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).

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.

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.

Integrative analysis of lung molecular signatures reveals key drivers of systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease is a significant comorbidity and the leading cause of mortality in patients with systemic sclerosis. Transcriptomic data of systemic sclerosis-associated interstitial lung disease (SSc-ILD) were analysed to evaluate the salient molecular and cellular signatures in comparison with those in related pulmonary diseases and to identify the key driver genes and target molecules in the disease module. METHODS: A transcriptomic dataset of lung tissues from patients with SSc-ILD (n=52), idiopathic pulmonary fibrosis (IPF) (n=549), non-specific interstitial pneumonia (n=49) and pulmonary arterial hypertension (n=81) and from normal healthy controls (n=331) was subjected to filtration of differentially expressed genes, functional enrichment analysis, network-based key driver analysis and kernel-based diffusion scoring. The association of enriched pathways with clinical parameters was evaluated in patients with SSc-ILD. RESULTS: SSc-ILD shared key pathogenic pathways with other fibrosing pulmonary diseases but was distinguishable in some pathological processes. SSc-ILD showed general similarity with IPF in molecular and cellular signatures but stronger signals for myofibroblasts, which in SSc-ILD were in a senescent and apoptosis-resistant state. The p53 signalling pathway was the most enriched signature in lung tissues and lung fibroblasts of SSc-ILD, and was significantly correlated with carbon monoxide diffusing capacity of lung, cellular senescence and apoptosis. EEF2, EFF2K, PHKG2, VCAM1, PRKACB, ITGA4, CDK1, CDK2, FN1 and HDAC1 were key regulators with high diffusion scores in the disease module. CONCLUSIONS: Integrative transcriptomic analysis of lung tissues revealed key signatures of fibrosis in SSc-ILD. A network-based Bayesian approach provides deep insights into key regulatory genes and molecular targets applicable to treating SSc-ILD.

Detection and Early Referral of Patients With Interstitial Lung Abnormalities: An Expert Survey Initiative.

BACKGROUND: Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILA are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral. RESEARCH QUESTION: Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs? STUDY DESIGN AND METHODS: Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement. RESULTS: Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System "S-modifier" [Lung-RADS; which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD. INTERPRETATION: Guidance was established for identifying clinically relevant ILA, subsequent referral, and follow-up. These results lay the foundation for developing practical guidance on managing patients with ILA.

Progressive fibrosing interstitial lung disease: prevalence and clinical outcome.

BACKGROUND: The progressive fibrosing (PF) phenotype of interstitial lung disease (ILD) is characterised by worsening respiratory symptoms, lung function, and extent of fibrosis on high-resolution computed tomography. We aimed to investigate the prevalence and clinical outcomes of PF-ILD in a real-world cohort and assess the prognostic significance of the PF-ILD diagnostic criteria. METHODS: Clinical data of patients with fibrosing ILD other than idiopathic pulmonary fibrosis (IPF) consecutively diagnosed at a single centre were retrospectively reviewed. A PF phenotype was defined based on the criteria used in the INBUILD trial. RESULTS: The median follow-up duration was 62.7 months. Of the total of 396 patients, the mean age was 58.1 years, 39.9% were men, and rheumatoid arthritis-ILD was the most common (42.4%). A PF phenotype was identified in 135 patients (34.1%). The PF-ILD group showed lower forced vital capacity and total lung capacity (TLC) than the non-PF-ILD group. The PF-ILD group also showed poorer survival (median survival, 91.2 months vs. not reached; P < 0.001) than the non-PF-ILD group. In multivariable Cox analysis adjusted for age, DLCO, HRCT pattern, and specific diagnosis, PF phenotype was independent prognostic factor (hazard ratio, 3.053; P < 0.001) in patients with fibrosing ILD. Each criterion of PF-ILD showed similar survival outcomes. CONCLUSIONS: Our results showed that approximately 34% of patients with non-IPF fibrosing ILD showed a progressive phenotype and a poor outcome similar to that of IPF, regardless of the diagnostic criteria used.

Progressive fibrosis in interstitial lung diseases - proposed definition and management.

Interstitial lung diseases may have an unpredictably progressive course, which is manifested as progression of pulmonary fibrosis, causing an increasing impairment of lung function affecting a poor prognosis. The possibility of an effective antifibrotic treatment is a chance for patients to slow down the progression of the disease, perhaps even extend their life. For this reason, standardization of the definition as well as identification criteria for progressive fibrosis interstitial lung disease is a method for optimizing the management in this group of patients.