[Interstitial Lung Disease associated with Connective Tissue Diseases]. / Interstitielle Pneumopathien bei Konnektivitiden.

INTRODUCTION: Interstitial Lung Disease associated with Connective Tissue Diseases Abstract: Interstitial lung diseases (ILD) are in up to one-third of cases associated with connective tissue diseases (CTD). In systemic sclerosis, rheumatoid arthritis, polymyositis/dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease, an associated ILD significantly increases morbidity and mortality. The diagnostic workup for suspected CTD-ILD includes a range of functional, radiological, laboratory, and, if necessary, invasive tests. A thorough medical history and physical examination with targeted rheumatological diagnosis is particularly important. Also, patients with unclassified ILDs should be evaluated thoroughly for any underlying CTD. Pharmacological treatment options for CTD-ILD differ significantly from those for other ILDs. In addition to short-term glucocorticoids, antimetabolites and biological agents are often used. Antifibrotic drugs have also been successfully used in CTD-ILDs. The decision on whether and which immunosuppressive and/or antifibrotic therapy is indicated depends on the underlying disease, disease activity, extrapulmonary manifestations, severity of organ involvement, ILD progression, comorbidities, and patient preferences. Complex treatment decisions are ideally made in multidisciplinary expert teams.

Multidisciplinary recommendations for essential baseline functional and laboratory tests to facilitate early diagnosis and management of immune-related adverse events among cancer patients.

Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2-3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment.

Pulmonary Recovery 12 Months after Non-Severe and Severe COVID-19: The Prospective Swiss COVID-19 Lung Study.

BACKGROUND: Lung function impairment persists in some patients for months after acute coronavirus disease 2019 (COVID-19). Long-term lung function, radiological features, and their association remain to be clarified. OBJECTIVES: We aimed to prospectively investigate lung function and radiological abnormalities over 12 months after severe and non-severe COVID-19. METHODS: 584 patients were included in the Swiss COVID-19 lung study. We assessed lung function at 3, 6, and 12 months after acute COVID-19 and compared chest computed tomography (CT) imaging to lung functional abnormalities. RESULTS: At 12 months, diffusion capacity for carbon monoxide (DLCOcorr) was lower after severe COVID-19 compared to non-severe COVID-19 (74.9% vs. 85.2% predicted, p < 0.001). Similarly, minimal oxygen saturation on 6-min walk test and total lung capacity were lower after severe COVID-19 (89.6% vs. 92.2%, p = 0.004, respectively, 88.2% vs. 95.1% predicted, p = 0.011). The difference for forced vital capacity (91.6% vs. 96.3% predicted, p = 0.082) was not statistically significant. Between 3 and 12 months, lung function improved in both groups and differences in DLCO between non-severe and severe COVID-19 patients decreased. In patients with chest CT scans at 12 months, we observed a correlation between radiological abnormalities and reduced lung function. While the overall extent of radiological abnormalities diminished over time, the frequency of mosaic attenuation and curvilinear patterns increased. CONCLUSIONS: In this prospective cohort study, patients who had severe COVID-19 had diminished lung function over the first year compared to those after non-severe COVID-19, albeit with a greater extent of recovery in the severe disease group.

Prevalence and assessment of frailty in interstitial lung disease - a systematic review and meta-analysis.

BACKGROUND: Frailty is a multisystem dysregulation that challenges homeostasis and increases vulnerability towards stressors. In patients with interstitial lung diseases (ILD) frailty is associated with poorer lung function, greater physical impairment, and higher symptom burden. Our understanding of the prevalence of frailty in ILD and consequently its impact on the ILD population is limited. OBJECTIVE AND METHODS: We aimed to systematically review frailty assessment tools and to determine frailty prevalence across different ILD cohorts. Meta-analyses were used to calculate the pooled prevalence of frailty in the ILD population. RESULTS: We identified 26 studies (15 full-texts, 11 conference abstracts) including a total of 4614 patients with ILD. The most commonly used frailty assessment tools were the Fried Frailty Phenotype (FFP), the Short Physical Performance Battery (SPPB), and the cumulative Frailty Index (FI). Data allowed for meta-analyses of FFP and SPPB prevalence. The pooled prevalence of frailty was 35% (95% CI 25%-45%) by FFP, and 19% (95% CI 12%-28%) by SPPB. CONCLUSIONS: Frailty is common in ILD, with considerable variability of frailty prevalence depending on the frailty assessment tool used. These findings highlight the importance of frailty in ILD and the need for a standardized approach to frailty assessment in this population.

Dehydroepiandrosterone in fibrotic interstitial lung disease: a translational study.

BACKGROUND: Dehydroepiandrosterone (DHEA) is a precursor sex hormone with antifibrotic properties. The aims of this study were to investigate antifibrotic mechanisms of DHEA, and to determine the relationship between DHEA-sulfate (DHEAS) plasma levels, disease severity and survival in patients with fibrotic interstitial lung diseases (ILDs). METHODS: Human precision cut lung slices (PCLS) and normal human lung fibroblasts were treated with DHEA and/or transforming growth factor (TGF)-ß1 before analysis of pro-fibrotic genes and signal proteins. Cell proliferation, cytotoxicity, cell cycle and glucose-6-phosphate dehydrogenase (G6PD) activity were assessed. DHEAS plasma levels were correlated with pulmonary function, the composite physiologic index (CPI), and time to death or lung transplantation in a derivation cohort of 31 men with idiopathic pulmonary fibrosis (IPF) and in an independent validation cohort of 238 men and women with fibrotic ILDs. RESULTS: DHEA decreased the expression of pro-fibrotic markers in-vitro and ex-vivo. There was no cytotoxic effect for the applied concentrations, but DHEA interfered in proliferation by modulating the cell cycle through reduction of G6PD activity. In men with IPF (derivation cohort) DHEAS plasma levels in the lowest quartile were associated with poor lung function and higher CPI (adjusted OR 1.15 [95% CI 1.03-1.38], p = 0.04), which was confirmed in the fibrotic ILD validation cohort (adjusted OR 1.03 [95% CI 1.00-1.06], p = 0.01). In both cohorts the risk of early mortality was higher in patients with low DHEAS levels, after accounting for potential confounding by age in men with IPF (HR 3.84, 95% CI 1.25-11.7, p = 0.02), and for age, sex, IPF diagnosis and prednisone treatment in men and women with fibrotic ILDs (HR 3.17, 95% CI 1.35-7.44, p = 0.008). CONCLUSIONS: DHEA reduces lung fibrosis and cell proliferation by inducing cell cycle arrest and inhibition of G6PD activity. The association between low DHEAS levels and disease severity suggests a potential prognostic and therapeutic role of DHEAS in fibrotic ILD.

A contemporary practical approach to the multidisciplinary management of unclassifiable interstitial lung disease.

Fibrotic interstitial lung diseases (ILDs) frequently have nonspecific and overlapping clinical and radiological features, resulting in ∼10-20% of patients with ILD lacking a clear diagnosis and thus being labelled with unclassifiable ILD. The objective of this review is to describe how patients with unclassifiable ILD should be evaluated, and what impact specific clinical, radiological and histopathological features may have on management decisions, focusing on patients with a predominantly fibrotic phenotype. We highlight recent data that have suggested an increasing role for antifibrotic medications in a variety of fibrotic ILDs, but justify the ongoing importance of making an accurate ILD diagnosis given the benefit of immunomodulatory therapies in many patient populations. We provide a practical approach to support management decisions that can be used by clinicians and tested by clinical researchers, and further identify the need for additional research to support a rational and standardised approach to the management of patients with unclassifiable ILD.

Pulmonary function and radiological features 4 months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.

BACKGROUND: The infectious coronavirus disease 2019 (COVID-19) pandemic is an ongoing global healthcare challenge. Up to one-third of hospitalised patients develop severe pulmonary complications and acute respiratory distress syndrome. Pulmonary outcomes following COVID-19 are unknown. METHODS: The Swiss COVID-19 lung study is a multicentre prospective cohort investigating pulmonary sequelae of COVID-19. We report on initial follow-up 4 months after mild/moderate or severe/critical COVID-19 according to the World Health Organization severity classification. RESULTS: 113 COVID-19 survivors were included (mild/moderate n=47, severe/critical n=66). We confirmed several comorbidities as risk factors for severe/critical disease. Severe/critical disease was associated with impaired pulmonary function, i.e. diffusing capacity of the lung for carbon monoxide (D LCO) % predicted, reduced 6-min walk distance (6MWD) and exercise-induced oxygen desaturation. After adjustment for potential confounding by age, sex and body mass index (BMI), patients after severe/critical COVID-19 had a D LCO 20.9% pred (95% CI 12.4-29.4% pred, p=0.01) lower at follow-up. D LCO % pred was the strongest independent factor associated with previous severe/critical disease when age, sex, BMI, 6MWD and minimal peripheral oxygen saturation at exercise were included in the multivariable model (adjusted odds ratio per 10% predicted 0.59, 95% CI 0. 37-0.87; p=0.01). Mosaic hypoattenuation on chest computed tomography at follow-up was significantly associated with previous severe/critical COVID-19 including adjustment for age and sex (adjusted OR 11.7, 95% CI 1.7-239; p=0.03). CONCLUSIONS: 4 months after severe acute respiratory syndrome coronavirus 2 infection, severe/critical COVID-19 was associated with significant functional and radiological abnormalities, potentially due to small-airway and lung parenchymal disease. A systematic follow-up for survivors needs to be evaluated to optimise care for patients recovering from COVID-19.

Performance of a diagnostic algorithm for fibrotic hypersensitivity pneumonitis. A case-control study.

BACKGROUND: The differential diagnosis fibrotic hypersensitivity pneumonitis (HP) versus idiopathic pulmonary fibrosis (IPF) is important but challenging. Recent diagnostic guidelines for HP emphasize including multidisciplinary discussion (MDD) in the diagnostic process, however MDD is not comprehensively available. We aimed to establish the diagnostic accuracy and prognostic validity of a previously proposed HP diagnostic algorithm that foregoes MDD. METHODS: We tested the algorithm in patients with an MDD diagnosis of fibrotic HP or IPF (case control study) and determined diagnostic test performances for diagnostic confidences of ≥ 90% and ≥ 70%. Prognostic validity was established using Cox proportional hazards models. RESULTS: Thirty-one patients with fibrotic HP and 50 IPF patients were included. The algorithm-derived ≥ 90% confidence level for HP had high specificity (0.94, 95% confidence interval [CI] 0.83-0.99), but low sensitivity (0.35 [95%CI 0.19-0.55], J-index 0.29). Test performance was improved for the ≥ 70% confidence level (J-index 0.64) with a specificity of 0.90 (95%CI 0.78-0.97), and a sensitivity of 0.74 (95%CI 0.55-0.88). MDD fibrotic HP diagnosis was strongly associated with lower risk of death (adjusted hazard ratio [HR] 0.10 [0.01-0.92], p = 0.04), whereas the algorithm-derived ≥ 70% and ≥ 90% confidence diagnoses were not significantly associated with survival (adjusted HR 0.37 [0.07-1.80], p = 0.22, and adjusted HR 0.41 [0.05-3.25], p = 0.39, respectively). CONCLUSION: The algorithm-derived ≥ 70% diagnostic confidence had satisfactory test performance for MDD-HP diagnosis, with insufficient sensitivity for ≥ 90% confidence. The lowest risk of death in the MDD-derived HP diagnosis validates the reference standard and suggests that a diagnostic algorithm not including MDD, might not replace the latter.

Functional ageing in fibrotic interstitial lung disease: the impact of frailty on adverse health outcomes.

BACKGROUND: Accelerated biological and functional ageing is common in fibrotic interstitial lung disease (ILD); however, their impact on adverse health outcomes has not been evaluated in this population. METHODS: Patients were prospectively recruited from a specialised ILD clinic. Functional ageing was determined by frailty index and biological age by measurement of absolute telomere length (aTL) from patients' peripheral blood leukocytes. Adverse health outcomes included health-related quality of life (St George's Respiratory Questionnaire), number and length of respiratory and non-respiratory hospitalisations, medication tolerability and time to death or lung transplantation. Multivariable models were used to determine the risks and rates of adverse health outcomes associated with the frailty index and aTL. RESULTS: 540 patients with fibrotic ILD, including 100 with idiopathic pulmonary fibrosis (IPF), provided 749 frailty index assessments, with 189 patients providing blood samples. The frailty index was strongly associated with quality of life, rate of hospitalisation, time to hospital discharge and mortality, including adjustment for age, sex, disease severity and IPF diagnosis. Mortality prognostication was improved by the addition of the frailty index to commonly used clinical parameters and previously validated composite indices. Conversely, aTL was not associated with most adverse health outcomes. The effect of chronological age on outcomes was mediated primarily by the frailty index, and to a lesser extent by aTL. CONCLUSIONS: Functional ageing is associated with adverse health outcomes in patients with fibrotic ILD, indicating the need for consideration of the individual functional age into clinical decision-making.

Progression of fibrosing interstitial lung disease.

Fibrotic interstitial lung diseases (ILDs) are often challenging to diagnose and classify, but an accurate diagnosis has significant implications for both treatment and prognosis. A subset of patients with fibrotic ILD experience progressive deterioration in lung function, physical performance, and quality of life. Several risk factors for ILD progression have been reported, such as male sex, older age, lower baseline pulmonary function, and a radiological or pathological pattern of usual interstitial pneumonia. Morphological similarities, common underlying pathobiologic mechanisms, and the consistently progressive worsening of these patients support the concept of a progressive fibrosing (PF)-ILD phenotype that can be applied to a variety of ILD subtypes. The conventional approach has been to use antifibrotic medications in patients with idiopathic pulmonary fibrosis (IPF) and immunosuppressive medications in patients with other fibrotic ILD subtypes; however, recent clinical trials have suggested a favourable treatment response to antifibrotic therapy in a wider variety of fibrotic ILDs. This review summarizes the literature on the evaluation and management of patients with PF-ILD, and discusses questions relevant to applying recent clinicial trial findings to real-world practice.

Frailty in patients with interstitial lung disease.

PURPOSE OF REVIEW: The incidence of age-related diseases such as interstitial lung disease (ILD) is rising, and the importance of multimorbidity and accumulation of health deficits in patients with chronic lung diseases is increasingly recognized. There are multiple relationships between aging and ILD on a demographic and a biological level. Frailty conceptualizes the decline of a patient's physiological reserves and complements the chronological and biological aspects of aging. RECENT FINDINGS: Frailty affects more than 50% of patients with ILD, with respiratory impairment, accelerated biological aging, comorbidities, medication adverse effects, and social factors collectively playing important roles. Frailty is an independent risk factor for adverse health outcomes such as hospitalizations and early mortality, including before and after lung transplant. Given the multicomponent determinants of frailty, programs such as pulmonary rehabilitation are promising strategies for managing this complex issue. SUMMARY: Frailty is a common risk factor for adverse outcomes in patients with ILD. The multiple pathways leading to frailty are not completely understood, and further studies are needed to determine the optimal tools for assessment and to develop strategies to prevent and counteract frailty in the aging ILD population.

Evaluation of a Novel Ear Pulse Oximeter: Towards Automated Oxygen Titration in Eyeglass Frames.

Current oxygen delivery modes lack monitoring and can be cumbersome for patients with chronic respiratory diseases. Integrating a pulse oximeter and nasal oxygen cannulas into eyeglasses would reduce the burden of current solutions. An ear pulse oximeter (OxyFrame) was evaluated on 16 healthy volunteers and 20 hypoxemic patients with chronic respiratory diseases undergoing a prespecified protocol simulating daily activities. Correlation, error, and accuracy root mean square error (ARMS) were calculated to compare SpO2 measured by OxyFrame, a standard pulse oximeter (MASIMO), and arterial blood gas analysis (aBGA). SpO2 measured by OxyFrame and MASIMO correlated strongly in volunteers, with low error and high accuracy (r = 0.85, error = 0.2 ± 2.9%, ARMS = 2.88%). Performances were similar in patients (r = 0.87, error 0 ± 2.5%, ARMS = 2.49% compared with MASIMO; and r = 0.93, error = 0.4 ± 1.9%, ARMS = 1.94% compared with aBGA). However, the percentage of rejected measurements was high (volunteers 77.2%, patients 46.9%). The OxyFrame cavum conchae pulse oximeter was successfully evaluated, and demonstrated accurate SpO2 measurements, compliant with ISO 80601-2-61:2017. Several reasons for the high rejection rate were identified, and potential solutions were proposed, which might be valuable for optimization of the sensor hardware.

Body composition, muscle function, and physical performance in fibrotic interstitial lung disease: a prospective cohort study.

BACKGROUND: Patients with fibrotic interstitial lung disease (ILD) are frequently physically inactive and many ILD subtypes are characterized by risk factors for myopathy; however, the importance of body composition, muscle strength, and physical performance in this population is largely unknown. METHODS: Patients were prospectively recruited from a specialized ILD clinic, baseline characteristics were collected from the clinical record, pulmonary function tests were performed per established protocols, and dyspnea was measured using the University of California San Diego Shortness of Breath Questionnaire. Dual-energy X-ray absorptiometry (DXA) was used to assess body composition; handgrip strength to determine muscle strength, and 4-m gait speed to measure physical performance. RESULTS: One hundred and fifteen patients with fibrotic ILD including 40 patients with idiopathic pulmonary fibrosis were recruited. The mean age was 69+/- 10 years in men (62% of the cohort), and 66+/- 9 years in women, with mild and moderate reduction in FVC and DLCO, respectively, for both sexes. ILD severity (measured by FVC %-predicted, DLCO %-predicted, or the Composite Physiologic Index in separate models) significantly predicted muscle mass and percent body fat including with adjustment for age, sex, and weight. ILD severity was associated with grip strength and gait speed independent from body composition. CONCLUSIONS: ILD severity has an important impact on body composition, particularly in men. Future studies are needed to confirm and further explore the possibility of additional pathways through which ILD directly impacts limb muscle function and physical performance.

Impact of Psychological Deficits and Pain on Physical Activity of Patients with Interstitial Lung Disease.

PURPOSE: The impact of psychological deficits and pain on physical activity has not been adequately studied in patients with fibrotic interstitial lung disease (ILD). We aimed to determine the association of depression, anxiety, sleep quality, and pain with physical activity in fibrotic ILD. METHODS: Waist ActiGraph activity monitors were worn for seven consecutive days to track step counts and moderate-to-vigorous physical activity (MVPA) minutes at baseline and 6-month follow-up. Psychological deficits and pain were assessed using the Hospital Anxiety and Depression Scale, the Pittsburgh Sleep Quality Index, and the Brief Pain Inventory. Multivariable linear regression was used to determine if each deficit independently predicted physical activity when adjusted for potential confounders. RESULTS: A total of 111 patients were recruited, with 91 of these patients completing the 6-month follow-up. Median step count and MVPA minutes were 3853 steps/day (interquartile range 2236-6805) and 87 (17-225) min/week at baseline, respectively, with no significant changes at follow-up. Borderline or abnormal depression and anxiety scores were present in 19% and 22% of patients, respectively. Poor sleep quality and moderate-to-severe pain were present in 61% and 9% of patients. Higher depression scores were associated with fewer baseline and follow-up step counts and lower MVPA minutes at follow-up on unadjusted analysis; higher pain severity scores were associated with fewer baseline step count. Pain severity remained an independent predictor of reduced step count after adjusting for patient's age, smoking status, ILD severity, and weather variables. CONCLUSIONS: Pain severity may be a potentially modifiable determinant of physical activity in patients with fibrotic ILD.

Unclassifiable interstitial lung disease: from phenotyping to possible treatments.

PURPOSE OF REVIEW: Accurate diagnosis of interstitial lung diseases (ILDs) can be challenging, and a substantial percentage of ILD patients remain unclassifiable even after thorough assessment by an experienced multidisciplinary team. In this review, we summarize the recent literature on the definition, prevalence, diagnosis, treatment, and prognosis of unclassifiable ILD, and also discuss important current issues and provide future perspectives on the classification of ILD. RECENT FINDINGS: Approximately 12% of patients with ILD are considered unclassifiable, with large variability across previous studies that is in part secondary to inconsistent definitions of unclassifiable ILD and other ILD subtypes. A recent International Working Group suggested that unclassifiable ILD should be defined by the absence of a leading diagnosis that is considered more likely than not after multidisciplinary discussion of all available information. Clinical features and outcomes of unclassifiable ILD are intermediate between idiopathic pulmonary fibrosis and nonidiopathic pulmonary fibrosis ILD cohorts, and choices for pharmacotherapy should be considered on a case-by-case basis. SUMMARY: Recent studies have provided additional data on the clinical features and prognosis of unclassifiable ILD, but also highlight the many uncertainties that still exist in ILD diagnosis and classification. New tools are needed to more accurately characterize patients with unclassifiable ILD.