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 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 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

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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 , 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 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 , 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 (FEV1/forced

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201 [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, , 259 203 or both. COPD results from an inflammatory and increased platelet activation. 260 204 response that can result in chronic pro- Of particular interest in the current discussion, 261 205 duction (chronic ) 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. 269 213 for cooking and heating. Occupational causes are Pink puffers were those with an emphysematous 270 214 also well described, such as irritants and fumes. phenotype of COPD, often with muscle wasting 271 215 Estimates are now that most COPD worldwide is and hyperinflation but without oxygen desatura- 272 216 non–smoking related, emphasizing caution about tion. The GOLD criteria are designed to be inclu- 273 217 labeling the disease as self-inflicted. COPD may sive to maximize disease recognition and prompt 274 218 present as dyspnea, wheezing, cough, sputum treatment and, therefore, do not highlight these 275 219 production, poor exercise tolerance, hypoxic distinctions. However, there may be critical differ- 276 220 and/or hypercarbic , and right ences in the pathophysiology among different 277 221 heart failure (cor pulmonale). There are Global phenotypes that are important when considering 278 222 Initiative for Chronic Obstructive Lung Disease OVS. 279 223 (GOLD)–defined stages of disease severity based 280 224 on pulmonary function testing (the FEV ) and 281 1 Sleep and COPD 225 symptoms. In the United States, more than 5% 282 226 of the population (at least 13.7 million people) is More than three-quarters of patients with COPD 283 227 burdened by COPD,2,3 which is a leading cause report bothersome nocturnal symptoms, such as 284 228 of morbidity. Worldwide, about 10% of the popula- dyspnea.15,16 Patients who report cough and 285 229 tion is affected.4 Although medications may during the day are more likely to have 286 230 improve symptomatic control of the disease and sleep disturbances than those who do not.17 Pa- 287 231 slow progression, the health-related conse- tients report trouble falling asleep, frequent awak- 288 232 quences of COPD remain high.3 As of 2011, ening, difficultly returning to sleep, and 289 233 COPD was the third leading cause of death in nonrestorative sleep. In a survey of patients with 290 234 the United States.5 Annual expenditures for the COPD, more than 60% had experienced at least 291 235 disease are approaching $40 billion when direct one sleep symptom in the preceding 28 days.15 292 236 and indirect costs are considered.6 Rates of clinical insomnia are high among patients 293 237 Although COPD is often considered a respira- with COPD, present in more than one-fourth.18 As 294 238 tory condition, the impact on other organ systems compared with controls, COPD confers an 295 239 and overall health is increasingly well recognized. increased risk of insomnia nearly twice that of 296 240 The most recent GOLD definition of the disease non-COPD patients.19 These sleep disturbances 297 241 highlights COPD as a systemic process with “sig- are chronic, persisting over many years.20 298 242 nificant extrapulmonary effects that may Sleep complaints increase with more severe dis- 299 243 contribute to the severity in individual patients.”7 ease. Although mild obstructive lung disease is 300 244 Indeed, depression, skeletal-muscle myopathy, associated with preserved sleep quality,21 a 301 245 anemia, and osteoporosis are all common in more severe obstructive disease is associated 302 246 COPD. Similarly, as is discussed later, sleep with increased sleep complaints.22 Severe disease 303 247 disturbance and its consequences could be negatively impacts several objective sleep param- 304 248 thought of as one of these extrapulmonary mani- eters, such as total sleep time, sleep efficiency, 305 249 festations. COPD is also associated with adverse rapid eye movement (REM) sleep,23 as well as 306 250 cardiac outcomes, which may be of particularly sleep-onset latency, arousals, and sleep-stage 307 251 importance when thinking about the overlap with transitions.24–27 308 252 OSA, which also has cardiovascular conse- The mechanisms behind the sleep disturbances 309 253 quences.8–12 Even after consideration of shared are likely multifactorial. Symptoms such as cough 310 254 risk factors, such as cigarette smoking, COPD is and wheezing may play a role as noted earlier.28,29 311 255 associated with higher rates of coronary artery dis- Recent work has also highlighted nonrespiratory 312 256 ease, congestive heart failure, and arrhyth- factors that also perturb sleep among patients 313 257 mias.13,14 Additional mechanisms by which with COPD.30 For example, restless leg syndrome 314

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315 has been found in up to one-third of patients with atonia (with the exception of certain muscles, 372 316 COPD, and periodic limb movements are associ- including the diaphragm); in addition to decreased 373 317 ated with worse insomnia.31 As a result of all of ventilation, the breathing pattern becomes very 374 318 these factors, the use of medications to aid sleep irregular (especially during bursts of REMs). The 375 319 is common, especially sedative hypnotics, which decrease in respiratory drive reflects both a 376 320 are used by 25% of patients with COPD.17 decrease in metabolic rate, which results in less 377 321 378 Although data are sparse, these medications carbon dioxide (CO2) production and, thus, 322 could theoretically worsen hypoxemia/hypercap- requirement for elimination, and an increase in 379 323 36 380 nia, though this may not be true for all the CO2 set point. The reduction in minute venti- 324 patients.32–35 lation is further pronounced during REM, when 381 325 ventilation may be 40% less compared with wake- 382 326 Changes in Respiration During Sleep with fulness.37,38 In addition to the decrease in the 383 327 COPD and Nocturnal Oxygen Desaturation respiratory set point, there is decreased respon- 384 328 385 Nocturnal oxygen desaturation (NOD) in chronic siveness to hypercapnia and hypoxia compared 329 39–41 386 lung disease is the result of the normal changes with wakefulness. Finally, upper airway resis- 330 387 that occur in ventilation with sleep. Put another tance increases during sleep, even in those 331 42 388 way, sleep is a stress test for those patients with without OSA. An overview of the changes is out- 332 389 chronic lung disease that leads to nocturnal hyp- lined in Fig. 1. 333 390 oxemia and hypercapnia. Understanding the 334 391 normal changes in respiration that occur with Sleep and Breathing with COPD 335 392 sleep is key to understanding NOD. 336 All of the aforementioned changes are physiologic 393 changes that occur from wakefulness to sleep. 337 Normal Changes in Respiration During Sleep 394 338 However, in the presence of lung disease, the con- 395 339 Sleep is divided into different stages based on sequences may be dramatic and lead to oxygen 396 340 electroencephalography waveforms, muscle desaturation. First, these patients may already 397 341 tone, eye movement, and breathing pattern, with have borderline hypoxemia, which puts them on 398 342 the main distinction being between non-REM the steep part of the oxygen hemoglobin binding 399 343 sleep and REM sleep. The main respiratory curve; that is, small changes in PaO2 lead to a 400 344 changes that occur during sleep are a decrease decrease in oxygen saturation. Second, patients 401 345 in ventilation (largely a decrease in tidal volume with COPD have increased minute ventilation for 402 346 without a compensatory increase in respiratory a variety of reasons and frequently rely on acces- 403 347 rate) and decreased accessory muscle activity. sory muscles to aid ventilation. As a result, ventila- 404 348 The changes in respiration are most pronounced tion can decrease dramatically during sleep and 405 349 in REM sleep, which is notable for skeletal muscle particularly in REM sleep when muscle activity 406 350 407 351 408 352 409 353 410 354 411 355 412 356 413 357 414 358 415 359 416 360 417 361 418 362 419 363 420 364 421 365 422 366 423 367 424 368 425 Fig. 1. The normal physiologic changes that occur with sleep. With sleep onset, respiratory drive is decreased, and 369 426 there is respiratory muscle hypotonia and a decrease in lung volumes. Even without OSA, the result is hypoven- 370 tilation compared with wakefulness. Particularly with OSA and COPD, there are further pathophysiologic changes 427 371 that lead to greater hypoventilation and hypoxemia. 428

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429 decreases. Furthermore, patients with COPD may described earlier in those patients with chronic 486 430 have chest hyperinflation, which stretches the dia- lung disease impacts the diagnosis of OSA. 487 431 phragm and impairs contractile function.43 Although the designation of apneas is straightfor- 488 432 NOD is perhaps the most common sleep abnor- ward and independent of oxygen desaturation, 489 433 mality attributed to COPD, occurring in anywhere hypopneas are based on flow limitation of at least 490 434 from one-quarter to three-quarters of patients 30% and require either an accompanying 3% 491 435 with an awake oxygen saturation greater than or greater oxygen desaturation or an arousal. 492 436 90% to 95%.44–46 During sleep, desaturations Based on the sigmoidal shape of the oxygen- 493 437 494 are frequent among patients with an FEV1/FVC hemoglobin desaturation curve, any small change 438 21 495 less than 65% ; increasing severity of obstructive in PaO2 that occurs during sleep will be reflected 439 disease is associated with more severe desatura- as a larger (scorable) change in oxygen satura- Q12 496 440 tions during sleep. Among those with severe tion. Put another way, 2 patients with the same 497 441 498 obstructive lung disease (FEV1<30%), a 20% upper airway tendency to collapse, but one 442 decrease of oxygen saturation can be seen during healthy and the other with chronic lung disease, 499 443 non-REM sleep and an impressive decline of 40% might have very different apnea-hypopnea 500 444 during REM.37 There is substantial variation in re- indices. A similar observation that makes the 501 445 ported NOD rates, in part caused by the heteroge- same point is that the AHI improves with descent 502 446 neous nature of COPD as well as the definition of from altitude, largely because of a decrease in the 503 447 NOD, which may be based either on nadir levels number of hypopneas.52 Nevertheless, there are 504 448 or the duration of low oxygen tension. no current alternative scoring criteria or guidelines 505 449 for OSA diagnosis in the setting of chronic lung 506 450 COPD and OSA: the OVS disease. 507 451 Among patients with COPD, there are clues to 508 OSA is a common disorder, characterized by par- 452 suggest OSA beyond the classic symptoms of 509 tial or complete collapse of the upper airway dur- 453 snoring, witnessed apneas, and daytime sleepi- 510 ing sleep, resulting in intermittent hypoxia and 454 ness. For example, headaches with the initiation 511 arousals. The repetitive nature of these breathing 455 of nocturnal supplemental oxygen suggest coexis- 512 events results in fragmented and nonrestorative 456 tent OSA (caused by increased hypercapnia). 513 sleep. Among middle-aged men (50–70 years 457 Hypercapnia, despite relatively preserved pulmo- 514 old), the prevalence of moderate to severe OSA 458 nary function tests, may also signal the presence 515 is predicted to be as high as 17% and slightly 459 of sleep-disordered breathing and prompt evalua- 516 lower but still concerning at 9% among middle- 460 tion. Indeed, based on findings from one cohort, 517 aged women.47 OSA is associated with an 461 FEV was severely decreased among patients 518 increased risk of serious neurocognitive and car- 1 462 with COPD only with hypercapnia but only moder- 519 diovascular consequences, including hyperten- 463 ately reduced in patients who had both COPD and 520 sion, congestive heart failure, and stroke.48–51 464 OSA. Despite this difference in pulmonary function 521 CPAP is the gold standard treatment of OSA and 465 tests, daytime PaCO was higher among those with 522 consists of a mask worn during sleep connected 2 466 OVS compared with COPD only.53,54 Additionally, 523 to a machine that delivers pressurized air, thereby 467 obesity is more common among hypercarbic pa- 524 splinting open the airway during sleep. Although 468 tients with COPD who have OSA as compared 525 CPAP is efficacious in treating OSA in almost all 469 with COPD only.54 For comparison, the character- 526 cases, its effectiveness is limited by patient adher- 470 istics of COPD alone, OSA alone, and OVS from 527 ence. Although adherence rates may be improved 471 one cohort are outlined in Table 1. 528 through intensive support and behavioral therapy, 472 The American Thoracic Society/European Res- 529 the real-world nonadherence rates may approach 473 piratory Society’s guidelines also highlight the 530 50%. In the context of OVS, these facts illustrate 474 role of referring for overnight testing among those 531 the potentially large number of patients with OSA 475 with mild COPD and evidence of pulmonary hyper- 532 at risk for OVS, that both OSA and COPD have 476 tension. Although only 16% of patients with OSA 533 substantial cardiovascular morbidity and mortality, 477 have been observed to have pulmonary hyperten- 534 and that positive airway pressure is unlikely to be 478 sion, this number jumps to 86% for those with 535 accepted by many patients. 479 OVS.55 This is an intriguing finding, given that 536 480 traditional markers of OSA severity and nocturnal 537 Diagnosing OSA Among Those Patients with 481 hypoxia in COPD are not predictive of pulmonary 538 COPD 482 hypertension. However, time spent with oxygen 539 483 OSA is diagnosed through polysomnography, saturation less than 90% is high among patients 540 484 with apneas and hypopneas recorded during with OVS, even without a severe obstructive 541 485 sleep. The tendency toward oxygen desaturation pattern on . 542

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543 Although the answer is not yet known, proposed 600 544 Table 1 601 Q18 Characteristics and physiologic measures of mechanisms of OSA risk in severe COPD include 545 602 patients with COPD only, OSA only, and OVS the following: fluid shifts in those with cor pulmo- 546 nale from lower extremity edema to the ,59 a 603 547 COPD Overlap Pure OSA generalized myopathy from COPD alone that 604 548 Group Group Group affects the upper airway muscles,60 or a steroid- 605 549 (n 5 32) (n 5 29) (n 5 152) induced myopathy from systemic or inhaled corti- 606 550 607 Age (y) 60.1 57.2 48.9 costeroids. All of these changes would increase 551 Æ 10.4 Æ 9.5 Æ 12.9 upper airway collapsibility. 608 552 609 Weight (kg) 87.6 102.2 106.8 553 610 Æ 17.5 Æ 20.6 Æ 28.8 Clinical Consequences of OSA and COPD 554 611 BMI (kg/m2)31Æ 736Æ 639Æ 10 555 The large aforementioned cohort studies did high- 612 Æ Æ Æ 556 FVC (% 60 19 72 17 87 20 light that among those with obstructive lung dis- 613 predicted) 557 ease and OSA, the nocturnal desaturations and 614 Æ Æ Æ 558 FEV1 (% 47 16 63 16 89 20 sleep disturbances are greater (both oxygen satu- 615 559 predicted) ration nadir and duration of hypoxemia) than would 616 Æ Æ Æ 560 FEV1/FVC (%) 59 9675879 be expected for either disease alone.21 Whether 617 Æ Æ Æ 561 PaO2 (mm Hg) 69 10 70 11 79 12 causal or not, more recent reports have suggested 618 Æ Æ Æ 562 PaCO2 (mm Hg) 40 5455394 an increased mortality in OVS compared with 619 563 AHI (events/h) 6 Æ 540Æ 20 42 Æ 23 COPD and OSA alone and have increased aware- 620 564 ness about OVSs. First, Marin and colleagues61 621 Time SpO2 16 Æ 28 48 Æ 28 30 Æ 28 565 Q19 <90% (%) found decreased survival among patients with 622 566 OVS compared with either COPD or OSA alone 623 567 Overlap refers to both COPD and OSA. (Fig. 2). There were differences in death from any 624 Abbreviation: 568 BMI, body mass index. cause and cardiovascular causes when patients 625 Q20 a Values are mean Æ SD. 569 Adapted from Resta O, Foschino Barbaro MP, Brindicci with OVS using CPAP were compared with those 626 570 C, et al. Hypercapnia in overlap syndrome: possible deter- not on CPAP. No differences were seen between 627 571 minant factors. Sleep Breath 2002;6(1):11–8; with COPD only and patients with OVS using CPAP.61 628 Q21 572 permission. That patients with OVS using CPAP have reduced 629 573 mortality compared with OVS without CPAP has 630 574 now also been reported in other cohorts62–64 631 575 Prevalence and Epidemiology of OVS Jaoude and colleagues64 found that CPAP only 632 576 In general, small studies from the early 1990s sug- improved outcomes from OVS in those patients 633 577 gested that severe COPD was a risk factor for 634 578 OSA.56 For example, one early study found greater 635 579 than 80% prevalence of OSA among patients with 636 580 COPD and excessive daytime sleepiness referred 637 581 for evaluation.12 In certain populations, too, such 638 582 as Veterans Administration patients, the coexis- 639 583 tence of OSA and COPD was high (29%) among 640 584 patients who had polysomnogram and spirometry 641

585 57 FPO 642 data available. = 586 More recently, larger epidemiology studies 643 587 including a more broad range of subjects, such 644 588 as the Sleep Heart Health Study and Multinational 645 589 Monitoring of Trends and Determinants in Cardio- 646

590 vascular Disease, have not demonstrated an print & web 4C 647 591 increased risk of OSA among those with obstruc- Fig. 2. Kaplan-Meier survival curves for patients with 648 592 tive lung disease, at least among those with mild COPD. Patients with OVS on CPAP, and patients with 649 593 obstructive lung disease.21,58 In these large co- OVS not on CPAP. Treatment with CPAP seems to pre- 650 594 vent against the excess mortality in patients with OVS. 651 horts, the prevalence of OSA was 11% to 14%, Adapted 595 Importantly, these data are observational. ( 652 which was similar in those with or without obstruc- from Marin JM, Soriano JB, Carrizo SJ, et al. Outcomes 596 21,58 653 tive lung disease. Thus, it seems likely that in patients with chronic obstructive pulmonary disease 597 654 there is little connection among those with mild and obstructive sleep apnea: the overlap syndrome. 598 COPD; whether more severe COPD can contribute Am J Respir Crit Care Med 2010;182(3):325–31; with 655 599 to OSA is not clear. permission.) 656

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657 who were also hypercapnic. Further exploring the has yet to be teased out, these studies suggest 714 658 observed therapeutic benefit of CPAP, Stanchina that optimizing COPD treatment can play a key 715 659 and colleagues63 found that greater time on role in the degree of nocturnal oxygen saturation. 716 660 CPAP was associated with reduced mortality in The impact on upper airway patency is unknown; 717 661 patients with OVS. some have hypothesized that (inhaled) steroids 718 662 Although the improvement with CPAP seems might predispose the upper airway to myopathy 719 663 dramatic, these are not randomized data; these and increased collapsibility. However, at least in 720 664 were cohort studies in which subjects chose to asthmatic patients receiving high-dose inhaled 721 665 adhere to or abandon CPAP therapy. Patients corticosteroids, there was no increase in 722 666 who did not adhere to CPAP may have been those collapsibility.71 723 667 with more COPD/less OSA; had more respiratory Nocturnal oxygen is a mainstay of therapy for 724 668 symptoms, such as dyspnea or sputum that limit hypoxemia in COPD with demonstrated mortality 725 669 CPAP use; or were less likely to adhere to other benefits.72,73 Among patients with OSA, nocturnal 726 670 medication therapy, which is also important for oxygen therapy alone may improve hypoxemia; 727 671 limiting poor outcomes (eg, statin therapy). Never- however, arousals, sleep architecture, and day- 728 672 theless, these findings highlight the need to focus time symptoms, such as sleepiness, are not 729 673 more resources on the care and understanding of impacted,74 pointing to the potential impact of 730 674 these patients. sleep fragmentation caused by arousals triggered 731 675 It is assumed, but not known, that the worse by airway obstruction, which is not addressed by 732 676 outcomes in OVS are caused by excess cardio- oxygen therapy. Thus, supplemental oxygen alone 733 677 vascular events. As discussed earlier, both for OSA seems unlikely to be of benefit. 734 678 COPD and OSA increase cardiovascular risk. 735 679 Some data support this potential mechanism, sug- 736 CPAP and Lung Function in COPD 680 gesting that OSA can augment vascular changes 737 681 among patients with COPD, such as arterial stiff- There are a few studies that have assessed treat- 738 682 ness.65 Sharma and colleagues66 found that pa- ment with CPAP in patients with OVS. Small 739 683 tients with OSA have more extensive remodeling studies have demonstrated improvements in day- 740 684 of the right ventricle seen on cardiac magnetic time oxygen saturation and degree of hypercarbia 741 685 resonance compared with those with COPD alone; with nocturnal CPAP use.75,76 Improvements in 742 686 743 the extent of right ventricle remodeling was corre- FEV1, echocardiogram estimates of mean pulmo- 687 744 lated with the oxygen desaturation index. nary artery pressure, PaO2, and PaCO2 have been 688 documented.75,77,78 Other studies have found a 745 689 decline in lung function among patients with OVS 746 Treatment of OVS 690 who were adherent to CPAP therapy.79 Given the 747 691 Treatment of OVS may be thought of as address- differences in study design, other factors such as 748 692 ing the underlying COPD, OSA, or both. Although weight loss, progression of underlying disease, 749 693 the specific goals of treatment remain poorly and selection bias of among those who choose Q13 750 694 defined, most clinicians strive to eliminate sleep- to use CPAP are all important considerations. 751 695 disordered breathing and eliminate NOD. What to The reason behind these improvements in gas ex- 752 696 target for ideal oxygen saturation, however, re- change may reflect an improvement in daytime 753 697 mains unclear, as does the impact of normalizing lung function, though the mechanism remains un- 754 698 hypercarbia. The most commonly applied therapy clear and controversial. The prevention of repeti- 755 699 is CPAP. tive upper airway collapse in an animal model 756 700 Before CPAP is applied, however, it is critical to seemed to improve lower .80 757 701 consider the use of therapies that target the under- Off-loading of respiratory muscles during sleep 758 702 lying COPD, such as and antiin- through CPAP may also be important, contributing 759 703 760 flammatories. Therapies aimed at COPD alone to decreased oxygen consumption, CO2 produc- 704 can improve nocturnal oxygen saturation as well tion, and reducing sleep hypoventilation. After 761 705 as decrease symptoms. Ipratropium and tio- CPAP initiation, fewer COPD-related hospital ad- 762 706 tropium, cholinergic bronchodilators, long-acting missions are seen in some populations.63,81 763 707 beta-agonists, and oral steroids all have data to As discussed earlier, recent papers suggest that 764 708 support improvements in oxygen saturation during the treatment of OVS with CPAP is associated with 765 709 sleep.67–70 Some of these agents, such as ipra- reduced mortality. First, in the Brazilian cohort, 766 710 tropium, have also been shown to improve sleep 5-year survival with CPAP was 71%, as compared 767 711 quality and increase REM and total sleep time, with 26% among patients using oxygen alone.62 768 712 although, surprisingly, tiotropium did not.67,68,70 This cohort included more than 600 patients who 769 713 Although the mechanism of these improvements required long-term oxygen therapy for hypoxemic 770

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771 COPD and had at least moderate OSA. Patients of weight loss among patients with OVS has not 828 772 with OSA were prescribed CPAP, and those who been examined; however, it is probably safe for 829 773 were nonadherent to CPAP continued to use oxy- obese patients with OVS to target weight loss.90 830 774 gen for COPD. Similarly, the findings from a Span- Although purely speculative, given the high rates 831 775 ish cohort of patients with OVS also suggested a of cardiovascular disease in OSA and COPD, it 832 776 benefit, lowering the mortality risk to that of may also make sense to consider cardioprotective 833 777 COPD alone.61 The striking improvement in both therapies (eg, aspirin, statin) as the primary pre- 834 778 cohorts supports a beneficial role of CPAP as vention in patients with OVS. 835 779 well as highlighting the very poor outcomes in Based on all of the aforementioned information, 836 780 those with OVS. Again, patients in both studies the authors propose the diagnostic and treatment 837 781 were not randomized but were self-selected algorithm in Fig. 3. 838 782 based on adherence to CPAP (or were not able 839 783 to afford CPAP therapy). That is, these are obser- 840 OSA AND ILD, WITH EMPHASIS ON IPF 784 vational studies comparing patients with OVS who 841 ILD/IPF Background 785 are and are not adherent to CPAP. Although these 842 786 studies do not elicit the mechanism for the ILD may refer to several heterogeneous condi- 843 787 reduced mortality, if caused by CPAP, this may tions, such as IPF; ; autoimmune- 844 788 be through the reduction in cardiac risk factors. related pulmonary disorders, such as systemic 845 789 Indeed, CRP levels, a nonspecific marker of sclerosis and hypersensitivity ; or sec- 846 790 inflammation, were significantly reduced in pa- ondary to an environmental or drug exposure, 847 791 tients with OVS using CPAP as compared with such as amiodarone. The common features of 848 792 pretreatment.82 the ILDs are (1) that these are distinct from 849 793 Noninvasive ventilation (NIV), such as bilevel obstructive lung diseases (such as COPD) and 850 794 positive airway pressure, is an attractive treatment demonstrate restrictive physiology and (2) that 851 795 modality in this population. Even in the absence of the anatomic basis of the disease is usually the in- 852 796 OSA, nocturnal NIV is often applied for patients terstitium (the alveolar epithelium, pulmonary 853 797 with more severe COPD to off-load respiratory capillary endothelium, basement membrane, peri- 854 798 muscles, supplement ventilation, decrease hyper- vascular, and perilymphatic tissues). The focus of 855 799 capnia, and reduce hypoxemia. Studies in this the authors’ discussion is primarily among patients 856 800 area have generally been small, nonrandomized, with IPF. 857 801 and in patients with stable disease. Taken IPF is a of unknown 858 802 together, these studies did not demonstrate any cause. It is characterized by chronic, progressive 859 803 improvements in lung function, gas, exchange, lung fibrosis of unknown cause.91 It is an irrevers- 860 804 sleep efficiency, or mortality according to a 2003 ible process, with an unpredictable course. Pro- 861 805 meta-analysis.83 Since that time, however, 2 areas gression can vary markedly on an individual 862 806 of investigation deserve to be highlighted. Among basis, from slow chronic decline to a rapid acceler- 863 807 patients with OVS with stable hypercapnic COPD ation of disease; acute exacerbations may also 864 808 (patients with OSA were excluded), one moder- punctuate the disease course. Prognosis is gener- 865 809 ately large randomized trial demonstrated a mor- ally very poor, and there are no known effective 866 810 tality benefit with NIV use, though NIV was medical treatments. Despite ongoing research, 867 811 accompanied by a decrease in quality of life.84 A the cause of the disease remains poorly under- 868 812 mortality benefit compared with historical controls stood. Histologically, IPF correlates with the 869 813 has also been seen using very high ventilation set- pattern of usual interstitial pneumonitis; the terms 870 814 tings.85 These investigators argue that so-called are sometimes used synonymously. 871 815 high-intensity noninvasive positive pressure venti- As compared with COPD, IPF is a rare condition, 872 816 lation (with very high driving pressures, for affecting approximately 14 to 28 per 100,000 peo- 873 817 92 874 example, inspiratory pressures of 28 cm of H2O ple in the United States. It is more common in 93 818 and respiratory rate of more than 20 breaths per older individuals and males. The relatively low Q14 875 819 minute) among patients with COPD does not prevalence of IPF means that, as compared with 876 820 seem to impact sleep quality and may have COPD, the prevalence of coexisting OSA and IPF 877 821 some benefits, such as improvement in gas ex- (or any ILD) is presumably also rare. However, 878 822 change and lung function.86–88 OSA and IPF might be worth studying if (1) IPF pre- 879 823 Weight loss is beneficial among patients with disposes to OSA, (2) symptoms traditionally 880 824 OSA and obesity.89 Among patients with COPD ascribed to IPF (eg, fatigue) are actually caused 881 825 alone, however, weight loss is often a concerning by OSA and can be successfully treated with 882 826 finding, stemming from pulmonary cachexia, OSA treatment, and (3) treatment of OSA in these 883 827 infection, malignancy, or deconditioning. The role patients improves outcomes. 884

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885 942 886 943 887 944 888 945 889 946 890 947 891 948 892 949 893 950 894 951 895 952 896 953 897 954 898 955 899 956 900 957 901 958 902 959 903 960 904 961 905 962 906 963 907 964 Q22 908 Fig. 3. Management algorithm for patients with COPD. Patients with COPD should be assessed for any red flags 965 that might suggest the presence of concurrent OSA. If present, COPD should be optimized before undergoing 909 966 polysomnography. Attention should be paid to the flow signal and apnea index when assessing the severity of 910 OSA. If hypercapnia is present, patients can begin on bilevel positive airway pressure (PAP). If flow limitation 967 911 is present without significant apneas, conservative therapy, such as a mandibular advancement device, weight 968 912 loss, and positional therapy, should be considered. If apneas predominate, CPAP should be started. Supplemental 969 913 oxygen should be added if hypoxemia persists. 970 914 971 915 972 94 916 Sleep in IPF prednisone, which may interfere with sleep 973 when used at high doses. Patients with IPF are 917 Poor sleep is common among patients with IPF. 974 often additionally burdened by depression and 918 Global measures of sleep quality and excessive 975 other mood disorders, which are often character- 919 daytime sleepiness are significantly different as 976 ized by sleep disturbances and changes in energy 920 compared with controls, with patients with IPF 977 level; the medications used to treat these disor- 921 complaining of poor sleep and excessive daytime 978 ders may also impact sleep and daytime function. 922 sleepiness.94 Insomnia is also a frequent occur- 979 923 rence, found in almost one-half of patients with 980 Respiration During Sleep in IPF 924 IPF, which may contribute to the high rates of day- 981 925 time symptoms.95 When sleep is objectively as- The pathologic changes in pulmonary fibrosis are 982 926 sessed by polysomnography, as compared with decreased lung compliance and increased ventila- 983 927 controls, patients with IPF have increased sleep tion/perfusion mismatch. These changes will in- 984 928 fragmentation and stage I sleep.96–98 Total sleep crease minute ventilation and the work of 985 929 time, sleep efficiency, and REM sleep are all breathing. As a result, patients with IPF exhibit 986 930 reduced.96–98 rapid, shallow breathing during wakefulness.98 987 931 The mechanisms for these sleep abnormalities During sleep, the tachypnea persists; as 988 932 remain incompletely understood, though are likely compared with normal controls, there is no 989 933 to be multifactorial. Disruption from cough has decrease in respiratory rate, although tidal volume 990 934 been frequently cited as one factor that contrib- decreases.98 Thus, similar to COPD as discussed 991 935 utes to sleep disturbance and the inability to earlier, among patients with ILD, sleep may serve 992 936 sleep.95,99–101 The effect of medications, such as as a stressor to the . Oxygen 993 937 corticosteroids, which are still used empirically desaturation is frequently more profound than dur- 994 938 given the lack of other treatment options, may ing wakefulness. The importance of evaluating 995 939 further contribute to some of the sleep abnormal- nighttime respiratory patterns has been recently 996 940 ities reported by patients with IPF. Nearly two- highlighted, as it may have prognostic value in as- 997 941 thirds of patients in one series were on sessing mortality in ILD.102 Specifically, among 998

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999 patients with newly diagnosed IPF, the degree of hypopneas were scored based on oxygen 1056 1000 nocturnal desaturation was greater than seen dur- desaturation. 1057 1001 ing exercise and was predictive of survival,103–105 In support of a mechanistic link between IPF and 1058 1002 possibly mediated through worsening pulmonary OSA, some investigators have invoked so-called 1059 1003 artery hypertension.103 tracheal traction, the link between lung volumes 1060 1004 and the upper airway.109,110 Briefly, in patients 1061 1005 ILD and Sleep-Disordered Breathing without lung disease, a decrease in lung volumes 1062 1006 leads to increased upper airway resistance, 1063 1007 The prevalence of sleep-disordered breathing is increased collapsibility, and worse OSA 1064 1008 reported to be extraordinarily high among patients severity.111,112 However, whether this relationship 1065 1009 with ILD. Symptoms such as fatigue, commonly still holds when compliance of the lung is altered 1066 1010 reported in patients with IPF, may be attributable 1067 98 is not clear; no formal measurement of airway 1011 to this. In published series, the incidence of resistance or collapsibility has been made in pa- 1068 1012 OSA ranges from more than two-thirds to nearly tients with IPF to test this hypothesis. Again, in 1069 106–108 Fig. 4 1013 90%. outlines the symptoms that the study by Lancaster and colleagues,108 total 1070 1014 are commonly reported in IPF and how they may lung capacity did not seem to predict OSA. 1071 1015 overlap with OSA. The nature of OSA in these pop- 1072 1016 ulations remains incompletely characterized, such Treatment 1073 1017 as whether events are caused by airway collapse 1074 1018 and flow limitation or oxygen desaturations. There are no proven therapies that target the un- 1075 1019 Among patients with IPF, AHI is not strongly corre- derlying disease process in IPF. Oxygen therapy 1076 1020 lated with the body mass index, again suggesting is widely used as supportive care. Studies suggest 1077 1021 that other mechanisms, aside from obesity, may that oxygen therapy can be associated with im- 1078 113,114 1022 be contributing to the diagnosis of OSA in this provements in exercise performance. How- 1079 108 1023 population. Indeed, as compared with controls, ever, no studies have demonstrated a mortality 1080 115 1024 patients with IPF spend more time with an oxygen benefit or improvement in exertional dys- 1081 116 1025 saturation less than 90%, even when the AHI is pnea, as rapid shallow breathing persists 1082 1026 similar. These observations raise the possibility despite addressing hypoxemia. 1083 1027 that the lower baseline oxygen saturation and Treatment with CPAP among patients with IPF 1084 1028 increased tendency toward desaturation are over- with at least moderate OSA results in gains in 1085 1029 estimating the collapsibility of the upper airway. sleep-related quality-of-life measures, though 1086 108 1030 The 2009 study by Lancaster and colleagues adherence to CPAP may be challenging in light 1087 117 1031 is helpful in this regard. First, their subjects with of chronic cough and other barriers. There are 1088 1032 mild OSA had a mean AHI of 10.7 events per no studies that have explored the impact of 1089 1033 hour, of which less than 1 event per hour was ap- CPAP on outcomes in IPF, such as disease pro- 1090 1034 nea. Additionally, approximately half of the hypo- gression or mortality. Taken together, OSA may 1091 1035 pneas were scored based on a 3% oxygen be common in IPF; treatment with CPAP may 1092 1036 desaturation (rather than arousal). In those with improve OSA symptoms. 1093 1037 moderate to severe OSA, the average AHI was 1094 1038 39.4 events per hour. But again, the apnea index Other OVS: Beyond COPD and IPF 1095 1039 was only 7.1 events per hour; nearly half of all From the earlier discussion, it is clear that there are 1096 1040 many research and clinical questions that remain 1097 1041 the 1098 IPF for OVS, even for OVS, which is relatively com- 1042 mon. Even less is known about the prevalence, 1099 1043 Pathophysiology consequences, and best management of OSA 1100 1044 Fibrosis with decreased lung compliance, 1101 decreased lung volumes. among other chronic lung diseases. However, 1045 Increased V/Q mismatch leads to hypoxemia Increased there are some pearls that the sleep physician 1102 upper airway 1046 collapsibility? should know regarding other lung diseases. 1103 1047 Increased hypopneas? 1104 Symptoms Sarcoidosis is a chronic condition of unknown 1048 1105 cough cause characterized by the formation of granu- 1049 fatigue OSA 1106 Sleep fragmentation lomas in many organs, most commonly the lung. dyspnea 1050 poor exercise tolerance Lung disease may range from mild to severe and 1107 1051 fibrosing in nature. Steroids are often given in 1108 1052 Fig. 4. Links between IPF and OSA. Many symptoms 1109 and findings among by patients with IPF overlap more severe disease. Fatigue and excessive day- 1053 1110 with those of OSA, including daytime fatigue, poor time sleepiness are more common among patients 1054 sleep, and nocturnal hypoxia. Similarly, the patho- with sarcoid as compared with controls.118–120 1111 1055 physiologic changes of IPF may contribute to OSA. Consideration of OSA among these patients is, 1112

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1113 therefore, important, particularly among those with 2. Pauwels RA, Buist AS, Calverley PM, et al, GOLD 1170 1114 abnormal lung function.118 There remains a popu- Scientific Committee. Global strategy for the diag- 1171 1115 lation of patients, however, with hypersomnolence nosis, management, and prevention of chronic 1172 1116 unrelated to OSA. Relevant for sleep medicine obstructive pulmonary disease. NHLBI/WHO 1173 1117 physicians, fatigue improves with stimulant ther- Global Initiative for Chronic Obstructive Lung Dis- 1174 1118 apy (armodafinil).121 This improvement may serve ease (GOLD) workshop summary. Am J Respir 1175 1119 as a paradigm for patients with chronic lung dis- Crit Care Med 2001;163(5):1256–76. 1176 1120 ease and fatigue to receive empiric therapy. 3. Ford ES, Croft JB, Mannino DM, et al. COPD sur- 1177 1121 Although most of the data are in pediatric popu- veillance–United States, 1999-2011. Chest 2013; 1178 1122 lations, OSA seems to be more common among 144(1):284–305. 1179 1123 patients with sickle cell anemia as compared 4. Buist AS, McBurnie MA, Vollmer WM, et al. Interna- 1180 1124 with controls.122–124 OSA among patients with tional variation in the prevalence of COPD (the 1181 1125 sickle cell disease is accompanied by more severe BOLD study): a population-based prevalence 1182 1126 nocturnal desaturations and hypercarbia.123 study. Lancet 2007;370(9589):741–50. 1183 1127 Although larger studies are needed to better 5. Hoyert DL, Xu J. Deaths: preliminary data for 2011. 1184 1128 describe the relationship, OSA, through nocturnal Natl Vital Stat Rep 2012;61(6):1–65. Hyattsville, 1185 1129 hypoxia, may serve as a trigger for vasoocclusive MD: National Center for Health Statistics. 2012. 1186 125 1130 Q15 sickle events. This highlights the potential 6. Foster TS, Miller JD, Marton JP, et al. Assessment 1187 1131 importance of recognizing and treating OSA of the economic burden of COPD in the U.S.: a re- 1188 1132 among those with sickle cell disease. view and synthesis of the literature. COPD 2006; 1189 1133 (CF) is a systemic disease char- 3(4):211–8. 1190 1134 acterized by abnormal chloride channel function. 7. Rabe KF, Hurd S, Anzueto A, et al. Global strategy 1191 1135 Obstructive lung disease, including for the diagnosis, management, and prevention of 1192 1136 and repeated pulmonary infections caused by chronic obstructive pulmonary disease: GOLD ex- 1193 1137 Q16 tenacious sputum, are common in among patients ecutive summary. Am J Respir Crit Care Med 1194 1138 with CF. Sleep apnea is common (in up to 70% of 2007;176(6):532–55. 1195 1139 children with CF).126 OSA presents at an early age 8. Shepard JW Jr, Schweitzer PK, Keller CA, et al. 1196 1140 as compared with controls, as young as preschool Myocardial stress. 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CSLP518_proof ■ 10 June 2014 ■ 8:04 pm Our reference: CSLP 518 P-authorquery-v9

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Location Query / Remark: Click on the Q link to find the query’s location in text in article Please insert your reply or correction at the corresponding line in the proof Q1 Please approve the short title to be used in the running head at the top of each right-hand page. Q2 This is how your name will appear on the contributor's list. Please add your academic title and any other necessary titles and professional affiliations, verify the information, and OK KATHERINE A. DUDLEY, MD, Boston, Massachusetts ATUL MALHOTRA, MD, Boston, Massachusetts ROBERT L. OWENS, MD, Boston, Massachusetts Q3 Are author names and order of authors OK as set? Q4 The affiliation is not provided for the authors “Katherine A. Dudley” and “Atul Malhotra”, hence the provided corresponding author affiliation address has been retained for both the authors. Please verify and provide the affiliation for the above mentioned authors. Q5 The following synopsis was created from the “Key points” section of your article because a separate abstract was not provided. Please confirm OK or submit a replacement (also less than 100 words). Please note that the synopsis will appear in PubMed: Overlap syndrome refers to the coexistence of chronic lung disease and obstructive sleep apnea (OSA) in the same patient. Recent data in chronic obstructive pulmonary disease and patients with OSA overlap highlight the increased morbidity and mortality of overlap syndromes compared with either underlying disorder alone. The underlying disorders in overlap syndrome may be of very different severity; thus, there is a great amount of patient heterogeneity. Unrecognized OSA may contribute to symptoms of sleepiness and fatigue in those with chronic lung disease. Thus, clinicians should be mindful of the overlap syndromes in these patients. Q6 Please verify the affiliation address and provide the missing information (department name, University/ Institute/Center). Q7 Please check the article to be sure the edits preserve your intent.

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