Lung Disease Research Articles

The cGAS–STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts

Ataxia-telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association between genome instability, cellular senescence, and aging. We found that lung fibroblasts derived from ATM-deficient mice provide a versatile experimental system to explore the mechanisms driving the premature senescence of primary fibroblasts lacking ATM. Atm-/- fibroblasts failed to proliferate under ambient oxygen conditions (21%). Although they initially proliferated under physiological oxygen levels (3%), they rapidly entered senescence. In contrast, wild-type (WT) lung fibroblasts did not senesce under 3% oxygen and eventually underwent immortalization and neoplastic transformation. However, rapid senescence could be induced in WT cells either by Atm gene ablation or persistent chemical inhibition of ATM kinase activity, with senescence induced by ATM inhibition being reversible upon inhibitor removal. Moreover, the concomitant loss of ATM and p53 led to senescence evasion, vigorous growth, rampant genome instability, and subsequent immortalization and transformation. Our findings reveal that the rapid senescence of Atm-/- lung fibroblasts is driven by the collaborative action of the cGAS-STING, p38 MAPK, and p53 pathways in response to persistent DNA damage, ultimately leading to the induction of interferon-α1 and downstream interferon-stimulated genes. We propose that accelerated cellular senescence may exacerbate specific A-T symptoms, particularly contributing to the progressive, life-threatening interstitial lung disease often observed in A-T patients during adulthood.

Predictors of Cryptococcus gattii clinical presentation and outcome: An international study.

Infection by Cryptococcus gattii can lead to pulmonary or central nervous system (CNS) disease, or both. Whether site of infection and disease severity are associated with C. gattii species and lineages or with certain underlying medical conditions, or both is unclear. We conducted a retrospective cohort study to identify factors associated with site of infection and mortality among C. gattii cases. We extracted data on 258 C. gattii cases from Australia, Canada and the United States reported from 1999 to 2011. We conducted unadjusted and multivariable logistic regression analyses to evaluate factors associated with site of infection and C. gattii mortality among hospitalized cases (N=218). Hospitalized C. gattii cases with CNS and other extrapulmonary disease were younger, more likely to reside in Australia and be infected with VGI lineage but less likely to have comorbidities and die as compared to pulmonary cases. The odds of having CNS and/or other extrapulmonary disease were 9 times higher in cases with VGI infection (aOR=9.21, 95%CI=3.28-25.89). Age >70 years (aOR=6.69, 95%CI=2.44-18.30), chronic lung disease (aOR=2.62, 95%CI=1.05-6.51) and an immunocompromised status (aOR=2.08, 95%CI=1.05-6.51) were associated with higher odds of C. gattii mortality. Among hospitalized cases, C. gattii species and lineage are associated with site of infection but not with the risk of death, whereas older age and comorbidities increase the risk of death.

The burden of illness of the organ manifestations of systemic sclerosis: a pragmatic, targeted review.

This structured, targeted literature review aimed to assess the mortality, humanistic and economic burden of eight organ manifestations which are commonly experienced by systemic sclerosis patients. Identification of relevant literature was carried out by searching in Ovid MEDLINE and EMBASE, PubMed, and NHS Economic Evaluation Database in August 2023. Studies reporting original data on patients with systemic sclerosis with at least one of eight organ manifestations (interstitial lung disease and/or pulmonary hypertension, skin, peripheral vascular, musculoskeletal, gastrointestinal, cardiac or renal involvement) published within the last 15 years were included. Meta-analyses with no publication limits were also included. A total of 50 studies were identified; 37 reported mortality outcomes (including 4 meta-analyses), 9 reported humanistic burden and 11 reported economic burden outcomes. Pulmonary hypertension, cardiac and renal manifestations were generally associated with a poorer survival prognosis. Furthermore, gastrointestinal, skin and peripheral vascular manifestations were found to negatively impact health-related quality of life outcomes. Pulmonary manifestations were associated with substantial economic costs; however, the cost burden of other manifestations is insufficiently reported, despite evidence that they often require healthcare resource use. Organ manifestations experienced by patients with systemic sclerosis significantly affect patient quality of life and mortality. The economic burden of organ manifestations that are widely experienced by SSc patients such as gastrointestinal issues, is poorly understood and requires further research to quantify and understand. Improvements in diagnosis and clinical management of these systemic sclerosis-associated organ manifestations have the potential for significant alleviation of disease-related burdens.

ANALYSIS OF MULTISYSTEMIC MANIFESTATIONS OF SJÖGREN'S SYNDROME: A FOCUS ON DERMATO-OPHTHALMOLOGICAL INTERRELATIONS

Sjögren’s Syndrome (SS) is a systemic autoimmune disease known for its hallmark symptoms of dry eye and dry mouth, but it also presents a spectrum of extraglandular manifestations affecting the skin, lungs, nervous system, and other organs. This systematic review examines the multisystemic impacts of SS, highlighting advancements in diagnostics, therapeutic strategies, and clinical challenges. A comprehensive search was conducted across PubMed, MEDLINE, and Embase for studies published between 2013 and 2024, using keywords such as "Sjögren’s Syndrome," "Multisystemic Manifestations," "Autoimmune Disease," and "Extraglandular Complications." Of the 56 initially identified articles, 13 met the inclusion criteria. Findings reveal that pulmonary complications, including interstitial lung disease, occur in 9–20% of SS cases, as reported by Flament et al. (2016), emphasizing the importance of imaging and biopsy for early detection. Dermatological manifestations, such as vacuolar interface dermatitis and vasculitis, were detailed in studies by El Hasbani et al. (2023) and Kakurai et al. (2021), which underscore the need for dermatological vigilance in systemic autoimmune diseases. Neurological symptoms, including peripheral neuropathies and neuropsychiatric complications, were identified as early indicators in studies by Posso-Osorio et al. (2019) and Salehi et al. (2024), suggesting that such presentations require immediate multidisciplinary evaluation. Therapeutic advancements include the use of corticosteroids, hydroxychloroquine, and biologic agents such as rituximab, which have shown efficacy in managing systemic manifestations. Chu et al. (2020) emphasized the benefits of immunosuppressive therapy in improving systemic outcomes while acknowledging the limited efficacy for glandular symptoms. Advanced diagnostic tools like PET/CT, explored by Sharma and Chatterjee (2015), have improved diagnostic precision, aiding in the differentiation of SS from other systemic conditions. Despite these advancements, challenges remain in addressing disease heterogeneity and atypical presentations, particularly in men, children, and patients without classic glandular involvement. Standardized diagnostic protocols and tailored therapeutic strategies are needed to improve outcomes and reduce the burden of extraglandular complications.

Reconsidering the Diagnosis: Abnormal Sweat Chloride Tests in Non-CF Bronchiectasis.

While the diagnosis of cystic fibrosis (CF) is often straightforward and reliant on correlation between genetic testing and clinical signs and symptoms, there is a subset where the distinction is not nearly as clearcut. This has previously been reported in patients identified through newborn screening but not meeting full CF diagnostic criteria, earning the label of CF Screen Positive, Inconclusive Diagnosis (CFSPID) instead. A homologous diagnostic category in adults is named CF Transmembrane Conductance Regulator-Related Disorder (CFTR-RD). Through a retrospective chart review, this study reports on a relatively large adult cohort (n = 23) that presented to pulmonology clinic at a single center with intermediate or positive sweat chloride tests but non-diagnostic full CFTR gene analysis. Median sweat chloride result was 48 mmol/L, and a majority of the cohort had chronic lung disease with atypical pathogens on sputum culture, including Pseudomonas aeruginosa, non-tuberculous Mycobacteria, Acinetobacter species, amongst others. This clinical picture suggests CFTR dysfunction or similar mechanism in the absence of an identified genetic cause. Alternate chloride channels and their respective genes or candidates of genetic modifiers to the CF-phenotype could be targets of further research in this cohort or similar patients. Such genetic modifiers include loci that have been implicated in inflammation, the CFTR interactome, and/or co-/post-translational modification of CFTR.

Study of Demographic Characteristics, Management Details and Early Life Outcomes of Indigenous Infants With Chronic Neonatal Lung Disease in North Queensland.

To study the demographic characteristics, risk factors, management details and clinical outcomes to 12 months corrected age in indigenous and non-indigenous infants with chronic neonatal lung disease in North Queensland. Retrospective cohort study of infants with chronic neonatal lung disease admitted to a tertiary neonatal intensive care unit in regional Queensland from January 2015 to December 2019. There were 139 infants with chronic neonatal lung disease and 425 controls. The incidence of chronic neonatal lung disease in infants born at < 33 weeks gestational age was 32.6% versus 20.4% in indigenous and non-indigenous infants, respectively (OR 1.8, p value 0.001). Indigenous infants had significantly lower birth weight (830 g vs. 1000 g, p value 0.039), higher rate of maternal smoking during the pregnancy (57.4% vs. 25%, p value < 0.001), were less likely to be inborn (71.4% vs. 88.2%, p value 0.017) or receive adequate course of antenatal corticosteroids (30.2% vs. 59.2%, p value < 0.001), had increased incidence of grade 2 intraventricular haemorrhage (17.5% vs. 4%, p value 0.01) and were more likely to reside in a very remote locality (17.4% vs. 3.9%, p < 0.001). Identified risk factors for chronic neonatal lung disease included lower birth weight (OR 0.99, p value 0.014), lower birth gestation (OR 1.57, p value 0.003), longer duration of continuous positive airway pressure (OR 1.004, p value < 0.001), longer duration of humidified high-flow nasal prongs (OR 1.003, p < 0.001), doses of surfactant (OR 1.55, p value 0.038) and receiving post-natal steroids (OR 19.03, p < 0.001). There were no other significant differences in comorbidities, management, complications, number of hospital admissions or weight to 12-months corrected age. Indigenous infants had increased antenatal risk factors for chronic neonatal lung disease and account for a disproportionate number of cases, however, their outcomes to 12 months corrected age were similar to non-indigenous infants.

Patient perspectives on educational needs in scleroderma-interstitial lung disease.

Systemic sclerosis is a chronic and rare connective tissue disease with multiorgan effects, including interstitial lung disease (ILD). Navigating systemic sclerosis-interstitial lung disease presents a challenge for patients due to the gaps in patient education, which can impact patient health and quality of life. This study utilized the nominal group technique to identify priority knowledge gaps among patients with systemic sclerosis-interstitial lung disease and inform future educational interventions and research. We conducted four structured group sessions using the nominal group technique. Patients with systemic sclerosis-interstitial lung disease were presented with two questions that aimed to identify knowledge gaps. Following participant ranking, investigators performed a thematic analysis of the patients' responses to categorize the generated knowledge gaps. Twenty-one patients were interviewed and ranked the top three themes for the first question (What questions about your scleroderma-lung disease that you have keep you awake at night?), based on total points, as: (1) Understanding progression, its impacts on the body, and managing health changes (39.7%); (2) anticipating future symptoms and implementing strategies for management and coping (19.8%); and (3) employing and understanding non-pharmacological interventions and self-management strategies (17.5%). The top three themes for the second question (What information do you want about your scleroderma-lung disease that you cannot find?) ranked by total points were: (1) understanding progression, its impacts on the body, and managing health changes (41.3%); (2) navigating health system barriers (16.7%); and (3) research efforts toward treating scleroderma (10.3%). Our study underscores the importance of understanding the educational needs of patients with systemic sclerosis-interstitial lung disease. Patient responses emphasize the need to comprehensively address concerns about disease management, coping with impacts on social life, and navigating the healthcare system. By addressing these multifaceted concerns, we can design and implement patient-centered education to empower patients through increased support.

Examining Cough's Role and Relief Strategies in Interstitial Lung Disease.

Chronic cough is a distressing and prevalent symptom in interstitial lung disease (ILD), significantly impairing quality of life (QoL) and contributing to disease progression, particularly in idiopathic pulmonary fibrosis (IPF). It is associated with physical discomfort, psychological distress, and social isolation and is often refractory to conventional therapies. The pathophysiology of cough in ILD is complex and multifactorial, involving neural hypersensitivity, structural lung changes, inflammatory processes, and comorbid conditions such as gastroesophageal reflux disease (GERD). Evaluating cough in ILD relies on subjective and objective tools to measure its severity, frequency, and impact on daily life, although standardization of these measures remains challenging. Management strategies span pharmacological interventions, including neuromodulators such as opiates, antifibrotic agents, pharmacologic and surgical GERD treatments, and non-pharmacological approaches like behavioral therapies, cough suppression techniques, and pulmonary rehabilitation and physiotherapy. Emerging treatments, such as P2X3 receptor antagonists and airway hydration therapies, offer promising avenues but require further investigation through robust clinical trials. This review aims to demonstrate the importance of addressing cough in ILD as a significant symptom and present objective and subjective methods of quantifying coughs, while providing insights into effective and emerging therapeutic options. By highlighting these potential therapies, we hope to guide healthcare practitioners in considering them through a thorough evaluation of benefits and risks on a case-by-case basis, with relevance both in the U.S. and internationally.

Longitudinal association between nailfold capillaroscopy and incident interstitial lung disease: A EUSTAR database analysis.

To evaluate (1) the association between nailfold capillaroscopy pattern and 5-year risk for incident interstitial lung disease and (2) the association between transition in nailfold capillaroscopy pattern and risk of incident interstitial lung disease. Data of adult patients from the EUSTAR database fulfilling the ACR-EULAR criteria with a disease duration ⩽5 years, having a scleroderma pattern at nailfold capillaroscopy with high-resolution computed tomography confirmed absence of interstitial lung disease (i.e. baseline) was used. Interstitial lung disease-free survival was assessed for up to 5 years of follow-up with a Cox proportional hazards model stratified on nailfold capillaroscopy pattern at baseline. The association of annual transition in nailfold capillaroscopy pattern on the risk to develop interstitial lung disease was assessed with a mixed logistic regression analysis. Out of 771 eligible patients, 283 (37%) had an early pattern, 377 (49%) had an active pattern, and 111 (14%) had a late pattern. The Cox proportional hazard model including the identified confounders did not show an association between severity of nailfold capillaroscopy pattern at baseline and increased risk for interstitial lung disease during 5-year follow-up (hazard ratio (95 confidence interval; p value): 1.09 (0.86-1.39; 0.47)). The mixed logistic regression analysis revealed an increased annual risk for incident interstitial lung disease with increasing severity of capillaroscopic pattern (odds ratio (95% confidence interval); p value 3.76 (1.99-7.11; <0.01)). Our study shows that worsening of nailfold capillaroscopy has a strong association with an increased annual risk to develop interstitial lung disease. Of note, a worse scleroderma pattern at nailfold capillaroscopy is not associated with the long-term risk to develop interstitial lung disease.

Blood urea nitrogen-to-albumin ratio as a new prognostic indicator of 1-year all-cause mortality in patients with IPF

BackgroundIdiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by chronic inflammation and progressive fibrosis. The blood urea nitrogen-to-albumin ratio (BAR) is a comprehensive parameter associated with inflammation status; however, it is unknown whether the BAR can predict the prognosis of IPF.MethodsThis retrospective study included 176 patients with IPF, and 1-year all-cause mortality of these patients was recorded. A receiver operating characteristic (ROC) curve was used to explore the diagnostic value of BAR for 1-year all-cause mortality in IPF patients, and the survival rate was further estimated using the Kaplan–Meier survival curve. Cox proportional hazards regression model and forest plot were used to assess the association between the BAR and 1-year all-cause mortality in IPF patients.ResultsThe BAR of IPF patients was significantly higher in the non-survivor group than in the survivor group [0.16 (0.13–0.23) vs. 0.12 (0.09–0.17) mmol/g, p = 0.002]. The area under the ROC curve for predicting 1-year all-cause mortality in IPF patients was 0.671, and the optimal cut-off value was 0.12 mmol/g. The Kaplan–Meier survival curve showed that the 1-year cumulative survival rate of IPF patients with a BAR ≥0.12 was significantly decreased compared with the patients with a BAR &amp;lt;0.12. The Cox regression model and forest plot showed that the BAR was an independent prognostic biomarker for 1-year all-cause mortality in IPF patients (HR = 2.778, 95% CI 1.020–7.563, p = 0.046).ConclusionThe BAR is a significant predictor of 1-year all-cause mortality of IPF patients, and high BAR values may indicate poor clinical outcomes.

Point-of-Care Lung Ultrasound in Small Animal Emergency and Critical Care Medicine: A Clinical Review

Thoracic point-of-care ultrasound (T-POCUS) has grown in popularity and usage in small animal emergencies and critical care settings due to its non-invasive nature, mobility, and ability to acquire images in real time. This review summarizes current understanding about T-POCUS in dogs and cats with respiratory illnesses, including normal thoracic ultrasonography appearance and numerous pathological situations. The basics of T-POCUS are covered, including equipment, scanning procedures, and picture settings. Practical applications in patients with respiratory distress are discussed, with an emphasis on pleural space abnormalities and lung diseases. Ultrasound results define pulmonary disorders such as pneumonia, atelectasis, cardiogenic and non-cardiogenic pulmonary edema, lung lobe torsion, pulmonary fibrosis, pulmonary thromboembolism, pulmonary neoplasms, and pulmonary bleeding. The evaluation focuses on T-POCUS diagnostic skills in a variety of clinical settings. Limitations and the need for more study to standardize techniques, establish agreed terminology, and create specialized educational routes are highlighted.

Maternal nutrition and offspring lung health: sex-specific pathway modulation in fibrosis, metabolism, and immunity.

Maternal nutrition profoundly influences offspring health, impacting both prenatal and early postnatal development. Previous studies have demonstrated that maternal dietary habits can affect key developmental pathways in the offsprings, including those related to lung function and disease susceptibility. However, the sex-specific impact of a maternal high-salt diet (HSD) on offspring lung injury remains poorly understood. This study aimed to investigate the sex-specific effects of maternal HSD on lung injury in mouse offsprings, focusing on pathways related to fibrosis, metabolism, immunity, and apoptosis. Pregnant C57BL/6J mice were subjected to either normal or HSD conditions during gestation. Lung tissues from the male and female offsprings were analyzed using high-throughput RNA sequencing and bioinformatics tools to examine transcriptomic changes. Wet-lab validation, including Masson trichrome staining, immunofluorescence for α-SMA, and qRT-PCR for fibrotic markers (α-SMA, collagen I, Fn1, and TGF-β), was conducted to confirm fibrosis and other injury markers. Lung structure and weight were also evaluated to assess physical alterations due to maternal diet. Maternal HSD significantly altered lung transcriptomes in a sex-specific manner. Male offsprings showed increased susceptibility to fibrosis, as confirmed by histological and molecular analyses, including elevated expression of α-SMA, collagen I, Fn1, and TGF-β. In contrast, female offsprings exhibited distinct changes in metabolic and immune pathways. These findings highlight the differential regulation of pulmonary injury mechanisms between male and female offsprings exposed to HSD. Maternal HSD induces sex-specific lung injury in offsprings by disrupting critical pathways involved in fibrosis, metabolism, immunity, and apoptosis. The combination of transcriptomic and orthogonal data underscores the need for balanced maternal nutrition during pregnancy to promote long-term respiratory health in offsprings. These results provide new insights into the sex-specific vulnerabilities to lung disease arising from maternal diet.

Utilising bioinformatics and systems biology methods to uncover the impact of dermatomyositis on interstitial lung disease.

Dermatomyositis (DM) is frequently associated with interstitial lung disease (ILD); however, the molecular mechanisms underlying this association remain unclear. This study aimed to employ bioinformatics approaches to identify potential molecular mechanisms linking DM and ILD. GSE46239 and GSE47162 were analysed to identify common differentially expressed genes (DEGs). These DEGs underwent Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis. A protein-protein interaction (PPI) network was constructed to identify hub genes and transcriptional regulators. Potential therapeutic drugs were predicted using the Drug-Gene Interaction Database (DGIDB). A total of 122 common DEGs were identified between the DM and ILD datasets. These DEGs were significantly enriched in signal transduction, transcriptional regulation, inflammation, and cell proliferation. Key pathways included the NOD-like receptor signalling pathway, cytokine-cytokine receptor interaction, and TNF signalling pathway. PPI network analysis revealed the top 10 hub genes: CD163, GZMB, IRF4, CCR7, MMP9, AIF1, CXCL10, CCL5, IRF8, and NLRP3. Additionally, interactions between hub genes and transcription factors/miRNAs were constructed. Eleven drugs targeting four hub genes (CXCL10, MMP9, GZMB, and NLRP3) were predicted using the DGIDB. In summary, the study identified 10 key genes involved in the molecular pathogenesis of DM and ILD. Moreover, 11 potential drugs were identified that may offer viable therapeutic options for treating DM and ILD in the future.

Clinical Profiles, Survival, and Lung Function Outcomes in ANCA-Associated Interstitial Lung Disease: An Observational Study.

Background/Objectives: Anti-neutrophil cytoplasmic antibodies (ANCAs) have been found in interstitial lung disease (ILD) in recent years, although its impact on ILD prognosis is less known. To date, ANCAs are not included in the interstitial pneumonia with autoimmune features (IPAF) definition criteria. Therefore, ANCA-ILD, in the absence of known ANCA-associated vasculitis (AAV), could be underdiagnosed. Our aim was to analyze the clinical profile and prognosis of ANCA-ILD patients. Methods: Patients diagnosed with ILD and positive ANCA were enrolled in a retrospective, monocentric cohort study. Lung function outcomes and mortality were assessed according to clinical, serological, radiological, and treatment characteristics. Survival was analyzed using Kaplan-Meier curves and Cox regression models. Results: A total of 23 patients were included, mostly women, with a median time from ILD diagnosis of 36 (24-68) months and a predominant anti-MPO pattern (56.5%). Nearly half of the patients had AAV, mostly microscopic polyangiitis (MPA). The presence of AAV was significantly associated with anti-MPO antibodies and an NSIP radiographic pattern. Overall, the fibrotic pattern (either UIP or fibrotic NSIP) was the most common (73.9%), mainly UIP (51.2%). However, it appeared less frequently in the AAV-ILD group. During follow-up, lung function impairment or radiological progression was observed in 65.2% of patients. Cumulative mortality incidence was high (43.4%), largely due to ILD itself (80%). A UIP pattern was associated with a higher and earlier mortality (HR 34.4 [1.36-132]), while the use of immunosuppressants showed a trend towards lower ILD-related death. Conclusions: In our cohort, ANCA-ILD patients mostly presented with fibrotic patterns, with AAV in almost half of the cases and a high and early mortality rate, which suggests the need to assess ANCA in all ILD patients.

Impact of Environmental Exposures on the Development and Progression of Fibrotic Interstitial Lung Disease.

Impact of Environmental Exposures on the Development and Progression of Fibrotic Interstitial Lung Disease.

The Prevalence and Clinical Manifestations of Post-Tuberculosis Lung Disease in Immunocompetent HIV-Negative Individuals: A Scoping Review

The Prevalence and Clinical Manifestations of Post-Tuberculosis Lung Disease in Immunocompetent HIV-Negative Individuals: A Scoping Review

Co-occurrence of bronchiectasis, airway wall thickening, and emphysema in Chinese low-dose CT screening.

To assess the co-occurrence of incidental CT lung findings (emphysema, bronchiectasis, and airway wall thickening) as well as associated risk factors in low-dose CT (LDCT) lung cancer screening in a Chinese urban population. Data from 978 participants aged 40-74 years from the Chinese NELCIN-B3 urban population study who underwent LDCT screening were selected. CT scans were reviewed for incidental lung findings: emphysema, bronchiectasis and airway wall thickness. Emphysema was defined in three ways (≥ trace, ≥ mild, or ≥ moderate) depending on severity. Participants were described and stratified by presence or absence of incidental lung findings. Logistic regression analyses were performed to examine the relationship between participant characteristics and CT findings. Mean age was 61.3 years ± 6.8 and 533 (54.6%) were female. 48% of participants had incidental lung findings: 19.9% had emphysema (≥ mild), 9.2% had bronchiectasis, and 35.7% had airway wall thickening. Among 978 participants, 2.1% showed all three findings. Multivariable analysis showed that higher age (OR: 1.06; 95% CI: 1.04-1.08; p < 0.001), male sex (OR: 1.68; 95% CI: 1.14-2.47; p = 0.008) smoking history (OR: 1.76; 95% CI: 1.02-3.03; p = 0.04 for former smokers; OR: 2.45; 95% CI: 1.59-3.78; p < 0.001 for current smokers), and the presence of respiratory symptoms (OR: 1.42; 95% CI: 1.01-2.00; p = 0.04) were associated with the risk of having at least one incidental lung findings. When different definitions of emphysema were used, the results remained consistent. In a Chinese urban population undergoing LDCT lung cancer screening, 48% had at least one incidental CT lung finding, which was associated with higher age, male sex, questionnaire-based respiratory symptoms and smoking history. Question Reporting of incidental lung findings that indicate lung disease risk lacks consensus in the cancer screening setting and needs evidence of co-occurrence in general populations. Findings Almost half of the 978 participants had at least one incidental lung CT finding; these were associated with older age, male sex, respiratory symptoms, and smoking history. Clinical relevance Incidental lung findings and related risk factors are often observed in low-dose CT lung cancer screening, and careful consideration of their relevance should be given to their inclusion in future screenings.

Convergent and divergent immune aberrations in COVID-19, post-COVID-19-interstitial lung disease, and idiopathic pulmonary fibrosis.

We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-interstitial lung disease (ILD), and persistence of idiopathic pulmonary fibrosis (IPF). Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from 227 subjects with COVID-19, post-COVID-19 interstitial lung disease (ILD), IPF, and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex. In addition, we performed single-cell RNA sequencing (scRNA-seq) in PBMCs (10x Genomics) to determine the cellular source of the 50-gene signature. We identified the presence of three genomic risk profiles in COVID-19 based on the 50-gene signature associated with low-, intermediate-, or high-risk of mortality and with significant differences in proinflammatory and profibrotic cytokines. Patients with COVID-19 in the high-risk group had increased expression of seven genes in CD14+HLA-DRlowCD163+ monocytic-myeloid-derived suppressive cells (7Gene-M-MDSCs) and decreased expression of 43 genes in CD4 and CD8 T cell subsets. The loss of 7Gene-M-MDSCs and increased expression of these 43 genes in T cells was seen in survivors with post-COVID-19-ILD. On the contrary, patients with IPF had low expression of the 43 genes in CD4 and CD8 T cells. Collectively, we showed that a 50-gene, high-risk profile, predictive of IPF and COVID-19 mortality is characterized by a genomic imbalance in monocyte and T-cell subsets. This imbalance reverses in survivors with post-COVID-19-ILD highlighting genomic differences between post-COVID-19-ILD and IPF.NEW & NOTEWORTHY Changes in the 50-gene signature, reflective of increase in CD14+HLA-DRlowCD163+ monocytes and decrease in CD4 and CD8 T cells, are associated with increased mortality in COVID-19. A reversal of this pattern can be seen in post-COVID-19-ILD, whereas its persistence can be seen in IPF. Modulating the imbalance between HLA-DRlow monocytes and T cell subsets should be investigated as a potential strategy to treat pulmonary fibrosis associated with severe COVID-19 and progressive IPF.

Association of Insulin Resistance With Radiographic Lung Abnormalities and Incident Lung Disease: The Framingham Offspring Study.

Insulin resistance (IR) may be a risk factor for lung disease, but objective evidence is limited. We sought to define the relationship of longitudinal IR with radiographic imaging outcomes and examiner-identified incident lung disease in the Framingham Offspring Study. Participants without baseline lung disease underwent repeated measurements of fasting insulin and glucose levels over an average period of 13.6 years, from which time-weighted average HOMA-IR was calculated. Each participant then underwent a cardiac gated whole-lung computed tomography scan, which was analyzed for the presence of emphysema, interstitial lung abnormalities (ILAs), and quantitative airway features. Incident lung disease was determined by a study examiner. The relationship of HOMA-IR to these outcomes was estimated in models adjusted for demographics, BMI, and lifetime smoking. A total of 875 participants with longitudinal IR data and outcomes were identified. Their mean age was 51.5 years, and BMI was 26.7 kg/m2. HOMA-IR was temporally unstable, with a within-person SD approximately two-thirds of the between-person SD. In adjusted models, a 1 SD increase in log(HOMA-IR) z score was associated with higher odds of qualitative emphysema (odds ratio [OR] 1.33; 95% CI 1.04-1.70), ILAs (OR 1.35; 95% CI 1.05-1.74), and modest increases in airway wall thickness and wall area percentage. These radiographic findings were corroborated by a positive association of HOMA-IR with incident lung disease. IR is associated with radiographic lung abnormalities and incident lung disease. Deeper phenotyping is necessary to define mechanisms of IR-associated lung injury.

Common Variable Immunodeficiency Associated With Noninfectious Pulmonary Complications and Its Treatment: Beyond Immunoglobulin Therapy.

Common variable immunodeficiency (CVID) is a type of primary immunodeficiency that presents as a heterogenous disorder characterized by hypogammaglobinemia, poor response to vaccines, recurrent sinopulmonary infections, and can have noninfectious systemic manifestations. We performed a single-center, retrospective, observational study of five patients with noninfectious complications of CVID. All patients had CVID as defined by the European Society of Immunodeficiencies criteria and had received intravenous immunoglobulin therapy. There were multiple pulmonary manifestations of CVID including frequent pneumonias, bronchiectasis, granulomatous lung disease, and pulmonary hypertension. All our patients were treated with pulmonary vasodilators for severe precapillary pulmonary hypertension along with individualized immunosuppression regimen for interstitial lung disease. Despite treatment for interstitial lung disease and PH, their conditions worsened over 2-3 years with all patients progressing toward organ transplant evaluation. Idiopathic thrombocytopenia and non-cirrhotic portal hypertension were common, with three patients probably suffering from nodular regenerative hyperplasia. Noninfectious complications of CVID can affect different organs and progress despite advanced therapies. Single or multiorgan transplantation is a treatment option for patients with end-stage organ involvement refractory to medical therapy.