Adult pulmonary Langerhans cell histiocytosis, tobacco smoking and quitting: an update| Tabaccologia

Abstract

Pulmonary Langerhans cell histiocytosis (PLCH), also known as histiocytosis X, belongs to the spectrum of diffuse interstitial cystic pneumonia that usually affects young adult, almost exclusively tobacco smokers or co-users of cannabis. A better understanding of the pathogenesis of PLCH has allowed a more individualized therapy approach. The potential severity of its evolution justifies an early diagnosis and a specific management including the abstinence from inhalants which conditions its prognosis. Patients suffering from PLCH often are hard-core smokers experiencing great difficulties to quit and require the involvement of healthcare professionals in smoking cessation management.

Introduction

Pulmonary Langerhans cell histiocytosis (PLCH), also known as histiocytosis X, is a diffuse cystic infiltrative lung disease. This rare disease affects young people of both sexes and almost exclusively smokers of tobacco and/or cannabis. Despite recent progress in understanding pathogenesis of PLCH, it remains poorly understood. Smoking cessation remains the cornerstone of treatment which determines the prognosis of the disease and helps to halt the deterioration of respiratory function by limiting the risk of respiratory failure or lung cancer, among other complications. Patients are highly dependent on tobacco and often require management in smoking cessation clinics.

Pulmonary Langerhans cell histiocytosis and tobacco smoking

Langerhans cell histiocytosis (LCH)

Langerhans cell histiocytosis (LCH) is a rare disease recognized as a hematopoietic neoplasm by the World Health Organization [1]; incidence in adult is estimated at 1-1.5 case per million population per year. It can affect patients from newborns to the elderly. The classification of clinical forms of LCH is based on the number and type of organs affected, There is a wide variety of clinical manifestations: unifocal or multifocal forms, pulmonary LCH, multisystem disease which combines to varying degrees bone, skin, hypothalamic-pituitary, lymph node, liver, spleen, lung and more rarely central neurological involvement [2]. The prognosis of LCH is variable: localized forms often affecting the bone or the lung have more indolent course with a high frequency of spontaneous remission in non -smokers, systemic form have often severe prognosis; a patient may progress from a localised form to systemic involvement [1,2]. LCH, whose aetiology remains unknown, is characterised by infiltration of tissues by dendritic cells that have the phenotypic characteristics of Langerhans cells, often organised in granulomas. BRAFV600E mutation is present in about 50% of LCH cases and studies have revealed MAPK pathway (RAS-RAF-MEK-ERK) mutations as well as that BRAF-wild type LCH may harbor other mutations in the MAPK-ERK pathway genes. All these molecular discoveries have implications for the diagnosis and the management of LCH [1].

Pulmonary Langerhans cell histiocytosis (PLCH)

Epidemiology

It is estimated that PLCH accounts for 3 to 5% of adults with diffuse lung infiltrative diseases [1-2]. It is most commonly diagnosed in patients aged 20 to 40 years, both sexes; 25 to 30,000 patients would be affected by PLCH in the world, including about 1,100 in the U.S.A. [3]. A national survey conducted in Japan estimated the prevalence of PLCH to be 0.27 per 100,000 males and 0.07 per 100,000 females in the Japanese population [4]. In France, the annual incidence of PLCH is 4 to 9 cases per million, which corresponds to 50 to 60 new cases per year [5].

Role of smoking in the pathogenesis of PLCH

The pathogenesis of PLCH is incompletely known; however, its process can be described as follows [1-3]:

1. Dendritic cells (DCs) harboring activating MAPK mutation accumulate in the pulmonary parenchyma, in patients genetically susceptible.
2. A second immune system activation by external antigen (such as cigarette smoke) and migration of DCs to the lungs; Langerhans cells (LCs) are a subset of DCs characterized by the presence of cell surface markers CD1a and langerine;
3. Accumulation of T-cells and immune cells around small airways with release cytotoxic mediators and matrix-degrading enzymes which contribute to bronchiolar destruction; CDs produce cytokines (IL1-β, GM-CSF, TNF-α, TGF-β, etc.) and help recruitment of immune cells forming nodules gradually replaced by fibroblastic proliferation with central scarring and peripheral cellular tentacles [6];
4. PLCH nodules have the ability for destruction of surrounding tissues by activating macrophages and cytotoxic-cells which leads to formation of cystic airspace dilations; lesions predominate in the upper and middle parts of the lungs and become larger and thin-walled as the disease progresses (Figure 1) [7].

Only a minority of cigarette smokers develop PLCH suggesting that cigarette smoke is not single causative agent but potentiator in pathogenesis in susceptible people. The almost exclusive occurrence of PLCH in smokers suggests the involvement of tobacco in pathogenesis [1-3]. More than 95% of patients diagnosed with PLCH are current or former smokers and It has been shown that children with extrapulmonary LCH have a much higher risk of developing pulmonary involvement in adulthood if they become smokers in adolescence [2,3]. Tobacco smoke causes recruitment, promotion of DCs and their survival by anti-apoptotic mechanisms in the lung, stimulating the local production of cytokines (TNF-α, TGF-β, GM-CSF, chemokine CCL20, CCL7); high levels of osteopontin that may attract leukocytes, macrophages and DCs is found in bronchoalveolar lavage fluid in smokers with PLCH [1-4]. The action of smoking in combination with the consequences of dendritic cell accumulation seems to be essential for the development of the disease in genetically susceptible patients harboring activating MAPK mutation in DCs (80% of PCLH), in particular the BRAF V600E mutation (50% of PCLH) [1]. One study showed no increase in alpha-1 antitrypsin-deficient phenotypes in a series of patients with PLCH [8]. A homozygous deletion of the glutathione S-transferase M1 gene in patients with PCHL has not been investigated (the GSTM1 0/0 genotype is frequently associated with severe COPD in smokers) [9]. It would be useful to investigate the presence of mutations affecting the CHRNA2/CHRNA3/CHRNB4 locus of chromosome 15q25 encoding the α5, α3, β4 subunits of the nicotinic receptors, which are associated with nicotine addiction (and risk of lung cancer or COPD) [10] which could explain that many patients with PLCH are heavy smokers.

Diagnosis and management of PLCH

PLCH generally is identified in the context of nonspecific respiratory symptoms (cough, dyspnea, wheezing), spontaneous pneumothorax (sometimes recurrent) or on routine chest X-ray [2,3,11]. However, the diagnosis can be made in a wide variety of situations: in children where the isolated form of PLCH is rarer than in adults [12], in elderly smokers [13], in second hand smoking exposure [14], associated with pulmonary tuberculosis [15] or HIV infection [16]. The occurrence of hemoptysis is unusual and justifies the search for a complication (infectious bronchitis, lung cancer or Aspergillus colonization) [2,3,11]. Bronchial fibroscopy with bronchoalveolar lavage may show macrophagic alveolitis with a moderate increase in eosinophils (<10%) and little benefit from CD1a cell testing. Lung biopsy reveals accumulation of Langerhans cells (expressing CD1a and langerin) organised in granulomas in the wall of the distal bronchioles [2,3,11]. Pulmonary function tests (PFTs) identify an obstructive ventilatory disorder in 90% of patients with decreased diffusing capacity of lung for carbon monoxide (DLCO) in 70% of patients PFTs can identify normal function (10%), restrictive or combined defects [2,3,11]. The check-up looks for pulmonary arterial hypertension (PAH) and other visceral locations of LCH [1-3,11].

The management of PLCH [1-3,11] includes infection prevention, treatment with bronchodilators, respiratory rehabilitation, and even long-term oxygen therapy. Treatment of pneumothorax. Cladribine is a purine analogue cytostatic used in progressive forms; at the stage of severe PAH, some patients may benefit from lung transplantation. Stopping smoking is imperative to halt the progression of PLCH.

Pulmonary Langerhans cell histiocytosis and smoking cessation

Benefits of stopping smoking

The course of PLCH is variable [5]. A retrospective multicenter study [17] has shown that 50% of the patients had an impairment of their ventilatory function at 5 years; 40% of the patients developed an obstructive ventilatory disorder preceding the extension of the lesions visible on the chest CT scan. Some of them had a rapid decrease in FEV after diagnosis, smoking status was a prognostic factor for the rapid deterioration of respiratory function. A study conducted in patients with PLCH has found that PAH occurs within 10 years [18]. A prospective, multicentre study [19] has included 58 patients newly diagnosed PLCH with a two year follow-up. The aims of the study were to estimate the incidence of early progression of the disease and to evaluate the impact of smoking status on lung function outcomes compared with baseline values. At each visit (every 3 months) smoking status was recorded on the patients’ self-reports and urinary cotinine measurements. The cumulative incidence of lung function deterioration at 24 months was 38% (22% for FEV₁ and DLCO, 9% for FVC). In the multivariate analysis, smoking status and PaO₂ at inclusion were the only factors associated with the risk of lung function defect. Being a non-smoker was associated with a decreased risk of lung function deterioration.

Cases reports have described improvement or complete resolution of extensive lesions visible on the chest CT scan of PLCH associated with normalization of the clinic after a few months of smoking abstinence [20-24]. Others have reported regression of pulmonary and extra-pulmonary involvement occurring after smoking cessation [25]. Studies emphasize the determining role of smoking in the prognosis of PLCH [26-27]. This justifies smoking abstinence which removes patients from exposure to cigarette smoke, which interrupts the pathophysiological cascade leading to tissue damage.

Barrriers to quitting

A cross-sectional study included adult patients with LCH seen at a French referral center between January 2012 and January 2013 [28]. Patients completed self-reported tests : the Hospital Anxiety and Depression Scale (HAD), the Barratt Impulsivity Scale, French version 10 (BIS-10), the Cannabis Use Disorders Identification Test (CUDIT) to determine the point prevalence of significant psychological symptoms and substance use disorders. Of the 71 patients whom 49 with PLCH (45 of them were active smokers), numerous disorders were detected: anxiety (31%), depressive symptoms (6%), impulsivity (14%), alcohol abuse (14%), 17% of the patients were regular cannabis users (50% had a CUDIT score suggestive of a cannabis use disorder). Brief advice to stop smoking may help patient to quit on their own at the diagnosis of PLCH. However, stopping smoking often is a challenge in heavy chronic smokers [29]; in a prospective, multicenter study, only 20% of patients with PLCH quit smoking after 24 months of follow-up [17].

Helping smokers with PCLH to quit smoking?

Early detection of chronic respiratory disease in young smokers

Many studies report less self-efficacy to stop smoking associated to depressive disorders with a negative impact on quitting in smokers with chronic respiratory diseases [30]. The diagnosis of respiratory defects which designates these smokers as hard-core smokers is often made too late. However, a recent meta-analysis has clearly demonstrated the efficacy and sensibility of portable spirometers (NEO-6, PIKO-6) in the diagnosis of early obstructive ventilatory disorder [31].

A multicenter survey of smokers (n=1,918) seeking treatment for the first time in smoking cessation clinics to assess predictors of smoking cessation analysed self-reported questionnaires (Richmond test, Fagerström Test for Nicotine Dependence, Hospital Anxiety Scale), clinical signs and the results of miniaturized spirometry. 7.5% of smokers presented an obstructive ventilatory disorder; they were more addicted to tobacco [32]. Professionals involved in the care of smokers should use these breath measurement tools as part of their support for smoking cessation.

Smoking cessation management

Smokers with PLCH require management in smoking cessation clinics. Complete smoking cessation is the only way to reduce the risk of rapid lung function deterioration, which cannot be achieved by simply reducing consumption [33]. The cessation intervention (Figure 2) begins after an exhaustive assessment of smoking [34]. In the general population, nicotine replacement therapies (NRT) provide higher 6-months abstinence rate (RR = 1.55; 95% CI: 1,49-1,1) vs. control [35]; combining two dosage forms provides higher smoking abstinence rates (RR = 1.25; 95% CI: 1.15-1.36) vs a single form [35], bupropion provides a similar abstinence rate to the patch (OR = 1.88; 95% CI: 1.60-2.06) [36], varenicline is the most effective smoking cessation medication (OR = 2.88; 95% CI: 2.40-3.47) [36]. Combined pharmacotherapy and behavioral interventions improves the abstinence rate (RR = 1.83; 95% CI: 1.01-3.31) vs single pharmacotherapy [37] Patients with psychiatric disorders tolerate these drugs well compared to placebo [38].

Standard interventions may be insufficient in hard-core smokers and alternative strategies are worth trying. They include pharmacotherapies (pre-quit treatment, assisted reduction with NRT to quit, extended or combined medications: NRT with bupropion, varenicline or other drugs, varenicline with bupropion, sertraline with buspirone) [39]. Physical exercise [40], non-invasive brain stimulation technics [41] reduce craving after intervention, virtual reality technologies [42] and behavioral interventions help prevent relapse after quitting.

Is harm reduction efficient in smokers with PLCH?

Heated tobacco products are forms of nicotine delivery intended as a less harmful alternative to cigarettes ; they have the potential to increase oxidative stress and respiratory tract infections and do not appear to be a compelling option for a risk reduction strategy [43].

Electronic cigarettes (e-cig.) generate a nicotine-containing aerosol that is much less toxic than conventional cigarette smoke when used exclusively and may help some smokers quit [44]. Its long-term harmfulness is not well known; e-cig aerosol could generate oxidative stress, inflammatory responses, and DNA damage [45] and a case of HLP has been reported in an e-cig user [46]. However, the potential toxicity of e-cig. must be balanced against the deleterious consequences of continued smoking [46].

Conclusion

The diagnosis of PLCH should be discussed in young tobacco smokers or cannabis users presenting nonspecific respiratory symptoms, spontaneous pneumothorax or breathing dysfunction. Smoking cessation is essential to control the course of the disease. Smokers with PLCH often experience difficulties in stopping smoking; this justifies the involvement of health care professionals in smoking cessation clinics to support them to quit.

Figures and tables

Figure 1.Chest CT in PLCH: irregular nodules, some of them excavated and thin-walled holes.

Figure 2.Management of smoking cessation in smokers with PLCH. Abbreviation: 5Rs = Relevance, encourage the patient to indicate why quitting is personally relevant. Risks, ask the patient to identify potential negative consequences of smoking. Rewards, ask the patient to identify potential benefits of quitting. Roadblocks, ask the patient to identify barriers or impediments to quitting. Repetition, repeat the motivational intervention at every interaction of clinician and patient; CBT = Cognitive and behavioral therapy; SUD = substance use disorder; PLCH = Pulmonary Langerhans cell histiocytosis; NRT = Nicotine replacement therapy; e-cig = Electronic cigarette; AA = Additional assistance (physical exercise, non-invasive brain stimulation, virtual reality technologies).

References

1. Goyal G, Tazi A, Go RS, Rech KL, Picarsic JL, Vassallo R. International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults. Blood. 2022; 139:2601-21. DOI
2. Vassallo R, Harari S, Tazi A. Current understanding and management of pulmonary Langerhans cell histiocytosis. Thorax. 2017; 72:937-45. Publisher Full Text
3. Shaw B, Borchers M, Zander D, Gupta N. Pulmonary Langerhans cell histiocytosis. Semin Respir Crit Care Med. 2020; 41:269-79. DOI
4. Watanabe R, Tatsumi K, Hashimoto S, Tamakoshi A, Kuriyama T, Respiratory Failure Research Group of Japan. Clinico-epidemiological features of pulmonary histiocytosis X. Intern Med. 2001; 40:998-1003. DOI
5. Obert J, Tazi A. Pulmonary manifestations of Langerhans cell histiocytosis. Rev Mal Respir. 2015; 32:850-66. DOI
6. Poellinger A, Berezowska S, Myers JL, Huber A, Funke-Chambour M, Guler S. The octopus sign - A new HRCT sign in pulmonary Langerhans cell histiocytosis. Diagnostics (Basel). 2022; 12:937. DOI
7. Radzikowska E. Update on pulmonary Langerhans cell histiocytosis. Front Med (Lausanne). 2021; 7:582581. DOI
8. McCarthy C, Bugnet E, Benattia A, Keane MP, Vedie B, Lorillon G. Clarifying the relationship between pulmonary Langerhans cell histiocytosis and alpha 1 antitrypsin deficiency. Orphanet J Rare Dis. 2021; 16:72. DOI
9. Baranova H, Perriot J, Albuisson E, Ivaschenko T, Baranov VS, Hemery B. Peculiarities of the GSTM1 0/0 genotype in French heavy smokers with various types of chronic bronchitis. Hum Genet. 1997; 99:822-6. DOI
10. Santoro A, Tomino C, Prinzi G, Lamonaca P, Cardaci V, Fini M. Tobacco smoking: risk to develop addiction, chronic obstructive pulmonary disease, and lung cancer. Recent Pat Anticancer Drug Discov. 2019; 14:39-52. DOI
11. Lorillon G, Tazi A. How I manage pulmonary Langerhans cell histiocytosis. Eur Respir Rev. 2017; 26:170070. DOI
12. Barclay M, Devaney R, Bhatt JM. Paediatric pulmonary Langerhans cell histiocytosis. Breathe. 2020; 16:200003. DOI
13. Jeelani HM, Ehsan H, Sheikh MM. Pulmonary Langerhans cell histiocytosis in a elderly smoker. Cureus. 2020; 12:e10377. DOI
14. Sawalha L, Kumar A, Arshad A, Riaz A, Mahboob H. Pulmonary Langerhans cell histiocytosis: radiologic resolution following cessation of second hand smoking. Clin Respir J. 2017; 11:1063-7. DOI
15. Gao L, Li H, Li G, Liu W, Li J, Zhang W. Pulmonary Langerhans cell histiocytosis with cervical lymph node involvement, and coexistence with pulmonary tuberculosis and right pneumothorax: a case report and review of literature. Int J Clin Exp Pathol. 2015; 8:2146-52.
16. Kuhnert C, Humblot S, Chaouat A, Lalanne H, Pasquali JL, Martin T. Pulmonary histiocytosis, then bronchiolo-alveolar cancer in HIV-1 infection. Presse Med. 2002; 31:885-7.
17. Tazi A, Marc K, Dominique S, de Bazelaire C, Crestani B, Chinet T. Serial computed tomography and lung function testing in pulmonary Langerhans’ cell histiocytosis. Eur Respir J. 2012; 40:905-12. DOI
18. Le Pavec J, Lorillon G, Jaïs X, Tcherakian C, Feuillet S, Dorfmüller P. Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest. 2012; 142:1150-7. DOI
19. Tazi A, de Margerie C, Naccache JM, Fry S, Dominique S, Jouneau S. The natural history of adult pulmonary Langerhans cell histiocytosis: a prospective multicentre study. Orphanet J Rare Dis. 2015; 10:30. DOI
20. Chong SG, Samaha M, Samaha G, Casserly B. Rapid resolution of pulmonary Langerhans cell histiocytosis. BMJ Case Rep. 2013; 2013:bcr2013009948. DOI
21. Wang FF, Liu YS, Zhu WB, Liu YD, Chen Y. Pulmonary Langerhans cell histiocytosis in adults: a case report. World J Clin Cases. 2019; 7:1892-8. DOI
22. Wolters PJ, Elicker BM. Subacute onset of pulmonary Langerhans cell histiocytosis with resolution after smoking cessation. Am J Respir Crit Care Med. 2014; 190:e64. DOI
23. Li Y, Cai HR, Ma M, Wang Lj, Yang J, Ding JJ. A case of pulmonary Langerhans cell histiocytosis with BRAF V600E-negative and MAP2K1-positive mutations presenting as diffuse nodules in chest high-resolution computed tomography after smoking cessation. Chin Med J (Engl). 2016; 129:1384-6. DOI
24. Ninaber M, Dik H, Peters E. Complete pathological resolution of pulmonary Langerhans cell histiocytosis. Respirol Case Rep. 2014; 2:76-8. DOI
25. Routy B, Hoang J, Gruber J. Pulmonary Langerhans cell histiocytosis with lytic bone involvement in an adult smoker: regression following smoking cessation. Case Rep Hematol. 2015; 2015:201536. DOI
26. Aydoğdu K, Günay E, Fındık G, Günay S, Ağaçkıran Y, Kaya S. Pulmonary Langerhans cell histiocytosis; characteristics of 11 cases. Tuberk Toraks. 2013; 61:333-41. DOI
27. Perriot J, Underner M, Peiffer G, Arvers P. Smoking cessation in smokers with pulmonary Langerhans cell histiocytosis - considerations from the management of ten patients. Rev Mal Respir. 2021; 38:157-63. DOI
28. Bugnet E, Gupta N, Lorillon G, Arbabzadeh-Bouchez S, Lemogne C, Chevret S. Psychological features of adult patients with Langerhans cell histiocytosis. PLoS One. 2021; 16:e0246604. DOI
29. Perriot J, Underner M, Peiffer G, Le Houezec J, Samalin L, Schmitt A. Helping the “hard-core” smokers. Rev Mal Respir. 2012; 29:448-61. DOI
30. Jiménez-Ruiz CA, Andreas S, Lewis KE, Tonnesen P, van Schayck CP, Hajek P. Statement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quit. Eur Respir J. 2015; 46:61-79. DOI
31. Zhou J, Li X, Wang X, Yu Na, Wang W. Accuracy of portable spirometers in the diagnosis of chronic obstructive pulmonary disease a meta-analysis. NPJ Prim Care Respir Med. 2022; 32:15. DOI
32. Pougnet R, Heno G, Zanin A, Christine L, Maryline le B, Ronan G. Screening for chronic obstructive pulmonary disease in smoking cessation clinics in France. Addict Health. 2016; 8:1-8.
33. Berlin I. Is harm and risk reduction efficient and what are its limits for tobacco?. Addictologie. 2017; 39:S107-16.
34. Perriot J., Underner M, Peiffer G. Helping smoking cessation in COPD, asthma, lung cancer, operated smokers. Rev Pneumol Clin. 2018; 74:170-80. DOI
35. Hartmann-Boyce J, Chepkin SC, Ye W. Nicotine replacement therapy versus control for smoking cessation. Cochrane Database Syst Rev. 2018; 5:CD000146. DOI
36. Cahill K, Stevens S, Perera R, Dautzenberg B. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013; 5:CD009329. DOI
37. Stead LF, Koilpillai P, Fanshawe TR, Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking cessation. Cochrane Database Syst Rev. 2016; 3:CD008286. DOI
38. Anthenelli RM, Benowitz NL, West R, St Aubin L, McRae T, Lawrence D. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016; 387:2507-20. DOI
39. Underner M, Perriot J, Peiffer G, Harika-Germaneau G, Jaafari N. Smoking cessation: pharmacological strategies different from standard treatments. Rev Pneumol Clin. 2018; 74:205-14. DOI
40. Abrantes AM, Farris SG, Minami H, Strong DR, Riebe D, Brown RA. Acute effects of aerobic exercise on affect and smoking craving in the weeks before and after a cessation attempt. Nicotine Tob Res. 2018; 20:575-82. DOI
41. Song S, Zilverstand A, Gui W, Pan X, Zhou X. Reducing craving and consumption in individuals with drug addiction, obesity or overeating through neuromodulation intervention: a systematic review and meta-analysis of its follow-up effects. Addiction. 2022; 117:1242-55. DOI
42. Keijsers M, Vega-Corredor MC, Tomintz M. Virtual reality technology use in cigarette craving and smoking interventions (I “virtually” quit): systematic review. J Med Internet Res. 2021; 23:e24307. DOI
43. Znyk M, Jurewicz J, Kaleta D. Exposure to heated tobacco products and adverse health effects, a systematic review. Int J Environ Res Public Health. 2021; 18:6651. DOI
44. Hartmann-Boyce J, McRobbie H, Lindson N, Bullen C, Begh R, Theodoulou A. Electronic cigarettes for smoking cessation. Cochrane Database Syst Rev. 2020; 10:CD010216. DOI
45. Wang L, Wang Y, Chen J, Liu P, Li M. A review of toxicity mechanism studies of electronic cigarettes on respiratory system. Int J Mol Sci. 2022; 23:5030. DOI
46. McCormick W, Baykara Y, Siddique A, Islam T, Kechter A, Krueger EA. Lung findings in a patient with a history of nicotine vaping and cannabis smoking. R I Med J. 2022; 105:36-40. DOI
47. Bates CD. POINT: e-cigarette use for harm reduction in tobacco use disorder?. Yes. Chest. 2021; 160:807-9. DOI