The acute effect of inhaled nitric oxide on the exercise capacity of patients with advanced interstitial lung disease: a randomized controlled trial.

BACKGROUND: Inhaled nitric oxide (iNO) selectively acts on the pulmonary vasculature of ventilated lung tissue by reducing pulmonary vascular resistance and intrapulmonary shunt. This effect may reduce ventilation/perfusion mismatch and decrease pulmonary hypertension in patients with interstitial lung disease. METHODS: In a prospective, single-blinded, randomized, placebo-controlled trial, participants with advanced interstitial lung disease, underwent two separate six-minute walk tests (6MWT): one with iNO and the other with a placebo. The primary outcome measured the difference in meters between the distances covered in the two tests. Secondary outcomes included oxygen saturation levels, distance-saturation product, and Borg dyspnea score. A predefined subgroup analysis was conducted for patients with pulmonary hypertension. RESULTS: Overall, 44 patients were included in the final analysis. The 6MWT distance was similar for iNO treatment and placebo, median 362 m (IQR 265-409) vs 371 m (IQR 250-407), respectively (p = 0.29). Subgroup analysis for patients with pulmonary hypertension showed no difference in 6MWT distance with iNO and placebo, median 339 (256-402) vs 332 (238-403) for the iNO and placebo tests respectively (P=0.50). No correlation was observed between mean pulmonary artery pressure values and the change in 6MWT distance with iNO versus placebo (spearman correlation Coefficient 0.24, P=0.33). CONCLUSION: In patients with advanced interstitial lung disease, both with and without concurrent pulmonary hypertension, the administration of inhaled nitric oxide failed to elicit beneficial effects on the six-minute walk distance and oxygen saturation. The use of inhaled NO was found to be safe and did not lead to any serious side effects. TRIAL REGISTRATION: (NCT03873298, MOH_2018-04-24_002331).

Prognostic value of serum oncomarkers for patients hospitalized with acute exacerbation of interstitial lung disease.

BACKGROUND: Different types of inflammatory processes and fibrosis have been implicated in the pathogenesis of interstitial lung disease (ILD), a heterogeneous, diffuse, parenchymal lung disease. Acute exacerbation (AE) of ILD is characterized by significant respiratory deterioration and is associated with high mortality rates. Several serum oncomarkers have been used to determine the prognosis of ILD; however, the prognostic value of serum oncomarker levels in patients with AE-ILD remains unclear. OBJECTIVE: To evaluate the prognostic value of serum oncomarker levels in patients with AE-ILD and its main subtypes. DESIGN: Retrospective study. METHODS: The serum levels of 8 oncomarkers in 281 patients hospitalized with AE-ILD at our institution between 2017 and 2022 were retrospectively reviewed. The baseline characteristics and serum oncomarker levels were compared between the survival and non-survival groups of AE-ILD and its main subtypes. Multivariate logistic regression analysis was performed to identify independent prognosis-related markers, and the best prognostic predictor was analyzed using receiver operating characteristic curve (ROC) analysis. RESULT: Idiopathic pulmonary fibrosis (IPF; n = 65), idiopathic nonspecific interstitial pneumonia (iNSIP; n = 26), and connective tissue disease-associated interstitial lung disease (CTD-ILD; n = 161) were the three main subtypes of ILD. The in-hospital mortality rate among patients with AE-ILD was 21%. The serum oncomarker levels of most patients with AE-ILD and its main subtypes in the non-survival group were higher than those in the survival group. Multivariate analysis revealed that ferritin and cytokeratin 19 fragments (CYFRA21-1) were independent prognostic risk factors for patients hospitalized with AE-ILD or AE-CTD-ILD. CYFRA21-1 was identified as an independent prognostic risk factor for patients hospitalized with AE-IPF or AE-iNSIP. CONCLUSION: CYFRA21-1 may be a viable biomarker for predicting the prognosis of patients with AE-ILD, regardless of the underlying subtype of ILD. Ferritin has a prognostic value in patients with AE-ILD or AE-CTD-ILD.

A study on the prevalence and prognosis of progressive pulmonary fibrosis: A retrospective observational study.

Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 diffuse parenchymal lung diseases with various clinical courses. Disease progression is one of the most important prognostic factors, and, the definition of progressive pulmonary fibrosis (PPF) has recently been established. This study aimed to estimate the prevalence, risk factors, and prognosis of PPF among patients with non-idiopathic pulmonary fibrosis (IPF) in real-world practice. A total of 215 patients were retrospectively analyzed between January 2010 and June 2023 at the Haeundae Paik Hospital in the Republic of Korea. According to the criteria proposed in 2022 by Raghu et al, PPF defined as a condition that satisfies 2 or more of the following in the past year: worsening of respiratory symptoms, physiological evidence of disease progression, and radiological evidence of disease progression. The median age of the subjects was 67 years and 63.7% were female. A total of 40% was diagnosed with PPF and connective tissue disease-associated ILD (52.3%) was the most common type, followed by nonspecific interstitial pneumonitis (NSIP) (25.6%) and cryptogenic organizing pneumonitis (16.3%). In multivariate logistic regression for predicting PPF, both the use of steroids and immunosuppressants (OR: 2.57, 95% CI: 1.41-4.67, P = .002) and home oxygen use (OR: 25.17, 95% CI: 3.21-197.24, P = .002) were independent risk factors. During the follow-up period, the mortality rate was significantly higher in the PPF group than in the non-PPF group (24.4% vs 2.3%, P < .001). In the survival analysis using the Cox proportional hazard regression model, disease progression, older age and lower forced vital capacity (FVC) were independent risk factors for mortality. Our study demonstrated that the prevalence of PPF was 40%. Concomitant therapy of steroids with an immunosuppressants and home oxygen use are risk factors for PPF. PPF itself was significantly associated with high mortality rates. Risk factors for mortality were disease progression, older age, and lower FVC.

Unravelling the health and economic burden of interstitial lung diseases in adults in Australia.

BACKGROUND: Interstitial lung diseases (ILD) are a heterogenous group of over 200 disorders affecting the pulmonary interstitium. Although there have been advances in knowledge on ILDs in Australia, the characterisation of the health and economic burden of disease remained largely undetermined until recently. OBJECTIVE: The main objective of this review is to provide a synopsis of health and economic burden of ILDs in Australia, based on recently completed research. DISCUSSION: Recent research has demonstrated that idiopathic pulmonary fibrosis (IPF) is the most frequent ILD in Australia. Incidence and prevalence of IPF have demonstrated an increasing trend over the past decades. Mortality has also increased over the past decades, but has shown a slight decreasing trend recently, since the introduction of antifibrotic medication. Health-related quality of life is poor in patients with IPF, and care is estimated to cost approximately AU$299 million per year in Australia. Early diagnosis and referral to tertiary care is crucial for favourable outcomes, and general practitioners are considerably important to this as the first interface to identify patients at risk and detect early symptoms of ILDs.

Untreated Obstructive Sleep Apnea in Interstitial Lung Disease and Impact on Interstitial Lung Disease Outcomes.

Subjects with interstitial lung disease (ILD) often suffer from nocturnal cough, insomnia, and poor sleep quality. Subjects with ILD and obstructive sleep apnea (OSA) seem to have relatively mild symptoms from sleep fragmentation compared to subjects with only ILD. The overlap of ILD, OSA, and sleeping hypoxemia may be associated with poor outcome, even though there is no agreement on which sleep parameter is mostly associated with worsening ILD prognosis. Randomized controlled trials are needed to understand when positive airway pressure (PAP) treatment is required in subjects with ILD and OSA and the impact of PAP treatment on ILD progression.

In-Person Versus Remote 6-Minute Walk and Incremental Shuttle Walk Distances in Advanced Lung Disease.

BACKGROUND: Field-based walk tests conducted remotely may provide an alternative method to a facility-based assessment of exercise capacity for people with advanced lung disease. This prospective study evaluated the level of agreement in the distance walked between a 6-min walk test (6MWT) and an incremental shuttle walk test performed by using standard in-person procedures and test variations and settings. METHODS: Adults with advanced lung disease underwent 4 study visits: (i) one in-person standard 6MWT (30-m corridor) and one in-person treadmill 6MWT, (ii) a remote 6MWT in a home setting (10-m corridor), (iii) 2 in-person standard incremental shuttle walk tests (10-m corridor), and (iv) a remote incremental shuttle walk test in a home setting (10-m corridor). A medical-grade oximeter measured heart rate and oxygen saturation before, during, and for 2 min after the tests. RESULTS: Twenty-eight participants were included (23 men [82%]; 64 (57-67) y old; 19 with interstitial lung disease [68%] and 9 with COPD [32%]; and 26 used supplemental oxygen (93%) [exertional [Formula: see text] of 0.46 ± 0.1]). There was no agreement between the tests. Greater walking distances were achieved with standard testing procedures: in-person 6MWT versus treadmill 6MWT (355 ± 68 vs 296 ± 97; P = .001; n = 28), in-person 6MWT versus remote 6MWT (349 ± 68 vs 293 ± 84; P = .001; n = 24), and in-person incremental shuttle walk test versus remote incremental shuttle walk test (216 ± 62 vs 195 ± 63; P = .03; n = 22). CONCLUSIONS: Differences in the distance walked may have resulted from different track lengths, widths, and walking surfaces. This should be considered in test interpretation if tests are repeated under different conditions.

Significance of preoperative exercise oxygen desaturation in lung cancer with interstitial lung disease.

OBJECTIVES: Evaluating the diffusing capacity for carbon monoxide (DLco) is crucial for patients with lung cancer and interstitial lung disease. However, the clinical significance of assessing exercise oxygen desaturation (EOD) remains unclear. METHODS: We retrospectively analysed 186 consecutive patients with interstitial lung disease who underwent lobectomy for non-small-cell lung cancer. EOD was assessed using the two-flight test (TFT), with TFT positivity defined as ≥5% SpO2 reduction. We investigated the impact of EOD and predicted postoperative (ppo)%DLco on postoperative complications and prognosis. RESULTS: A total of 106 (57%) patients were identified as TFT-positive, and 58 (31%) patients had ppo% DLco < 30%. Pulmonary complications were significantly more prevalent in TFT-positive patients than in TFT-negative patients (52% vs 19%, P < 0.001), and multivariable analysis revealed that TFT-positivity was an independent risk factor (odds ratio 3.46, 95% confidence interval 1.70-7.07, P < 0.001), whereas ppo%DLco was not (P = 0.09). In terms of long-term outcomes, both TFT positivity and ppo%DLco < 30% independently predicted overall survival. We divided the patients into 4 groups based on TFT positivity and ppo%DLco status. TFT-positive patients with ppo%DLco < 30% exhibited the significantly lowest 5-year overall survival among the 4 groups: ppo%DLco ≥ 30% and TFT-negative, 54.2%; ppo%DLco < 30% and TFT-negative, 68.8%; ppo%DLco ≥ 30% and TFT-positive, 38.1%; and ppo%DLco < 30% and TFT-positive, 16.7% (P = 0.001). CONCLUSIONS: Incorporating EOD evaluation was useful for predicting postoperative complications and survival outcomes in patients with lung cancer and interstitial lung disease.

Mechanisms and consequences of excess exercise ventilation in fibrosing interstitial lung disease.

The causes and consequences of excess exercise ventilation (EEV) in patients with fibrosing interstitial lung disease (f-ILD) were explored. Twenty-eight adults with f-ILD and 13 controls performed an incremental cardiopulmonary exercise test. EEV was defined as ventilation-carbon dioxide output (⩒E-⩒CO2) slope ≥36 L/L. Patients showed lower pulmonary function and exercise capacity compared to controls. Lower DLCO was related to higher ⩒E-⩒CO2 slope in patients (P<0.05). 13/28 patients (46.4%) showed EEV, reporting higher dyspnea scores (P=0.033). Patients with EEV showed a higher dead space (VD)/tidal volume (VT) ratio while O2 saturation dropped to a greater extent during exercise compared to those without EEV. Higher breathing frequency and VT/inspiratory capacity ratio were observed during exercise in the former group (P<0.05). An exaggerated ventilatory response to exercise in patients with f-ILD is associated with a blunted decrease in the wasted ventilation in the physiological dead space and greater hypoxemia, prompting higher inspiratory constraints and breathlessness.

Enhancing exercise tolerance in interstitial lung disease with high-flow nasal cannula oxygen therapy: A randomized crossover trial.

BACKGROUND AND OBJECTIVE: Interstitial lung disease (ILD) is characterized by dyspnoea on exertion and exercise-induced hypoxaemia. High-flow nasal cannula (HFNC) therapy reduces the respiratory workload through higher gas flow and oxygen supplementation, which may affect exercise tolerance. This study aimed to examine the effects of oxygen and gas flow rates through HFNC therapy on exercise tolerance in ILD patients. METHODS: We conducted three-treatment crossover study. All ILD patients performed the exercises on room air (ROOM AIR setting: flow, 0 L/min; fraction of inspired oxygen [FiO2], 0.21), HFNC (FLOW setting: flow 40 L/min, FiO2 0.21), and HFNC with oxygen supplementation (FLOW + OXYGEN setting: flow 40 L/min, FiO2 0.6). The primary endpoint was the endurance time, measured using constant-load cycle ergometry exercise testing at a peak work rate of 80%. RESULTS: Twenty-five participants (10 men, 71.2 ± 6.7 years) were enrolled. The increase in exercise duration between the ROOM AIR and FLOW was 46.3 s (95% CI, -6.1 to 98.7; p = 0.083), and the FLOW and FLOW + OXYGEN was 91.5 s (39.1-143.9; p < 0.001). The percutaneous oxygen saturation (SpO2) at rest was significantly higher with the FLOW + OXYGEN setting than with the ROOM AIR and FLOW settings, and the difference persisted during exercise. At equivalent time points during exercise, the SpO2 with the FLOW setting was significantly higher than that with the ROOM AIR setting. CONCLUSION: Oxygen supplementation in HFNC therapy improved exercise tolerance and SpO2. We found that gas flow alone did not improve exercise tolerance, but improved SpO2 during exercise.

Contribution of Left Ventricular Diastolic Dysfunction to Survival and Breathlessness in Systemic Sclerosis-Associated Interstitial Lung Disease.

OBJECTIVE: To explore the effect of left ventricular (LV) diastolic dysfunction (LVDD) in systemic sclerosis (SSc)-associated interstitial lung disease (ILD), and to investigate SSc-specific associations and clinical correlates of LVDD. METHODS: There were 102 Australian Scleroderma Cohort Study participants with definite SSc and radiographic ILD included. Diastolic function was classified as normal, indeterminate, or abnormal according to 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for assessment of LV diastolic function. Associations between clinical features and patient- and physician-reported dyspnea were evaluated using logistic regression. Survival analyses were performed using Kaplan-Meier survival estimates and Cox regression modeling. RESULTS: LVDD was identified in 26% of participants, whereas 19% had indeterminate and 55% had normal diastolic function. Those with ILD and LVDD had increased mortality (hazard ratio 2.4, 95% CI 1.0-5.7; P = 0.05). After adjusting for age and sex, those with ILD and LVDD were more likely to have severe dyspnea on the Borg Dyspnoea Scale (odds ratio [OR] 2.6, 95% CI 1.0-6.6; P = 0.05) and numerically more likely to record World Health Organization Function Class II or higher dyspnea (OR 4.2, 95% CI 0.9-20.0; P = 0.08). Older age (95% CI 1.0-6.4; P = 0.05), hypertension (OR 5.0, 95% CI 1.8-13.8; P < 0.01), and ischemic heart disease (OR 4.8, 95% CI 1.5-15.7; P < 0.01) were all associated with LVDD, as was proximal muscle atrophy (OR 5.0, 95% CI 1.9-13.6; P < 0.01) and multimorbidity (Charlson Comorbidity Index scores ≥ 4, OR 3.0, 95% CI 1.1-8.7; P = 0.04). CONCLUSION: LVDD in SSc-ILD is more strongly associated with traditional LVDD risk factors than SSc-specific factors. LVDD is associated with worse dyspnea and survival in those with SSc-ILD.

Peripheral interstitial lung abnormalities on LDCT in an asymptomatic, nonsmoking Chinese urban cohort.

To retrospectively investigate the imaging features and the related influencing factors of peripheral interstitial lung abnormalities (PILA) that caused "normal aging" by low-dose computed tomography (LDCT) in an nonsmoking, asymptomatic Chinese urban cohort. The clinical data of 733 subjects who underwent chest LDCT were retrospectively collected. The computed tomography (CT) signs of PILA (interlobular septal thickening [ILST], intralobular interstitial thickening [ILIT], ground-glass opacity [GGO], reticular shadow [RS], subpleural line [SL]) were evaluated at 6 levels and statistically analyzed. The effects of age, sex, body mass index (BMI), blood pressure (BP), and blood biochemistry parameters on ILST, ILIT, and RS were analyzed by Binary Logistic regression analysis. Significant age differences in PILA were found. None of the 5 PILA CT signs (GGO, ILST, ILIT, RS, and SL) was observed in subjects under 40 years old, while in subjects over 40 years old, the incidence of PILA increased with age. All 5 CT signs of PILA were significantly different among the subjects aged 18 to 49, 50 to 69, and 70 to 79 (P < .05). There was no significant sex difference in PILA. Among age, sex, BMI, BP, and laboratory biochemistry parameters, only age had a significant effect on ILST, ILIT, and RS. LDCT can be used as a noninvasive method to evaluate the PILA. PILA were mainly affected by age, while sex, BMI, BP, and laboratory biochemistry parameters had little effect on PILA. PILA observed before the age of 40 years should be considered an abnormal finding, whereas it is common in individuals over 70.

[Profile of patients evaluated with the Carbon Monoxide Diffusion Capacity Test: A Chilean experience]. / Perfil de pacientes evaluados con el Test de Capacidad de Difusión de Monóxido de Carbono: Una experiencia chilena.

BACKGROUND: The carbon monoxide diffusion capacity test (DLCO) is a clinically useful, routine, non-invasive lung function assessment to determine the status of lung function in patients with chronic disorders such as interstitial lung disease (ILD). AIM: To describe the sociodemographic and clinical profile of users of the DLCO test in Valdivia, Chile. MATERIALS AND METHODS: Observational, retrospective, documentary-based study. From the records of 490 patients who underwent the DLCO test between 2017 and 2019, sociodemographic and clinical characteristics and reports of cigarette consumption are described, such as cigarettes/d and pack-year index (PYI), comparing by sex. RESULTS: The highest proportion of those evaluated were women (61%), with a median age of 65 years, higher in women (66 vs. 64 years; p = 0.0361). The majority consulted for ILD (54.5%). According to nutritional status, 38% presented pre-obesity and 24.7% obesity I (24.7%), highlighting that 40.5% of women and 33% of men were in some category of obesity. Among those who reported information on cigarette consumption (n = 346, 70.6%), 14.7% (n = 51) were current consumers, with a median consumption of 10 cigarettes/d, without differences by sex. Among exsmokers (n = 144; 50% men/women) there was significantly less daily (5 vs 15; p = 0.0300) and IPA (7 vs 18; p = 0.0083) consumption in women. CONCLUSIONS: In DLCO users, the main consultation diagnosis was ILD. High frequency of obesity and smoking stood out, with no difference in consumption by sex in current smokers, but yes in ex-smokers.

Fisiología respiratoria: fisiología de las enfermedades pulmonares restrictivas / Pathophysiology of pulmonary restrictive diseases

Las enfermedades restrictivas comprenden un grupo heterogéneo de trastornos que se caracterizan por una alteración en la distensibilidad pulmonar, generada por enfermedades del parénquima o intersticio pulmonar o por problemas extrapulmonares (alteraciones de la caja torácica o enfermedades neuromusculares). Presentan un patrón característico en las pruebas de función pulmonar, relación VEF1/ FVC normal o aumentada con CVF disminuida, VEF1 disminuido leve o normal y capacidad pulmonar total disminuida (CPT). Su manejo es complejo debido a la dificultad para establecer el diagnóstico diferencial, por lo que se recomienda una derivación precoz a un especialista en enfermedades respiratorias y el enfrentamiento por un equipo multidisciplinario.

Restrictive diseases comprise a heterogeneous group of disorders characterized by an alteration in lung compliance, generated by diseases of the lung parenchyma or interstitium, as well as by extrapulmonary problems (abnormalities of the rib cage or neuromuscular diseases). They present a characteristic pattern in pulmonary function tests, with decreased FVC (forced vital capacity), slightly decreased or normal FEV1 (forced expiratory volume in 1 second), normal or increased FEV1/FVC ratio, and decreased total lung capacity. Its management is complex due to the difficulty in establishing the differential diagnosis, so early referral to a specialist in respiratory diseases and confrontation by a multidisciplinary team is recommended.

Quantitative evaluation of disease severity in connective tissue disease-associated interstitial lung disease by dual-energy computed tomography.

BACKGROUND: High-resolution computed tomography (HRCT) is recommended diagnosing and monitoring connective tissue disease-associated interstitial lung disease (CTD-ILD). Quantitative computed tomography has the potential to precisely assess the radiological severity of CTD-ILD, but has still been under study. OBJECTIVE: To investigate whether dual-energy computed tomography (DECT), a novel quantitative technique, can be used for quantitative severity assessment in CTD-ILD. METHODS: This cross sectional study recruited adult CTD-ILD patients who underwent DECT scans from the ICE study between October 2019 and November 2021. DECT parameters, including effective atomic number (Zeff), lung (lobe) volume, and monochromatic CT number (MCTN) of each lung lobe, were evaluated. CTD-ILD was classified into extensive CTD-ILD and limited CTD-ILD by staging algorithm using combined forced vital capacity (FVC)%predicted and total extent of ILD (TEI) on CT. Dyspnea, cough, and life quality were scored by Borg dyspnea score, Leicester cough questionnaire (LCQ), and short-form 36 health survey questionnaire (SF-36), respectively. RESULTS: There was a total of 147 patients with DECT scans enrolled. Higher Zeff value (3.104 vs 2.256, p < 0.001), higher MCTN (- 722.87 HU vs - 802.20 HU, p < 0.001), and lower lung volume (2309.51cm3 vs 3475.21cm3, p < 0.001) were found in extensive CTD-ILD compared with limited CTD-ILD. DECT parameters had significant moderate correlations with FVC%predicted (|r|= 0.542-0.667, p < 0.01), DLCO%predicted (|r|= 0.371-0.427, p < 0.01), and TEI (|r|= 0.485-0.742, p < 0.01). Receiver operating characteristic (ROC) analysis indicated MCTN averaged over the whole lung had the best performance for extensive CTD-ILD discrimination (AUC = 0.901, cut-off: - 762.30 HU, p < 0.001), with a sensitivity of 82.1% and a specificity of 85.4%. The Zeff value was the independent risk factor for dyspnea (OR = 3.644, 95% CI: 1.846-7.192, p < 0.001) and cough (OR = 3.101, 95% CI: 1.528-6.294, p = 0.002), and lung volume significantly contributed to the mental component summary (MCS) in SF-36 (standardized ß = 0.198, p < 0.05). CONCLUSIONS: DECT can be applied to evaluate the severity of CTD-ILD.

Longstanding Phenytoin Use as a Cause of Progressive Dyspnea.

CASE PRESENTATION: A 54-year-old South African man with a medical history of type 2 diabetes mellitus, seizure disorder, OSA, and latent TB presented to the ER with gradually progressive dyspnea over months. He also reported occasional dry cough and fatigue at presentation but denied fever, chills, chest pain, leg swelling, palpitations, or lightheadedness. He was treated with a course of levofloxacin for presumed community-acquired pneumonia as an outpatient without improvement and had tested negative for COVID-19. He denied occupational or environmental exposures or sick contacts, though he had traveled back to South Africa 1 year before presentation. He had complex partial seizures for the past 22 years, which had been well controlled on phenytoin (300 mg daily). His other home medications included dulaglutide, sertraline, and atorvastatin and had no recent changes. He quit smoking 30 years ago after smoking one pack per day for 10 years.