Medicine, Faculty of
Medicine, Department of
DSpace
UBCV
Saleem, Ferhan
Doctor of Philosophy - PhD
University of British Columbia
Background: Interstitial lung disease (ILD) is a collection of diseases that cause fibrosis and/or inflammation of lung parenchyma, often resulting in the adverse consequence of hypoxemia that can be alleviated by domiciliary oxygen. Objectives: 1) Derive and validate a risk model to predict new-onset exertional and resting hypoxemia in patients with ILD. 2) Identify oxygen guidelines worldwide and compare these to national domiciliary oxygen criteria. 3) Compare costs of domiciliary oxygen for patients with ILD and chronic obstructive pulmonary disease (COPD). Methods: 1) A multivariable model that predicted new-onset exertional and resting hypoxemia was derived and validated in international cohorts using time-varying Cox regression, with the final model optimizing Harrell's C-index and goodness-of-fit (GoF). 2) Clinical practice guidelines for domiciliary oxygen were identified and compared to oxygen criteria and funding source used by the 193 member countries in the United Nations obtained from an Internet-based literature review. 3) A retrospective chart review determined monthly costs of oxygen in ILD and COPD within a large domiciliary oxygen program from 2010-2017. Results: 1) The best-performing prediction model for both exertional and resting hypoxemia included age, body mass index, idiopathic pulmonary fibrosis diagnosis, percent-predicted forced vital capacity, and diffusing capacity of carbon monoxide. Good performance was exhibited for prediction of exertional (C-index=0.70, GoF=0.85) and resting hypoxemia (C-index=0.77, GoF=0.27) in the derivation cohort, with performance replicated in the validation cohort except for calibration for prediction of resting hypoxemia (GoF=0.001). 2) Guidelines for continuous oxygen were obtained for 30 respiratory societies and criteria for 46 countries with public funding for oxygen. No public funding was available in 145 countries (5.9 billion people). 3) Cost of oxygen declined after month 1 (ILD: ($202.57 ± $88.88 in month 1 versus $142.21 ± $59.01 in month 2-24, P<0.001; COPD: $222.85 ± $102.52 versus $156.65 ± $60.50, P<0.001). Long-term cost of oxygen in COPD was more than in ILD (P=0.02). Conclusions: These studies will help patients prepare for oxygen initiation, identify variability in oxygen criteria worldwide and quantify the limited access in many countries, and provide funders with a better understanding of costs.
OPTIMIZING IMPLEMENTATION OF ADULT DOMICILIARY OXYGEN THERAPY IN FIBROTIC INTERSTITIAL LUNG DISEASE by Ferhan Saleem B.Sc., University of Calgary, 2011 M.D., American University of Integrative Sciences, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate and Postdoctoral Studies (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2022 © Ferhan Saleem, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Domiciliary oxygen therapy and predicting hypoxemia in fibrotic interstitial lung disease submitted by Ferhan Saleem in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Experimental Medicine Examining Committee: Chris Ryerson, Associate Professor, Medicine, UBC Supervisor John Fleetham, Professor, Medicine, UBC Supervisory Committee Member Jordan Guenette, Assistant Professor, Medicine, UBC Supervisory Committee Member Najib Ayas, Associate Professor, Medicine, UBC University Examiner Ben Mortenson, Associate Professor, Medicine, UBC University Examiner iii Abstract Background Interstitial lung disease (ILD) is a collection of diseases that cause fibrosis and/or inflammation of lung parenchyma, often resulting in the adverse consequence of hypoxemia that can be alleviated by domiciliary oxygen. Objectives 1) Derive and validate a risk model to predict new-onset exertional and resting hypoxemia in patients with ILD. 2) Identify oxygen guidelines worldwide and compare these to national domiciliary oxygen criteria. 3) Compare costs of domiciliary oxygen for patients with ILD and chronic obstructive pulmonary disease (COPD). Methods 1) A multivariable model that predicted new-onset exertional and resting hypoxemia was derived and validated in international cohorts using time-varying Cox regression, with the final model optimizing Harrell's C-index and goodness-of-fit (GoF). 2) Clinical practice guidelines for domiciliary oxygen were identified and compared to oxygen criteria and funding source used by the 193 member countries in the United Nations obtained from an Internet-based literature review. iv 3) A retrospective chart review determined monthly costs of oxygen in ILD and COPD within a large domiciliary oxygen program from 2010-2017. Results 1) The best-performing prediction model for both exertional and resting hypoxemia included age, body mass index, idiopathic pulmonary fibrosis diagnosis, percent-predicted forced vital capacity, and diffusing capacity of carbon monoxide. Good performance was exhibited for prediction of exertional (C-index=0.70, GoF=0.85) and resting hypoxemia (C-index=0.77, GoF=0.27) in the derivation cohort, with performance replicated in the validation cohort except for calibration for prediction of resting hypoxemia (GoF=0.001). 2) Guidelines for continuous oxygen were obtained for 30 respiratory societies and criteria for 46 countries with public funding for oxygen. No public funding was available in 145 countries (5.9 billion people). 3) Cost of oxygen declined after month 1 (ILD: ($202.57 ± $88.88 in month 1 versus $142.21 ± $59.01 in month 2-24, P<0.001; COPD: $222.85 ± $102.52 versus $156.65 ± $60.50, P<0.001). Long-term cost of oxygen in COPD was more than in ILD (P=0.02). Conclusions: These studies will help patients prepare for oxygen initiation, identify variability in oxygen criteria worldwide and quantify the limited access in many countries, and provide funders with a better understanding of costs. v Lay Summary Interstitial lung disease consists of a group of diseases that result in scarring and/or inflammation of the lungs, making it difficult to breathe and causing low blood oxygen (hypoxemia). Study one identified routinely available measures that can predict if hypoxemia will soon occur, giving patients sufficient time to prepare for initiation of home oxygen. However, the guidelines used to prescribe oxygen vary worldwide and not everyone has access. Study two compared oxygen guidelines from 30 respiratory societies and criteria from 84 countries and identified the 145 countries that did not provide public funding. Study three quantified the costs of oxygen therapy and found that chronic obstructive pulmonary disease was more costly than interstitial lung disease in the long-term. It is hoped that these studies will help identify patients that may need oxygen, recognise variability in oxygen criteria worldwide, and provide patients and funders with a better understanding of costs. vi Preface The three original studies that comprise the thesis were conducted using data from different sources. I developed the research questions, collected the data with collaborating authors, performed the statistical analyses, and wrote each manuscript and the thesis. My supervisor, Dr. Chris Ryerson aided with the research design, statistical analysis, and writing of the manuscripts and thesis. My PhD committee members, Drs. John Fleetham and Jordan Guenette, provided feedback on research deign, manuscripts, and thesis. Chapter two was completed with Dr. Yet Khor serving as the principal investigator, who made significant contributions to research design, provided statistics advice, and reviewed the manuscript. Ethics approval for chapter two was obtained from the University of British Columbia as the coordinating center for the Canadian Registry for Pulmonary Fibrosis (CARE-PF; H19-01989) and for other sites from the Austin Health Human Research Ethics Committee (LNR/18/Austin/388). Data for chapter three were obtained from publicly available resources, with ethics approval waived by the University of British Columbia. Ethics approval for chapter four was obtained from the University of British Columbia-Providence Health Care Research Institute (research ethics board number: H19-00898). Chapter four has been published: Ferhan Saleem, Sana Vahidy, John Fleetham, Loretta Pavan, Claire Normandin, Jordan A. Guenette, Yet H. Khor, Christopher J. Ryerson. Costs of oxygen vii therapy for interstitial lung disease and chronic obstructive pulmonary disease: A retrospective study from a universal healthcare system. 2022. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. DOI: 10.1080/24745332.2022.2057882. viii Table of Contents Abstract .......................................................................................................................... iii Lay Summary .................................................................................................................. v Preface ........................................................................................................................... vi Table of Contents ........................................................................................................ viii List of Tables ................................................................................................................. xi List of Figures ............................................................................................................... xii List of Abbreviations ................................................................................................... xiii Acknowledgments ........................................................................................................ xv Dedication .................................................................................................................... xvi Chapter 1: Introduction .................................................................................................. 1 1.1 Background ....................................................................................................................... 1 1.1.1 Epidemiology .................................................................................................... 1 1.1.2 Quality of Life ................................................................................................... 2 1.1.3 Diagnosis ......................................................................................................... 2 1.1.4 Management .................................................................................................... 3 1.2 Hypoxemia ......................................................................................................................... 4 1.2.1 Fibrosis ............................................................................................................. 4 1.2.2 Ventilation ........................................................................................................ 5 1.2.3 Predicting Hypoxemia ...................................................................................... 6 1.2.4 Prognostic Prediction Models in ILD ................................................................ 7 1.3 Measuring Oxygen ............................................................................................................ 8 1.3.1 Arterial Partial Pressure of Oxygen .................................................................. 9 1.3.2 Oxygen Saturation ........................................................................................... 9 1.3.3 Arterial Partial Pressure and Oxygen Saturation Relationship ......................... 9 1.3.4 Limitations of Oxygen Measurements ............................................................ 10 1.4 Domiciliary Oxygen Therapy ......................................................................................... 11 1.4.1 Benefits .......................................................................................................... 12 1.4.2 Oxygen Delivery ............................................................................................. 13 1.4.3 Criteria ............................................................................................................ 14 1.4.4 Cost ................................................................................................................ 15 1.5 Barriers to Oxygen Therapy ........................................................................................... 17 1.5.1 Education ....................................................................................................... 17 1.5.2 Unified Theory of Acceptance and Use of Technology .................................. 18 1.5.3 Availability ...................................................................................................... 19 1.5.4 Smoking ......................................................................................................... 19 1.5.5 Cost ................................................................................................................ 20 1.6 Thesis Summary and Significance ................................................................................ 20 ix Chapter 2: Predicting New-onset Exertional and Resting Hypoxemia in Fibrotic Interstitial Lung Disease .............................................................................................. 23 2.1 Introduction ..................................................................................................................... 23 2.2 Study Design and Methods ............................................................................................ 24 2.2.1 Population ...................................................................................................... 24 2.2.2 Definition of Hypoxemia ................................................................................. 24 2.2.3 Candidate Predictor Variables ....................................................................... 25 2.2.4 Statistical Analysis ......................................................................................... 25 2.3 Results ............................................................................................................................. 27 2.3.1 Study Population ............................................................................................ 27 2.3.2 Prediction Model Derivation with Scoring System Development and Sensitivity Analyses .................................................................................................................. 30 2.3.3 External Validation ......................................................................................... 32 2.3.4 Risk Prediction ............................................................................................... 33 2.4 Discussion ....................................................................................................................... 35 2.5 Conclusion ...................................................................................................................... 38 Chapter 3: International Domiciliary Oxygen Criteria ............................................... 39 3.1 Introduction ..................................................................................................................... 39 3.2 Methods ........................................................................................................................... 40 3.2.1 Study Design .................................................................................................. 40 3.2.2 Oxygen Guideline Identification ..................................................................... 41 3.2.3 Oxygen Criteria Identification ......................................................................... 41 3.2.4 Statistical Analysis ......................................................................................... 42 3.3 Results ............................................................................................................................. 44 3.3.1 Oxygen Guidelines ......................................................................................... 44 3.3.2 Oxygen Funding Source ................................................................................ 45 3.3.3 Oxygen Eligibility Criteria ............................................................................... 47 3.4 Discussion ....................................................................................................................... 50 3.5 Conclusion ...................................................................................................................... 53 Chapter 4: Costs of Oxygen Therapy for Interstitial Lung Disease and Chronic Obstructive Pulmonary Disease: A Retrospective Study from a Universal Healthcare System ....................................................................................................... 54 4.1 Introduction ..................................................................................................................... 54 4.2 Methods ........................................................................................................................... 55 4.2.1 Study Design .................................................................................................. 55 4.2.2 Study Population ............................................................................................ 56 4.2.3 Domiciliary Oxygen Program ......................................................................... 56 4.2.4 Data Collected ................................................................................................ 57 4.2.5 Oxygen Cost Components ............................................................................. 58 4.2.6 Statistical Analysis .......................................................................................... 59 4.3 Results ............................................................................................................................. 59 x 4.3.1 Study Population ............................................................................................ 59 4.3.2 Oxygen Flow Rate .......................................................................................... 60 4.3.3 Oxygen Equipment ......................................................................................... 61 4.3.4 Per Capita Cost of Oxygen ............................................................................ 62 4.4 Discussion ....................................................................................................................... 65 4.5 Conclusion ...................................................................................................................... 68 Chapter 5: Conclusion ................................................................................................. 69 5.1 Summary and Significance ............................................................................................ 69 5.2 Strengths ......................................................................................................................... 72 5.3 Limitations ....................................................................................................................... 72 5.4 Future Directions ............................................................................................................ 73 Bibliography .................................................................................................................. 74 Appendices ................................................................................................................... 89 Appendix A ............................................................................................................................ 89 Appendix A.1: Baseline characteristics of the validation cohort. ............................. 89 Appendix A.2: The best-subset selection of predictors for the derivation cohort. ... 91 Appendix A.3: Sensitivity and specificity for each scoring system point. ................ 93 Appendix A.4: Area under curve for receiver operating characteristic curves for sensitivity and specificity analysis. .......................................................................... 94 Appendix A.5: Sensitivity analyses using the derivation cohort. ............................. 95 Appendix B ............................................................................................................................ 96 Appendix B.1: Respiratory society or healthcare organization guidelines for domiciliary continuous, ambulatory, and nocturnal oxygen. .................................... 96 Appendix B.2: International continuous, ambulatory, and nocturnal domiciliary oxygen eligibility criteria for public and non-publicly funded countries. ................. 103 xi List of Tables Table 1-1: Major clinical drug trials in interstitial lung disease. ........................................ 3 Table 1-2: Selected mortality prediction models in fibrotic ILD. ....................................... 7 Table 1-3: Major domiciliary oxygen therapy trials. ........................................................ 12 Table 1-4: Domiciliary oxygen prescription criteria in British Columbia, Canada. .......... 15 Table 2-1: Patient characteristics of the derivation and validation cohorts. ................... 29 Table 2-2: Scoring system and risks of new-onset exertional and resting hypoxemia at six months. ..................................................................................................................... 31 Table 2-3: Scoring system prediction model performance metrics. ............................... 31 Table 3-1: Number of publicly and exclusively privately funded countries using oxygen saturation and/or arterial partial pressure of oxygen to determine eligibility thresholds for continuous, ambulatory, and nocturnal oxygen. ............................................................. 46 Table 4-1: Patient characteristics at baseline. ................................................................ 60 xii List of Figures Figure 2-1: Flow diagram of the (a) derivation and (b) validation cohort for the evaluation of new-onset exertional and resting hypoxemia. ............................................................ 28 Figure 2-2: Cumulative incidence of (a) new-onset exertional hypoxemia and (b) resting hypoxemia (b) for low, moderate, and high-risk categories. ........................................... 34 Figure 3-1: Gross domestic product per capita (2019 United States Dollar) for countries with public oxygen funding compared to countries with no reported public oxygen funding. ........................................................................................................................... 46 Figure 3-2: Thresholds for continuous, ambulatory, and nocturnal oxygen for countries with reported public oxygen funding. .............................................................................. 49 Figure 4-1: Mean monthly oxygen flow rates for ILD and COPD. .................................. 61 Figure 4-2: Oxygen equipment cost components in ILD and COPD. ............................. 62 Figure 4-3: Monthly per capita cost of domiciliary oxygen therapy for ILD and COPD. . 63 Figure 4-4: Total monthly per capita costs of domiciliary oxygen therapy for ILD and COPD. ............................................................................................................................ 63 Figure 4-5: Composition of domiciliary oxygen therapy costs in ILD and COPD. .......... 64 xiii List of Abbreviations 6MWD 6-minute walk distance 6MWT 6-minute walk test ABG Arterial blood gas AIC Akaike information criterion ATS American Thoracic Society BAL Bronchoalveolar lavage BC British Columbia BMI Body mass index BPAP Bi-level positive airway pressure CAD Canadian dollar CARE-PF Canadian Registry for Pulmonary Fibrosis CF Cystic Fibrosis COPD Chronic obstructive pulmonary disease COVID Coronavirus disease of 2019 CPAP Continuous positive airway pressure CPI Consumer price index CTD-ILD Connective tissue disease-associated Interstitial lung disease DLCO Diffusing capacity for carbon monoxide FEV1 Forced expiratory volume in one second FVC Forced vital capacity GAP Gender, age, physiology GBP Great Britain pound GDP Gross domestic product GoF Goodness-of-fit HCT Hypoxic challenge test HP Hypersensitivity pneumonitis HRCT High-resolution computed tomography ILD Interstitial lung disease INOX International nocturnal oxygen IPF Idiopathic pulmonary fibrosis IQR Interquartile range xiv O2 Oxygen K-BILD King’s Brief Interstitial Lung Disease questionnaire LED Light-emitting diode MRC Medical Research Council NOTT Nocturnal oxygen therapy trial NSCLC Non-small cell lung cancer NSIP Nonspecific interstitial pneumonia OSA Obstructive sleep apnea PF Pulmonary fibrosis PH Pulmonary hypertension PaO2 Arterial partial pressure of oxygen RR Respiratory rate SARS-COV-2 Severe acute respiratory syndrome coronavirus 2 SD Standard deviation SpO2 Pulse oximetry oxygen saturation TLC Total lung capacity UCD University of California, Davis UIP Usual interstitial pneumonia UK United Kingdom USA United States of America USD United States dollar VCH HOP Vancouver Coastal Health Home Oxygen Program VE Minute ventilation VO2 Oxygen uptake VT Tidal volume xv Acknowledgments I am grateful for my supervisor, Dr. Chris Ryerson for his support throughout the years. There were many challenges along the way, including a pandemic; however, his commitment and patience towards the completion of this dissertation was persistent. He was always available to provide advice within hours, no matter the day or time. I also thank Dr. Yet Khor for serving as the principal investigator for chapter two. Her valuable time commitment at every step of this chapter is immensely appreciated. She inspired me to continue advancing my knowledge in statistics. Drs. John Fleetham’s and Jordan Guenette’s guidance as committee members helped me develop a deeper understanding of the topics forming this dissertation. Their valuable advice filled in the gaps in each of the three chapters. I also appreciate the feedback provided from my lab members from beginning to end. Their assistance in research design and dissemination will always remain a part of this dissertation. Last, but not least, I thank the University of British Columbia for providing the necessary means to pursue this degree. Without the provided scholarships and awards, this journey would have been much more difficult. xvi Dedication This dissertation is dedicated to Dr. Chris Ryerson who was more than a supervisor. He is a role model and source of inspiration. 1 Chapter 1: Introduction 1.1 Background Interstitial lung disease (ILD) consists of a collection of diseases that result in fibrosis and/or inflammation of the lung parenchyma, resulting in thickening of the pulmonary interstitium and impaired gas exchange.1 Although many ILDs have similar physiology and histopathology, their etiologies are diverse. There are over 200 subtypes of ILD in which a majority can be classified into six main categories: idiopathic, autoimmune, exposure-related, ILD with cysts or airspace filling, sarcoidosis, and others (eosinophilic pneumonia, malignancy diseases-associated ILD).2 Without radiological and/or histopathological evidence of fibrosis, some ILDs can be considered non-fibrotic.3 1.1.1 Epidemiology Although each ILD is rare, ILD as a whole is a common problem. The incidence of ILD is estimated to be 31.5/100,000 per year in men and 26.1/100,000 per year in women.4 In an American study, the prevalence of ILD was estimated at 81/100,000 in males and 67/100,000 in females and ranged from 6.3 to 76.0/100,000 in four European studies.4,5 Both the incidence and prevalence of ILD is increasing.6 This is likely due at least in part to an ageing population, greater recognition of the disease, and ongoing improvements in diagnosis methodology (e.g., more widespread availability of computed tomography). The survival time for ILD is dependent upon etiology and estimated at 3-5 years for idiopathic pulmonary fibrosis (IPF), but typically longer for other ILDs.7-10 2 1.1.2 Quality of Life Patients with ILD typically present with dyspnea and a chronic non-productive cough.11 Dyspnea initially begins with exertion, then occurs at rest in advanced disease. Nonspecific symptoms can also include fever, fatigue, and weight loss,11 while other symptoms and signs are dependent on etiology. Eventually, ILD progresses with development of debilitating symptoms that reduce quality of life. Further reduction in quality of life occurs due to the frequent presence of comorbidities such as pulmonary hypertension (PH), lung cancer, gastroesophageal reflux disease, obstructive sleep apnea, and cardiovascular disease.2 Beyond the personal impact of ILD, patients with ILD also have a profound impact on their caregiver's quality of life. In a qualitative study, caregivers of patients with IPF reported feeling hopeless, anxious, and living in a strained relationship.12 Spouses may experience ambivalence and a sense of loneliness as they prepare for a future without their significant other.13 1.1.3 Diagnosis The diagnosis of ILD requires a multidisciplinary approach that is based on a careful examination of clinical, radiological, and sometimes pathological features.1 In addition to the typical dyspnea and dry cough, clinical presentation is dependent on initial cause, most notably including a variety of extrapulmonary manifestations in patients with CTD-ILD, vasculitis-associated ILD, and sarcoidosis. Specific radiological patterns on high-resolution computed tomography (HRCT) also have an important role in the diagnosis, for example identifying a usual interstitial pneumonia (UIP) pattern that is observed in IPF.14 Histological studies such as bronchoalveolar lavage (BAL), transbronchial and/or 3 surgical biopsies can also aid in the establishment of a confident diagnosis when this is unclear based on clinical and radiological features.3,14 Pulmonary function testing plays an important role in monitoring disease progression. 1.1.4 Management There are no treatments that can effectively reverse the course of the disease, and the primary aim of ILD management is to slow the rate of progression. When possible, treatment of ILD is based on removal of the causative agent or treatment of the underlying condition that caused the disease. The two main antifibrotic medications approved for the treatment of fibrotic ILD are pirfenidone and nintedanib, both of which target fibrogenesis processes.15,16 Pirfenidone and nintedanib both slow decline in forced vital capacity (FVC) in IPF;17,18 however, both drugs are costly and have adverse effects. Major clinical drug trials in ILD are summarized in Table 1-1. Table 1-1: Major clinical drug trials in interstitial lung disease. Trial Study design Population Primary outcome CAPACITY (Pirfenidone) (2011)15 Two replicate randomized placebo-controlled trials of pirfenidone (2403 or 1197mg/day) in IPF Aged 40-80 years in 13 countries and diagnosed with IPF Slowed decline in FVC ASCEND (Pirfenidone) (2014)17 Randomized placebo-controlled trial of pirfenidone (2403mg /day) in IPF 555 patients aged 40-80 years in 9 countries with IPF Slowed decline in FVC INPULSIS (Nintedanib) (2014)18 Two replicate randomized placebo-controlled trials of nintedanib (300mg/day) in IPF 1066 patients in 24 countries aged ≥40 years diagnosed with IPF Slowed decline in FVC INBUILD (Nintedanib) (2019)16 Randomized placebo-controlled trial of nintedanib (300mg/day) 663 patients from 15 countries aged ≥18 years with a variety of non-IPF ILDs Slowed decline in FVC 4 Trial Study design Population Primary outcome in progressive fibrosing ILD Abbreviations: FVC = Forced vital capacity, IPF = Idiopathic pulmonary fibrosis, ILD = Interstitial lung disease There are also several non-pharmacological interventions that are considered for patients with fibrotic ILD. Pulmonary rehabilitation, which is a structured educational and exercise program for patients with chronic lung disease, can improve exercise capacity and quality of life in patients with ILD, although improvements vary with disease severity and potentially etiology.19 Smoking cessation as well as influenza and pneumococcal vaccines are also commonly used supportive measures, although with limited supportive data in patients with ILD. Finally, lung transplantation is reserved for patients who are refractory to other therapies. 1.2 Hypoxemia Hypoxemia is defined as having low oxygen in the blood. The degree of hypoxemia is dependent upon the severity of disease, with resting hypoxemia being a late-stage finding that is most detrimental. Deprivation of oxygen to bodily tissues results in adverse consequences on end-organ function, and eventually impairs quality of life. The pathophysiological mechanisms that result in hypoxemia in fibrotic ILD are complex. 1.2.1 Fibrosis The exact biological mechanisms leading to lung parenchymal injury and subsequent hypoxemia in fibrotic ILD vary depending on etiology. In IPF, injury to type I pneumocytes results in hyperplastic proliferation of type II pneumocytes.20 This leads to the accumulation of fibroblasts, which play a key role in fibrosis through extracellular 5 matrix deposition. The amount of fibroblastic foci correlates with survival in patients with IPF,21 further illustrating their clinical relevance. Fibroblasts express many genes coding for profibrotic proteins such as type I collagen and growth factors.20 Additionally, fibroblasts deposit elastin increasing lung elastic recoil. This increases the work of breathing,22 thus contributing to hypoxemia. Macrophages, T lymphocytes, and B lymphocytes also aid in the creation of the profibrotic environment through a variety of complex interactions. Ultimately, the fibrosis thickens the interstitium, which impairs gas exchange across the alveolar epithelium. With this oxygen diffusion impairment, less oxygen is present in the pulmonary vasculature and hypoxemia ensues. The degree of fibrosis is correlated with arterial oxygen pressure. Chronic vasoconstriction due to hypoxemia as well as vessel ablation initiated by alveolar damage and fibrosis can lead to PH, further exacerbating the problem.23 Areas with alveolar epithelial destruction are poorly ventilated, while areas with vessel ablation are poorly perfused, thus resulting in ventilation-perfusion mismatching. 1.2.2 Ventilation Ventilatory limitations also contribute to the development of hypoxemia in fibrotic ILD. Minute ventilation (VE) = respiratory rate (RR) x tidal volume (VT). Therefore, to increase VE and facilitate oxygen uptake (VO2), there must be an increase in RR or VT. Since lung volumes are reduced in ILD, RR is the main mechanism for increasing VE through rapid shallow breathing.24 Increased anatomical dead space increases the dead space to VT ratio.25 Rapid shallow breathing exhibited by patients with ILD is insufficient to correct this ratio. This dead space ventilation imposes a metabolic demand on 6 respiratory muscles without increasing oxygen levels in the blood, thus contributing to hypoxemia. 1.2.3 Predicting Hypoxemia Oxygen is prescribed for the treatment of hypoxemia in fibrotic ILD, therefore predicting hypoxemia in advance can have significant prognostic implications. In an international cohort study, the 2-year cumulative incidence was 17.3% and 5.6% for exertional and resting hypoxemia, respectively.26 There are significant lifestyle modifications required for patients and caregivers before the commencement of domiciliary oxygen therapy. These may involve quitting smoking, gaining knowledge with regards to equipment usage, making occupational accommodations, and changing daily routines. All these modifications require time, which is often not available for patients given the potential for rapid progression contrasted with intermittent testing that often appears to suddenly demonstrate the presence of hypoxemia that had been worsening over a longer term. Inadequate preparation for oxygen initiation can lead to unnecessary frustration overriding the benefits of oxygen, resulting in compliance issues, and incurring avoidable costs to organizations that fund oxygen. There are few studies examining risk factors that can predict hypoxemia in ILD. In a study examining pre-flight risk assessments for IPF patients, it was determined that patients with PaO2 ≤9.42 kPa and diffusing capacity of carbon monoxide (DLCO) ≤50% predicted had a higher risk of failing the hypoxic challenge test (HCT) and patients with forced expiratory volume in one second (FEV1) >85% predicted, FVC >81.5% predicted, DLCO % >50% predicted, resting pulse oximetry oxygen saturation (SpO2) >95%, gender, age, physiology (GAP) 7 index <0.45, and 6MWT distance >333m were identified as more likely to pass the HCT.27 A recent sub-study from the AmbOx trial developed a scoring system that found that DLCO ≤40% and resting SpO2 ≤95% were significant predictors of exertional desaturation.28,29 Also, patients with ILD who have lower muscle mass were found to have a longer duration of hypoxia during 24-hour oximetry.30 DLCO appears to be strongest predictor of exertional hypoxemia in both ILD and chronic obstructive pulmonary disease (COPD).31 1.2.4 Prognostic Prediction Models in ILD Understanding prognostic parameters can aid researchers in targeted treatment towards significant predictors of disease progression such as hypoxemia, which is associated with mortality in ILD.26 Some of the major multivariable prognostic prediction models are summarized in Table 1-2, most of which focus on survival. FVC and DLCO are consistent predictors of mortality in ILD. There are many studies associating mortality with a single predictor and/or investigating specific ILD subtypes exclusively.32-35 However, making clinical decisions based on a single risk factor is difficult given the variability in most clinical measurements. Table 1-2: Selected mortality prediction models in fibrotic ILD. Model Aim Population Derivation Predictors Clinical, Radiological and Physiological Scoring System (2001)36 Predict survival in newly diagnosed patients • IPF • n=238 • Cox proportional hazards modelling • Log-rank testing • AIC subset selection • Age, smoking, clubbing, extent of profusion of interstitial opacities, presence or absence of pulmonary hypertension, 8 Abbreviations: AIC = Akaike information criteria, CTD-ILD = Connective tissue disease-interstitial lung disease, DLCO = Diffusing capacity of carbon monoxide, FVC = Forced vital capacity, FEV1 = Forced expiratory volume in one second, HP = Hypersensitivity pneumonitis, IPF = Idiopathic pulmonary fibrosis, NSIP = Nonspecific interstitial pneumonia, PaO2 = Arterial partial pressure of oxygen, TLC = Total lung capacity *ILD Gender Age Physiology Index extended models include: ILD-GAP-O2 index, ILD-NSCLC-GAP index,39 GAP-K40 †Age, carcinoembryonic antigen, cytokeratin 21-1, diffusing capacity of carbon monoxide % predicted, smoking history 1.3 Measuring Oxygen There are three main ways of measuring oxygen in the blood, including arterial partial pressure of oxygen (PaO2), SpO2, and arterial oxygen saturation (SaO2). Model Aim Population Derivation Predictors TLC% predicted, PaO2 at end of maximal exercise Composite Physiological Index (2003)37 Predict the extent of fibrosis on computed tomography • IPF • n=212 • Stepwise regression • Split-sample testing • DLCO % predicted, FVC % predicted, FEV1 % predicted Du Bois Index (2011)38 Development a scoring system to predict 1-yr probability of death • IPF cohorts combined from two clinical trials • n=1,099 • Cox proportional hazards regression, AIC using backward and forward selection • Age, history of respiratory hospitalization, FVC % predicted, 24- week change in FVC % predicted, DLCO % predicted, 24-week change in DLCO % predicted, 24-week change in health-related quality of life • C-statistic: 0.75 ILD Gender Age Physiology Index (2014)*7 Develop a scoring system to predict 1-yr, 2-yr, 3-yr mortality • Chronic HP, CTD-ILD, idiopathic NSIP, unclassifiable ILD) • n=1,012 • Models with 4-7 predictor variables screened using 20 repetitions of 10-fold cross validation of Harrell’s c-index • Fine-Gray modelling for survival • ILD subtype (IPF, unclassifiable ILD, CTD ILD/idiopathic NSIP, chronic HP, sex, age, FVC % predicted, DLCO % predicted • C-index: 0.746 9 1.3.1 Arterial Partial Pressure of Oxygen A partial pressure of a gas refers to the pressure the gas exerts on its container’s walls. PaO2 is most accurately measured through an arterial blood gas (ABG) analyzer, commonly applied to blood obtained from the radial artery.41 The Clark electrode inside the ABG analyzer contains a platinum cathode and silver anode.42 An electrical potential is applied, and oxygen diffuses across a semipermeable membrane into an aqueous solution and is reduced at the cathode, which results in oxidation at the anode. Higher oxygen concentration produces a higher flow of electrons that is measured as the arterial partial pressure of oxygen. 1.3.2 Oxygen Saturation SpO2 is measured using spectrophotometry using a pulse oximeter, which provides a measure of oxygen bound to iron in hemoglobin. A pulse oximeter contains a pair of light emitting diodes (LEDs), one that emits red light at approximately 660 nm wavelength and the other infrared light at approximately 940 nm.43 Deoxyhemoglobin absorbs more red light, while oxyhemoglobin absorbs more infrared light. The ratio of infrared light to red light is measured by the pulse oximeter and converted into a SpO2 reading, essentially providing a measure of oxygenated hemoglobin to hemoglobin that is not attached to oxygen. SaO2 is also measured using spectrophotometry, but using an ABG analyzer. 1.3.3 Arterial Partial Pressure and Oxygen Saturation Relationship The relationship between PaO2 and SaO2 can be described using the sigmoid-shaped hemoglobin dissociation curve.44 Generally, higher arterial partial pressures of oxygen 10 result in a higher percentage of oxygen binding to hemoglobin. At sea level, PaO2 and corresponding SaO2 is represented by the upper flatter portion of the hemoglobin dissociation curve. The affinity of oxygen bound to hemoglobin is affected by pH, carbon dioxide, 2,3-diphosphoglycerate, and temperature, which can all affect the curve,45 resulting in changes in the affinity for hemoglobin to bind oxygen. SaO2 and SpO2 are therefore correlated;46,47 however, the strength of this correlation depends on a variety of factors. 1.3.4 Limitations of Oxygen Measurements PaO2 measurements can be affected by air bubbles and temperature.48 Furthermore, PaO2 and SaO2 are invasive and cannot be measured continuously. In comparison, SpO2 is non-invasive, but is prone to more limitations, some of which also extend to SaO2 measurements. Smoking can result in an inaccurate measure of SpO2 by increasing carboxyhemoglobin levels. This can affect pulse oximeter readings.49 Similarly, a person exposed to significant vehicle exhaust (e.g., in a garage with limited ventilation) on the day of hypoxemia testing can have inaccurate readings due to the inhaled carbon monoxide. Pulmonary rehabilitation techniques can also influence pulse oximeter readings. For example, patients trained in breathing techniques such as deep diaphragmatic breathing can increase SpO2 levels,50 and may employ these methods to various degrees during hypoxemia testing. Similarly, recent alcohol or sedative use can also impact oxygen levels.51 Stimulants can increase metabolic rate and oxygen utilization, thus increase the likelihood of desaturation, especially during exertion. During movement of the upper extremities, the pulse oximeter is often unable to obtain accurate results for SpO2.52 This motion artifact is a consequence of the pulse oximeter 11 LEDs not being able to directly focus light onto the measurement source. Ambient light variability can also impact pulse oximeter accuracy, especially if a surgical, fluorescent, or heating lamp is close by.49 This is because these oximeters, although designed to subtract ambient light interference, may not be able to do so accurately if the frequency of the power supplied to the building is close to the frequency of the LEDs. Skin pigmentation can decrease pulse oximetry accuracy as well. In a study of 1,609 patients receiving supplemental oxygen and patients in intensive care units, it was found dark skinned patients had a three times greater frequency of undetected hypoxemia compared to light skinned patients.53 Lastly, patients with respiratory diseases with comorbid circulatory limitation to the periphery can compromise pulse oximeter accuracy. For example, this can occur due to peripheral vascular disease in smokers or those with Raynaud's syndrome.54 Raynaud’s can occur in autoimmune conditions (e.g., systemic sclerosis), which are also associated with ILD. Therefore, in a colder environment, perfusion to the site of pulse oximeter placement may be limited due to vasoconstriction of peripheral arteries, and readings can be more accurate on a warmer day or with use of a forehead or earlobe saturation probe. 1.4 Domiciliary Oxygen Therapy Oxygen therapy plays an important role in the management of ILD, which can be used acutely during inpatient management or prescribed for longer-term domiciliary usage (i.e., usage at home).55 Aside from lung transplantation, oxygen is the only therapy that can treat persistent hypoxemia after maximal medical treatment. Providing supplementary oxygen increases the amount of oxygen available for gas exchange 12 inside the damaged alveoli, therefore overcoming at least some of the pathological limitations contributing to hypoxemia. 1.4.1 Benefits Oxygen therapy primarily has a palliative role in patients with ILD, without any proven impact on the biology of the underlying disease itself. Continuous oxygen therapy may be able to prevent PH and organ dysfunction caused by hypoxemia as well as reducing breathlessness.55 Ambulatory oxygen may also alleviate dyspnea and improve exercise ability.28 Nocturnal oxygen decreases heart rate and breathing frequency in ILD.56 The survival benefits of domiciliary oxygen in ILD have yet to be demonstrated, with only indirect evidence supporting this potential benefit from older clinical trials having predominantly male cohorts and limited demographical diversity (Table 1-3). More studies are therefore needed to demonstrate the impact of continuous, ambulatory, and nocturnal oxygen therapy in ILD and COPD. More clinical trials are currently underway.57-59 Table 1-3: Major domiciliary oxygen therapy trials. Trial Study design Population Primary outcome Limitations Nocturnal oxygen therapy (1980)60 Randomized trial comparing continuous oxygen to nocturnal oxygen 203 hypoxemic patients with COPD and mean age of 65.7 Mortality benefit for continuous greater versus nocturnal oxygen Caucasian, male-predominant cohort Medical research council working party (1981)61 Randomized trial comparing continuous oxygen to no oxygen 87 hypoxemic patients with COPD aged under 70 years Mortality benefit for oxygen greater versus no oxygen Male predominant cohort Long-term oxygen treatment trial research group Randomized trial comparing continuous or 738 patients with COPD, moderate resting, or ambulatory No mortality benefit with continuous or ambulatory oxygen versus no oxygen Lack of race diversity, unknown response to 13 Trial Study design Population Primary outcome Limitations (2016)62 ambulatory oxygen to no oxygen hypoxemia with mean age of 68.3 ± 7.5 years (oxygen) and 69.3 ± 7.4 years (no oxygen) oxygen in highly symptomatic patients Ambulatory oxygen (AmbOx) (2018)28 Prospective, open-label, mixed-method, crossover randomised controlled trial comparing ambulatory oxygen to no oxygen 84 patients with ambulatory hypoxemia, ILD, and mean age of 67.9±10.4 years Ambulatory oxygen provided improvement in total K-BILD scores, scores in breathlessness, activity, and chest symptoms compared to no oxygen Relatively short follow-up period (2-week crossover) International nocturnal oxygen (2020)63 Double blinded randomized placebo-controlled trial comparing nocturnal oxygen to no oxygen 243 patients with nocturnal hypoxemia, COPD, and mean age of 69 ± 8 (oxygen) and 69 ± 9 (no oxygen) years No mortality benefit of nocturnal oxygen Male- predominant underpowered study Abbreviations: COPD = Chronic obstructive pulmonary disease, ILD = Interstitial lung disease, K-BILD = King’s brief interstitial lung disease questionnaire 1.4.2 Oxygen Delivery Domiciliary oxygen therapy can be divided into three types: continuous (resting), ambulatory (exertional), and nocturnal. Although exact criteria and duration vary, continuous oxygen is delivered at least 15 hours per day, while ambulatory oxygen is provided only during exertion, and nocturnal oxygen only during sleep. Oxygen prescribed for 24 hours per day can result in compliance issues compared to oxygen prescribed for at least 18 hours a day and oxygen administered for 15-16 hours per day may not provide additional mortality benefit compared to 24 hours per day in COPD.64,65 Oxygen is delivered through three main equipment types: liquid oxygen canisters, gas cylinders, and concentrators.55 Liquid oxygen cannisters store cryogenic oxygen in a stationary reservoir that can be used to refill a portable cannister. Gas cylinders contain 14 oxygen at high pressure and may be stationary or portable.66 A regulator or oxygen conserving device attached to the cylinder allows control of oxygen administration. Oxygen concentrators filter room air and absorb nitrogen, thus concentrating the oxygen.66 These are also available in stationary or portable types and can deliver oxygen continuously or in a pulsatile fashion. Concentrators have lower long-term costs but have an initial cost that is higher than that of a cylinder and may need power backups in regions with frequent power outages or for situations in which a patient is in a location without nearby electrical supply. Cylinders contribute to continuous financial loss as patients must take time off work, arrange for transportation, and pay for refills. Cylinders and certain oxygen concentrators are suggested to provide similar oxygen delivery in ILD during ambulation.67 However, cylinders can achieve higher flow rates which may be necessary for patients with more severe disease. 1.4.3 Criteria The American Thoracic Society (ATS) guidelines recommend domiciliary oxygen therapy for ILD for at least 15 hours per day in patients with severe resting hypoxemia, which is defined as either:55 • Resting PaO2 ≤55 mmHg or SpO2 ≤88% • Resting PaO2 56-59 mmHg or SpO2 = 89% with edema, hematocrit ≥55%, or P pulmonale on an electrocardiogram These criteria are based on studies in COPD that showed a mortality benefit of long-term oxygen,60,61 with more limited data available for patients with ILD. Oxygen during exertion is recommended if severe exertional hypoxemia is demonstrated by SpO2 ≤88% on room air during exertion,55 typically assessed using a 6-minute walk test 15 (6MWT). Patients with ILD have a greater degree of exertional hypoxemia than patients with COPD for a given severity of pulmonary function,31 suggesting extrapolation of data from COPD to ILD may not be appropriate. Nocturnal oxygen is often prescribed to patients who meet resting hypoxemia criteria; however, these patients usually undergo overnight oximetry or polysomnography that provides evidence of nocturnal desaturation. The lack of universally accepted oxygen criteria has led to unexplored patient care gaps across the world, especially in developing countries. A specific example of oxygen prescription criteria for all three domiciliary oxygen therapy types from British Columbia, Canada is provided in Table 1-4. Table 1-4: Domiciliary oxygen prescription criteria in British Columbia, Canada. Oxygen Type Criteria68 Continuous 1) Resting PaO2 ≤55 mmHg on room air OR 2) Resting SpO2 <88% sustained continuously for six minutes OR 3) Resting PaO2 ≤60 mmHg AND 1 of: • Heart failure • Pulmonary hypertension Ambulatory 1) SpO2 <88% continuously for ≥1 minute on room air and improvement in 6-minute walk test as tolerated on oxygen compared to room air showing: • Distance traveled increases by ≥25% AND • ≥30 meters OR 2) SpO2 <80% with ambulation for ≥1 minute Nocturnal SpO2 <88% for >30% of ≥4-hour nocturnal oximetry study on room air Abbreviations: PaO2 = Arterial partial pressure of oxygen, SpO2 = Pulse oximetry oxygen saturation 1.4.4 Cost There are many costs associated with managing ILD, including healthcare personnel salaries, laboratory studies, diagnostic procedures, time spent at hospitals, and medications. Oxygen is an important additional cost in patients with ILD, although little is known about how much domiciliary oxygen costs the healthcare system. Domiciliary 16 oxygen funding varies internationally and may be private, public, or both private and public, with oxygen not available in some countries. Excluding medications, the annual cost for IPF patients aged ≥65 in the United States was estimated to be approximately USD 2 billion, with 32.4% of these patients requiring oxygen therapy post-diagnosis.69 In a Canadian study, the annual cost of IPF was estimated to be CAD 12,978 per capita two years post-diagnosis.70 Domiciliary oxygen is a minor component of these overall costs, but is still a substantial amount. In Canada, the estimated per-patient cost of continuous oxygen in a 2005 study was CAD 383 per month with 3% of patients with moderate COPD and 9.4% of patients with severe COPD requiring oxygen;71 however, no specific breakdown was provided as to what components of oxygen delivery amounted to the cost. Additionally, a 2020 study from the UK appraised the biweekly cost of ambulatory oxygen in ILD to be GBP 91.72 For COPD, the cost of continuous oxygen was assessed at USD 232 per month and nocturnal oxygen at USD 149 per month in 1999 and USD 198 per month in 2007.73,74 There is an expected cost increase of 12-13% per year for oxygen alone in COPD in the United States,75 which is likely due in part to healthcare expenditure inflation as well as longer survival times in the ageing population and the use of new medications that delay mortality. Given these major costs and very few recent domiciliary oxygen economic studies, investigating the financial impact is important for governments and other funding sources as they require accurate cost estimates to make informed decisions with regards to allocation of their limited resources. 17 1.5 Barriers to Oxygen Therapy There are many barriers that can limit patient access to oxygen therapy as summarized below. 1.5.1 Education There is a lack of educational resources on the use of oxygen for multiple stakeholders, including insufficient resources for oxygen suppliers, healthcare providers, patients, and caregivers. 1) Oxygen suppliers: Many suppliers lack trained personnel for dealing with equipment distribution and maintenance. The diminished role of respiratory therapists in some countries or their complete absence in others has increased the burden on these suppliers to educate patients on equipment operation and safety.76 In some developing countries, oxygen administration staff may not have any training.77 2) Healthcare providers: There are no comprehensive clinical practice guidelines for prescribing oxygen across the wide variety of diseases for which oxygen is used, with previous guidelines focusing mostly on COPD and less frequently ILD. Conversely, many clinicians are not up to date with oxygen equipment technology best suited for patients and lack knowledge with regards to equipment manufacturer quality and patient compliance. A Nigerian study surveying healthcare workers found that most had never read an oxygen guideline and were not trained to administer oxygen.78 18 1.5.2 Unified Theory of Acceptance and Use of Technology Although originally intended for usage in information technology, the unified theory of acceptance and use of technology can explain many of the barriers imposed to patients while using oxygen.79 This theory has four main constructs that can influence patient acceptance of oxygen usage: performance expectancy, effort expectancy, social influence, and facilitating conditions. There is a mismatch between patient expectations and experiences upon initiation of oxygen. Many expect oxygen to relieve dyspnea, but after initiation instead report benefits other than dyspnea such as improvement in cough and feeling less fatigued.80 Oxygen equipment is often burdensome for patients,55 and the physical demands imposed by the equipment may deter some patients who are not adequately informed of potential mitigating strategies. Many prefer oxygen concentrators over cylinders perhaps due to the form-factor,67 which may not be available and do not provide the higher flow rates required by some. Social influence also plays an important role and can result in patient confusion and creation of another barrier. Patients must deal with incoming information from many sources, including the Internet, their clinicians, and oxygen suppliers, with potentially conflicting information from these sources. Furthermore, societal norms may prevent patients from starting oxygen therapy as it may be deemed a sign of increased mortality.81 Lastly, many patients need facilitating accommodations before the initiation of oxygen therapy such as modifications to their workplace and/or job description. Caregivers and other family members also require education in order to support the lifestyle changes that are necessary to optimize the use and benefit of domiciliary oxygen. 19 1.5.3 Availability Oxygen is widely available in some countries, while it is a rare commodity used only in life threatening situations in many countries facing economic challenges. This became apparent during the COVID-19 pandemic when some countries struggled to obtain necessary oxygen without additional external support.82 Furthermore, countries and regions are limited by the lack of local oxygen manufacturing infrastructure and the need to import necessary components from within a competitive and often expensive marketplace that may not be accessible to some regions based on local economics. Oxygen equipment may also not be available for purchase in some areas due to constraints imposed by limited manufacturing capability, supply chain logistics, and technical support.83 Additionally, misperceptions such as believing the burden of hypoxemia is too minimal for government intervention and disregarding evidence on benefits of oxygen therapy also contribute to the lack of availability.84 1.5.4 Smoking A cigarette will burn faster and at higher temperatures when in an oxygen rich environment, with the potential for severe burns. From December 2017 to August 2019, there were 311 reported fires attributed to domiciliary oxygen in the United States, which resulted in 164 deaths and 71 serious injuries.85 In a Canadian study examining patients with COPD found that between 2004 and 2018, 11 deaths occurred due to smoking while using oxygen.86 This is likely a significant underestimate. Some of these incidents were due to household smokers around the oxygen user. Depending on the 20 regional guidelines, smoking may disqualify a patient from being able to obtain oxygen.87,88 Another source of ignition can be a gas stove. 1.5.5 Cost Domiciliary oxygen has costs associated with equipment (cylinders, concentrators, ancillary equipment, healthcare workers, support staff, etc.) that can be paid for by the user and/or public entities. Developing countries may not have the financial resources to fund oxygen therapy, while its citizens may not be able to afford it. In countries with predominantly private insurance such as the United States, access is also limited by the availability of this private insurance, as well as Medicare and Medicaid coverage, with many not having health insurance. 1.6 Thesis Summary and Significance The main objectives of this thesis were to predict hypoxemia in patients with ILD, identify domiciliary oxygen criteria worldwide used to treat hypoxemia, and provide funders with a better understanding of costs associated with oxygen therapy. These studies have several important implications for patients with chronic lung disease, as well as for their clinicians, caregivers, and policymakers. Chapter two presents an international multicohort study using CARE-PF as the derivation cohort and Alfred, Austin Health, and the University of California, Davis (UCD) as the validation cohorts to derive a clinically applicable prediction tool to predict new-onset exertional and resting hypoxemia in patients with fibrotic ILD. Time-varying 21 Cox regression with best-subset selection was used to identify the predictors of hypoxemia and performance assessed using Harrell’s C-index and GoF likelihood ratio test. Furthermore, total scores for the clinical prediction tool were categorized into risk categories to ease clinical applicability. It is hoped that by being better able to predict the need for oxygen in advance, patients will have sufficient time to receive education and training in terms of oxygen equipment usage and safety as recommended by ATS. Additionally, this work identifies those at highest risk of progression who clinicians may target with more aggressive treatment, potentially including earlier consideration of lung transplantation. The absence of universal criteria that define the threshold for hypoxemia have resulted in substantial variability in oxygen use around the world. Chapter three was a descriptive study identifying adult domiciliary oxygen guidelines as well as national criteria for continuous, ambulatory, nocturnal oxygen, and funding sources for the 193 member countries of the United Nations. Data were obtained using Internet searches, Medline, Embase, emailing physicians, and contacting oxygen suppliers worldwide. Oxygen guidelines including hypoxemia thresholds recommended by respiratory societies and healthcare organizations worldwide were compared with oxygen criteria used by countries. Quantifying the limitations in access to oxygen on a global perspective will provide an urgently needed assessment of where international efforts would be best targeted to maximize the impact of these resources. Comparing oxygen availability to recommendations made in recent clinical practice guidelines can further 22 provide a roadmap for where there is greatest need of either more robust evidence or improved knowledge translation. Chapter four was a retrospective study conducted at Vancouver Coastal Health Home Oxygen Program (VCH HOP) comparing costs of domiciliary oxygen therapy between patients with ILD and COPD. A chart review was performed to identify the per capita monthly costs of oxygen equipment, home visits by oxygen providers and respiratory therapists, and overnight oximetry studies. It is hoped that by quantifying the costs associated with oxygen use in patients with a variety of chronic lung diseases, oxygen funders and patients will be able to make appropriate financial decisions in comparison to other competing priorities. Chapter five summarizes the three studies and their contributions to the field of ILD and chronic lung diseases. Furthermore, strengths, limitations, and application of the thesis are addressed. Future research needs are discussed. 23 Chapter 2: Predicting New-onset Exertional and Resting Hypoxemia in Fibrotic Interstitial Lung Disease 2.1 Introduction Fibrotic interstitial lung diseases (ILDs) consist of a collection of disorders with varying amounts of inflammation and fibrosis in lung parenchyma,89 resulting in thickening of pulmonary interstitium.90 This leads to a loss of ventilation, impaired gas exchange, and ventilation/perfusion mismatching.91,92 As a result, hypoxemia can occur during exertion,28,55,93-95 with a five-year cumulative incidence of 40.1% and may eventually progress to hypoxemia at rest.26 Both exertional and resting hypoxemia are associated with increased mortality in fibrotic ILD.26,96-98 Furthermore, chronic hypoxemia can contribute to the development of PH, which is a predictor of mortality in fibrotic ILD.36,99,100 Limited studies have evaluated risk factors for the development of hypoxemia in ILD, which have focused on exertional hypoxemia. Being able to predict the development of new-onset exertional and resting hypoxemia can be beneficial for patient and caregiver education in preparation for domiciliary oxygen therapy, as well as allowing clinicians to determine appropriate follow-up intervals for timely assessments. This study aimed to derive and validate a tool to predict new-onset exertional and resting hypoxemia in patients with fibrotic ILD. 24 2.2 Study Design and Methods 2.2.1 Population This international multicohort study used prospective data from the Canadian Registry for Pulmonary Fibrosis (CARE-PF; 2015-2019) as the derivation cohort.101 The external validation cohort used data from Alfred Health (Australia; 2010-2019), Austin Health (Australia; 2015-2019), and the University of California at Davis (United States; 2008-2020). Consecutive patients aged ≥19 years with a multidisciplinary diagnosis of fibrotic ILD of any subtype and at least two 6-minute walk tests (6MWTs) at separate visits were included. Patients with existing exertional and/or resting hypoxemia at the initial assessment were excluded. Ethics approval was obtained from the University of British Columbia as the coordinating center for CARE-PF (H19-01989) and for other sites from the Austin Health Human Research Ethics Committee (LNR/18/Austin/388). 2.2.2 Definition of Hypoxemia The outcomes of interest were new-onset exertional hypoxemia and new-onset resting hypoxemia. Exertional hypoxemia was defined as a documented nadir pulse oximetry oxygen saturation (SpO2) <88% during 6MWT on room air and resting hypoxemia was defined as resting SpO2 <88% on room air. Given the potential for qualifying walk tests to be missing from the patient chart and the use of standard oxygen funding criteria for all participating regions, a new prescription for oxygen use with exertion and/or at rest was used as secondary criteria for exertional and resting hypoxemia, respectively. 25 2.2.3 Candidate Predictor Variables Candidate predictors for new-onset exertional and resting hypoxemia included age, sex, smoking status, body mass index (BMI), ILD subtype, pulmonary function, 6-minute walk distance (6MWD), and resting and nadir SpO2. For pulmonary function, absolute and percent predicted values of forced expiratory volume in one second (FEV1), FVC, FEV1/FVC ratio, total lung capacity, residual volume, and diffusing capacity for carbon monoxide (DLCO) were included. Additionally, the 2-year change of absolute and percent predicted values for each pulmonary function parameter was calculated using the slope of linear regression. 2.2.4 Statistical Analysis Statistical analyses were performed using Stata version 16 (StataCorp, USA). Data are reported as median (interquartile range), unless otherwise specified. Performance of prediction models was assessed using the Harrell's C-index for discrimination and goodness-of-fit (GoF) likelihood ratio test for calibration. A C-index value of ≥0.7 was considered good discrimination.102 A p≥0.05 was considered a good calibration. Prediction model derivation with scoring system development Two multivariable time-varying Cox regression analyses were performed to evaluate the association between candidate predictors with new-onset exertional and resting hypoxemia measured at six months. In these analyses, the follow-up is divided into time intervals to use serial measurements of time-varying predictors (age, BMI, pulmonary function, and 6MWT measurements) in predicting the development of hypoxemia for 26 each six-month interval. Given varying intervals for clinical follow-up visits, a window period of three to nine months was allowed for each interval. The top ten best performing candidate prediction models for new-onset exertional and resting hypoxemia were selected using the Akaike information criterion (AIC). Routine availability and collinearity between candidate predictors, as well as model discrimination and calibration, were considered for selection of the most desirable prediction models. This was done independently for new-onset exertional and resting hypoxemia. After selecting the best performing prediction models for new-onset exertional and for resting hypoxemia, continuous predictors were converted to categorical variables by graphical examination of their relationships with outcomes for threshold effects using histograms.103 To facilitate model utilization in clinical practice, a risk prediction tool was developed using the regression coefficients for different categories of each predictor. Performance for this tool was evaluated using discrimination and calibration. Sensitivity and specificity analysis was conducted for each of the risk scores at initial (baseline) assessment as well as all assessments. Two sensitivity analyses were conducted to evaluate performance of the risk prediction tool using the derivation cohort. One was to assess the effect of a strict definition of normoxemia by only including clinic visits with 6MWT and/or documented oxygen usage and removing those with missing values. In the primary analysis, all clinic visits without the 6MWT and/or documented oxygen usage were assumed to be normoxemic. The other sensitivity analysis evaluated whether the presence of suspected PH, defined as 27 right ventricular systolic pressure ≥35 mmHg on transthoracic echocardiogram, versus non-suspected PH meaningfully affected results. External validation The risk prediction tool to predict new-onset exertional and resting hypoxemia at six months was evaluated in the external validation cohort for its discrimination, calibration, sensitivity, and specificity. Risk prediction Using the combined derivation and validation cohorts, risk stratification schemas for new-onset exertional and resting hypoxemia at six months were developed by grouping risk scores at the initial and last follow-up into low, moderate, and high-risk based on the observed incidence. The 5-year cumulative incidence of new-onset exertional and resting hypoxemia was determined for each risk category using the Kaplan-Meier method. 2.3 Results 2.3.1 Study Population The analysis evaluating new-onset exertional hypoxemia included 1,969 patients in the derivation cohort and 413 patients in the validation cohort (Figure 2-1). During follow-up, 25% (n=487) of the derivation cohort and 38% (n=156) of the validation cohort developed exertional hypoxemia over a median follow-up of 2.4 (1.2-4.9) years and 2.3 (1.0-4.8) years, respectively. The evaluation of new-onset resting hypoxemia included 28 2,186 patients in the derivation cohort and 495 patients in the validation cohort. Resting hypoxemia developed in 11% (n=232) of the derivation cohort and 18% (n=87) in the validation cohort over a median follow-up of 2.7 (1.4-5.3) years and 3.1 (1.5-5.5) years, respectively. Connective tissue disease-associated ILD (CTD-ILD) was the most common ILD subtype in the derivation cohorts, while IPF was the most common subtype in the validation cohorts (Table 2-1, Appendix A.1). Compared to the derivation cohorts, the validation cohorts included more men and had lower DLCO % predicted at the initial assessment. Both the derivation and validation cohorts contained Caucasian as the most common race. Figure 2-1: Flow diagram of the (a) derivation and (b) validation cohort for the evaluation of new-onset exertional and resting hypoxemia. 29 Reasons for exclusion included baseline exertional or resting hypoxemia, or uncertain date of exertional or resting hypoxemia onset. aDerivation cohort: Canadian Registry for Pulmonary Fibrosis bValidation cohort: Alfred Health, Austin Health, and University of California, Davis Table 2-1: Patient characteristics of the derivation and validation cohorts. Data are reported as n (%), mean ± SD, or median (IQR) Abbreviations: 6MWD = 6-minute walk distance; BMI = Body mass index; CARE-PF = Canadian Registry for Pulmonary Fibrosis; CTD-ILD = Connective tissue disease associated interstitial lung disease; DLCO = Diffusing capacity of carbon monoxide; FEV1 = Forced expiratory volume in one second; FVC = Forced vital capacity; HP = Hypersensitivity pneumonitis; IPF = Idiopathic pulmonary fibrosis; SpO2 = Pulse oximetry oxygen saturation Characteristics Derivation cohort (n = 2,515) Validation cohort (n = 508) Exertional hypoxemia evaluation (n = 1,969) Resting hypoxemia evaluation (n = 2,186) Exertional hypoxemia evaluation (n = 413) Resting hypoxemia evaluation (n = 495) Age at initial assessment (years) 61 ± 13 61 ± 13 66 ± 12 66 ± 12 Male sex 907 (46) 1,024 (47) 258 (62) 314 (63) Ever smokers at initial assessment 1,156 (59) 1,296 (59) 254 (62) 306 (62) Racea • African American 27 (1) 34 (2) 0 0 • Asian 196 (10) 217 (10) 20 (9) 26 (10) • Caucasian 1,386 (70) 1,556 (71) 192 (90) 239 (90) • Otherb 24 (1) 27 (1) 1 (1) 2 (1) • Unknown 336 (17) 352 (16) 0 0 BMI at initial assessment (kg/m2) 29 ± 6 29 ± 6 29 ± 5 29 ± 5 Pulmonary function at initial assessment • FEV1 (% predicted) 82 ± 19 81 ± 19 83 ± 19 81 ± 19 • FVC (% predicted) 82 ± 19 81 ± 19 80 ± 20 78 ± 20 • DLCO (% predicted) 66 ± 20 65 ± 20 56 ± 18 54 ± 17 • 6MWD (m) 450 (133) 442 (142) 393 (168) 394 (179) • Nadir exertional SpO2 (%) 94 (91-96) 92 (87-95) 93 (90-95) 91 (87-94) • Resting SpO2 (%) 97 (96-98) 97 (95-98) 97 (96-98) 97 (95-98) ILD subtypes • CTD-ILD 805 (41) 881 (40) 98 (24) 113 (23) • Fibrotic HP 130 (7) 147 (7) 46 (11) 58 (12) • IPF 470 (24) 537 (25) 147 (36) 179 (36) • Sarcoidosis 86 (4) 88 (4) 20 (5) 20 (4) • Unclassifiable ILD 326 (17) 370 (17) 72 (17) 87 (18) • Other ILDc 152 (8) 163 (8) 30 (7) 38 (8) Suspected PH during study periodd 453 (23) 519 (24) - - Initiation of domiciliary therapy during study periode 112 (6) 226 (10) 63 (15) 80 (16) 30 aValidation cohort race data only available for Alfred and Austin Health bOther race: Afro-Caribbean, American Indian (Alaska native), Native Hawaiian or other Pacific Islander cOther ILD: Aspiration-related ILD, Cystic/airspace related ILD, Drug-induced ILD, Eosinophilic pneumonia, Non- idiopathic pulmonary fibrosis idiopathic interstitial pneumonia, Pneumoconiosis, Pulmonary alveolar microlithiasis, Radiation related ILD, Smoking related ILD, Unknown subtype, Vasculitis dDefined as right ventricular systolic pressure ≥35mmHg on transthoracic echocardiogram eAmbulatory oxygen therapy for exertional hypoxemia and long-term oxygen therapy for resting hypoxemia 2.3.2 Prediction Model Derivation with Scoring System Development and Sensitivity Analyses Based on AIC values for model fitness and complexity, together with consideration of clinical applicability, predictors for both prediction models of new-onset exertional and resting hypoxemia at six months included age, BMI, FVC % predicted, DLCO % predicted, and the diagnosis of IPF (Appendix A.2). The prediction model based on continuous variables had good discrimination (C-index: 0.71) and calibration (GoF: P=0.46) for new-onset exertional hypoxemia, and good discrimination (C-index: 0.79) but suboptimal calibration (GoF: P=0.03) for new-onset resting hypoxemia. The risk prediction tool developed for both new-onset exertional and resting hypoxemia had total possible scores of 0 to 11 (Table 2-2). There were two score categories for age, BMI, and ILD subtypes, and three categories for FVC % predicted and DLCO % predicted. The risk prediction tool for new-onset exertional hypoxemia continued to exhibit good performance (C-index: 0.70) and calibration (GoF: P=0.85) (Table 2-3). For the risk prediction tool of new-onset resting hypoxemia, discrimination remained good (C-index: 0.77) with improved calibration (P=0.27). Specificity increased as risk score point values increased (Appendix A.3). Good and consistent area under the receiver operating characteristic curve was demonstrated for both initial (baseline) and all assessments analysis (Appendix A.4) 31 Table 2-2: Scoring system and risks of new-onset exertional and resting hypoxemia at six months. Predictor Points Age (years) ≤60 0 >60 1 BMI (kg/m2) <25 0 ≥25 2 FVC (% predicted) >75 0 50-75 2 <50 3 DLCO (% predicted) >55 0 36-55 2 ≤35 or cannot performa 3 ILD subtypes Not IPF 0 IPF 2 Total possible score 11 Risk category Total score Initial risk (%)b Last follow-up risk (%)c Exertional hypoxemia Resting hypoxemia Exertional hypoxemia Resting hypoxemia Low 0 – 3 3.8 0.2 12.2 1.4 Moderate 4 – 5 8.3 2.6 28.1 9.4 High >5 19.0 7.3 46.3 24.3 Abbreviations: BMI = Body mass index; DLCO = Diffusing capacity of carbon monoxide; FVC = Forced vital capacity; IPF = Idiopathic pulmonary fibrosis aPatients missing DLCO data with FVC <50% predicted were assumed to be unable to perform DLCO testing bRisk of new-onset exertional and resting hypoxemia at the initial assessment cRisk of new-onset exertional and resting hypoxemia for patients with >2 follow-up assessments Table 2-3: Scoring system prediction model performance metrics. Statistic Derivation cohort Validation cohort Exertional hypoxemia evaluation Resting hypoxemia evaluation Exertional hypoxemia evaluation Resting hypoxemia evaluation Harrell's C-index 0.70 0.77 0.72 0.78 GoF likelihood ratio test 0.85 0.27 1.00 0.001 Risk category (%)a Observed Expected Observed Expected Observed Expected Observed Expected • Low 20 22 6 11 10 9 0 3 • Moderate 32 29 28 23 20 25 6 12 • High 48 49 66 66 70 66 94 85 Abbreviations: GoF = Goodness-of-fit aObserved versus expected new-onset hypoxemia events for low, moderate, and high-risk categories with total scores of 0 to 3, 4 to 5 and >5, respectively 32 In the sensitivity analysis using the strict definition of normoxemia, the risk prediction tool for new-onset exertional hypoxemia had reduced discrimination (C-index: 0.67) with calibration remaining acceptable (GoF: P=0.76), while performance of the risk prediction tool for new-onset resting hypoxemia were comparable to that of the primary analysis (C-index: 0.78, GoF: P=0.11) (Appendix A.5). In the sensitivity analysis of patients with and without suspected PH, the risk prediction tool for new-onset exertional hypoxemia showed similar performance to the primary analysis (C-index: 0.69, GoF: 1.00). For the risk prediction tool of new-onset resting hypoxemia, patients with suspected PH had good discrimination (C-index: 0.72) but borderline calibration (P=0.05), with discrepancy in the observed versus expected event rates with overestimation of the event rate in the low-risk category and slight underestimation in the moderate-risk category (Appendix A.5). For patients with non-suspected PH, the risk prediction tool for new-onset resting hypoxemia had good performance (C-index: 0.80, GoF: 0.10). 2.3.3 External Validation Performance of the risk prediction tool for new-onset exertional hypoxemia remained satisfactory in the validation cohort (C-index: 0.72, GoF: 1.00) (Table 2-3). The risk prediction tool for new-onset resting hypoxemia had similar discrimination (C-index: 0.78) compared to the derivation cohort, but suboptimal calibration (GoF: 0.001) with overestimation of the event rate in the low and moderate-risk categories (Table 2-3). Specificity increased with increasing risk score point values (Appendix A.3). The area under the receiver operating characteristic curve analysis demonstrated similar performance as in the derivation cohorts (Appendix A.4). 33 2.3.4 Risk Prediction Risk scores were categorised into low (0 to 3), moderate (4 to 5), and high (>5) risk of developing exertional and resting hypoxemia at six months during the initial and last follow-up for patients with more than two assessments (Table 2-2). The incidence of new-onset exertional hypoxemia at initial baseline was 3.8%, 8.3%, and 19.0% for low, moderate, and high-risk categories, respectively. The incidence of new-onset exertional hypoxemia was 12.2%, 28.1%, and 46.3% for last follow-up, respectively. The incidence of new-onset resting hypoxemia at initial baseline was 0.2%, 2.6%, and 7.3% for low, moderate, and high-risk categories, respectively. The incidence of new-onset resting hypoxemia was 1.4%, 9.4%, and 24.3% for last follow-up, respectively. Cumulative incidence of new-onset exertional hypoxemia at one and five years according to risk categories at the initial assessment were 5.0 and 17.7% for low-risk, 11.3 and 37.1% for moderate-risk, and 24.3 and 56.9% for high-risk (Figure 2-2). Cumulative incidence of new-onset resting hypoxemia at one and five years according to risk categories at the initial assessment was 0.3 and 4.0% for low-risk, 3.2 and 15.0% for moderate-risk, and 9.1 and 32.0% for high-risk. 34 Figure 2-2: Cumulative incidence of (a) new-onset exertional hypoxemia and (b) resting hypoxemia (b) for low, moderate, and high-risk categories. 35 2.4 Discussion This study derived and externally validated a clinical-friendly risk prediction tool for predicting new-onset exertional and resting hypoxemia at six months in patients with fibrotic ILD. The predictors of hypoxemia included age, BMI, FVC % predicted, DLCO % predicted, and the diagnosis of IPF, all of which are readily available in clinical practice. The risk prediction tool demonstrated largely consistent performance across a diverse range of ILD subtypes in geographically distinct populations of varying patient characteristics and disease severity, supporting its generalizability. This risk assessment tool for new-onset hypoxemia in patients with fibrotic ILD will aid patient discussion about treatment expectations with oxygen therapy and support scheduling of clinical follow-up for re-assessments. The functioning of all organ systems requires adequate blood oxygenation. Hypoxemia in ILD results in dyspnea, imposes limits on exercise endurance, and carries a poor prognosis.104-106 Ambulatory oxygen therapy can alleviate dyspnea, cough, and impaired exercise performance in patients with fibrotic ILD.28,107-109 While limited data is available for long-term oxygen therapy in ILD, improved survival in studies of chronic obstructive pulmonary disease has been extrapolated with the recommendation of using long-term oxygen therapy in patients with ILD and resting hypoxemia.55 It is therefore critical that patients with clinically significant hypoxemia are identified early for consideration of oxygen supplementation to provide symptomatic benefit and potentially improve survival. However, regular screening for hypoxemia with walk tests is costly, 36 resource intensive, and burdensome for patients. This clinical prediction tool for new-onset hypoxemia allows patient prioritisation for future assessments. There are few studies examining risk factors for new-onset exertional and resting hypoxemia in fibrotic ILD. The DLCO % predicted has consistently been a predictor for the development of exertional hypoxemia,29,31,110 most likely due to its direct relationship to impaired gas exchange with disruption of the alveolar-capillary membrane in the fibrotic lungs. Furthermore, patients with ILD have ventilatory restriction due to low lung compliance with reduced lung volume and vital capacity, leading to ventilation/perfusion mismatch. High BMI can also contribute to the development of hypoxemia due to its association with reduced expiratory reserve volume through airway closure.111 Given the relationship between hypoxemia and disease severity in fibrotic ILD,106 it is not surprising that there is substantial overlap between our scoring system and the predictors of mortality in ILD including age, DLCO % predicted, FVC % predicted, and the diagnosis of IPF.26,38,112,113 Our risk prediction tool for new-onset exertional and resting hypoxemia at six months in fibrotic ILD demonstrated favorable discrimination and calibration in most analyses. The suboptimal calibration for predicting new-onset resting hypoxemia in the validation cohort was likely due a combination of factors associated with differences in participants characteristics and event rates, most notably the higher proportion of CTD-ILD in the derivation cohort, and the higher proportion of IPF and lower DLCO % predicted at the initial assessment in the validation cohort. Miscalibration was also noted for new-onset 37 resting hypoxemia in patients with suspected PH, with overestimation of the event rate in the low-risk category and slight underestimation in the moderate-risk category. Reassuringly, overestimation of the risk prediction tool will increase the number of patients identified as being at risk of hypoxemia, which is less concerning compared to underestimation in which patients with the potential of developing hypoxemia may be missed. Further evaluation with a larger patient population is needed, especially in the low and moderate-risk categories; however, the impact of miscalibration is reduced in prediction models with good discrimination.114 The initiation of oxygen therapy is a critical moment signifying disease progression and reduced independence in patients with fibrotic ILD.115 Some challenges include learning how to operate and carry oxygen equipment, unmet expectations with regards to dyspnea, and embarrassment when using oxygen in public places.55 Patients and caregivers need time to plan life when using domiciliary oxygen therapy including physically accommodating equipment when outdoors and/or at home and joining a suitable support group. This risk prediction tool for new-onset exertional and resting hypoxemia allows clinicians to prioritize follow-up visits for these patients to discuss treatment options including oxygen therapy as well as provide counselling. Furthermore, high-risk patients can be assessed for PH given its role in worsening hypoxemia and emerging therapies in the ILD population.116-118 Our study had some limitations. Firstly, criteria for prescribing oxygen vary across different regions, and may affect clinical application of this risk prediction tool depending 38 on what thresholds are used to define hypoxemia.119 We used SpO2 instead of arterial partial pressure of oxygen (PaO2) as part of the definition of hypoxemia, as it is more readily obtainable worldwide. Secondly, there may be additional factors contributing to new-onset exertional and resting hypoxemia that were not evaluated in this study, such as altitude, treatment with ILD-targeted medications, and comorbidities; however, we chose to prioritize clinical usability of the scoring system by including only variables that are readily available and easily applied. Thirdly, all study sites for the derivation and validation cohorts were specialized ILD centers, which may have different patient characteristics compared to other clinical settings. Nevertheless, our risk prediction tool was derived using data from a large multicenter national cohort and validated in a geographically diverse cohort of different ILD subtypes, supporting its generalizability. Finally, our cohorts were primarily Caucasian, and it is possible that findings would vary in other populations, potentially related to differences in ILD subtypes, rate of progression, or accuracy of pulse oximetry.120,121 2.5 Conclusion In this study, we derived and externally validated a risk prediction tool to predict new-onset exertional and resting hypoxemia in patients with fibrotic ILD, with risk stratification into low, moderate, and high-risk categories. This risk prediction tool uses readily available data in routine care of patients with fibrotic ILD to facilitate its application in clinical practice to support discussion regarding future need of domiciliary oxygen therapy and timing for assessments of oxygenation status. 39 Chapter 3: International Domiciliary Oxygen Criteria 3.1 Introduction Oxygen is an essential medicine as designated by the World Health Organization,122 reflecting its critical importance to patients with a variety of acute and chronic diseases. Domiciliary oxygen (i.e., oxygen prescribed for use in the home) is used in many chronic diseases. Although the potential benefits of oxygen vary across these diseases, oxygen typically improves dyspnea and functional capacity in patients who have significant hypoxemia, including improved survival in patients with chronic obstructive pulmonary disease (COPD).28,55,60,61 Based on these data, recent clinical practice guidelines from the American Thoracic Society (ATS) recommend domiciliary oxygen if there is either significant hypoxemia or moderate hypoxemia combined with evidence of end organ damage.55 Domiciliary oxygen can be provided throughout most of the day, including at rest (continuous), only during ambulation (ambulatory), or only during sleep (nocturnal). These three regimes have specific criteria based on hypoxemia thresholds measured through pulse oximetry or arterial blood gas (ABG); however, the precise thresholds and additional secondary criteria vary across and often within countries. This variability is also present in recommendations made by respiratory societies and healthcare organizations, and there is corresponding heterogeneity in the funding and availability of equipment used to deliver oxygen. As a result, access to this essential medicine is limited in many parts of the world, but the few studies quantifying these limits have 40 focused on only a small selection of countries, specific regions, or respiratory societies.123-126 There is a particularly poor understanding of domiciliary oxygen availability and use in low- and middle-income countries, resulting in significant patient care gaps for much of the world. To address this uncertainty, we aimed to identify eligibility criteria used for domiciliary continuous, ambulatory, and nocturnal oxygen in each of the 193 member countries of the United Nations and then compared these criteria against recommendations provided by respiratory societies and healthcare organizations. We further identified countries without reported public funding for domiciliary oxygen in order to describe populations for which domiciliary oxygen is not typically available. Our overall intent is that this knowledge will help catalyze efforts by the many necessary stakeholders to improve global access to this essential medicine. 3.2 Methods 3.2.1 Study Design This was a descriptive study identifying and comparing recommendations made in domiciliary oxygen guidelines against real-world eligibility criteria used by the 193 member countries of the United Nations.127 Data for domiciliary continuous, ambulatory, and nocturnal oxygen, as well as funding sources for oxygen and oxygen equipment were obtained from publicly available resources and survey of health professionals and oxygen suppliers. Ethics approval was waived by the University of British Columbia. 41 3.2.2 Oxygen Guideline Identification A literature search using both Embase and Medline was used to identify oxygen guidelines published by respiratory societies and other healthcare organizations using the keywords: “oxygen” AND “guideline*” AND “criteria”. This was supplemented by an Internet search on Google using the following terms: oxygen AND (guidelines OR criteria) AND society name, with each society identified from the list of peer organizations produced by the ATS.128 Specific criteria for continuous, ambulatory, and nocturnal oxygen were extracted from each document. All documents not in English were translated using macOS Preview version 11.0 (Cupertino, California, USA) or Google translate. Documents published prior to 1990 were excluded to allow greater focus on guidelines that were based on contemporary evidence and that were more likely to still be in clinical use. 3.2.3 Oxygen Criteria Identification Domiciliary oxygen eligibility criteria and the availability of public oxygen funding for each country were identified by an Internet search using Google that was conducted between December 2021 and April 2022. The following search strategy was used for each country and region: oxygen AND (criteria OR funding OR eligibility) AND (country OR region). Priority was given to government oxygen criteria pertaining to multiple chronic respiratory disorders; however, COPD criteria were documented if more broadly applicable criteria were unavailable. Regional criteria were collected if criteria varied within a country. 42 Attempts were made to contact physicians (preferably pulmonary subspecialists) or oxygen equipment suppliers via email or online contact forms for each country or region that did not have information available online. Email addresses for physician contacts were obtained from the Member Directory of the ATS and the United Nations Examining Physicians Directory.129 These contacts were asked to provide the specific eligibility criteria currently used in their country or region for domiciliary continuous, ambulatory, and nocturnal oxygen, as well as information pertaining to oxygen funding (public or private). Public funding was defined as oxygen funded by the government or other organizations that reduced by any amount or eliminated cost to the patient. Additional documentation was requested to corroborate these responses (e.g., electronic copies of local criteria or application forms). Physicians and suppliers were reminded weekly for three weeks if a response was not received. For the primary analysis, it was assumed that public oxygen funding was not available for countries with no information available online nor from attempted direct contact. The population and gross domestic product (GDP) per capita were collected for each country or region from online sources as of 2019 (the most recent year with reliable data).130-135 3.2.4 Statistical Analysis Recommendations made by guidelines were summarized, including the oxygen saturation (SaO2 or SpO2) and arterial partial pressure (PaO2) thresholds used to qualify for continuous, ambulatory, and nocturnal oxygen. Similarly, the proportion of guidelines 43 that recommended for or against ambulatory and nocturnal oxygen were calculated as percentages. Analyses on criteria used in each country were stratified according to the provision of oxygen with or without reported public funding. A Wilcoxon Rank Sum Test was used to compare 2019 GDP per capita in United States Dollar (USD) for countries with and without public funding as well as GDP per capita for countries that followed their corresponding national guidelines to those that did not.130,132 The number of countries and their total population were calculated for each oxygen saturation and PaO2 threshold used to qualify for publicly funded continuous, ambulatory, and nocturnal oxygen. Thresholds are presented using map charts (Microsoft Excel 365 version 16, Redmond, Washington, USA), with priority given to displaying the oxygen saturation threshold for countries that have both oxygen saturation and PaO2 thresholds. Inequality symbols referenced in criteria were removed from the map chart (e.g., oxygen saturation of 88% represented countries with a stated oxygen saturation threshold of either <89% or ≤88%). A weighted average threshold was calculated for countries with multiple regional criteria based on the population of each region and its corresponding threshold.133-135 The proportion of countries following their national respiratory society and/or healthcare organization was calculated. Analyses were conducted using Stata 16 (College Station, Texas, USA). 44 3.3 Results 3.3.1 Oxygen Guidelines Recommended criteria for domiciliary continuous oxygen were provided in 30 guidelines (Appendix B.1). Of the 14 guidelines (47%) providing an oxygen saturation threshold (SaO2 or SpO2) for continuous oxygen, thresholds of <88% and ≤88% were used by 6 (20%) and 7 (23%) guidelines, respectively, with 1 (3%) recommending <90%. A PaO2 <55 mmHg (<7.3 kPa) was the recommended threshold for commencement of continuous oxygen for 8 (27%) and a PaO2 ≤55 mmHg (≤7.3 kPa) for 19 (63%) of the 30 guidelines that provided a specific PaO2 threshold, with the remaining 3 (10%) recommending <56 mmHg (<7.4 kPa), <60 mmHg (<8 kPa), or only SpO2 ≤88%. Additional secondary PaO2 criteria were provided in 26 guidelines but were highly variable, including a combination of different thresholds of PaO2 (typically >55 and <60, or ≤60 mmHg), along with some or all of pulmonary hypertension, polycythemia, edema, and/or signs of heart failure. The use of oxygen during ambulation was addressed in 18 guidelines, with ambulatory oxygen recommended in 13 guidelines (72%) and not recommended in 5 (28%). The use of nocturnal oxygen was addressed in 16 guidelines, with oxygen during sleep recommended in 10 guidelines (63%) and not recommended in 6 (38%). Oxygen saturation was the primary method used to determine eligibility for both ambulatory and nocturnal oxygen in the guidelines, with one society also providing a PaO2 threshold of <55 mmHg for ambulatory oxygen. 45 3.3.2 Oxygen Funding Source Of the 193 member countries in the United Nations, 46 countries provided eligibility criteria for publicly funded continuous oxygen (total population 1.6 billion), 34 for ambulatory oxygen (total population: 1.4 billion), and 23 for nocturnal oxygen (total population: 1.0 billion) (Figure 3-1). Two publicly funded countries did not provide specific criteria (total population: 45 million). Eligibility criteria for privately funded oxygen (i.e., oxygen paid for by private insurance coverage) were provided for an additional 28 countries for continuous oxygen (total population: 4.0 billion), 13 countries for ambulatory oxygen (total population: 2.0 billion), and 10 countries for nocturnal oxygen (total population: 0.5 billion) (Table 3-1). The funding source was not specified and unable to be ascertained for 10 countries providing criteria for continuous oxygen (total population: 0.3 billion), 4 for ambulatory oxygen (total population: 37 million), and 1 for nocturnal oxygen (total population: 10 million). Regional criteria were available for Australia, Canada, and the United Kingdom (Appendix B.2). A total of 145 countries (total population: 5.9 billion) did not have public funding (either private funding or no funding source specified), of which 50 were in Africa (total population: 1.2 billion), 36 in Asia (total population: 4.1 billion), 20 in Europe (total population: 0.3 billion), 17 in North America (total population: 0.2 billion), 12 in Oceania (total population: 12 million), and 10 in South America (total population: 0.1 billion). Countries with public access to oxygen funding had a higher GDP per capita in 2019 compared to the remainder (median 30,451 vs 4,036 USD; P<0.001). 46 Figure 3-1: Gross domestic product per capita (2019 United States Dollar) for countries with public oxygen funding compared to countries with no reported public oxygen funding. Table 3-1: Number of publicly and exclusively privately funded countries using oxygen saturation and/or arterial partial pressure of oxygen to determine eligibility thresholds for continuous, ambulatory, and nocturnal oxygen. Continuous Ambulatory Nocturnal Funding Public Private Public Private Public Private SaO2 or SpO2 (%) 4 9 16 7 15 6 PaO2 (mmHg) 21 5 1 0 0 0 Either of the above 21 14 13 4 5 4 Based on physician discretion 0 0 4 2 3 0 Total 46 28 34 13 23 10 Abbreviations: PaO2 = arterial partial pressure of oxygen, SaO2 = arterial oxygen saturation, SpO2 = pulse oximetry oxygen saturation 47 3.3.3 Oxygen Eligibility Criteria There was varying overlap of oxygen eligibility criteria for the 28 countries with corresponding national guidelines, with 36% of countries having a substantial difference (Appendix B.1, Appendix B.2). The median GDP per capita was higher (44,651 USD) for countries that were concordant with their corresponding guideline compared to countries that had substantial difference (15,312 USD); however, this comparison was underpowered and not statistically significant (P=0.10). Of the 46 publicly funded countries with continuous oxygen criteria, eligibility criteria were based on only oxygen saturation thresholds in 4 countries (9%; total population 8 million), only PaO2 thresholds in 21 countries (46%; total population 0.4 billion), and either oxygen saturation or PaO2 thresholds in 21 countries (46%; total population 1.2 billion) (Table 3-1). An oxygen saturation ≤88% was the most common threshold for publicly funded countries with continuous oxygen criteria, which was used by 12 of the 46 countries (total population 1.0 billion), while others used thresholds ranging from <85 to <92% (Figure 3-2a). A PaO2 ≤55 mmHg (≤7.3 kPa) was the most common threshold, which was used for 22 publicly funded countries in determining continuous oxygen eligibility (total population: 1.3 billion), while others had thresholds ranging from <55 mmHg (<7.3 kPa) to <60 mmHg (<8 kPa) or did not report specific PaO2 thresholds. Of the 34 publicly funded countries with ambulatory oxygen criteria (total population: 1.4 billion), only oxygen saturation thresholds were used in 16 countries (47%; total population 0.3 billion), only PaO2 thresholds in 1 country (3%; total population 3 million), 48 either oxygen saturation or PaO2 in 13 countries (38%; total population 1.1 billion), and physician discretion in 4 countries (12%; total population 39 million) (Table 3-1). A saturation threshold ≤88% was used for 6 of these countries (total population 0.6 billion), with other countries using a variety of thresholds that ranged from ≤83 to ≤90% (Figure 3-2b). Of the 23 publicly funded countries with nocturnal oxygen criteria (total population: 1.0 billion), 15 countries used only oxygen saturation thresholds (65%; total population 0.3 billion), none used only PaO2, 5 used either oxygen saturation or PaO2 (22%; total population 0.7 billion), and 3 used physician discretion (13%; total population 23 million) (Table 3-1). An oxygen saturation threshold ≤88% was used for nocturnal oxygen criteria for 6 of these countries (total population 0.6 billion), with other countries using a variety of thresholds ranging from <88 to ≤90% (Figure 3-2c). 49 Figure 3-2: Thresholds for continuous, ambulatory, and nocturnal oxygen for countries with reported public oxygen funding. Thresholds are reported based on the value at which a patient would qualify for oxygen supplementation. Weighted averages of oxygen saturation and PaO2 based on regional population size were calculated for countries that contained multiple regional oxygen criteria thresholds. The total population with public oxygen funding and the percentage of global population was based on 2019 data from the United Nations. Abbreviations: PaO2 = arterial partial pressure of oxygen, SaO2 = arterial oxygen saturation, SpO2 = pulse oximetry oxygen saturation 50 3.4 Discussion There are no universally accepted criteria for domiciliary oxygen in patients with chronic hypoxemia, resulting in highly variable recommendations from oxygen guidelines, and limited availability of this essential medication. We used a detailed and comprehensive evaluation of both oxygen guidelines and national eligibility criteria for continuous, ambulatory, and nocturnal oxygen, including all 193 members of the United Nations. Our overall goal was to identify these patient care gaps such that the many stakeholders involved in domiciliary oxygen can more appropriately direct necessary resources to this critical resource. Despite some similarities, we show that recommended criteria for domiciliary oxygen differed across the many identified guidelines. These included variability in hypoxemia assessment methods such as recommendation for pulse oximetry (SpO2) versus ABG (SaO2 or PaO2), as well as inclusion of secondary criteria based on presence of pulmonary hypertension, polycythemia, and/or cor pulmonale. More consistently, all guidelines except one recommended a PaO2 threshold for continuous oxygen, with the NOTT criteria being most similar to the provided recommendations.60 This included PaO2 ≤55 mmHg or PaO2 ≤59 mmHg and at least one of peripheral edema, hematocrit ≥55%, or P-pulmonale on electrocardiogram. An important limitation of these criteria is the reliance upon ABG measurements, which is more invasive and likely more expensive, with a minority of studies providing pulse oximetry thresholds. Pulse oximetry accuracy may be limited by skin pigmentation and comorbidities.53,54 Recommendations for ambulatory and nocturnal oxygen also varied, with many guidelines not providing recommendations for oxygen use in these settings. This variability likely relates to the 51 less consistent findings from studies of ambulatory and nocturnal oxygen. For example, the International Nocturnal Oxygen (INOX) trial suggested no impact of nocturnal oxygen on survival in COPD;63 however, this study may have been underpowered, resulting in persistent uncertainty regarding the potential benefit of nocturnal oxygen. In contrast, the shorter-term Ambulatory Oxygen (AmbOx) study suggested benefit of ambulatory oxygen in patients with interstitial lung disease.28 These limitations indicate the need for adequately powered studies to investigate the impact of oxygen in these settings for patients with chronic lung disease, such that guideline recommendations can be based on appropriate evidence. The variability of recommended criteria in previous oxygen guidelines is further reflected in the heterogeneous eligibility criteria used in different countries around the world. As with guideline criteria, there were discrepancies in hypoxemia assessment methods such as the usage of oxygen saturation versus PaO2, as well as secondary eligibility criteria based on presence of pulmonary hypertension, polycythemia, and/or cor pulmonale. There are many potential reasons for the frequent discordance between the guidelines and eligibility criteria, including financial constraints and lack of convincing evidence. A better understanding of these and other potential reasons would enable a more targeted and efficient approach to ensure effective translation of new evidence into patient care. The limited availability of publicly funded oxygen is of greater public health concern than the varying eligibility criteria. We identified public funding sources with criteria for only 24% of the 193 members of the United Nations, representing only 1.6 billion people residing in countries with publicly funded domiciliary oxygen, meaning that a majority of the world has limited access 52 to oxygen. This limited access is made more concerning by oxygen frequently being indicated for older individuals who are retired or have tenuous employment with constrained personal finances, contrasted with the significant expense associated with this treatment.136 Further compounding this issue is the finding that countries with lower GDP per capita less frequently provided public oxygen funding, likely creating insurmountable barriers to oxygen access for people living in areas with more limited financial resources. Additional granular studies are needed to identify the many barriers that hinder access to domiciliary oxygen. First, initiation of domiciliary oxygen begins with identification of patients at high risk and subsequent testing to confirm the presence of clinically significant hypoxemia; however, there are currently no validated criteria that predict onset of hypoxemia, and many countries lack equipment and resources needed to support widespread testing.137 Second, patient preferences and societal norms may impact willingness to commence oxygen, including perceptions that patients might become dependent upon oxygen or that oxygen initiation may signal short-term mortality.81 Third, clinicians may be unfamiliar with oxygen guidelines and be uncertain as to when testing is appropriate or when to prescribe oxygen therapy.77,78 These issues were further exaggerated in the context of the COVID-19 pandemic, with many patients needing long-term oxygen following initial recovery,138 and increased need for oxygen exceeding the available supply in some countries during early waves.139 Collectively, these concerns highlight the importance of a concerted effort by multiple stakeholders to improve access to oxygen in many parts of the world. 53 Our study was limited primarily by the challenges in identifying eligibility criteria for many countries. Eligibility criteria were obtained based on available information either online or via email responses, and it is possible some countries have criteria that were not identified through this process. However, the inability to identify such criteria despite a rigorous attempt suggests the likelihood of poor access to oxygen for these countries even if criteria do exist. In addition, identified criteria may not be representative of actual practice patterns and may vary across physicians or within more specific geographic regions, although this variability would again likely result in more limited access to domiciliary oxygen, rather than better access. Finally, we report SaO2 and SpO2 thresholds together, as many documents and respondents used these terms interchangeably. This represents an important area for clarification in future guidelines as well as knowledge translation activities, as perpetuation of this ambiguity would likely result in more frequent use of ABGs when obtaining SaO2, which are more invasive and likely more costly than pulse oximetry. 3.5 Conclusion In summary, this comprehensive global study shows that most of the world lacks adequate access to domiciliary oxygen despite this therapy playing a critical role in the treatment of chronic lung disease and being classified as an essential medication by the World Health Organization. We identify the variability in oxygen criteria used around the world and highlight the need for additional data, including clinical trials and cost-effectiveness analyses to support future evidence-based guidelines. We further hope that these results will call attention to international public health needs related to domiciliary oxygen, identifying major priority areas where efforts are most urgently needed to address these issues. 54 Chapter 4: Costs of Oxygen Therapy for Interstitial Lung Disease and Chronic Obstructive Pulmonary Disease: A Retrospective Study from a Universal Healthcare System 4.1 Introduction Interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are chronic diseases that often lead to respiratory dysfunction and early mortality. The hypoxemia and dyspnea frequently seen in both diseases may be at least partially relieved by continuous supplemental oxygen.140 Continuous oxygen therapy (i.e. oxygen used for ≥15 hours per day) lowers mortality in patients with COPD who meet specific criteria for resting hypoxemia.60,61 These benefits have also been used to support recommendations for the use of continuous oxygen therapy in patients with fibrotic ILD who have resting hypoxemia;141 however, specific indications for domiciliary oxygen in patients with fibrotic ILD are uncertain.142 In particular, the benefits of ambulatory oxygen supplementation (i.e. oxygen only used during ambulation) are unclear in either fibrotic ILD or COPD, given the limited and conflicting evidence. The American Thoracic Society clinical practice guideline states that ambulatory oxygen should be considered for patients with exertional hypoxemia who demonstrate clinical improvement on oxygen. Ambulatory oxygen may alleviate dyspnea and improve exertional ability in ILD.28,93,143-145 The estimated incidence of the most common subtype of ILD, IPF, is 10 cases per 100,000 persons per year in Canada.101 In Canadian dollars (CAD), the annual cost of IPF is estimated to be CAD 12,978 per patient 2 years post-diagnosis.70 About two million Canadians are currently living with COPD.146 The annual cost of COPD is CAD 4.52 billion/year and is expected to reach CAD 7.33 billion/year by 2035.147 The substantial costs of both ILD and COPD are rising with increasing disease prevalence, longer survival and more frequent use of 55 expensive new medications and devices. Domiciliary oxygen is a major cost in both diseases, but with poorly understood details of this healthcare expense. Accordingly, the specific objective of this study was to determine the monthly costs associated with continuous and ambulatory oxygen use in patients with fibrotic ILD and COPD. Our overall goal was to provide robust data that allow precise estimation of current and future costs such that funders are better able to make informed decisions regarding resource allocation. 4.2 Methods 4.2.1 Study Design This study was based on a retrospective chart review utilizing patient data from the Vancouver Coastal Health Home Oxygen Program (VCH HOP) from 2010-2017. Patients diagnosed by a referring physician with either ILD or COPD aged ≥19 years old who qualified for domiciliary oxygen therapy were included. Patients provided with only short-term oxygen supplementation were excluded (i.e., initiated during admission to hospital for a respiratory illness and continued for <1 month after discharge), as were those with obstructive sleep apnea (OSA) and/or combined ILD and COPD. Chart reviews were performed from the time of oxygen initiation until discontinuation, death, or censoring. These were used to obtain relevant information regarding patient demographics and disease subtype (ILD or COPD). Details on disease severity and other therapies were not available given the limited data provided to the VCH HOP regarding each patient. This study was approved by the University of British Columbia-Providence Health Care Research Institute (research ethics board number: H19-00898). 56 4.2.2 Study Population In British Columbia (BC), continuous oxygen therapy is funded based on the following provincial guidelines:68 • Continuous oxygen; one of: o a) Resting SpO2 <88% for a minimum of six minutes or o b) PaO2 ≤55 mmHg on room air or o c) PaO2 ≤60 mmHg with evidence of one of: heart failure or PH. • Ambulatory oxygen; one of: o a) SpO2 <88% for at least 1 minute during ambulation while breathing room air and improvement in 6-minute walk test (6MWT) by a minimum of 25% and 30m when breathing oxygen, or o b) SpO2 <80% upon ambulation for at least one minute. • Nocturnal oxygen: a minimum 4-hour overnight oximetry performed while breathing room air with SpO2 <88% for >30% of the recording time. 4.2.3 Domiciliary Oxygen Program Patients who meet the criteria and are prescribed supplemental oxygen are managed and monitored by the VCH HOP, which is a centralized program that works with oxygen suppliers to coordinate delivery of oxygen and necessary oxygen-related equipment to a predominantly urban patient population. Since requiring continuous oxygen is a sign of advanced disease progression, those who are hypoxemic at rest are also prescribed oxygen during ambulation. 57 Initial flow rates are based on the first walking oximetry and the physician prescription. Subsequently, the VCH HOP will titrate flow rates based on in-home assessments that more closely reflect usual daily activities. VCH HOP respiratory therapists visit patient homes upon oxygen initiation and then every 3-12 months, or more frequently when needed to perform diagnostic testing to ensure oxygen needs are met. If a patient desaturates during ambulatory oxygen testing, an overnight oximetry test is ordered to rule out need for nocturnal oxygen. Overnight oximetry is also done to ensure that the oxygen flow rate is adequate. These tests are ordered at the recommendation of the VCH HOP Medical Director based on previous assessments and file review. For longer-term patients, overnight oximetry is done periodically to ensure adequate nocturnal oxygen support. Equipment suitability is assessed by VCH HOP respiratory therapists upon initial patient assessment based on data submitted to the HOP. Patients using ambulatory oxygen exclusively are offered portable supplies for outside use only during ambulation. Those requiring high flow rates need cylinders to deliver this amount of oxygen. Data from one of the five BC Health Authorities were available for this analysis (total VCH population 1.25 million in 2018).148 4.2.4 Data Collected The following data were collected from the VCH HOP: • Age • Sex • Diagnosis (ILD vs COPD) • Type of supplemental oxygen (continuous, ambulatory, nocturnal) • Oxygen flow rates 58 • Monthly billed cost of oxygen therapy • Cost of home visits by VCH HOP and supplier personnel • Cost of overnight oximetry tests per patient • Reason for cessation of oxygen We also collected the following data, but encountered sufficient missingness that these details could not be analyzed: • Comorbidities • 6MWT (“walking oximetry” was performed for all patients; however, this is not performed according to the more standardized 6MWT criteria and does not provide analyzable information) • Pulmonary function tests • Baseline resting and ambulatory SpO2 4.2.5 Oxygen Cost Components The total costs of oxygen utilization were comprised of four main components: 1) Oxygen equipment: concentrators (stationary or portable), cylinders (compressed or liquid oxygen), or both; determined by billed invoices to the VCH HOP by oxygen equipment suppliers. 2) VCH HOP respiratory therapist home visits: calculated based on salary and travel compensation. Respiratory therapists visit patient homes upon oxygen initiation, every 3-12 months, or when needed to perform diagnostic testing to ensure oxygen needs are met. 59 3) Oxygen equipment supplier home visits: calculated from supplier respiratory therapist and oxygen equipment technician salaries. 4) Overnight oximetry monitoring studies (e.g., tests used to confirm or support modification of flow rate settings): calculated based on provincial billing rates for each test. All costs were adjusted to 2018 Canadian dollars using the 12-month average Canadian Consumer Price Index (CPI) for health and personal care in 2018.149 4.2.6 Statistical Analysis Data are reported as mean ± standard deviation. A P-value ≤0.05 was considered statistically significant. Total domiciliary oxygen therapy costs for month 1 versus months 2-24 within each disease were compared using a paired t-test. The Wilcoxon Rank Sum Test was used to compare total per capita oxygen costs and oxygen flow rates between males and females within each disease for month 1 as well as months 2-24. The mean oxygen flow rate for month 1 was a simple average of all the resting or ambulatory oxygen flow rates. For months 2-24, the average of each patient’s flow rate was taken for all months for which oxygen was used, and a final mean was then calculated by averaging these values across the full cohort. Spearman correlation was utilized to evaluate any association between age and total oxygen cost for each disease. The analysis was conducted using Stata 16 (College Station, Texas, USA). 4.3 Results 4.3.1 Study Population Between 2010 and 2017, 99 patients with ILD and 1,017 with COPD who met eligibility criteria initiated domiciliary oxygen therapy (Table 4-1). The 50 patients with concurrent OSA and 14 60 patients with both ILD and COPD were excluded. The majority of patients with both diseases used either continuous oxygen or exclusively ambulatory oxygen (Table 4-1). Within the first 24 months of oxygen initiation, 35 patients with ILD and 393 with COPD had died. Another 37 with ILD and 330 with COPD discontinued oxygen due to no longer meeting eligibility criteria upon repeat assessment, noncompliance with therapy or other safety concerns (e.g., continued smoking cigarettes), leaving the VCH HOP region, admission to hospital or hospice or personal reasons of not wanting to continue oxygen. Table 4-1: Patient characteristics at baseline. ILD COPD Number of patients 99 1,017 Age, years 73 ± 12 77 ± 11 Male 55 (56%) 488 (48%) Oxygen delivery type Continuous oxygen 34 (34%) 527 (52%) Ambulatory oxygen only 60 (61%) 413 (41%) Nocturnal oxygen only 0 30 (3%) Ambulatory & nocturnal 5 (5%) 44 (4%) Unknown 0 3 (0.3%) Data shown are number (percent) or mean ± standard deviation. Abbreviations: COPD = Chronic obstructive pulmonary disease; ILD = Interstitial lung disease 4.3.2 Oxygen Flow Rate There was no statistically significant difference between ILD and COPD for continuous oxygen flow rates in month 1 (P=0.36) or months 2-24 (P=0.30); however, the mean ambulatory oxygen flow rate was higher in month 1 for ILD compared to COPD (P<0.001) as well as in months 2-24 (P<0.001) (Figure 4-1). In the ILD cohort, males had a greater continuous oxygen flow rate compared to females for months 2-24 (3.8 L/min ± 2.1 vs 2.6 L/min ± 1.0, P=0.03). In the COPD cohort, continuous flow rate was higher for male patients for month 1 (2.7 L/min ± 1.4 vs 2.5 L/min ± 1.1, P=0.04) and months 2-24 (2.9 L/min ± 1.1 vs 2.6 L/min ± 1.0, P=0.002) and 61 ambulatory oxygen flow rate for months 2-24 (3.6 L/min ± 1.4 vs 3.3 L/min ± 1.4, P=0.001). Figure 4-1: Mean monthly oxygen flow rates for ILD and COPD. Abbreviations: COPD = Chronic obstructive pulmonary disease; ILD = Interstitial lung disease; SD = Standard deviation 4.3.3 Oxygen Equipment Patients with ILD and COPD increasingly used both cylinders and concentrators with longer oxygen use (Figure 4-2). In month 1, 60% of ILD patients used only oxygen cylinders. For months 2-24, 51% of the observed months were spent using both cylinders and concentrators. For patients with COPD, 50% used both cylinders and concentrator in month 1. In the remaining months, 62% of all observed months for patients with COPD included the use of both equipment types. The per capita monthly cost of concentrators from months 2-24 for ILD and COPD was $115.47 ± $47.39 and $105.12 ± $59.43, respectively. The cost of cylinders for ILD 62 and COPD for months 2-24 was $98.72 ± $40.41 and $109.76 ± $42.84 per month, respectively. Figure 4-2: Oxygen equipment cost components in ILD and COPD. Abbreviations: COPD = Chronic obstructive pulmonary disease; ILD = Interstitial lung disease 4.3.4 Per Capita Cost of Oxygen Monthly per capita costs were higher in the first month of oxygen use for both ILD and COPD populations and then declined in month 2 with minimal change in monthly costs over the subsequent time period (Figure 4-3). Patients with ILD and COPD both had a higher per capita cost of home oxygen therapy in month 1 compared to months 2-24 (ILD: $202.57 ± $88.88 vs $142.21 ± $59.01, P <0.001; COPD: $222.85 ± $102.52 vs $156.65 ± $60.50, P<0.001; (Figure 4-4)). Costs of oxygen supplementation were similar comparing ILD and COPD in month 1, but with greater monthly costs for COPD compared to ILD in months 2-24 (Figure 4-4). 63 Figure 4-3: Monthly per capita cost of domiciliary oxygen therapy for ILD and COPD. Abbreviations: COPD = Chronic obstructive pulmonary disease; ILD = Interstitial lung disease; VCH HOP = Vancouver Coastal Health Home Oxygen Program Figure 4-4: Total monthly per capita costs of domiciliary oxygen therapy for ILD and COPD. Error bars represent standard error of the mean. There was no statistically significant difference detected comparing month 1 costs in ILD and COPD. Domiciliary oxygen therapy was more costly for COPD than for ILD in months 2-24. Month 1 costs were higher than months 2-24 for both ILD and COPD (P<0.001 for both groups). Abbreviations: COPD = Chronic obstructive pulmonary disease; ILD = Interstitial lung disease; VCH HOP = Vancouver Coastal Health Home Oxygen Program 64 Patients with ILD and COPD had similar distribution of costs for each cost component in month 1 and months 2-24, including oxygen equipment, oxygen service provider home visits, VCH HOP home visits and overnight oximetry studies (Figure 4-5). For months 2-24, ILD continuous oxygen equipment costed $157.16 ± $56.69 and ambulatory oxygen equipment usage costed $99.76 ± $40.22, while COPD continuous oxygen equipment costed $157.33 ± $62.38 and ambulatory oxygen equipment usage costed $112.54 ± $44.63. During this period, patients with COPD spent 67% of the time utilizing continuous oxygen compared to 47% in ILD. Subgroup analyses in each disease did not identify any association of total costs with patient age at the time of oxygen initiation or any significant differences in domiciliary oxygen cost in males compared to females. There was no change in annual per capita costs of supplemental oxygen during the study period. Figure 4-5: Composition of domiciliary oxygen therapy costs in ILD and COPD. Oxygen equipment includes oxygen cylinders and/or concentrator. The area of each pie is proportional to the total cost of oxygen in each disease. Abbreviations: COPD = Chronic obstructive pulmonary disease; ILD = Interstitial lung disease; VCH HOP = Vancouver Coastal Health Home Oxygen Program 65 4.4 Discussion This study provides a comparison of cost estimates for domiciliary oxygen therapy with direct comparison of patients with ILD to COPD. In our study, both ILD and COPD cohorts had a higher per capita cost of domiciliary oxygen therapy in month 1 compared to months 2-24. The greater per capita costs of oxygen supplementation in COPD were related to a greater proportion of time patients with COPD spent using continuous oxygen, with similar costs of each type of oxygen therapy for each disease. These results will aid financial planning for oxygen funding providers, particularly if this funding is publicly sourced and shared between the two diseases. We found that oxygen-related costs in the first month of oxygen therapy were greater for both ILD and COPD compared to subsequent monthly per capita costs. A previous Canadian study determined the monthly cost of continuous oxygen therapy at $383 in COPD;71 however, this study did not provide details on what components contributed to this value. There are less available data on domiciliary oxygen costs for patients with ILD. A recent British study estimated the cost of ambulatory oxygen to be GBP 91.02 biweekly,72 using data from the AmbOx trial.28 Our data contributes to the very limited number of studies available examining costs of domiciliary oxygen in patients with chronic lung disease. Excluding the first month of therapy, monthly oxygen costs were less in patients with ILD compared to COPD. This difference was related to continuous oxygen equipment costing approximately 50% more than ambulatory oxygen equipment, coupled with the finding that patients with COPD spent more time utilizing continuous oxygen compared to patients with ILD. Oxygen equipment was the greatest contributor to domiciliary oxygen costs for both ILD and 66 COPD, with usage of both concentrator and cylinders increasingly needed after the first month of therapy. Cylinders and selected portable oxygen concentrators have been suggested to provide similar oxygen delivery in patients with ILD during exertion.67 The small sample size for patients with ILD using only concentrators precludes a robust statistical analysis; however, the monthly per capita cost for the concentrators and cylinders was similar between months 2 to 24. Concentrators are rented from suppliers by the VCH HOP, with this monthly cost including the concentrator rent, a 24/7 customer support line, maintenance costs and ancillary equipment (cannula, tubing). These additional relatively fixed costs explain the similar overall monthly costs for these devices. Modeling long-term trends for the costs of oxygen is difficult for several reasons. The sample size for COPD was about 10-fold that of ILD. It is likely that a larger ILD sample size would decrease monthly fluctuations. Furthermore, ILD is a heterogenous disease with more variable rates of progression compared to COPD, likely leading to greater variability in oxygen-related costs in patients with ILD. After adjusting for inflation, the annual per capita domiciliary oxygen costs in ILD and COPD did not change significantly and were similar between the two diseases over the 5-year follow-up period from 2013-2017. VCH HOP had a single contract with its oxygen providers during this time period, precluding a potential stepwise change that can occur when transitioning to a new contract. An additional key factor is the aging population.150 More effective therapies have resulted in slower progression and increased survival, which may delay onset of oxygen initiation, but may also prolong the overall time that each patient receives oxygen supplementation during the course of their disease. The vast majority of the patients included in this study did not continue oxygen beyond 24 months, resulting in a small sample 67 size that prohibited analysis beyond this time. Additional data are needed to better incorporate these and other factors into models that attempt to predict long-term trends in oxygen costs. This study aimed to identify some of the major cost components that contribute to oxygen therapy and provide a relative comparison between ILD and COPD with the understanding that the costs can change over time. There are likely some regional differences, but our universal healthcare system and similar oxygen criteria across most of Canada exert financial pressures that likely results in relatively consistent costs across the country. The relative costs between ILD and COPD would likely be the same across jurisdictions, although future evidence may affect the use of oxygen in these two conditions. For example, oxygen is primarily prescribed for ILD only based on evidence that it improves symptoms and exercise capacity,151 with no proven mortality benefit in this population. Conversely, the previously document mortality benefit is a major factor justifying the prescription of oxygen in COPD. Outcomes of future continuous oxygen clinical trials may influence funding decisions and impact the relative relationship in costs between the two diseases. This may be especially true in regions where funding is more limited where scarce resources are allocated differently. The study was limited by the lack of granularity in some patient characteristics given the inability to link VCH HOP charts to other medical records. For example, we were unable to confidently identify the underlying diagnosis, clarify details of medications, or quantify pulmonary function. Also, we were unable to confirm compliance (e.g., number of hours per day of oxygen use) for each patient or the number of cylinders used each month, as this information was only recorded by the oxygen supplier and was not shared with the VCH HOP. Furthermore, the cost of oxygen therapy is dependent on the contract with suppliers, which can result in 68 significant fluctuations in oxygen equipment pricing. There are also potential regional differences based on population density that might affect efficiency of travel to patients’ homes. 4.5 Conclusion In summary, we quantify the overall costs of domiciliary oxygen therapy for patients with ILD and COPD in British Columbia, with implications that likely apply across much of Canada. Additional data are needed to evaluate domiciliary oxygen costs with healthcare utilization in patients with ILD versus COPD, which will allow more robust estimation of future total healthcare costs. It is hoped that the results of this study will aid in financial decisions for publicly funded ILD and COPD oxygen providers. 69 Chapter 5: Conclusion The three original research chapters in this thesis provide important insights for patients, clinicians, organizations that fund and supply oxygen, and other stakeholders with interest in domiciliary oxygen therapy in fibrotic ILD. The knowledge collectively gained from these studies will improve the lives of patients with chronic lung disease by helping ensure that this therapy is available in a timely manner to patients who need this support. 5.1 Summary and Significance Chapter two describes the development and validation of a risk prediction tool that calculates the likelihood of a patient developing exertional or resting hypoxemia within the next six months. This major undertaking included multiple large registries from Canada, Australia, and the United States and used cutting edge statistical techniques to provide robust and precise estimates of risk. This study specifically used time-varying Cox regression with best-subset selection to identify the best prediction model according to the AIC and clinical usability, with model performance assessed using Harrell's C-index and GoF using a likelihood ratio test. The risk factors for developing both exertional and resting hypoxemia were older age, higher body mass index, diagnosis of IPF, lower FVC, and lower DLCO (or inability to perform this test). A risk prediction tool for hypoxemia was developed from these risk factors and total scores obtained from this tool were categorized into low, moderate, and high-risk. This risk prediction tool was then validated in a separate international cohort to confirm its accuracy and potential clinical utility. Accurately predicting new onset hypoxemia and the imminent need for domiciliary oxygen therapy allows patients sufficient time to make necessary lifestyle modifications (e.g., smoking cessation) and receive appropriate training with regards to oxygen equipment. 70 Additionally, treatment can be aimed at the risk factors for hypoxemia and its consequences (e.g., PH), allowing clinicians to prioritize high-risk patients. The results of chapter 3 thus provide patients with the foresight necessary to plan for future oxygen need, which is one of the major milestones of chronic lung disease. Predicting future hypoxemia is of little use if domiciliary oxygen therapy is not accessible, leading to the analysis presented in chapter three that shows major deficiencies in oxygen availability and funding in many countries around the world. This was a descriptive study comparing adult domiciliary guidelines to national criteria for continuous, ambulatory, and nocturnal oxygen established by the 193 member countries of the United Nations. Additionally, countries that provided public funding for oxygen were identified. Recommendations from guidelines and national oxygen eligibility criteria were obtained using Internet searches, from publications identified from Medline and/or Embase, and by contacting physicians and oxygen suppliers worldwide. Of the 14 guidelines providing an oxygen saturation threshold (SaO2 or SpO2) for continuous oxygen, thresholds of <88% and ≤88% were used by 6 (20%) and 7 (23%) guidelines, respectively, with 1 (3%) guideline recommending <90%. A PaO2 <55 mmHg (<7.3 kPa) was the recommended threshold for the commencement of continuous oxygen for 8 (27%) and a PaO2 ≤55 mmHg (≤7.3 kPa) for 19 (63%) of the 30 guidelines that provided a specific PaO2 threshold, with the remaining 3 (10%) recommending either <56 mmHg (<7.4 kPa) or <60 mmHg (<8 kPa), or only SpO2 ≤88%. A total of 145 countries did not have public funding. An oxygen saturation ≤88% was the most common threshold for publicly funded countries for all three types of oxygen therapy based on population size. There was varying overlap of oxygen eligibility criteria with a corresponding national guideline, with 36% of 71 countries having substantial difference between eligibility criteria and their most recent guideline. Since oxygen is designated as an essential medication by the World Health Organization, it is important to ensure that gaps between practice guidelines and real-world criteria be identified and that national and international efforts be made to ensure appropriate delivery of oxygen to patients who have limited access. Lastly, chapter four provides detailed data on the costs of domiciliary oxygen in Canada for patients with ILD and COPD, representing two of the most common indications for this therapy. This was a retrospective study conducted at a regional domiciliary oxygen program comparing the cost of oxygen in patients with fibrotic ILD and COPD. Monthly per capita costs of oxygen equipment, home visits by oxygen providers and respiratory therapists, as well as overnight oximetry studies, were collected and compared across diseases. The cost of oxygen therapy was nearly 50% greater in month 1 compared to subsequent months of therapy for both ILD and COPD, with higher initial start-up costs related to the costs of tests and personnel and most long-term costs related to oxygen equipment. Although overall costs were similar in ILD and COPD, COPD was more costly than ILD after month 1, most likely due to a greater frequency of continuous oxygen usage in COPD that requires more intensive resources. These findings provide initial estimates for the costs of domiciliary oxygen in developed countries that can help policy makers and funders make more appropriate financial decisions, with these data also providing some initial data to support cost estimates in countries that currently lack adequate oxygen funding. 72 5.2 Strengths Both chapters two and three are highly generalizable, with chapter two providing data that apply to a wide variety of fibrotic ILD subtypes and chapter three providing data on a global scale. The generalizability and impact of the findings reported in chapter two are enhanced by defining hypoxemia using SpO2 thresholds (i.e., by pulse oximetry), rather than using PaO2 that requires a more invasive ABG. Furthermore, the hypoxemia risk prediction tool described in chapter two was externally validated across three cohorts from three different countries across two continents with a diverse variety of ILD subtypes. Chapter three was a large-scale multinational study and is therefore inherently highly generalizable with direct public health implications for a large segment of the global population. Chapter four offers a relative comparison of costs of domiciliary oxygen between ILD and COPD, since both share the same eligibility criteria. This relative comparison can be applied to other publicly funded countries to aid in healthcare budget decisions. 5.3 Limitations Despite the above strengths, there were also some limitations for all chapters. As apparent from chapter three, the hypoxemia threshold of SpO2 <88% used to derive the risk prediction tool in chapter two is not utilized by all guidelines and countries, which may limit generalizability in countries that do not adhere to common guideline recommendations. The major limitation for chapter three was that there may be national or regional domiciliary oxygen criteria that we were unable to obtain through the search strategy. We were also unable to determine whether there were potential mechanisms for individuals to purchase oxygen using their own funds, regardless of meeting criteria. The main limitation for chapter four was that it was conducted 73 within a single domiciliary oxygen program. The exact costs associated with oxygen therapy depend on the economics of individual countries, financial contracts, and other factors. However, the relative comparison of cost of oxygen between ILD and COPD is likely applicable to different regions and countries, which may facilitate future cost estimates. 5.4 Future Directions It is anticipated that the findings from this thesis will help advance knowledge with regards to domiciliary oxygen therapy particularly in fibrotic ILD; however, further studies are needed to develop evidence-based domiciliary oxygen guidelines specifically for fibrotic ILD as current oxygen guidelines are based on evidence from decades old COPD studies. Future studies need to have ethical study designs that investigate not only the impact of continuous, ambulatory, and nocturnal oxygen on survival specifically in ILD, but also patient quality of life and the impact of oxygen on caregivers. Justifications for the discrepancies between guidelines and country specific oxygen eligibility criteria need to be investigated, as well as the impact that these discrepancies have on both access to oxygen and patient outcomes. Furthermore, large studies are needed to evaluate the costs and cost-effectiveness of oxygen in ILD and other chronic lung diseases. These studies, through robust extrapolation methods, can model future costs of oxygen and aid in the development of viable and sustainable budgets for oxygen funding. Together, the three chapters of this thesis provide the essential data that support ongoing efforts to improve access to oxygen as well as additional research that will further improve our understanding of how to optimally support delivery of an essential medication to patients who have the greatest need for oxygen supplementation. 74 Bibliography 1. Travis WD, Costabel U, Hansell DM, et al. 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Oxygen therapy for interstitial lung disease: Physicians' perceptions and experiences. Ann Am Thorac Soc. Dec 2017;14(12):1772-1778. doi:10.1513/AnnalsATS.201705-372OC 89 Appendices Appendix A Appendix A.1: Baseline characteristics of the validation cohort. Characteristic Alfred Health (Australia) (n = 138) Austin Health (Australia) (n = 130) UCD (United States) (n = 240) Exertional hypoxemia evaluation (n = 97) Resting hypoxemia evaluation (n = 137) Exertional hypoxemia evaluation (n = 116) Resting hypoxemia evaluation (n = 130) Exertional hypoxemia evaluation (n = 200) Resting hypoxemia evaluation (n = 228) Age at baseline (years) 64 ± 10 64 ± 10 64 ± 12 64 ± 12 68 ± 12 69 ± 12 Male sex 60 (62) 89 (65) 76 (66) 87 (67) 122 (61) 138 (61) Race • Afro-Caribbean 1 (1) 2 (1) 0 0 - - • Asian 8 (8) 12 (9) 12 (10) 14 (11) - - • Caucasian 88 (91) 123 (90) 104 (90) 116 (89) - - Ever smokers at baseline 62 (64) 90 (66) 74 (64) 83 (64) 118 (59) 133 (58) BMI at baseline (kg/m2) 30 ± 6 30 ± 6 30 ± 5 30 ± 5 29 ± 5 29 ± 5 Pulmonary function at baseline • FEV1 (% predicted) 83 ± 19 81 ± 19 88 ± 18 86 ± 19 80 ± 19 79 ± 19 • FVC (% predicted) 79 ± 19 77 ± 19 86 ± 18 85 ± 19 77 ± 20 75 ± 20 • DLCO (% predicted) 56 ± 17 54 ± 16 59 ± 18 57 ± 18 55 ± 18 53 ± 18 • 6MWD (m) 450 (115) 463 (129) 448 (123) 448 (141) 372 (190) 365 (201) • Nadir exertional SpO2 (%) 94 (89-95) 87 (84-93) 93 (91-95) 92 (87-94) 93 (90-95) 92 (89-94) • Resting SpO2 (%) 97 (96-98) 96 (95-98) 97 (96-98) 97 (95-98) 97 (96-98) 97 (96-98) ILD subtypes • CTD-ILD 11 (11) 15 (11) 25 (22) 27 (21) 62 (31) 71 (31) • Fibrotic HP 8 (8) 14 (10) 11 (9) 13 (10) 27 (14) 31 (14) • IPF 43 (44) 61 (45) 34 (29) 39 (30) 70 (35) 79 (35) • Sarcoidosis 9 (9) 9 (7) 11 (9) 11 (8) 0 0 • Unclassifiable ILD 14 (14) 21 (15) 28 (24) 32 (25) 30 (15) 34 (15) • Other ILDa 12 (12) 17 (12) 7 (6) 8 (6) 11 (6) 13 (6) • Initiation of domiciliary 14 (14) 15 (11) 27 (23) 25 (19) 22 (11) 40 (18) 90 Characteristic Alfred Health (Australia) (n = 138) Austin Health (Australia) (n = 130) UCD (United States) (n = 240) Exertional hypoxemia evaluation (n = 97) Resting hypoxemia evaluation (n = 137) Exertional hypoxemia evaluation (n = 116) Resting hypoxemia evaluation (n = 130) Exertional hypoxemia evaluation (n = 200) Resting hypoxemia evaluation (n = 228) therapy during study periodb Data are reported as n (%), mean ± SD, or median (IQR) Abbreviations: 6MWD = 6-minute walk distance; BMI = Body mass index; CARE-PF = Canadian Registry for Pulmonary Fibrosis; CTD-ILD = Connective tissue disease associated interstitial lung disease; DLCO = Diffusing capacity of carbon monoxide; FEV1 = Forced expiratory volume in one second; FVC = Forced vital capacity; HP = Hypersensitivity pneumonitis; IPF = Idiopathic pulmonary fibrosis; SpO2 = Pulse oximetry oxygen saturation; UCD = University of California, Davis aOther ILD: Drug-induced ILD, Non-idiopathic pulmonary fibrosis idiopathic interstitial pneumonia, Pneumoconiosis, Pulmonary alveolar microlithiasis, Smoking related ILD, Unknown subtype, Vasculitis bAmbulatory oxygen therapy for exertional hypoxemia and long-term oxygen therapy for resting hypoxemia 91 Appendix A.2: The best-subset selection of predictors for the derivation cohort. Number Exertional hypoxemia evaluation Resting hypoxemia evaluation AIC Variables AIC Variables 1 5091.04 Age BMI DLCO (% predicted) FEV1 (% predicted) FEV1/FVC IPF Sex 431.32 Age BMI DLCO (% predicted) IPF TLC (% predicted) 2 5091.17 Age BMI DLCO (% predicted) FVC (% predicted) IPF Sex 431.63 Age BMI DLCO (% predicted) FEV1 (% predicted) IPF TLC (% predicted) 3 5091.34 Age BMI DLCO (% predicted) FVC (% predicted) IPF 431.69 Age BMI DLCO (% predicted) FVC (% predicted) IPF 4 5092.08 Age BMI DLCO (% predicted) FEV1 (% predicted) FEV1/FVC IPF 431.73 6MWD Age BMI DLCO (% predicted) FVC (% predicted) IPF 5 5092.80 Age BMI DLCO (% predicted) FEV1 (% predicted) FEV1/FVC IPF Sex Smoking 431.82 6MWD Age BMI DLCO (% predicted) IPF TLC (% predicted) 6 5092.85 Age BMI DLCO (% predicted) FVC (% predicted) IPF Smoking 431.90 BMI Age DLCO (% predicted) FVC (% predicted) IPF TLC (% predicted) 7 5092.96 Age BMI DLCO (% predicted) FVC (% predicted) IPF Sex Smoking 431.94 BMI 6MWD Age DLCO (% predicted) FEV1 (% predicted) IPF TLC (% predicted) 8 5092.98 Age BMI DLCO (% predicted) FEV1 (% predicted) FVC (% predicted) IPF 432.03 BMI DLCO (% predicted) IPF TLC (% predicted) 92 Number Exertional hypoxemia evaluation Resting hypoxemia evaluation AIC Variables AIC Variables Sex 9 5092.99 Age BMI DLCO (% predicted) FEV1 (% predicted) FEV1/FVC FVC (% predicted) IPF Sex 432.10 Age BMI DLCO (% predicted) IPF Smoking TLC (% predicted) 10 5093.04 Age BMI DLCO (% predicted) FEV1/FVC FVC (% predicted) IPF Sex 432.27 BMI 6MWD Age DLCO (% predicted) FVC (% predicted) IPF TLC (% predicted) Abbreviations: 6MWD = 6-minute walk distance; AIC = Akaike information index; BMI = Body mass index; DLCO = Diffusing capacity of carbon monoxide; FEV1 = Forced expiratory volume in one second; FVC = Forced vital capacity; IPF = Idiopathic pulmonary fibrosis; TLC = Total lung capacity 93 Appendix A.3: Sensitivity and specificity for each scoring system point. Derivation cohort Validation cohort Exertional hypoxemia evaluation Resting hypoxemia evaluation Exertional hypoxemia evaluation Resting hypoxemia evaluation Initiala Allb Initial All Initial All Initial All Cut point Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) Sn (%) Sp (%) ≥0 100.0 0.0 100.0 0.0 100.0 0.0 100.0 0.0 100.0 0.0 100.0 0.0 100.0 0.0 100.0 0.0 ≥1 97.6 7.5 98.1 7.6 100.0 6.6 99.5 6.5 98.3 0.9 99.3 1.9 100.0 0.9 100.0 1.3 ≥2 96.8 12.9 97.1 13.7 100.0 11.5 99.5 11.7 98.3 3.0 99.3 4.5 100.0 2.5 100.0 2.9 ≥3 91.1 30.8 91.3 30.5 97.9 27.5 96.9 26.0 96.5 12.7 97.3 14.7 100.0 9.8 100.0 9.8 ≥4 75.8 50.2 80.4 50.3 95.7 46.3 94.2 44.1 93.0 32.8 89.9 33.2 100.0 26.4 100.0 23.7 ≥5 63.7 61.6 69.7 62.7 80.9 57.9 85.3 56.7 93.0 41.3 87.9 40.8 95.0 33.1 98.8 29.7 ≥6 43.6 79.8 48.2 79.4 61.7 76.8 66.0 74.8 73.7 68.1 69.8 69.9 90.0 58.4 94.1 55.4 ≥7 34.7 84.3 37.8 85.8 42.6 81.9 53.4 82.3 59.7 74.1 57.1 74.6 75.0 65.8 77.4 62.8 ≥8 13.7 94.1 15.5 94.8 21.3 93.7 26.2 93.1 31.6 92.8 28.2 92.5 55.0 87.5 53.6 84.4 ≥9 7.3 97.1 9.0 97.3 6.4 96.9 15.7 96.7 26.3 95.5 19.5 95.1 25.0 91.7 29.8 89.3 ≥10 3.2 99.4 2.2 99.6 2.1 99.3 3.7 99.5 7.0 99.1 4.7 99.6 5.0 97.1 8.3 97.5 ≥11 0.8 99.8 0.2 99.9 0.0 99.8 0.0 99.9 - - 0.7 99.9 0.0 99.6 1.2 99.6 Abbreviations: Sn = Sensitivity; Sp = Specificity aSensitivity and specificity using initial assessment bSensitivity and specificity using all assessments 94 Appendix A.4: Area under curve for receiver operating characteristic curves for sensitivity and specificity analysis. Derivation cohort: (a) Initial assessment exertional hypoxemia (b) All assessments exertional hypoxemia (c) Initial assessment resting hypoxemia (d) All assessments resting hypoxemia Validation cohort: (e) Initial assessment exertional hypoxemia (f) All assessments exertional hypoxemia (g) Initial assessment resting hypoxemia (h) All assessments resting hypoxemia Abbreviations: ROC = Receiver operating characteristic 95 Appendix A.5: Sensitivity analyses using the derivation cohort. Statistic Strict definition for normoxemia Suspected PH Non-suspected PH Exertional hypoxemia Evaluation (n = 1,570) Resting hypoxemia Evaluation (n = 1,947) Exertional hypoxemia Evaluation (n = 453) Resting hypoxemia Evaluation (n = 519) Exertional hypoxemia Evaluation (n = 1,516) Resting hypoxemia Evaluation (n = 1,667) Harrell's C-index 0.67 0.78 0.69 0.72 0.69 0.80 GoF likelihood ratio test 0.76 0.11 1.00 0.05 1.00 0.10 Risk category (%)a Observed Expected Observed Expected Observed Expected Observed Expected Observed Expected Observed Expected • Low 23 26 5 11 15 17 5 10 22 25 6 12 • Moderate 35 30 28 24 34 31 38 26 31 28 22 22 • High 42 44 67 66 50 52 58 64 47 47 72 67 Abbreviations: GoF = Goodness-of-fit; PH = Pulmonary hypertension aObserved versus expected new-onset hypoxemia events for low, moderate, and high-risk categories with total scores of 0-3, 4-5 and >5, respectively 96 Appendix B Appendix B.1: Respiratory society or healthcare organization guidelines for domiciliary continuous, ambulatory, and nocturnal oxygen. Society or Organization Year Continuous Ambulatory Nocturnal American Association of Respiratory Care1 (United States) 2007 PaO2 ≤55 mmHg or SaO2 ≤88% on room air OR PaO2 of 56-59 mmHg or SaO2 ≤89% in association with cor pulmonale, congestive heart failure, or erythrocythemia with hematocrit >56% SaO2 ≤88% during exertion SaO2 ≤88% during sleep American College of Chest Physicians2 (United States) 2021 PaO2 ≤55 mmHg or SaO2 ≤88% on room air while awake OR SaO2 >88% and evidence of edema, pulmonary hypertension or hematocrit >56% SaO2 ≤88% during exertion on room air or oxygen SaO2 ≤88% for 5 minutes on overnight oximetry for ≥2 hours American College of Physicians3 (United States) 2011 PaO2 ≤55 mmHg or SpO2 ≤88% OR PaO2 55-59 mmHg with cor pulmonale or polycythemia American Thoracic Society4 (United States) 2020 PaO2 ≤55 mmHg (7.3 kPa) or SpO2 ≤88% OR PaO2 = 56-59 mm Hg (7.5-7.9 kPa) or SpO2 = 89% plus 1 of the following: edema, hematocrit ≥55%, or P pulmonale on electrocardiogram SpO2 ≤88% during exertion Asociación Latinoamericana de Tórax5 (Mixed) 2019 PaO2 ≤55 mmHg or SaO2<88% OR PaO2 56-59 mmHg or SaO2 89% associated with: pulmonary hypertension, peripheral edema, suggestive 97 Society or Organization Year Continuous Ambulatory Nocturnal of congestive heart failure or polycythemia (hematocrit >55%) British Thoracic Society6 (United Kingdom) 2015 If PaO2 ≤7.3 kPa oxygen assessment indicated OR PaO2 ≤8 kPa with evidence of peripheral edema, polycythemia (hematocrit ≥55%) or pulmonary hypertension 1) Assessment should be offered to patients already on resting oxygen therapy and if they are mobile outdoors 2) Oxygen should be offered to patients for use during exercise in a pulmonary rehabilitation program or during an exercise program following a formal assessment demonstrating improvement in exercise endurance Canadian Thoracic Society7 (Canada) 2008 PaO2 ≤55 mmHg OR PaO2 <60 mmHg with bilateral ankle edema, cor pulmonale or hematocrit >56% Dansk Lungemedicinsk Selskab8 (Denmark) 2022 PaO2 <7.3 kPa on room air OR PaO2 <8 kPa with cor pulmonale or hematocrit >55% and increase in PaO2 after oxygen initiation Federatie Medisch Specialisten9 (Netherlands) 2021 PaO2 ≤55 mmHg (≤7.3 kPa) German Respiratory Society10 (Germany) 2020 PaO₂ ≤55 mmHg OR PaO2 55-60 mmHg and/or cor pulmonale or polycythemia and/or signs of right sided heart failure In text: oxygen saturation increases during exercise constantly >90% and the walking distance under oxygenation increases by ≥10% and the patient perceives an improvement in dyspnea (At least 1 point change on the Borg scale or the Visual Analogue Scale) If hypoxemia (no specified threshold) during sleep refer to sleep laboratory 98 Society or Organization Year Continuous Ambulatory Nocturnal Example order form: PaO₂ <55 mmHg or SpO2 <88% and symptom improvement during exertion Global Initiative for Chronic Obstructive Pulmonary Disease11 (Mixed) 2022 PaO2 <55 mmHg (7.3 kPa) or SaO2 <88% OR PaO2 55-60 mmHg (7.3-8 kPa) with right heart failure or erythrocytosis Irish Thoracic Society12 (Ireland) 2015 PaO2 ≤7.3 kPa OR PaO2 ≤8 kPa with evidence of peripheral edema, polycythemia (hematocrit ≥55%) or pulmonary hypertension SpO2 drops ≥4% to <90% during baseline endurance shuttle walk test or 6-minute walk test. Repeat test should be carried out on ambulatory oxygen after 20 minutes rest if drop in saturation is evident. If improvement in exercise tolerance/dyspnea, ambulatory oxygen can be prescribed. Do not prescribe if do not meet resting criteria. Kwaliteitsinstituut Voor De Gezondheidszorg13 (Netherlands) 2001 PaO2 <60 mmHg (8 kPa) at rest on room air ≥2 measurements within interval of ≥3 weeks National Health Service14 (United Kingdom) 2011 PaO2 ≤7.3 kPa or 8 kPa with edema SpO2 <90% and patient must demonstrate 4% drop to <90% during exercise (6-minute walk test or shuttle walk test) National Institute for Health and Care Excellence15 (United States) 2019 PaO2 <7.3 kPa OR PaO2 >7.3 but <8 kPa with secondary polycythemia, peripheral edema, or pulmonary hypertension Pakistan Chest Society16 (Pakistan) 2020 PaO2 <55 mmHg or SaO2 <88% OR PaO2 55-60 mmHg and cor pulmonale or polycythemia 99 Society or Organization Year Continuous Ambulatory Nocturnal Reseau Quebecois De L'Asthme et de la Maladie Pulmonaire Obstructive Chronique17 (Canada) 2012 PaO2 ≤55 mmHg OR ≤59 mmHg with peripheral edema, hematocrit ≥55% or pulmonary "P" waves at electrocardiogram SpO2 <85% on 6-minute walk test and leave home ≥4 hours a week SpO2 <90% for >30% of night with clinical signs of cor pulmonale or arrhythmias Russian Respiratory Society18 (Russia) 2016 PaO2 <55 mmHg or SaO2 <88% OR PaO2 56-59 mmHg or SaO2 = 89% in presence of cor pulmonale or hematocrit >55% Titrate oxygen to maintain SaO2 >90% during exercise Titrate oxygen to maintain SaO2 >90% during sleep Saudi Thoracic Society19 (Saudi Arabia) 2014 PaO2 <55 mmHg or <7.3 kPa or SaO2 <88% room air and free of acute exacerbation ≥2 months OR PaO2 55-60 mmHg with cor pulmonale, peripheral edema or hematocrit ≥55% Singapore Thoracic Society20 (Singapore) 2017 SpO2 ≤88% Sociedad Española de Neumología y Cirugía Torácica21 (Spain) 2021 PaO2 ≤55 mmHg OR PaO2 55-59 mmHg and pulmonary hypertension, hematocrit >55%, arrhythmia, ischemic disorders, or signs of right heart failure SpO2 ≤88% during stress test SpO2 <90% and/or a percentage of time with SpO2 <90% for >30% of night and who from the point of view of the pulmonology specialist could benefit from oxygen Sociedad Uruguaya de Neumologia22 (Uruguay) 2021 PaO2 ≤55 mmHg or SpO2 <90% OR PaO2 ≥56 mmHg but <59 mmHg with evidence of polyglobulia, cor pulmonale or pulmonary hypertension Sociedade Brasileira de Pneumologia e Tisiologia23 (Brazil) 2004 PaO2 ≤55 mmHg or saturation ≤88% at rest OR PaO2 56-59 mmHg with cor pulmonale or polycythemia 100 Society or Organization Year Continuous Ambulatory Nocturnal Société de Pneumologie de Langue Française24 (France) 2003 2 blood gas measurements ≥3 weeks apart PaO2 ≤55 mmHg (≤7.3 kPa) OR PaO2 56-59 mmHg (7.4-7.8 kPa) and pulmonary hypertension, cor pulmonale or polyglobulia (hematocrit >55%) SpO2 <90% during sleep for >30% of recording time South African Thoracic Society25 (South Africa) 2019 PaO2 <7.3 kPa or <55 mmHg at sea level or SpO2 <88% on 2 occasions ≥1 month apart Swedevox26 (Sweden) 2021 ≥2 arterial blood gas despite optimal treatment for ≥3 weeks: PaO2 <7.4 kPa on room air OR PaO2 7.4-8.0 kPa on room air and polycythemia (hematocrit >54%) Can be considered if fall under American Thoracic Society criteria and benefit can be supported if walking distance >30m increase in the 6-minute walk test or reduction in dyspnea Swiss Respiratory Society27 (Switzerland) 2013 PaO2 ≤55 mmHg (7.3 kPa) confirmed twice over 3 weeks OR 55 mmHg (7.3 kPa)-59 mmHg (8.0 kPa) and pulmonary hypertension, polycythemia (hematocrit >55%) SaO2 <90% during exercise SaO2 <90% during sleep Thoracic Society of Australia and New Zealand28 (Australia and New Zealand) 2016 Stable daytime PaO2 is ≤55 mmHg (7.3 kPa) at rest; OR Stable daytime PaO2 is 56-59 mmHg (7.4-7.8 kPa) and there is evidence for hypoxic organ damage (including right heart failure, pulmonary hypertension, or polycythemia) SpO2 ≤88% for >1/3 of night particularly if have pulmonary hypertension or polycythemia Tunisian Society of Respiratory Diseases and Allergology29 (Tunisia) 2017 PaO2 <55 mmHg on room air or PaO2 <60 mmHg and polycythemia, pulmonary hypertension, or signs of right heart failure 101 Society or Organization Year Continuous Ambulatory Nocturnal Veterans Health Administration30 (United States) 2020 PaO2 ≤55 mmHg or SpO2 ≤88% in absence of hypocapnia OR PaO2 ≥56 mmHg and ≤59 mmHg or SpO2 ≤89% and pulmonary hypertension, cor pulmonale, polycythemia (hematocrit ≥55%), or impairment of cognitive processes SpO2 ≤88% during exercise SpO2 ≤88% and 1 of: nocturnal restlessness, morning headaches, polycythemia, cor pulmonale, pulmonary hypertension, unexplained daytime somnolence, obstructive sleep apnea with SpO2 not maintained despite treatment OR SpO2 <89% for ≥5 minutes and 1 of: ≥1 measure of SpO2 ≤85%, >30% sleep at SpO2 <89% Abbreviations: PaO2 = partial pressure of oxygen, SaO2 = arterial oxygen saturation, SpO2 = pulse oximetry oxygen saturation 1. AARC Clinical Practice Guideline. Oxygen therapy in the home or alternate site health care facility--2007 revision & update. Respir Care. Aug 2007;52(8):1063-8. 2. Does your patient need oxygen therapy? Accessed April 15, 2022. https://foundation.chestnet.org/wp-content/uploads/2021/10/Provider_Booklet_Single.pdf 3. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: A clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. Aug 2 2011;155(3):179-91. doi:10.7326/0003-4819-155-3-201108020-00008 4. Jacobs ss, krishnan ja, lederer dj, et al. Home oxygen therapy for adults with chronic lung disease. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. Nov 15 2020;202(10):e121-e141. doi:10.1164/rccm.202009-3608ST 5. Guía de Práctica Clínica Latinoamericana de EPOC. Basada en evidencia. Accessed January 17, 2022. https://alatorax.org/es/guias/guia-de-practica-clinica-latinoamericana-de-epoc-basada-en-evidencia 6. Hardinge m, annandale j, bourne s, et al. British Thoracic Society guidelines for home oxygen use in adults. Thorax. Jun 2015;70 Suppl 1:i1-43. doi:10.1136/thoraxjnl-2015-206865 7. O'Donnell DE, Hernandez P, Kaplan A, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2008 update - highlights for primary care. Can Respir J. Jan-Feb 2008;15 Suppl A:1A-8A. doi:10.1155/2008/641965 8. Iltbehandling i Hjemmet. Accessed September 30, 2022. https://lungemedicin.dk/wp-content/uploads/2021/05/Iltbehandling_DLS_Juli22.pdf 9. Zuurstof bij COPD. Accessed August 17, 2022. https://richtlijnendatabase.nl/richtlijn/palliatieve_zorg_bij_copd/dyspneu_bij_copd/niet-medicamenteuze_behandeling_van_dyspneu_bij_copd/zuurstof_bij_copd.html 10. Haidl P, Jany B, Geiseler J, et al. [Guideline for long-term oxygen therapy - S2k-guideline published by the German Respiratory Society]. Pneumologie. Dec 2020;74(12):813-841. Leitlinie zur Langzeit-Sauerstofftherapie. doi:10.1055/a-1252-1492 11. Pocket guide to COPD diagnosis, management, and prevention. Accessed January 17, 2022. https://goldcopd.org/2022-gold-reports-2/ 12. Irish guidelines on long term oxygen therapy (LTOT) in Adults 2015. Accessed January 16, 2022. https://irishthoracicsociety.com/wp-content/uploads/2017/05/LTOT-guideline-2015-1.pdf 13. Kampelmacher M, Rooyackers J, Lammers J-W. CBO-richtlijn ‘Zuurstofbehandeling thuis’. Ned Tijdschr Geneeskd. 2001;145(41):1975-1980. 14. Home oxygen service - assessment and review good practice guide. Accessed April 17, 2022. https://silo.tips/download/home-oxygen-service-assessment-and-review 15. Chronic Obstructive Pulmonary Disease in over 16s: diagnosis and management. London: National Institute for Health and Care Excellence (NICE). Accessed September 30, 2022. https://www.ncbi.nlm.nih.gov/books/NBK542426/ 16. Guidelines for the management of COPD. Accessed April 23, 2022. http://www.pakistanchestsociety.pk/wp-content/uploads/2020/09/COPD-Update.pdf 17. Nault D. Oxygénothérapie à domicile de nouvelles lignes directrices et un nouveau cadre de référence en vigueur au Québec. Accessed October 1, 2022. https://studylibfr.com/doc/1228996/oxygénothérapie-à-domicile---de-nouvelles-lignes-directrices 102 18. Клинические рекомендации Хроническая обструктивная болезнь легких. Accessed June 8, 2022. https://spulmo.ru/upload/federal_klinicheskie_rekomendaciy_hobl.pdf 19. Khan JH, Lababidi HM, Al-Moamary MS, et al. The Saudi Guidelines for the diagnosis and management of COPD. Ann Thorac Med. Apr 2014;9(2):55-76. doi:10.4103/1817-1737.128843 20. Chronic obstructive pulmonary disease MOH clinical practice guidelines 2/2017. Accessed October 1, 2022. https://www.moh.gov.sg/docs/librariesprovider4/guidelines/copd.pdf 21. Guía Separ para la teleconsulta en pacientes con terapia respiratoria domiciliaria. Accessed June 6, 2022. https://separ.es/node/2016 22. Guía de práctica clínica de EPOC. Accessed June 5, 2022. 23. Consenso brasileiro sobre doença pulmonar obstrutiva crônica - DPOC - 2004. Jornal Brasileiro de Pneumologia. 2004;30(5) 24. Prise en charge à l’état stable oxygénothérapie et ventilation au long cours. Rev Mal Respir. 2003;20 25. Abdool-Gaffar MS, Calligaro G, Wong ML, et al. Management of chronic obstructive pulmonary disease-A position statement of the South African Thoracic Society: 2019 update. J Thorac Dis. Nov 2019;11(11):4408-4427. doi:10.21037/jtd.2019.10.65 26. Riktlinjer LTOT i Hemmet. Accessed May 12, 2022. https://www.ucr.uu.se/swedevox/ 27. Russi EW, Karrer W, Brutsche M, et al. Diagnosis and management of chronic obstructive pulmonary disease: The Swiss guidelines. Official guidelines of the Swiss Respiratory Society. Respiration. 2013;85(2):160-74. doi:10.1159/000346025 28. McDonald CF, Whyte K, Jenkins S, Serginson J, Frith P. Clinical practice guideline on adult domiciliary oxygen therapy: executive summary from the Thoracic Society of Australia and New Zealand. Respirology. Jan 2016;21(1):76-8. doi:10.1111/resp.12678 29. Kammoun S, Hayouni A, Ghrairi H, et al. Chronic obstructive pulmonary disease: Tunisian Society of Respiratory Diseases and Allergology guidelines. Tunis Med. Aug - Sep 2017;95(8-9):722-733. 30. VHA Prosthetic Clinical Management Program (PCMP) clinical practice recommendations home use of supplemental oxygen. Accessed June 5, 2022. https://www.prosthetics.va.gov/psas/CPR.asp 31. 103 Appendix B.2: International continuous, ambulatory, and nocturnal domiciliary oxygen eligibility criteria for public and non-publicly funded countries. Country by Continent Region Continuous Ambulatory Nocturnal Africa Algeria PaO2 <55 mmHg OR PaO2 <60 mmHg with a cardiac comorbidity Botswana SpO2 <88% Burkina Faso SpO2 target ≥95% with 4-5 liters of oxygen Burundi SpO2 ≤90% and hematocrit ≥55% Dyspnea and SpO2 <90% during 6MWT SpO2 <90% for >20% sleep time with sleep oximetry test Cameroon PaO2 <55 mmHg OR PaO2 <60 mmHg with pulmonary hypertension Baseline SpO2 <95% and 3% SpO2 drop during walking test SpO2 <90% during sleep Ethiopia SpO2 <85% OR SpO2 <88% if pulmonary hypertension or secondary polycythemia SpO2 <85% on 6MWT Nocturnal SpO2 <88% Mozambique PaO2 <55 mmHg or SpO2 <88% OR PaO2 = 56-59 mmHg or SpO2 = 89% with hematocrit >55 PaO2 <55 mmHg or SpO2 <88% during exercise PaO2 <55 mmHg or SaO2 <88% during sleep with evidence of cor pulmonale, erythrocytosis Namibia PaO2 ≤7.3 kPa oxygen assessment indicated OR PaO2 ≤8 kPa with evidence of peripheral edema, polycythemia (hematocrit ≥55%) or pulmonary hypertension 1) Assessment should be offered to patients already on resting oxygen therapy if they are mobile outdoors 2) Oxygen should be offered to patients for use during exercise in a pulmonary rehabilitation program or during an exercise program following a formal assessment demonstrating improvement in endurance South Africa SpO2 <85% OR PaO2 <7.5 kPa South Sudan PaO2 ≤7.3 kPa then oxygen assessment indicated OR 1) Assessment should be offered to patients already on 104 Country by Continent Region Continuous Ambulatory Nocturnal PaO2 ≤8 kPa with evidence of peripheral edema, polycythemia (hematocrit ≥55%) or pulmonary hypertension resting oxygen therapy if they are mobile outdoors 2) Oxygen should be offered to patients for use during exercise in a pulmonary rehabilitation programme or during an exercise programme following a formal assessment demonstrating improvement in exercise endurance Tunisia Maintain SpO2 88-92% Asia Afghanistan PaO2 <55 mmHg OR PaO2 55-60 mmHg with secondary polycythemia and right ventricle failure OR PaO2 56-59 mmHg with cor pulmonale Nocturnal oxygen saturation <90% OR PaO2 <60 mmHg during sleep ≥30% of sleep time Armenia PaO2 ≤7.3 kPa oxygen assessment indicated OR PaO2 ≤8 kPa with evidence of peripheral edema, polycythemia (hematocrit ≥55%) or pulmonary hypertension 1) Assessment should be offered to patients already on resting oxygen therapy if they are mobile outdoors 2) Should be offered to patients for use during exercise in a pulmonary rehabilitation programme or during an exercise programme following a formal assessment demonstrating improvement in exercise endurance Bahrain PaO2 <55 mmHg or SpO2 ≤88% SpO2 <90% during exertion SpO2 ≤88% for ≥5min during sleep Bangladesh PaO2 ≤55 mmHg or SpO2 <88% OR Stable daytime PaO2 is 56-59 mmHg and evidence for hypoxic sequelae (including right heart failure, pulmonary hypertension, or polycythemia) PaO2 <55 mmHg or SpO2 <88% during exertion Patients demonstrating desaturation of SpO2 ≤88% for >1/3 night, particularly with hypoxic sequelae such as pulmonary hypertension or polycythemia 105 Country by Continent Region Continuous Ambulatory Nocturnal Bhutan SpO2 ≤88% following improvement in underlying condition OR SpO2 ≤90% for patients with right heart failure and pulmonary hypertension SpO2 ≤88% and fall in SpO2 by 4% during 6MWT SpO2 ≤88% and dyspnea during sleep Brunei Darussalam PaO2 ≤7.3 kPa oxygen assessment indicated OR PaO2 ≤8 kPa with evidence of peripheral edema, polycythemia (hematocrit ≥55%) or pulmonary hypertension 1) Assessment should be offered to patients already on resting oxygen therapy if they are mobile outdoors 2) Oxygen should be offered to patients for use during exercise in a pulmonary rehabilitation programme or during an exercise programme following a formal assessment demonstrating improvement in exercise endurance Cambodia PaO2 <60 mmHg OR SpO2 <90% Physician discretion China PaO2 ≤55 mmHg or SaO2 ≤88% OR PaO2 55-60 mmHg with pulmonary hypertension or right heart failure or hematocrit ≥55% South Korea1 PaO2 ≤55 mmHg or SaO2 <88% OR PaO2 55-60 mmHg or SaO2 = 89% in the presence of pulmonary hypertension, peripheral edema from congestive heart failure, or erythrocytosis India PaO2 <55 mmHg or SpO2 <88% SpO2 <88% during walk test Indonesia PaO2 <70 mmHg and/or SpO2 <92% and/or partial pressure of carbon dioxide >50 mmHg with >2 weeks of hospital care 106 Country by Continent Region Continuous Ambulatory Nocturnal without any progression to be weaned off Japan2 PaO2 ≤55 mmHg or SpO2 ≤88% at rest and whose doctors determine that oxygen is necessary PaO2 ≤60 mmHg or SpO2 ≤90% on exertion and whose doctors determine that oxygen is necessary PaO2 ≤60 mmHg or SpO2 ≤90% during sleep and whose doctors determine that oxygen is necessary Kuwait PaO2 ≤55 mmHg or SpO2 ≤88% OR PaO2 = 56-59 mmHg (7.5-7.9 kPa) or SpO2 = 89% plus 1 of: edema, hematocrit ≥55%, or P pulmonale on an electrocardiogram SpO2 ≤88% during exertion SpO2 <88% at night Kyrgyzstan SpO2 <90% Myanmar PaO2 <55 mmHg or SaO2 <88% OR PaO2 >55 but <60 mmHg with right heart failure or erythrocytosis Nepal PaO2 <60 mmHg and SpO2 <90% Oman PaO2 ≤55 mmHg or SpO2 ≤88% PaO2 ≤55 mmHg or SpO2 ≤88% on exercise Pakistan SpO2 ≤88% OR PaO2 56-60 mmHg with pulmonary hypertension, pedal edema, or polycythemia SpO2 <89% on walk test Philippines PaO2 ≤55 mmHg or SpO2 ≤88% OR PaO2 = 56-59 mmHg or SpO2 = 89% with cor pulmonale or hematocrit ≥55% PaO2 ≤55 mmHg or SpO2 <90% during exertion Qatar3 PaO2 ≤7.3 kPa (55 mmHg) OR PaO2 ≤8 kPa (60 mmHg) with 1 of: secondary polycythemia (hematocrit ≥55%), peripheral edema, pulmonary hypertension Russian Federation4 PaO2 ≤55 mmHg or SaO2 ≤88% OR 107 Country by Continent Region Continuous Ambulatory Nocturnal PaO2 55-59 mmHg or SaO2 = 89% with cor pulmonale, edema, polycythemia (hematocrit >55%) Saudi Arabia PaO2 ≤55 mmHg (7.32 kPa) or SaO2 ≤88% OR PaO2 ≤59 mmHg (7.85 kPa) or SaO2 ≤89% with electrocardiogram evidence of P pulmonale, hematocrit >55% with evidence of right heart failure Physician discretion Singapore5 SpO2 ≤88% Sri Lanka PaO2 of <55 mmHg or SpO2 <88% on 2 occasions ≥3 weeks apart OR PaO2 <60 mmHg or SpO2 88-92% and evidence of: pulmonary hypertension, congestive cardiac failure, polycythemia, or hematocrit of >55% Ambulatory oxygen may be prescribed in those who have had a positive 6MWT. Ambulatory oxygen therapy during physical activity/ pulmonary rehabilitation can be prescribed in who are already on resting oxygen therapy. SpO2 <88% (repeatedly) for >2/3 of the night Syria SpO2 <88% Turkiye6 PaO2 ≤55 mmHg OR SaO2 ≤88% OR 55-59 mmHg or SaO2 ≤89% with cor pulmonale, congestive heart failure, hematocrit >55% PaO2 ≤55 mmHg or SaO2 ≤88% during exertion and >4% desaturation with exercise United Arab Emirates7 PaO2 <55 mmHg or SaO2 <88% confirmed twice over 3 weeks OR PaO2 55- 60 mmHg (7.4-8 kPa) with pulmonary hypertension, peripheral edema suggesting congestive cardiac failure, or polycythemia (hematocrit>55%) Vietnam SpO2 <90% at rest SpO2 ≤89% for >30% sleep time 108 Country by Continent Region Continuous Ambulatory Nocturnal Oceania Australia8,9 Australian Capital Territory PaO2 ≤55 mmHg (7.3 kPa) and/or SpO2<90% and chronic hypoxemia or cor pulmonale PaO2 56-59 mmHg and/or a completed application form from an authorised prescriber including: a. Type of equipment prescribed b. ABG and/or oxygen saturation results c. Prescription (flow rate, delivery method etc.) In patients commencing resting oxygen who wish to maximise the number of hours they receive oxygen supplementation during the 24-hour period can supplement stationary concentrator use with portable oxygen for physical activities outside the home SpO2 ≤88% for >1/3 of the night, particularly if suffer sequelae such as pulmonary hypertension or polycythemia Australia10 New South Wales Daytime PaO2 ≤55 mmHg at rest and breathing room air when clinically stable OR daytime PaO2 56-59 mmHg while at rest and breathing room air when clinically stable with objective evidence or confirmation (in physician letter) of significant end-organ damage due to hypoxia e.g., pulmonary hypertension, right heart failure, polycythemia Confirmation provided by the prescriber of resting oxygen need for portable oxygen. Patient is aware of and willing to partially fund the therapy including charges for cylinder refills and any delivery charges and agrees to use portable oxygen as recommended by the prescriber. Patients requiring oxygen (24 hours/day): i. The person is currently in receipt of and is compliant with oxygen 24 hours/day via concentrator. Patients requiring oxygen ≥16 hours/day: i. The person is currently in receipt of and is compliant with resting (≥16 hours/day via concentrator) and there is: ii. Evidence of significant desaturation during exercise (SpO2 <88%) while breathing room air AND Oxygen may be provided for patients who meet criteria i, ii or iii, plus ALL of criteria iv, v and vi: i. Isolated nocturnal hypoxaemia (oximetry or polysomnography) while breathing room air with artifact free nocturnal SpO2 ≤88% for ≥30% of sleep time OR ii. Artifact-free nocturnal SpO2 ≤80% for ≥10% of sleep time OR iii. Significant nocturnal desaturation not meeting the above criteria but with evidence of hypoxia related sequelae (polycythemia, right heart failure, pulmonary hypertension) and: iv. Objective evidence of improvement (e.g., improved mean nocturnal SpO2 on either a 109 Country by Continent Region Continuous Ambulatory Nocturnal iii. Distance walked in 6MWT while on oxygen improves by ≥25m or by >50% in people with baseline 6-minute walk distance <50m polysomnography or pulse oximetry) on nocturnal oxygen. Nocturnal investigations of oxygenation were carried out during a period of clinical stability i.e., at least 4 weeks following an acute exacerbation. vi. If applicable: for people who are unable to tolerate positive airway pressure and are prescribed oxygen as an alternative treatment for sleep-disordered breathing, a letter of justification is required outlining why the person is unable to tolerate positive airway pressure and the reason for prescribing oxygen Australia Northern Territory Stable daytime PaO2 is ≤55 mmHg (7.3 kPa) at rest OR stable daytime PaO2 is 56-59 mmHg (7.4-7.8 kPa) and there is evidence for hypoxic organ damage (right heart failure, pulmonary hypertension, or polycythemia) In patients commencing resting oxygen who wish to maximise the number of hours they receive oxygen supplementation during the 24-hour period can supplement stationary concentrator use with portable oxygen for physical activities outside the home SpO2 ≤88% for >1/3 of the night, particularly if suffer sequelae such as pulmonary hypertension or polycythemia Australia11 Queensland PaO2 is ≤55 mmHg OR PaO2 ≤59 mmHg with cor pulmonale, pulmonary hypertension or polycythemia OR SpO2 ≤90% with cor pulmonale, pulmonary hypertension or polycythemia SpO2 ≤88% and at least 4% improvement in SpO2 with oxygen OR 20% improvement in distance walked with oxygen SaO2 ≤88% for >1/3 of sleep period OR SaO2 ≤88% plus hypoxia related sequelae 110 Country by Continent Region Continuous Ambulatory Nocturnal Australia South Australia Stable daytime PaO2 is ≤55 mmHg (7.3 kPa) at rest OR sable daytime PaO2 is 56-59 mmHg (7.4-7.8 kPa) and there is evidence for hypoxic organ damage (right heart failure, pulmonary hypertension, or polycythemia In patients commencing resting oxygen who wish to maximise the number of hours they receive oxygen supplementation during the 24-hour period can supplement stationary concentrator use with portable oxygen for physical activities outside the home SpO2 ≤88% for >1/3 of the night, particularly if suffer sequelae such as pulmonary hypertension or polycythemia Australia Tasmania PaO2 <55 mmHg OR PaO2 55-59 mmHg and evidence of pulmonary hypertension or hypoxic organ damage (right ventricular failure or polycythemia) SpO2 <90% during exercise. Correction of desaturation with supplemental oxygen and increase in exercise performance by 20% (usually measured by walking distance) Australia Victoria Stable daytime PaO2 ≤55 mmHg (7.3 kPa) at rest OR stable daytime PaO2 56-59 mmHg (7.4-7.8 kPa) and evidence for hypoxic organ damage (right heart failure, pulmonary hypertension, or polycythemia In patients commencing resting oxygen who wish to maximise the number of hours they receive oxygen supplementation during the 24-hour period can supplement stationary concentrator use with portable oxygen for physical activities outside the home SpO2 ≤88% for >1/3 of the night, particularly if suffer sequelae such as pulmonary hypertension or polycythemia Australia12 Western Australia Stable daytime PaO2 ≤55 mmHg OR Stable daytime PaO2 56-59 mmHg and evidence of organ damage (right heart failure, cor pulmonale, or polycythemia) and/or pulmonary hypertension. ABG must be performed when stable, ≥4 weeks after hospital discharge, after initiation of appropriate medical therapy and after smoking cessation. ABG must be taken on room air at rest (i.e., at least 10 minutes This option should be carefully considered for patients without resting hypoxia but who may benefit in exercise endurance, with dyspnea and exertional oxygen desaturation.6MWT on room air when stable should demonstrate a nadir SpO2 <84%. For ongoing therapy >3 months, benefits in exercise ability, daily functional capacities (e.g., Improvement in 6MWT >30m) and/or improvement in dyspnea score SpO2 <88% for >1/3 of night, especially in the presence of pulmonary hypertension or polycythemia (hematocrit >0.55). In those not suspected of sleep apnea or nocturnal hypoventilation, overnight recorded pulse oximetry is suitable (intermittent observation and documentation of oxygen 111 Country by Continent Region Continuous Ambulatory Nocturnal after exertion). 6MWT is required if prescription for ambulatory oxygen flow rate is above that used for rest or sleep or if ≥6L/min is required. >1, improvement in endurance walk test or supportive clinician/allied health functional assessment outcome) are needed. saturations in a hospital setting is not appropriate). In those suspected of sleep apnea or sleep hypoventilation (e.g., a serum bicarbonate >28mMol/L) a sleep study is preferred. New Zealand PaO2 <55 mmHg on 2 occasions 2-3 weeks apart OR PaO2 consistently between 55-60 mmHg with secondary polycythemia or pulmonary hypertension (cor pulmonale on electrocardiogram or echo) SaO2 <88% on exercise SaO2 <88% for at least 30% of night Europe Albania PaO2 <60 mmHg or SpO2 <92% Andorra PaO2 <55 mmHg or SpO2 <90% SpO2 <90% >2 minutes on a walking test SpO2 sleep <90% for >50% of time at night Austria PaO2 <55 mmHg OR alveolar-arterial oxygen difference>45 mmHg OR PaO2 <60 mmHg if cor pulmonale (echocardiography), pulmonary hypertension is present or accompanied by polyglobulia (hematocrit >55%) ABG during exercise PaO2 <55 mmHg at 0.5 watts/kg load for 5 minutes or corresponding to everyday stresses. If no resting hypoxemia, but there is a drop in PaO2 only during exercise/load, 2 of the following must occur with supplemental oxygen: increase in SpO2 >90% during exercise, increase in walking distance by ≥10%, subjective improvement in shortness of breath (Borg or Visual Analogue Scale) SpO2 <88% for >30% of sleep duration after exclusion of sleep-related breathing disorders using polysomnography Belarus Stable disease (3-4 weeks post-exacerbation) with PaO2 <55 mmHg or SaO2 <88% at rest OR PaO2 55-60 mmHg or SaO2 88% in the presence of PaO2 <55 mmHg or SaO2 <88% with physical activity PaO2 <55 mmHg or SaO2 <88% during sleep 112 Country by Continent Region Continuous Ambulatory Nocturnal pulmonary hypertension, peripheral edema, cardiac insufficiency, or erythrocytosis (hematocrit >55%) Belgium Despite receiving appropriate drug and/or physical therapy and having stopped smoking, in ambient air, while awake, exhibit a PaO2 of ≤55 mmHg (7.33 kPa) on 2 measurements with an interval of at least 3 months (can be reduced to 15 days) OR PaO2 >55 but <60 mmHg and hematocrit of >55% and/or cor pulmonale (on right heart catheterization or cardiac/Doppler ultrasound) If not meeting resting criteria, but desaturate with exercise with a diffusion capacity of carbon monoxide to be <40 % and/or shows a FEV1 <30% and who during daytime 6MWT has SaO2 <88 % (on 2 measurements with interval at least 3 months (can be reduced to 15 days) outside disease flare-ups) estimated over 1 normal week of daily life. Must spend an average of at least 30 minutes per day outside the home. Exercise improvement should be demonstrated with supplemental oxygen. Despite receiving appropriate drug and/or physical treatment and having stopped smoking, suffer from nocturnal hypoxemia and show a hematocrit of >55 %, chronic cor pulmonale (on right heart catheterization or doppler ultrasound) and SaO2 <90 % has been established during >30 % of the recording time by transcutaneous recording during the entire night (minimum 8 hours recording) Czech Republic PaO2 <7.3 kPa OR PaO2 <8.0 kPa and at the same time the patient has signs of pulmonary hypertension or right ventricular hypertrophy, secondary polycythemia After a load of 50 watts for 5 minutes the PaO2 drops below 8 kPa Nocturnal monitoring with SpO2 <90% Denmark Central Denmark Region PaO2 <7.3 kPa OR PaO2 <8 kPa with cor pulmonale, heart failure or hematocrit >0.55 SpO2 <90% or decrease >4% during walking OR increase in walk distance on 6MWT ≥30m with oxygen Finland13 PaO2 <7.3 kPa on 2 samples ≥3 weeks apart OR PaO2 7.3-8.0 kPa and 1 of: edema, polycythemia (hematocrit >55%), significant hypoxia at night due to concomitant sleep apnea diagnosed by oximetry and corrected by oxygen therapy, 113 Country by Continent Region Continuous Ambulatory Nocturnal significant neuropsychological symptoms that resolve with oxygen therapy France14 PaO2 <55 mmHg OR 56-59 mmHg and signs of tissue hypoxia PaO2 <60 mmHg OR fall in SpO2 of ≤5% to a value <90% Germany PaO2 ≤55 mmHg OR PaO2 55-60 mmHg with cor pulmonale, polycythemia and/or signs of right sided heart failure PaO₂ <55 mmHg or SpO2 <88% and symptom improvement during exertion Greece Patients with a resting PaO2 ≤55 mmHg or SpO2 ≤88%OR PaO2 ≤60 mmHg or SpO2 ≤90% with evidence of right heart failure polycythemia (hematocrit ≥55%) or pulmonary hypertension PaO2 during exercise ≤55 mmHg or SpO2 ≤88% OR PaO2 during exercise ≤60 mmHg or SpO2 ≤90% with evidence of right heart failure, polycythemia (hematocrit ≥55%) or pulmonary hypertension Nocturnal PaO2 ≤55 mmHg or SpO2 ≤88% OR PaO2 ≤60 mmHg or SpO2 ≤90% with evidence of right heart failure polycythemia (hematocrit ≥55%) or pulmonary hypertension Hungary PaO2 <60 mmHg or SpO2 <88% OR PaO2 <55 mmHg with pulmonary hypertension Iceland SpO2 <88% OR PaO2 55-60 mmHg with heart failure SpO2 <88% on 6MWT SpO2 <90% for 40% of sleep time Ireland15 PaO2 ≤7.3 kPa OR PaO2 ≤8 kPa with evidence of peripheral edema, polycythemia (hematocrit ≥55%) or pulmonary hypertension SpO2 drops ≥4% to <90% during baseline endurance shuttle walk test or 6MWT. Repeat test should be carried out on ambulatory oxygen after 20 minute rest if drop in saturation is evident. If improvement in exercise tolerance/dyspnea, ambulatory oxygen can be prescribed. Do not prescribe if do not meet resting criteria. Should not be prescribed if patients do not meet the resting oxygen criteria Italy PaO2 ≤55 mmHg and SpO2 ≤90% with ABG on room Sleep oximetry study showing SpO2 ≤90% 114 Country by Continent Region Continuous Ambulatory Nocturnal air (with normal hemoglobin and excluding heart failure) Latvia16 2 ABG (≥3 weeks apart) showing PaO2 ≤55 mmHg OR PaO2 ≤60 mmHg with polycythemia (hematocrit ≥55%), pulmonary hypertension, or peripheral edema 2 ABG (at least 3 weeks apart) have PaO2 ≤60 mmHg and SpO2 <90% at least ≥30% of the sleep time Liechtenstein PaO2 <55 mmHg OR PaO2 55-60 mmHg if pulmonary hypertension, cor pulmonale, or polyglobulia PaO2 <55 mmHg or SpO2 <90% at exercise/walk test/ cardiopulmonary exercise testing and improvement of physical performance (e.g., 6MWT distance) with ambulatory oxygen Luxembourg PaO2 <60 mmHg for 3 months Malta PaO2 <7.3 kPa or SpO2 <92% SpO2 <88% during mobility Netherlands17 PaO2 <60 mmHg (8 kPa) on room air ≥2 measurements within an interval of ≥3 weeks, SaO2 ≤90% Norway PaO2 ≤7.3 kPa or SaO2 ≤88% OR PaO2 7.3-8.0 kPa or SaO2 = 89% with pulmonary hypertension, peripheral edema on the basis of heart failure or secondary polycythemia Poland PaO2 ≤55 mmHg OR PaO2 55-60 mmHg and 1 of: hematocrit ≥55%, pulmonary hypertension, right ventricular hypertrophy SaO2 <90% during exercise and PaO2 >60 mmHg during resting Portugal18 PaO2 ≤55 mmHg OR PaO2 55-60 mmHg in presence of cor pulmonale, pulmonary hypertension, polycythemia (hematocrit >55%) In cases where daily ambulation is promoted, verified and guaranteed: 1) PaO2 ≤55 mmHg OR 2) PaO2 55-60 mmHg with cor pulmonale or pulmonary 115 Country by Continent Region Continuous Ambulatory Nocturnal hypertension and/or polyglobulia (hematocrit >55%) OR 3) Normoxemic patients at rest who in the 6MWT, have SpO2 <88% or a 4% reduction in SpO2 to a value <90%, which is corrected after oxygen Romania19 PaO2 <55 mmHg or SaO2 ≤88% OR PaO2 55-59 mmHg or SatO2 <90% and 1 of: chronic pulmonary heart disease, clinical signs of pulmonary hypertension, polyglobulia (hematocrit>55%) Slovakia PaO2 <7.3 kPa OR PaO2 7.3-8.0 kPa (55-60 torr) if following criteria are met: precapillary pulmonary hypertension, electrocardiogram findings of hypertrophy of right ventricle, or hematocrit >55 % or partial pressure of carbon dioxide >6.1 kPa or FEV1 <1.51 Slovenia PaO2 <7.4 kPa OR PaO2 <7.8 kPa with signs of hypercapnia and/or right heart failure Physician discretion Physician discretion Spain PaO2 <55 mmHg OR PaO2 between 55-59 mmHg with: cardiac heart failure, polycythemia, pulmonary hypertension 6MWT SpO2 ≤88% and improvement of distance of at least 30m with oxygen Nocturnal pulse oximetry SpO2 <90% for >30% of total recording time Switzerland PaO2 <55 mmHg/7.3 kPa OR PaO2 55-60 mmHg/7.3-8.0 kPa if pulmonary hypertension, cor pulmonale, polyglobulia PaO2 <55 mmHg (7.3 kPa) OR SpO2 <90% at exercise or walk test OR cardiopulmonary exercise testing and improvement of 116 Country by Continent Region Continuous Ambulatory Nocturnal physical performance (e.g., 6MWT) with ambulatory oxygen Sweden20 PaO2 of <55 mmHg OR PaO2 56-59 mmHg with signs of: right-sided heart failure or pulmonary hypertension or secondary polycythemia Exertional SpO2 ≤88% Ukraine21 PaO2 ≤55 mmHg or SaO2 ≤88% OR PaO2 ≤59 mmHg or SaO2 ≤89% with heart disease or hypercapnia United Kingdom22 England PaO2 <7.3 kPa or SpO2 <92% OR PaO2 7.3-8 kPa and secondary polycythemia, peripheral edema or pulmonary hypertension Decrease in SaO2 of 4% to <90% on exercise and an improvement in exercise capacity on oxygen United Kingdom Scotland PaO2 is <7.3 kPa when clinically stable OR PaO2 7.3-8 kPa when stable and secondary polycythemia, peripheral edema, cor pulmonale), or pulmonary hypertension Fall of SaO2 ≥4% to <90% on exertion SaO2 <90% for >30% sleep time North America Canada23 Alberta PaO2 ≤55 mmHg on room air OR PaO2 56-59 mmHg and cor pulmonale, secondary polycythemia, pulmonary hypertension 1.The client desaturates to a SpO2 <80%, regardless of dyspnea or distance walked OR 2.Distance walked increases by 25% (≥30m) on oxygen OR 3. Dyspnea improves by 4 Borg Scale points on walking with oxygen compared to air On CPAP/BPAP, must first meet short term criteria: 1. A recent Level 1 sleep study with interpretation showing optimal titration: a. Apnea Hypopnea Index less than 10 with CPAP/BPAP titration b. Raw data showing SpO2 ≤83% for at least 5min on room air with CPAP/BPAP. c. Evidence of SpO2 >85 % on oxygen with CPAP/BPAP Long term criteria with 117 Country by Continent Region Continuous Ambulatory Nocturnal CPAP/BPAP: 1. Meet short term criteria 2. SpO2 ≤83% for ≥5 minutes with level 3 sleep study Not on CPAP/BPAP: 1. Diagnosed with pulmonary hypertension 2. If not followed by a pulmonary hypertension clinic, client receives ≥1 pulmonary hypertension medication 3. A recent level 1 sleep study with interpretation, histogram and summary showing: a. No evidence of sleep disordered breathing b. Apnea Hypopnea Index <10 and c. At least 1 episode of SpO2 ≤89% for 1 minute OR Level 3 sleep study with: a. At least a continuous recording of oxygen saturation, heart rate, and a direct measurement of airflow or nasal pressure. Technical quality must be good and free of excessive artifact b. No evidence of sleep disordered breathing c. Respiratory Disturbance Index less than 10; and d. ≥1 episode of ≤89% for 1 continuous minute 118 Country by Continent Region Continuous Ambulatory Nocturnal Canada24 British Columbia PaO2 ≤55 mmHg on room air OR SpO2 <88% sustained for 6 minutes OR PaO2 ≤60 mmHg and heart failure or pulmonary hypertension SpO2 <88% sustained minimum of 1 minute on room air showing 1) The distance traveled increases by ≥25% and ≥30m OR 2) SpO2 <80% with ambulation ≥1 minute SpO2 must be <88% for >30% of a minimum 4-hour nocturnal oximetry study on room air Canada25 Manitoba PaO2 ≤59 mmHg ABG room air PaO2 >59 mmHg and 1 of: 1. Evidence of desaturation on room air during exertion to SpO2 <89% for a minimum of 1 minute (Blinded 6MWT with documented improved performance on oxygen versus room air (including distance walked increases by 25% and a minimum of 30m)) OR 2. During the blinded 6MWT, evidence of desaturation on room air during exertion to SpO2 <80% for a minimum of 1 minute Respiratory sleep study that demonstrates minimum 5% sleep time at SpO2 ≤85%. Non-invasive positive pressure ventilation alone not adequate to maintain SpO2 >85% on room air. Sleep study demonstrates titrated oxygen administration is required to maintain SpO2 >85% during sleep. Canada New Brunswick A diagnosis of hypoxemia confirmed on ABG with PaO2 ≤55 mmHg on room air at rest for ≥30 minutes OR PaO2 56 -59 mmHg and evidence of: cor pulmonale, pulmonary hypertension, erythrocytosis, edema from right heart failure, hypoxemia-associated impaired mental status ≤88% SpO2 considered if ABG draw not appropriate SpO2 <85% on 6MWT or equivalent and who are responsive to oxygen therapy according to a respirologist, cardiologist, or internist SpO2 <90% >30% of the recorded time (≥4 hours) with evidence of cor pulmonale OR with significant nocturnal cardiac arrhythmias, according to a respirologist, cardiologist, or internist Canada Newfoundland PaO2 <55 mmHg OR <60 mmHg with evidence of chronic hypoxia (pulmonary hypertension, cor pulmonale, polycythemia SpO2 <90% during 6MWT 119 Country by Continent Region Continuous Ambulatory Nocturnal Canada26 Nova Scotia PaO2 <55 mmHg on room air or SpO2 level ≤89% OR PaO2 56-59 mmHg at rest room air with evidence of cor pulmonale or secondary polycythemia SpO2 ≤80% regardless of dyspnea or distance walked Nocturnal desaturation must be confirmed by polysomnography or nocturnal oximetry tests. Applicants usually exhibit severe episodes of arterial desaturation on 1 or 2 occasions per night, persisting for at least 2 minutes. This type of individual spends ≥5% of sleep time with an oxygen saturation ≤85% without nocturnal oxygen therapy. Canada27 Ontario PaO2 ≤55 mmHg or SpO2 ≤88% OR PaO2 56-60 mmHg or SpO2 89-90% and 1 of the following: a. cor pulmonale, pulmonary hypertension or persistent erythrocytosis or b. exercise limited by hypoxemia (SpO2 ≤88%) or c. nocturnal hypoxemia Only recommended for exercise tolerance restricted due to severe breathlessness and motivated to improve activity level with oxygen therapy. Funding available if do not qualify under resting criteria, exhibit exertional hypoxemia (SpO2 ≤88% during exercise or activities of daily living) and improve with oxygen on exercise assessment. Improvements include: a. SpO2 <80% on walking, regardless of dyspnea or distance b. ≥5 minutes walking on room air as measured improvement in walk time by 25% with oxygen and ≥1 unit improvement Borg score at end-exercise point of shortest test Canada28 Prince Edward Island Minimum 2 ABG performed at rest on room air (taken at 3-month intervals). Nocturnal desaturation ≥5% sleep time with an SpO2 ≤85% confirmed by 120 Country by Continent Region Continuous Ambulatory Nocturnal Chronic hypoxemia at rest with: a. PaO2 ≤55 mmHg OR Chronic hypoxemia at rest with a. PaO2 56- 59 mmHg and evidence of cor pulmonale, evidence of secondary polycythemia, evidence of pulmonary hypertension polysomnography or a sleep screening study. A diagnosis of obstructive sleep apnea or periodic breathing must be excluded. Canada29 Quebec PaO2 ≤55 mmHg OR PaO2 ≤59 mmHg in the presence of peripheral edema, hematocrit ≥55%, pulmonary “P” waves on electrocardiogram Must be active and demonstrate leaving home a ≥4 hours per week. Significant desaturation during exercise (<85% during a walk test of 6 minutes carried out in a specialized center). Correction of the desaturation during the effort (saturation ≥90%). May be considered for patients with significant primary pulmonary hypertension (i.e., >40 mmHg) and who present with desaturation on exercise <90%. Oxygen therapy should improve SpO2 beyond 90%. >30% of the recording time of a nocturnal oximetry showing SpO2 <90% and absence of severe daytime hypoxemia (PaO2 ≥60 mmHg) when clinical evidence of cor pulmonale is observed or when a user presents with significant nocturnal cardiac arrhythmias according to the opinion of a cardiologist Canada30 Saskatchewan ABG (after resting for 10 minutes on room air): 1) PaO2 ≤55 mmHg 2) PaO2 ≤59 mmHg if the client has cor pulmonale or polycythemia OR Oximetry with supplementary oxygen test: 1) Saturation results ≤87% continuously for 2 minutes 2) Saturation results ≤90% continuously for 2 minutes if the client has cor pulmonale or polycythemia AND evidence that the client’s saturation Resting SpO2 >87% for minimum of 20 seconds of continuous oxygen saturation with ≤87% with walking at comfortable pace and improvement in exercise capacity of 20% with supplementary oxygen 1. An oximetry oxygen saturation of ≤87% >30% of the night 2. The second night’s test must also show a significant improvement with oxygen 121 Country by Continent Region Continuous Ambulatory Nocturnal results improved with the use of oxygen Guatemala 1) PaO2 ≤55 mmHg or SpO2 ≤88% 2) PaO2 = 56-59 mmHg (7.5-7.9 kPa) or SpO2 = 89% plus 1 of the following: edema, hematocrit ≥55%, or P pulmonale on an electrocardiogram SpO2 ≤88% during exertion Honduras PaO2 <55 mmHg OR PaO2 <60 mmHg with pulmonary hypertension, congestive heart failure, cor pulmonale, hematocrit >55%, cardiac arrhythmias, or impact on intellectual capacity SpO2 ≤88% for 2 minutes during exercise test. Improves SpO2 to ≥90% with oxygen with improvement in dyspnea and/or increase in 6MWT walking distance by 10% or at least 25-30 meters PaO2 <55 mmHg or SpO2 ≤88% OR decrease in PaO2 >10 mmHg and/or SpO2 >5% during minimum 30% of polysomnogram recording Panama SpO2 <90% at rest SpO2 <88% on exertion SpO2 <88% during sleep United States31 1) PO2 ≤55 mmHg or SaO2 ≤88% on room air OR 2) PO2 56-59 mmHg or SaO2 = 89% if either: edema suggesting congestive heart failure, pulmonary hypertension, cor pulmonale, erythrocythemia (hematocrit >56%) PO2 ≤55 mmHg or SaO2 ≤88% during exercise for a patient who demonstrates PO2 ≥56 mmHg or SaO2 ≥89% during the day while at rest. In this case, supplemental oxygen is provided during exercise if the use of oxygen improves the hypoxemia that was demonstrated during exercise when the patient was breathing room air. PO2 ≤55 mmHg or SaO2 ≤88% during sleep for a patient who demonstrates PO2 ≥56 mmHg or SaO2 ≥89%, while awake OR decrease in arterial PO2 >10 mm Hg, or decrease in SaO2 >5% during sleep associated with symptoms or signs reasonably attributable to hypoxemia (e.g., impairment of cognitive processes and nocturnal restlessness or insomnia) South America Argentina32 PaO2 ≤55 mmHg at rest OR PaO2 >55 mmHg, but ≤60 mmHg with 1 or more of the following: polycythemia related to chronic lung disease (hematocrit PaO2 at rest between 55-60 mmHg who do not qualify for chronic home oxygen or PaO2 >60 mmHg and dyspnea on usual exertion and/or signs of Significant nocturnal desaturation criterion: >30% of the total time in bed with saturation <90%. Titrate oxygen flow to ensure SpO2 ≥90% 122 Country by Continent Region Continuous Ambulatory Nocturnal ≥55%), cor pulmonale, pulmonary hypertension. Candidates must have clinical stability and optimal medical treatment. The effectiveness of the indication must be confirmed by obtaining a PaO2 of 60 mmHg or higher during the administration of oxygen at the indicated flow. pulmonary heart disease should perform a 6MWT, with criteria: a. Decrease in SpO2 <86% b. If SpO2 86-90%, perform progressive stress test with PaO2 measurement at different load levels. Oxygen flow must be titrated to SpO2 >90% or PaO2 >60 mmHg Brazil PaO2 ≤55 mmHg or SaO2 ≤88% OR PaO2 56-59 mmHg or SpO2 = 89%, associated with signs of pulmonary hypertension, edema due to heart failure or evidence of cor pulmonale or hematocrit ≥55% SaO2 ≤88% or PaO2 ≤55 mmHg during physical activity SaO2 ≤88% or PaO2 ≤55 mmHg during sleep OR Fall in SaO2 ≥5% with signs and symptoms of hypoxemia (decrease in cognitive ability, fatigue, or insomnia) Chile PaO2 <55 mmHg OR <60 mmHg plus polyglobulia, cor pulmonale, pulmonary hypertension Ecuador PaO2 <55 mmHg or SpO2 <88% Guyana PaO2 ≤55 mmHg or SpO2 ≤88% SpO2 ≤88% OR ≥25% improvement on walk test with oxygen Suriname SpO2 <90% Uruguay PaO2 <55 mmHg PaO2 <55 mmHg and patient must be ambulatory Abbreviations: 6MWT = 6-minute walk test, ABG = arterial blood gas, BPAP = Bi-Level Positive Airway Pressure, CPAP = Continuous positive airway pressure, FEV1 = forced expiratory volume in the first second, PaO2 = arterial partial pressure of oxygen, SaO2 = arterial oxygen saturation; SpO2 = pulse oximetry oxygen saturation 1. Kim Y, Kim HI, Park JY, et al. Korean physician prescription patterns for home oxygen therapy in chronic obstructive pulmonary disease patients. Korean J Intern Med. 1 2022;37(1):119-126. doi:10.3904/kjim.2020.470 2. Kida K. Home oxygen therapy in Japan: clinical application and considerations for practical implementation. Japan Medical Association Journal. 2011;54(2):99-104. 3. National clinical guidelines the assessment & management of chronic obstructive pulmonary disease in adults. Accessed September 30, 2022. https://www.moph.gov.qa/_layouts/download.aspx?SourceUrl=/Admin/Lists/ClinicalGuidelinesAttachments/Attachments/6/The%20Assessment%20and%20Management%20of%20Chronic%20Obstructive%20Pulmonary%20Disease%20in%20Adults.pdf 4. ДЛИТЕЛЬНАЯ КИСЛОРОДОТЕРАПИЯ ПРИ ХРОНИЧЕСКОЙ ДЫХАТЕЛЬНОЙ НЕДОСТАТОЧНОСТИ. Accessed September 30, 2022. https://lim-nn.ru/upload/iblock/607/jffmmegifaqjzcwq%20hjnjypvk.pdf 123 5. Chronic obstructive pulmonary disease MOH clinical practice guidelines 2/2017. Accessed October 1, 2022. https://www.moh.gov.sg/docs/librariesprovider4/guidelines/copd.pdf 6. SOSYAL GÜVENLİK KURUMU SAĞLIK UYGULAMA TEBLİĞİNDE DEĞİŞİKLİK YAPILMASINA DAİR TEBLİĞ. Accessed September 30, 2022. https://www.resmigazete.gov.tr/eskiler/2012/06/20120622-24.htm 7. HAAD guidelines for the diagnosis and management of chronic obstructive pulmonary disease (COPD). Accessed October 1, 2022. https://www.doh.gov.ae/-/media/5F0DAD19158E46268C0D067BB50B93F4.ashx 8. Equipment loan and supply. Accessed October 1, 2022. https://www.canberrahealthservices.act.gov.au/services-and-clinics/equipment-loan-and-supply 9. McDonald CF, Whyte K, Jenkins S, Serginson J, Frith P. Clinical practice guideline on adult domiciliary oxygen therapy: executive summary from the Thoracic Society of Australia and New Zealand. Respirology. Jan 2016;21(1):76-8. doi:10.1111/resp.12678 10. Adult home oxygen funding criteria. Accessed October 1, 2022. https://www.enable.health.nsw.gov.au/__data/assets/pdf_file/0010/491293/Adult-Home-Oxygen-Funding-Criteria.pdf 11. Medical Aids Subsidy Scheme (MASS) application guidelines for oxygen. Accessed October 1, 2022. https://www.health.qld.gov.au/__data/assets/pdf_file/0028/428455/guidelines-oxygen.pdf 12. Western Australian domiciliary oxygen referral form. Accessed October 1, 2022. https://ww2.health.wa.gov.au/~/media/Files/Corporate/general-documents/Health-Networks/Respiratory/Statewide-Domiciliary-Oxygen-Referral-Form.pdf 13. Keuhkoahtaumatauti. Accessed October 1, 2022. https://www.kaypahoito.fi/hoi06040 14. Oxygénothérapie à long terme : choisir la source la mieux adaptée. Accessed October 1, 2022. https://www.has-sante.fr/upload/docs/application/pdf/2012-07/fs_buts_oxygene_v_finale.pdf 15. Irish guidelines on long term oxygen therapy (LTOT) in Adults 2015. Accessed January 16, 2022. https://irishthoracicsociety.com/wp-content/uploads/2017/05/LTOT-guideline-2015-1.pdf 16. Skābekļa Terapija Mājās. Accessed October 1, 2022. https://www.vmnvd.gov.lv/lv/skabekla-terapija-majas 17. Kampelmacher M, Rooyackers J, Lammers J-W. CBO-richtlijn ‘Zuurstofbehandeling thuis’. Ned Tijdschr Geneeskd. 2001;145(41):1975-1980. 18. Cuidados respiratórios domiciliários: prescrição de oxigenoterapia. Accessed October 1, 2022. http://nocs.pt/wp-content/uploads/2015/11/Cuidados-Respiratórios-Domiciliários-Prescrição-de-Oxigenoterapia.pdf 19. Conditiile acordarii Echipamentelor pentru oxigenoterapie. Accessed October 1, 2022. http://cas.cnas.ro/casmb/media/files/20210705_Anexa%20la%20prescriptia%20medicala%20(concentratoare%20de%20oxigen)_2021.pdf 20. Ekstrom M, Ahmadi Z, Larsson H, et al. A nationwide structure for valid long-term oxygen therapy: 29-year prospective data in Sweden. Int J Chron Obstruct Pulmon Dis. 2017;12:3159-3169. doi:10.2147/COPD.S140264 21. 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Thesis/Dissertation
eng
Experimental Medicine
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Ryerson, Christopher J.
Optimizing implementation of adult domiciliary oxygen therapy in fibrotic interstitial lung disease
Text