1 Pulmonary Overlap 2 3 4 Syndromes, with a Focus 5 6 on COPD and ILD 7 8 Katherine A. Dudley, MD, Atul Malhotra, MD, Q2Q3 Robert L. Owens, MD* Q4Q5 9 10 KEYWORDS 11 Overlap syndrome Sleep Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis 12 Obstructive sleep apnea 55 13 56 14 57 15 Q7 KEY POINTS 58 16 59 17 Overlap syndrome refers to the coexistence of chronic lung disease and obstructive sleep apnea 60 18 (OSA) in the same patient. To date, overlap syndromes have been poorly studied for a variety of 61 19 reasons. 62 20 Nevertheless, recent data in chronic obstructive pulmonary disease (COPD) and patients with OSA 63 21 overlap highlight the increased morbidity and mortality of overlap syndromes compared with either 64 22 underlying disorder alone. 65 23 The underlying disorders in overlap syndrome (OSA and chronic lung disease) may be of very 66 24 different severity. Thus, there is a great amount of patient heterogeneity; the goals of therapy 67 25 may differ in different patients. 68 26 Unrecognized OSA may contribute to symptoms of sleepiness and fatigue in those patients with 69 27 chronic lung disease. Thus, clinicians should be mindful of the overlap syndromes in these patients. 70 28 71 29 72 30 73 31 Q8 First described in the 1980s by pulmonologist Da- OVS does, as Flenley thought, have worse out- 74 32 Q9 vid Flenley,1 overlap syndromes (OVSs) refer to the comes than either disease in isolation. These find- 75 33 coexistence of chronic lung disease and obstruc- ings have highlighted the urgent need for further 76 34 tive sleep apnea (OSA). Although it could refer to study of both the OVS and all overlaps between 77 35 78 Q10 any of the lung diseases and OSA, the OVS is usu- OSA and chronic lung disease. 36 ally reserved for the coexistence of OSA and 79 37 chronic obstructive pulmonary disease (COPD), 80 38 which Flenley thought to have unique adverse CLINICAL AND RESEARCH CHALLENGES OF 81 39 health consequences distinct from either condition THE OVS Q11 82 40 alone. Given the high prevalence of each disorder 83 41 OVSs are poorly understood for many reasons. 84 alone, OVS is also likely to be common and clini- Using the OVS as a prototype 42 cally relevant. However, although OVS has been 85 43 described in the literature for nearly 30 years, the 1. The diagnosis of OVS is nebulous, as both OSA 86 44 lack of standard diagnostic criteria for the syn- and COPD are heterogeneous disorders. 45 drome has limited rigorous discussion of diag- COPD and OSA both have wide ranges of 46 nosis, prevalence, pathophysiology, treatment, severity, in terms of both objective measure- 47 and outcomes. These challenges are explored in ments of disease (eg, forced expiratory volume 48 more detail later and throughout this review. in 1 second [FEV1], and apnea-hypopnea index 49 Importantly, several recent studies suggest that [AHI]) and patient-reported symptoms (eg, 50 51 52 Q6 221 Longwood Avenue, BLI 035Q, Boston, MA 02115, USA 53 * Corresponding author. 54 E-mail address: [email protected] Sleep Med Clin - (2014) -–- http://dx.doi.org/10.1016/j.jsmc.2014.05.008 1556-407X/14/$ – see front matter Ó 2014 Published by Elsevier Inc. sleep.theclinics.com CSLP518_proof ■ 10 June 2014 ■ 8:04 pm 2 Dudley et al 87 dyspnea and daytime tiredness). OVS is eliminate apneic events. For a patient with evi- 144 88 defined by the presence of both conditions dence of hypoventilation, the goal may be to 145 89 regardless of the relative burden of one or the improve nocturnal gas exchange and hypercar- 146 90 other. Therefore, patients with OVS may repre- bia. Maybe the best approach would be inten- 147 91 sent a very heterogeneous population, falling sive modification of cardiovascular risk factors 148 92 into one of many potential categories: mild (eg, blood pressure, cholesterol modification). 149 93 COPD with mild OSA, mild COPD with severe These uncertainties contribute to the confusion 150 94 OSA, severe COPD with mild OSA, severe as to the ideal therapy to use. 151 95 COPD with severe OSA, and so forth. Prog- 5. The optimal treatment of OVS is unknown. Few 152 96 nosis and treatment, therefore, could be large clinical trials have been undertaken, and 153 97 considerably different depending on the rela- no large studies have compared long-term out- 154 98 tive impact of each condition. Although it is a comes between randomized therapies. 155 99 minor point, there is not a single International Although continuous positive airway pressure 156 100 Classification of Diseases, Ninth Revision code (CPAP) is the most commonly applied therapy, 157 101 for OVS, which impedes even epidemiologic some groups have used bilevel positive airway 158 102 research. pressure, which provides a higher pressure 159 103 2. The diagnosis of OSA in the setting of hypox- during inspiration than during expiration. Bilevel 160 104 emic lung disease is uncertain. The definition may have benefits over CPAP for some pa- 161 105 of OSA includes hypopneas and reductions in tients, particularly among patients with severe 162 106 airflow with associated desaturation, which is COPD whereby it may aid with nocturnal venti- 163 107 more likely to occur in those with chronic lung lation and resting of respiratory muscles. 164 108 disease. The AHI, used to grade OSA severity, Finally, the role of oxygen therapy, another 165 109 does not differentiate between apneas and hy- treatment used clinically, has not been fully 166 110 popneas. Thus, a patient with severe COPD explored in this population. The role of medical 167 111 might have the same AHI consistent with se- therapy aimed at limiting cardiovascular events 168 112 vere OSA (based on a large number of hypo- has also not been explored. 169 113 pneas) as another patient with a very 6. An additional under-recognized consideration 170 114 collapsible upper airway without lung disease is that sleep is poor in chronic lung diseases, in- 171 115 (who predominantly has apneas). In addition, dependent of upper airway collapse. Many 172 116 a 10-minute prolonged desaturation caused studies have highlighted the high prevalence 173 117 by hypoventilation may be scored as a single of sleep complaints among patients with 174 118 hypopnea because the event duration has min- chronic lung diseases. There are many reasons 175 119 imal effect on the definitions used. More behind this finding, ranging from cough inter- 176 120 rigorous definitions of OSA might be useful, fering with sleep, increased anxiety and 177 121 such as the apnea index or scoring based on insomnia, side effects of medications (eg, 178 122 airflow alone and arousals independent of oxy- chronic glucocorticoids, beta agonists), and 179 123 gen desaturation. frequent arousals. Although treatment of OVS 180 124 3. The interactions of COPD and OSA are not un- with CPAP may improve upper airway patency, 181 125 derstood. Thus, it is unknown at a pathophysi- CPAP will not address many of the nonrespira- 182 126 ologic level whether each disorder might tory problems that plague sleep in this popula- 183 127 predispose to the other disease. As discussed tion. Thus, CPAP adherence may be 184 128 earlier, the baseline hypoxemia of COPD likely challenged in ways that are unique compared 185 129 predisposes to a diagnosis of OSA. But other with those without chronic lung disease. 186 130 links are possible; for example, the changes in 187 131 lung volumes that occur with COPD might These points are illustrated as the authors 188 132 impact upper airway collapsibility. How COPD discuss what is known about OVS (and OSA and 189 133 and OSA interact to cause the increased idiopathic pulmonary fibrosis [IPF]), perhaps the 190 134 morbidity and mortality attributable to OVS is most common of the interstitial lung diseases (ILDs). 191 135 not known. Is it simply from more prolonged 192 136 hypoxemia or hypercapnia than either disorder COPD AND OSA 193 137 alone? Or are poor outcomes caused by the in- 194 Throughout this section, OVS refers exclusively to 138 direct effects of the disorders, such as cardio- 195 those with COPD and OSA. 139 vascular disease? 196 140 4. Thus, the goals of therapy in OVS are poorly 197 COPD 141 defined. For a patient with severe OSA with 198 142 many apneas, the goal of therapy may be to COPD is a progressive lung disease characterized 199 143 200 support patency of the upper airway and by irreversible airway obstruction (FEV1/forced CSLP518_proof ■ 10 June 2014 ■ 8:04 pm Q1 Pulmonary Overlap Syndromes 3 201 vital capacity [FVC]<70%). This disease can COPD may play a role in cardiovascular disease 258 202 involve the small airways, pulmonary parenchyma, include increased oxidative stress, inflammation, 259 203 or both. COPD results from an inflammatory and increased platelet activation. 260 204 response that can result in chronic sputum pro- Of particular interest in the current discussion, 261 205 duction (chronic bronchitis) as well as the destruc- COPD is a heterogeneous disorder, with variable 262 206 tion of alveolar walls distal to the terminal amounts of airway and parenchymal disease. 263 207 bronchioles, leading to enlargement of the air- Most patients have a predominance of one pheno- 264 208 spaces (emphysema). Although tobacco use is type, though there is usually some overlap. In the 265 209 strongly associated with the development of past, patients with chronic bronchitis were 266 210 COPD, it is not the only risk factor. In developing described as blue bloaters, referring to hypox- 267 211 countries, exposure to indoor air pollution plays a emia, polycythemia, and cor pulmonale that often 268 212 critical role, in particular as a result of fuels burned accompanies patients with this form of COPD.