscle? Studies in smooth muscle from cows showed that high temperatures directly disrupt the actin-myosin interaction, likely through denaturation of motor proteins.²³ This immediate loss of muscle cell function is not likely to be the result of apoptosis, autophagy, or necrosis, or mediated by heat-shock proteins, in view of the relatively quick muscle response and lack of progressive changes. Tissue responsiveness is substantially reduced a few seconds after application of 60°C of heat and is subsequently abolished within 5 minutes after treatment.²³

The intervention appears to be dose-dependent. Responsiveness to cholinergic stimulation is lessened by treatment, and the desired effect is seen within seconds and does not progress.

Therefore, we can surmise that disruption of myosin function is likely the mechanism of the therapeutic effect, breaking the cascade of airway smooth muscle spasm. Now that we know about the airway smooth muscle as a possible target of therapy, and that it may play only a vestigial role, we can think about other therapies that focus on it.^18,23

BRONCHIAL THERMOPLASTY PROTOCOLS

Patients are assessed before and on the day of the procedure to make sure their disease is stable (ie, their postbronchodilator FEV₁ is within 15% of baseline values, and they have no evidence of asthma exacerbation or active infection), similar to the protocol used in the AIR2 trial,⁶ before proceeding with the treatment.

Patients are given 50 mg of prednisone 3 days before and again on the day of the procedure. Nebulized albuterol (2.5–5.0 mg) is given before the patients undergo screening spirometry and again before the procedure. If the preprocedure FEV₁ is lower than 15% below baseline, we postpone the procedure to another day.

The procedure is performed with the patient under moderate conscious sedation, typically using fentanyl (Sublimaze), midazolam (Versed), and topical lidocaine in a monitored environment. The bronchoscope is inserted via either the mouth or nose, and supplemental oxygen is provided.

Thermoplasty is performed with the Alair system (Asthmatx, Inc., Sunnyvale, CA), which delivers a specific amount of radiofrequency (thermal) energy through a dedicated catheter. The catheter is deployed through a 2.0-mm channel of a flexible bronchoscope, starting in distal airways as small as 3 mm in diameter and working proximally to sequentially treat all airways to the mainstem lobar bronchi. The sites treated are meticulously recorded on a bronchial airway map to ensure that treatment sites are not skipped or overlapped (FIGURE 1).

An array of four electrodes is manually expanded to make contact with the airway walls; each electrode has 5 mm of exposed wire. As the energy is delivered, the control unit measures electrical resistance converted to thermal energy and turns off the current when an appropriate dosage is given. This thermal energy is what is responsible for altering the airway smooth muscle.

A full course of treatment requires three separate bronchoscopy sessions, each separated by 2 to 3 weeks. The left lower lobe and the right lower lobe are treated in separate procedures, and then both upper lobes are treated in a third procedure to minimize any respiratory symptoms. Each procedure usually requires 50 to 75 activations of the device and takes up to 60 minutes.

After each procedure the patient should be observed for 3 to 4 hours, and spirometry should be repeated to make sure the FEV₁ (percent predicted) is within 20% of the baseline value. An additional 50-mg dose of prednisone is prescribed for the day after the procedure.²⁴

FDA CLEARANCE AND LONG-TERM FOLLOW-UP

The FDA approved the Alair device for treating severe refractory asthma in early 2010.³ The indications for it are based on the study populations in the published trials. Patients can be evaluated for this treatment if they have well-documented severe persistent asthma not well controlled on inhaled corticosteroids and long-acting beta agonists and have no significant contraindications to bronchoscopy.

As part of the conditions of approval, the FDA required a postapproval study based on the long-term follow-up of the AIR2 trial. They specifically wanted to compare patients who have desirable long-term outcomes and those in whom any treatment effect wanes with time. Since we have only a few years of follow-up data, we still do not know all the possible late effects of the treatment; we have an opportunity to learn more.

Another question that needs to be studied is whether thermoplasty will help other forms of bronchospastic lung disease, such as chronic obstructive pulmonary disease.

A second postapproval study will be a prospective, open-label, single-arm, multicenter study conducted in the United States to assess the treatment effect and short-term and long-term safety profile of thermoplasty in asthma.

As experience with the procedure increases, we will be better able to characterize which patients may benefit from it. In addition, the knowledge gained by the longer-term study of airway smooth muscle function alterations will potentially drive the discovery of other innovative therapies for severe asthma.

Asthma now has a new treatment, but it isn’t for everybody. Called bronchial thermoplasty, it is reserved for patients whose asthma is severe and refractory, as it involves three sessions of bronchoscopy, each lasting up to 1 hour, during which the smooth muscle layer is methodically ablated from the airway using radiofrequency energy.^1,2

See related editorial

The US Food and Drug Administration (FDA) has approved bronchial thermoplasty,³ and although it does not cure asthma or completely eliminate its symptoms, patients with severe asthma that was not well controlled with medical therapy who underwent this procedure in clinical trials subsequently had fewer symptoms, enjoyed better quality of life, and needed less intensive health care (such as emergency room visits) than patients who did not undergo the procedure.^4–6

Here, we present an overview of the pathophysiology of severe refractory asthma and the clinical trials of bronchial thermoplasty, its current protocols, and the status of this new treatment.

WHAT IS SEVERE REFRACTORY ASTHMA?

Asthma is a chronic inflammatory condition of the airways characterized by episodic symptoms of breathlessness, cough, and wheezing, which can wax and wane over time. Approximately 8.2% of the general population is affected.⁷

Our understanding of the pathophysiology of asthma has improved over the past 20 years, and with the publication of clinical guidelines from the National Asthma Education and Prevention Program in 1991,⁸ 1997,⁹ and 2002,¹⁰ outcomes have improved. Most people with asthma can control their symptoms if they adhere to anti-inflammatory therapies and avoid triggers. Yet 5% to 10% of asthma patients have severe refractory disease, and asthma accounts for nearly half a million hospitalizations every year.¹¹

The latest guidelines, published in 2007, emphasize the importance of assessing the severity of asthma, including the patient’s impairment (symptoms and limitations) and risk (likelihood of exacerbations).¹²

Workshop consensus definition of severe refractory asthma

A consensus group convened by the American Thoracic Society¹³ defined asthma as severe and refractory if the patient meets at least one of the following major criteria:

• Takes oral corticosteroids continuously or nearly continuously (> 50% of year)
• Takes high-dose inhaled corticosteroids.

In addition, the patient must meet at least two minor criteria, ie:

• Takes a controller medication such as a long-acting beta-agonist, theophylline, or a leukotriene antagonist every day
• Takes a short-acting beta agonist every day or nearly every day
• Has persistent airway obstruction, ie, a forced expiratory volume in 1 second (FEV₁) less than 80% of predicted, or a peak expiratory flow that has a diurnal variability greater than 20%
• Has one or more urgent care visits for asthma per year
• Needs three or more oral corticosteroid “bursts” per year
• Has prompt deterioration when the dose of oral or inhaled corticosteroid is reduced by 25% or less
• Has had a near-fatal asthma event in the past.

Compared with people with mild asthma, people who have severe refractory asthma tend to be older, have fewer allergies, and make more use of intensive and urgent health care.¹⁴

Asthma is due to both inflammation and bronchoconstriction

The pathophysiology of asthma involves both chronic airway inflammation and bronchoconstriction, the latter characterized by a greater response to methacholine. Histologic findings include excessive mucus secretion, epithelial cell injury, and smooth muscle hypertrophy. These changes can lead to persistent airflow obstruction that can be difficult to control with medical therapies.¹²

Bronchoconstriction can be reversed temporarily with bronchodilators, but no longlasting therapy to reduce it has been available until now. Bronchial thermoplasty targets this gap in asthma management.

STUDIES OF BRONCHIAL THERMOPLASTY

Radiofrequency ablation has been used to treat other medical conditions such as lung cancer and cardiac arrhythmias.^15,16 Its use to treat asthma by eradicating smooth muscle cells from the airway wall began with studies in animals.¹ Later, studies were done in people without asthma,² then in patients with mild to moderate asthma,¹⁷ and finally in patients with moderate to severe refractory asthma.^4–6

These studies helped clarify which type of patients would be appropriate candidates and the outcomes to be anticipated, including adverse events.

Early studies

Danek et al,¹ in a study in nonasthmatic dogs, found that thermoplasty at 65°C or 75°C (149°F or 167°F) attenuated the airway’s response to methacholine up to 3 years after treatment. As early as 1 week after treatment, airway smooth muscle was seen to be degenerating or absent, and the effect was inversely proportional to airway responsiveness.

Adverse effects of the procedure were cough, inflammatory edema of the airway wall, retained mucus, and blanching of the airway wall at the site of catheter contact. Three years later, there was no evidence of smooth muscle regeneration.

Miller et al² next performed a feasibility study in eight patients, mean age 58 ± 8.3 years, who were scheduled to undergo lung resection for lung cancer. Five to 20 days before surgery, the investigators performed thermoplasty at 55°C or 65°C (131°F or 149°F) in three to nine sites per patient, 1 cm from known tumors but within areas to be resected. There were no significant adverse events such as hemoptysis, respiratory infections, or excess bronchial irritation.

Cox et al¹⁷ performed the first study of bronchial thermoplasty in patients with mild to moderate asthma. This was a prospective observational study in 16 patients who were younger than the patients in the previous study, with an average age of 30 years (range 24–58). They were given prednisone 30 or 50 mg the day before the procedure and on the day of the procedure. Three treatments were done, 3 weeks apart. The right middle lobe was not treated because the bronchus leading to it is relatively long and narrow, raising concern about damaging it.¹⁸

Results. The most frequent side effects were symptoms of airway irritation such as cough, dyspnea, wheezing, and bronchospasm. The mean time to onset was less than 1.7 days, and the mean time to resolution was 4.6 days after the most recent procedure. None of the patients needed to be hospitalized in the immediate postprocedure period.

In the 2 years after the procedure, there were 312 adverse events, mainly mild. Three (1%) of the adverse events were reported as severe, but they were deemed not related to the procedure. Yearly computed tomographic scans of the chest showed no structural changes such as bronchiectasis in the parenchyma or bronchial wall.

The FEV₁ was higher at 12 weeks and at 1 year after thermoplasty than at baseline but was not significantly different from baseline at 2 years.

At baseline, the patients reported that 50% of their days were symptom-free; this increased to 73% at 12 weeks (P = .015).

In addition, airway hyperresponsiveness decreased significantly, and the effect persisted over 2 years. The provocative concentration of methacholine that caused a 20% reduction in FEV₁ (the PC₂₀) was:

• 0.92 mg/mL at baseline (95% confidence interval 0.42–1.99)
• 4.75 mg/mL at 12 weeks (2.51–8.85)
• 5.45 mg/mL at 1 year (1.54–19.32)
• 3.40 mg/mL at 2 years (1.35–8.52).

Limitations of this study include the relatively small number of patients enrolled and their relatively stable asthma.

The AIR trial: A randomized trial in moderate or persistent asthma

The first large multicenter trial of bronchial thermoplasty, the Asthma Intervention Research (AIR) trial,⁴ was prospective and randomized but not blinded. The aim was to determine whether bronchial thermoplasty would improve asthma control after long-acting beta agonists were discontinued.

Patients could be enrolled if they were 18 to 65 years old, had moderate or persistent asthma, and needed to take an inhaled corticosteroid (beclomethasone [Qvar] 200 μg or more or an equivalent drug) and a long-acting beta agonist (salmeterol [Serevent] 100 μg or more or an equivalent drug) every day. They also needed to have FEV₁ values of 60% to 85% of predicted and airway reactivity (PC₂₀ < 8 mg/mL), and their asthma had to have been stable for 6 weeks.

At baseline, the long-acting beta agonist was withdrawn temporarily; the final criterion for entry was that their asthma had to become worse when this was done.

Then, 112 patients were randomized to receive either bronchial thermoplasty with medical care (inhaled corticosteroids and long-acting beta agonists) or usual care, ie, medical therapy alone. Treatments were done in three sessions over 9 weeks, followed by attempts to discontinue their long-acting beta agonists at 3, 6, and 9 months after the procedure without exacerbations.

An exacerbation was defined as at least one of the following for 2 consecutive days: a reduction of peak flow by 20% of baseline average, the need for more than three additional puffs of rescue inhaler, or nocturnal awakenings caused by asthma symptoms. The patients kept a daily diary of their symptoms and rescue inhaler use, and they completed the Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ).

Results. The number of mild (but not severe) exacerbations per week was significantly lower at 3 and 12 months than at baseline in the thermoplasty group, with 10 fewer mild exacerbations per patient per year, but was unchanged in the control group. There were significantly greater improvements in morning peak flow at 3, 6, and 12 months from baseline in the treatment group than in the usual-care group. Rescue medication use was also significantly less at 3 and 12 months. Symptom scores, AQLQ scores, and ACQ scores were all significantly better than at baseline as well.

Not surprisingly, in this cohort with unstable asthma, there were 407 adverse events in the treatment group and 106 adverse events in the control group. Most of these occurred within 1 day and resolved within 7 days after the procedure. There were more hospitalizations in the treatment group as well, for reasons that included exacerbations of asthma, collapse of the left lower lobe, and pleurisy.⁴

Therefore, this trial found that thermoplasty improved asthma symptoms within 3 months and that the effect lasted 1 year, with an encouraging reduction in the number of mild exacerbations. However, it was not blinded, and there is a strong placebo effect in asthma. Needed was a randomized trial in which the control group would undergo a sham treatment.

The RISA trial: A randomized trial in severe asthma

The Research in Severe Asthma (RISA) trial⁵ included patients with more severe asthma than those in the AIR trial. Entry criteria were:

• Taking high doses of an inhaled corticosteroid (> 750 μg of fluticasone or its equivalent per day)
• Taking prednisone (≤ 30 mg/day)
• An FEV₁ of at least 50% of predicted without a bronchodilator
• A positive methacholine test.

Seventeen patients were randomized to undergo bronchial thermoplasty, and another 17 were randomized to receive medical treatment.

After a 2-week run-in period, the thermoplasty patients underwent three treatments, performed 3 weeks apart. For the next 16 weeks, the corticosteroid doses were kept stable in both groups, followed by a 14-week corticosteroid-weaning phase and then a 16-week reduced-corticosteroid phase. During this time, attempts were made to decrease the oral or inhaled corticosteroid doses according to a protocol (eg, a 20%–25% reduction every 2–4 weeks) unless there were mild exacerbations lasting more than 7 days.

Results. There were more adverse events in the thermoplasty group than in the medical management group in the treatment period, including seven hospitalizations for exacerbations of asthma and a partial collapse of the left lower lobe. There were no significant differences in adverse events between groups in the posttreatment period (up to 6 weeks after the last treatment). Forty-nine percent of the events were mild in each group; 10% of the events were severe in the thermoplasty group vs 4% in the control group.

During the steroid-stable phase, patients in the thermoplasty group used rescue inhalers significantly less than those in the control group, and their prebronchodilator FEV₁ and AQLQ and ACQ scores were better. The differences in rescue inhaler use and questionnaire scores remained significant at 1 year.

Comment. As expected, serious adverse events occurred more often in patients with severe asthma in the treatment group than in the control group. However, 1 year after the procedure, the adverse-event rates were similar in the treatment and control groups, suggesting that this procedure can be safely performed in similar patient populations. Although there was significant potential for a placebo effect, these patients with severe persistent asthma showed significant improvement in clinical measures of asthma compared with the control group.

The latest trial of this new therapy in severe asthma was the AIR2 trial.⁶ A major difference in its design compared with the earlier ones was that the control group underwent sham thermoplasty, allowing the trial to be truly double-blinded. (The bronchoscopy team knew which patients got which treatment, but the patients and the study physicians following them did not).

The primary outcome was the change in AQLQ score from baseline at 6, 9, and 12 months. Secondary outcomes included absolute changes in the asthma control scores, symptom scores, peak flows, rescue medication use, and FEV₁.

The randomized groups (196 patients in the thermoplasty group and 101 in the sham treatment group) were well matched, and more than 80% in each group met the American Thoracic Society criteria for severe refractory asthma.

On the AQLQ, a change of more than 0.5 is considered clinically meaningful. Interestingly, there was a significant and clinically meaningful improvement in AQLQ in 64% of the sham treatment group, highlighting the placebo effect in asthma treatment.¹⁹ However, a larger proportion (79%) of the treated group had a clinically meaningful improvement on the AQLQ than in the sham treatment group.

Adverse events occurred in both groups; however, during the treatment phase, 16 patients in the bronchial thermoplasty group needed to be hospitalized for respiratory symptoms including worsening asthma, atelectasis, lower respiratory tract infections, decreased FEV₁, and an aspirated tooth. One episode of hemoptysis required bronchial artery embolization. In contrast, only two patients in the sham treatment group needed hospitalization.

Therefore, this trial showed that patients with severe asthma treated with bronchial thermoplasty had a long-term improvement in quality of life and needed less health care.⁶

Translating these trials into practice

To summarize, these clinical trials showed that bronchial thermoplasty was feasible, was relatively safe, and produced better clinical outcomes in patients with severe asthma when medical therapies did not control their symptoms.

In practice, patient selection is likely to be important. A key question will be, Does the patient truly have severe refractory asthma, or is the patient not taking his or her medication? Adherence to therapy should be evaluated.

In addition, patients need to be observed and monitored closely during and after the treatment period, as airway complications and asthma exacerbations can occur up to 6 weeks after the last procedure. About 80% of all study patients had multiple symptoms of asthma and other symptoms in the treatment period. Rarely did these symptoms result in hospitalization, but they were more common in the treatment group in the AIR2 trial.

Long-term studies have evaluated the duration of effect and the safety of bronchial thermoplasty, and outcomes appear favorable.^20,21

WHY DOES IT WORK?

The role of airway smooth muscle in asthma is yet to be fully elucidated. The trials outlined here showed that although asthma is a disease of the airways, including the small airways, treatment of airways 3 mm or larger improves asthma symptoms, quality of life, and health care utilization.⁶ Thus, the role of airway smooth muscle in asthma and as a target of therapy has not previously been fully realized.²¹

Early investigations into the mechanisms of airflow obstruction and airway resistance found that 75% of postnasal resistance occurs in the first six to eight generations (ie, branchings) of the airways, indicating that larger airways are involved.²² (The number of generations varies depending on the size of the person but it typically is 10 to 12.) Findings from the study in dogs introduced the idea that smooth muscle alterations contributed to the changes in airway resistance, and that subtle changes in airway smooth muscle could clinically benefit asthma patients.¹

The speculated purpose of the airway smooth muscle layer is to support the airway, allow gas exchange, propel mucus for clearance, defend the airway, enhance cough, and promote lymphatic flow. However, the airway smooth muscle layer may also be vestigial. In asthma, airway smooth muscle adds to bronchoconstriction and hyperresponsiveness, and has a role in mediating inflammation and airway remodeling.²¹ No definitive studies have shown that eliminating airway smooth muscle greatly inhibits normal airway function.¹⁸

What exactly does thermoplasty do to the smooth muscle? Studies in smooth muscle from cows showed that high temperatures directly disrupt the actin-myosin interaction, likely through denaturation of motor proteins.²³ This immediate loss of muscle cell function is not likely to be the result of apoptosis, autophagy, or necrosis, or mediated by heat-shock proteins, in view of the relatively quick muscle response and lack of progressive changes. Tissue responsiveness is substantially reduced a few seconds after application of 60°C of heat and is subsequently abolished within 5 minutes after treatment.²³

The intervention appears to be dose-dependent. Responsiveness to cholinergic stimulation is lessened by treatment, and the desired effect is seen within seconds and does not progress.

Therefore, we can surmise that disruption of myosin function is likely the mechanism of the therapeutic effect, breaking the cascade of airway smooth muscle spasm. Now that we know about the airway smooth muscle as a possible target of therapy, and that it may play only a vestigial role, we can think about other therapies that focus on it.^18,23

BRONCHIAL THERMOPLASTY PROTOCOLS

Patients are assessed before and on the day of the procedure to make sure their disease is stable (ie, their postbronchodilator FEV₁ is within 15% of baseline values, and they have no evidence of asthma exacerbation or active infection), similar to the protocol used in the AIR2 trial,⁶ before proceeding with the treatment.

Patients are given 50 mg of prednisone 3 days before and again on the day of the procedure. Nebulized albuterol (2.5–5.0 mg) is given before the patients undergo screening spirometry and again before the procedure. If the preprocedure FEV₁ is lower than 15% below baseline, we postpone the procedure to another day.

The procedure is performed with the patient under moderate conscious sedation, typically using fentanyl (Sublimaze), midazolam (Versed), and topical lidocaine in a monitored environment. The bronchoscope is inserted via either the mouth or nose, and supplemental oxygen is provided.

Thermoplasty is performed with the Alair system (Asthmatx, Inc., Sunnyvale, CA), which delivers a specific amount of radiofrequency (thermal) energy through a dedicated catheter. The catheter is deployed through a 2.0-mm channel of a flexible bronchoscope, starting in distal airways as small as 3 mm in diameter and working proximally to sequentially treat all airways to the mainstem lobar bronchi. The sites treated are meticulously recorded on a bronchial airway map to ensure that treatment sites are not skipped or overlapped (FIGURE 1).

An array of four electrodes is manually expanded to make contact with the airway walls; each electrode has 5 mm of exposed wire. As the energy is delivered, the control unit measures electrical resistance converted to thermal energy and turns off the current when an appropriate dosage is given. This thermal energy is what is responsible for altering the airway smooth muscle.

A full course of treatment requires three separate bronchoscopy sessions, each separated by 2 to 3 weeks. The left lower lobe and the right lower lobe are treated in separate procedures, and then both upper lobes are treated in a third procedure to minimize any respiratory symptoms. Each procedure usually requires 50 to 75 activations of the device and takes up to 60 minutes.

After each procedure the patient should be observed for 3 to 4 hours, and spirometry should be repeated to make sure the FEV₁ (percent predicted) is within 20% of the baseline value. An additional 50-mg dose of prednisone is prescribed for the day after the procedure.²⁴

FDA CLEARANCE AND LONG-TERM FOLLOW-UP

The FDA approved the Alair device for treating severe refractory asthma in early 2010.³ The indications for it are based on the study populations in the published trials. Patients can be evaluated for this treatment if they have well-documented severe persistent asthma not well controlled on inhaled corticosteroids and long-acting beta agonists and have no significant contraindications to bronchoscopy.

As part of the conditions of approval, the FDA required a postapproval study based on the long-term follow-up of the AIR2 trial. They specifically wanted to compare patients who have desirable long-term outcomes and those in whom any treatment effect wanes with time. Since we have only a few years of follow-up data, we still do not know all the possible late effects of the treatment; we have an opportunity to learn more.

Another question that needs to be studied is whether thermoplasty will help other forms of bronchospastic lung disease, such as chronic obstructive pulmonary disease.

A second postapproval study will be a prospective, open-label, single-arm, multicenter study conducted in the United States to assess the treatment effect and short-term and long-term safety profile of thermoplasty in asthma.

As experience with the procedure increases, we will be better able to characterize which patients may benefit from it. In addition, the knowledge gained by the longer-term study of airway smooth muscle function alterations will potentially drive the discovery of other innovative therapies for severe asthma.

Asthma now has a new treatment, but it isn’t for everybody. Called bronchial thermoplasty, it is reserved for patients whose asthma is severe and refractory, as it involves three sessions of bronchoscopy, each lasting up to 1 hour, during which the smooth muscle layer is methodically ablated from the airway using radiofrequency energy.^1,2

See related editorial

The US Food and Drug Administration (FDA) has approved bronchial thermoplasty,³ and although it does not cure asthma or completely eliminate its symptoms, patients with severe asthma that was not well controlled with medical therapy who underwent this procedure in clinical trials subsequently had fewer symptoms, enjoyed better quality of life, and needed less intensive health care (such as emergency room visits) than patients who did not undergo the procedure.^4–6

Here, we present an overview of the pathophysiology of severe refractory asthma and the clinical trials of bronchial thermoplasty, its current protocols, and the status of this new treatment.

WHAT IS SEVERE REFRACTORY ASTHMA?

Asthma is a chronic inflammatory condition of the airways characterized by episodic symptoms of breathlessness, cough, and wheezing, which can wax and wane over time. Approximately 8.2% of the general population is affected.⁷

Our understanding of the pathophysiology of asthma has improved over the past 20 years, and with the publication of clinical guidelines from the National Asthma Education and Prevention Program in 1991,⁸ 1997,⁹ and 2002,¹⁰ outcomes have improved. Most people with asthma can control their symptoms if they adhere to anti-inflammatory therapies and avoid triggers. Yet 5% to 10% of asthma patients have severe refractory disease, and asthma accounts for nearly half a million hospitalizations every year.¹¹

The latest guidelines, published in 2007, emphasize the importance of assessing the severity of asthma, including the patient’s impairment (symptoms and limitations) and risk (likelihood of exacerbations).¹²

Workshop consensus definition of severe refractory asthma

A consensus group convened by the American Thoracic Society¹³ defined asthma as severe and refractory if the patient meets at least one of the following major criteria:

• Takes oral corticosteroids continuously or nearly continuously (> 50% of year)
• Takes high-dose inhaled corticosteroids.

In addition, the patient must meet at least two minor criteria, ie:

• Takes a controller medication such as a long-acting beta-agonist, theophylline, or a leukotriene antagonist every day
• Takes a short-acting beta agonist every day or nearly every day
• Has persistent airway obstruction, ie, a forced expiratory volume in 1 second (FEV₁) less than 80% of predicted, or a peak expiratory flow that has a diurnal variability greater than 20%
• Has one or more urgent care visits for asthma per year
• Needs three or more oral corticosteroid “bursts” per year
• Has prompt deterioration when the dose of oral or inhaled corticosteroid is reduced by 25% or less
• Has had a near-fatal asthma event in the past.

Compared with people with mild asthma, people who have severe refractory asthma tend to be older, have fewer allergies, and make more use of intensive and urgent health care.¹⁴

Asthma is due to both inflammation and bronchoconstriction

The pathophysiology of asthma involves both chronic airway inflammation and bronchoconstriction, the latter characterized by a greater response to methacholine. Histologic findings include excessive mucus secretion, epithelial cell injury, and smooth muscle hypertrophy. These changes can lead to persistent airflow obstruction that can be difficult to control with medical therapies.¹²

Bronchoconstriction can be reversed temporarily with bronchodilators, but no longlasting therapy to reduce it has been available until now. Bronchial thermoplasty targets this gap in asthma management.

STUDIES OF BRONCHIAL THERMOPLASTY

Radiofrequency ablation has been used to treat other medical conditions such as lung cancer and cardiac arrhythmias.^15,16 Its use to treat asthma by eradicating smooth muscle cells from the airway wall began with studies in animals.¹ Later, studies were done in people without asthma,² then in patients with mild to moderate asthma,¹⁷ and finally in patients with moderate to severe refractory asthma.^4–6

These studies helped clarify which type of patients would be appropriate candidates and the outcomes to be anticipated, including adverse events.

Early studies

Danek et al,¹ in a study in nonasthmatic dogs, found that thermoplasty at 65°C or 75°C (149°F or 167°F) attenuated the airway’s response to methacholine up to 3 years after treatment. As early as 1 week after treatment, airway smooth muscle was seen to be degenerating or absent, and the effect was inversely proportional to airway responsiveness.

Adverse effects of the procedure were cough, inflammatory edema of the airway wall, retained mucus, and blanching of the airway wall at the site of catheter contact. Three years later, there was no evidence of smooth muscle regeneration.

Miller et al² next performed a feasibility study in eight patients, mean age 58 ± 8.3 years, who were scheduled to undergo lung resection for lung cancer. Five to 20 days before surgery, the investigators performed thermoplasty at 55°C or 65°C (131°F or 149°F) in three to nine sites per patient, 1 cm from known tumors but within areas to be resected. There were no significant adverse events such as hemoptysis, respiratory infections, or excess bronchial irritation.

Cox et al¹⁷ performed the first study of bronchial thermoplasty in patients with mild to moderate asthma. This was a prospective observational study in 16 patients who were younger than the patients in the previous study, with an average age of 30 years (range 24–58). They were given prednisone 30 or 50 mg the day before the procedure and on the day of the procedure. Three treatments were done, 3 weeks apart. The right middle lobe was not treated because the bronchus leading to it is relatively long and narrow, raising concern about damaging it.¹⁸

Results. The most frequent side effects were symptoms of airway irritation such as cough, dyspnea, wheezing, and bronchospasm. The mean time to onset was less than 1.7 days, and the mean time to resolution was 4.6 days after the most recent procedure. None of the patients needed to be hospitalized in the immediate postprocedure period.

In the 2 years after the procedure, there were 312 adverse events, mainly mild. Three (1%) of the adverse events were reported as severe, but they were deemed not related to the procedure. Yearly computed tomographic scans of the chest showed no structural changes such as bronchiectasis in the parenchyma or bronchial wall.

The FEV₁ was higher at 12 weeks and at 1 year after thermoplasty than at baseline but was not significantly different from baseline at 2 years.

At baseline, the patients reported that 50% of their days were symptom-free; this increased to 73% at 12 weeks (P = .015).

In addition, airway hyperresponsiveness decreased significantly, and the effect persisted over 2 years. The provocative concentration of methacholine that caused a 20% reduction in FEV₁ (the PC₂₀) was:

• 0.92 mg/mL at baseline (95% confidence interval 0.42–1.99)
• 4.75 mg/mL at 12 weeks (2.51–8.85)
• 5.45 mg/mL at 1 year (1.54–19.32)
• 3.40 mg/mL at 2 years (1.35–8.52).

Limitations of this study include the relatively small number of patients enrolled and their relatively stable asthma.

The AIR trial: A randomized trial in moderate or persistent asthma

The first large multicenter trial of bronchial thermoplasty, the Asthma Intervention Research (AIR) trial,⁴ was prospective and randomized but not blinded. The aim was to determine whether bronchial thermoplasty would improve asthma control after long-acting beta agonists were discontinued.

Patients could be enrolled if they were 18 to 65 years old, had moderate or persistent asthma, and needed to take an inhaled corticosteroid (beclomethasone [Qvar] 200 μg or more or an equivalent drug) and a long-acting beta agonist (salmeterol [Serevent] 100 μg or more or an equivalent drug) every day. They also needed to have FEV₁ values of 60% to 85% of predicted and airway reactivity (PC₂₀ < 8 mg/mL), and their asthma had to have been stable for 6 weeks.

At baseline, the long-acting beta agonist was withdrawn temporarily; the final criterion for entry was that their asthma had to become worse when this was done.

Then, 112 patients were randomized to receive either bronchial thermoplasty with medical care (inhaled corticosteroids and long-acting beta agonists) or usual care, ie, medical therapy alone. Treatments were done in three sessions over 9 weeks, followed by attempts to discontinue their long-acting beta agonists at 3, 6, and 9 months after the procedure without exacerbations.

An exacerbation was defined as at least one of the following for 2 consecutive days: a reduction of peak flow by 20% of baseline average, the need for more than three additional puffs of rescue inhaler, or nocturnal awakenings caused by asthma symptoms. The patients kept a daily diary of their symptoms and rescue inhaler use, and they completed the Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ).

Results. The number of mild (but not severe) exacerbations per week was significantly lower at 3 and 12 months than at baseline in the thermoplasty group, with 10 fewer mild exacerbations per patient per year, but was unchanged in the control group. There were significantly greater improvements in morning peak flow at 3, 6, and 12 months from baseline in the treatment group than in the usual-care group. Rescue medication use was also significantly less at 3 and 12 months. Symptom scores, AQLQ scores, and ACQ scores were all significantly better than at baseline as well.

Not surprisingly, in this cohort with unstable asthma, there were 407 adverse events in the treatment group and 106 adverse events in the control group. Most of these occurred within 1 day and resolved within 7 days after the procedure. There were more hospitalizations in the treatment group as well, for reasons that included exacerbations of asthma, collapse of the left lower lobe, and pleurisy.⁴

Therefore, this trial found that thermoplasty improved asthma symptoms within 3 months and that the effect lasted 1 year, with an encouraging reduction in the number of mild exacerbations. However, it was not blinded, and there is a strong placebo effect in asthma. Needed was a randomized trial in which the control group would undergo a sham treatment.

The RISA trial: A randomized trial in severe asthma

The Research in Severe Asthma (RISA) trial⁵ included patients with more severe asthma than those in the AIR trial. Entry criteria were:

• Taking high doses of an inhaled corticosteroid (> 750 μg of fluticasone or its equivalent per day)
• Taking prednisone (≤ 30 mg/day)
• An FEV₁ of at least 50% of predicted without a bronchodilator
• A positive methacholine test.

Seventeen patients were randomized to undergo bronchial thermoplasty, and another 17 were randomized to receive medical treatment.

After a 2-week run-in period, the thermoplasty patients underwent three treatments, performed 3 weeks apart. For the next 16 weeks, the corticosteroid doses were kept stable in both groups, followed by a 14-week corticosteroid-weaning phase and then a 16-week reduced-corticosteroid phase. During this time, attempts were made to decrease the oral or inhaled corticosteroid doses according to a protocol (eg, a 20%–25% reduction every 2–4 weeks) unless there were mild exacerbations lasting more than 7 days.

Results. There were more adverse events in the thermoplasty group than in the medical management group in the treatment period, including seven hospitalizations for exacerbations of asthma and a partial collapse of the left lower lobe. There were no significant differences in adverse events between groups in the posttreatment period (up to 6 weeks after the last treatment). Forty-nine percent of the events were mild in each group; 10% of the events were severe in the thermoplasty group vs 4% in the control group.

During the steroid-stable phase, patients in the thermoplasty group used rescue inhalers significantly less than those in the control group, and their prebronchodilator FEV₁ and AQLQ and ACQ scores were better. The differences in rescue inhaler use and questionnaire scores remained significant at 1 year.

Comment. As expected, serious adverse events occurred more often in patients with severe asthma in the treatment group than in the control group. However, 1 year after the procedure, the adverse-event rates were similar in the treatment and control groups, suggesting that this procedure can be safely performed in similar patient populations. Although there was significant potential for a placebo effect, these patients with severe persistent asthma showed significant improvement in clinical measures of asthma compared with the control group.

The latest trial of this new therapy in severe asthma was the AIR2 trial.⁶ A major difference in its design compared with the earlier ones was that the control group underwent sham thermoplasty, allowing the trial to be truly double-blinded. (The bronchoscopy team knew which patients got which treatment, but the patients and the study physicians following them did not).

The primary outcome was the change in AQLQ score from baseline at 6, 9, and 12 months. Secondary outcomes included absolute changes in the asthma control scores, symptom scores, peak flows, rescue medication use, and FEV₁.

The randomized groups (196 patients in the thermoplasty group and 101 in the sham treatment group) were well matched, and more than 80% in each group met the American Thoracic Society criteria for severe refractory asthma.

On the AQLQ, a change of more than 0.5 is considered clinically meaningful. Interestingly, there was a significant and clinically meaningful improvement in AQLQ in 64% of the sham treatment group, highlighting the placebo effect in asthma treatment.¹⁹ However, a larger proportion (79%) of the treated group had a clinically meaningful improvement on the AQLQ than in the sham treatment group.

Adverse events occurred in both groups; however, during the treatment phase, 16 patients in the bronchial thermoplasty group needed to be hospitalized for respiratory symptoms including worsening asthma, atelectasis, lower respiratory tract infections, decreased FEV₁, and an aspirated tooth. One episode of hemoptysis required bronchial artery embolization. In contrast, only two patients in the sham treatment group needed hospitalization.

Therefore, this trial showed that patients with severe asthma treated with bronchial thermoplasty had a long-term improvement in quality of life and needed less health care.⁶

Translating these trials into practice

To summarize, these clinical trials showed that bronchial thermoplasty was feasible, was relatively safe, and produced better clinical outcomes in patients with severe asthma when medical therapies did not control their symptoms.

In practice, patient selection is likely to be important. A key question will be, Does the patient truly have severe refractory asthma, or is the patient not taking his or her medication? Adherence to therapy should be evaluated.

In addition, patients need to be observed and monitored closely during and after the treatment period, as airway complications and asthma exacerbations can occur up to 6 weeks after the last procedure. About 80% of all study patients had multiple symptoms of asthma and other symptoms in the treatment period. Rarely did these symptoms result in hospitalization, but they were more common in the treatment group in the AIR2 trial.

Long-term studies have evaluated the duration of effect and the safety of bronchial thermoplasty, and outcomes appear favorable.^20,21

WHY DOES IT WORK?

The role of airway smooth muscle in asthma is yet to be fully elucidated. The trials outlined here showed that although asthma is a disease of the airways, including the small airways, treatment of airways 3 mm or larger improves asthma symptoms, quality of life, and health care utilization.⁶ Thus, the role of airway smooth muscle in asthma and as a target of therapy has not previously been fully realized.²¹

Early investigations into the mechanisms of airflow obstruction and airway resistance found that 75% of postnasal resistance occurs in the first six to eight generations (ie, branchings) of the airways, indicating that larger airways are involved.²² (The number of generations varies depending on the size of the person but it typically is 10 to 12.) Findings from the study in dogs introduced the idea that smooth muscle alterations contributed to the changes in airway resistance, and that subtle changes in airway smooth muscle could clinically benefit asthma patients.¹

The speculated purpose of the airway smooth muscle layer is to support the airway, allow gas exchange, propel mucus for clearance, defend the airway, enhance cough, and promote lymphatic flow. However, the airway smooth muscle layer may also be vestigial. In asthma, airway smooth muscle adds to bronchoconstriction and hyperresponsiveness, and has a role in mediating inflammation and airway remodeling.²¹ No definitive studies have shown that eliminating airway smooth muscle greatly inhibits normal airway function.¹⁸

What exactly does thermoplasty do to the smooth muscle? Studies in smooth muscle from cows showed that high temperatures directly disrupt the actin-myosin interaction, likely through denaturation of motor proteins.²³ This immediate loss of muscle cell function is not likely to be the result of apoptosis, autophagy, or necrosis, or mediated by heat-shock proteins, in view of the relatively quick muscle response and lack of progressive changes. Tissue responsiveness is substantially reduced a few seconds after application of 60°C of heat and is subsequently abolished within 5 minutes after treatment.²³

The intervention appears to be dose-dependent. Responsiveness to cholinergic stimulation is lessened by treatment, and the desired effect is seen within seconds and does not progress.

Therefore, we can surmise that disruption of myosin function is likely the mechanism of the therapeutic effect, breaking the cascade of airway smooth muscle spasm. Now that we know about the airway smooth muscle as a possible target of therapy, and that it may play only a vestigial role, we can think about other therapies that focus on it.^18,23

BRONCHIAL THERMOPLASTY PROTOCOLS

Patients are assessed before and on the day of the procedure to make sure their disease is stable (ie, their postbronchodilator FEV₁ is within 15% of baseline values, and they have no evidence of asthma exacerbation or active infection), similar to the protocol used in the AIR2 trial,⁶ before proceeding with the treatment.

Patients are given 50 mg of prednisone 3 days before and again on the day of the procedure. Nebulized albuterol (2.5–5.0 mg) is given before the patients undergo screening spirometry and again before the procedure. If the preprocedure FEV₁ is lower than 15% below baseline, we postpone the procedure to another day.

The procedure is performed with the patient under moderate conscious sedation, typically using fentanyl (Sublimaze), midazolam (Versed), and topical lidocaine in a monitored environment. The bronchoscope is inserted via either the mouth or nose, and supplemental oxygen is provided.

Thermoplasty is performed with the Alair system (Asthmatx, Inc., Sunnyvale, CA), which delivers a specific amount of radiofrequency (thermal) energy through a dedicated catheter. The catheter is deployed through a 2.0-mm channel of a flexible bronchoscope, starting in distal airways as small as 3 mm in diameter and working proximally to sequentially treat all airways to the mainstem lobar bronchi. The sites treated are meticulously recorded on a bronchial airway map to ensure that treatment sites are not skipped or overlapped (FIGURE 1).

An array of four electrodes is manually expanded to make contact with the airway walls; each electrode has 5 mm of exposed wire. As the energy is delivered, the control unit measures electrical resistance converted to thermal energy and turns off the current when an appropriate dosage is given. This thermal energy is what is responsible for altering the airway smooth muscle.

A full course of treatment requires three separate bronchoscopy sessions, each separated by 2 to 3 weeks. The left lower lobe and the right lower lobe are treated in separate procedures, and then both upper lobes are treated in a third procedure to minimize any respiratory symptoms. Each procedure usually requires 50 to 75 activations of the device and takes up to 60 minutes.

After each procedure the patient should be observed for 3 to 4 hours, and spirometry should be repeated to make sure the FEV₁ (percent predicted) is within 20% of the baseline value. An additional 50-mg dose of prednisone is prescribed for the day after the procedure.²⁴

FDA CLEARANCE AND LONG-TERM FOLLOW-UP

The FDA approved the Alair device for treating severe refractory asthma in early 2010.³ The indications for it are based on the study populations in the published trials. Patients can be evaluated for this treatment if they have well-documented severe persistent asthma not well controlled on inhaled corticosteroids and long-acting beta agonists and have no significant contraindications to bronchoscopy.

As part of the conditions of approval, the FDA required a postapproval study based on the long-term follow-up of the AIR2 trial. They specifically wanted to compare patients who have desirable long-term outcomes and those in whom any treatment effect wanes with time. Since we have only a few years of follow-up data, we still do not know all the possible late effects of the treatment; we have an opportunity to learn more.

Another question that needs to be studied is whether thermoplasty will help other forms of bronchospastic lung disease, such as chronic obstructive pulmonary disease.

A second postapproval study will be a prospective, open-label, single-arm, multicenter study conducted in the United States to assess the treatment effect and short-term and long-term safety profile of thermoplasty in asthma.

As experience with the procedure increases, we will be better able to characterize which patients may benefit from it. In addition, the knowledge gained by the longer-term study of airway smooth muscle function alterations will potentially drive the discovery of other innovative therapies for severe asthma.