Clinical characteristics, radiological features and outcomes in pulmonary involvement of cryoglobulinemia.

BACKGROUND: Cryoglobulinemia with pulmonary involvement is rare, and its characteristics, radiological findings, and outcomes are still poorly understood. METHODS: Ten patients with pulmonary involvement of 491 cryoglobulinemia patients at Peking Union Medical College Hospital were enrolled in this retrospective study. We analyzed the characteristics, radiological features and management of pulmonary involvement patients, and compared with those of non-pulmonary involvement with cryoglobulinemia. RESULTS: The 10 patients with pulmonary involvement (2 males; median age, 53 years) included three patients with type I cryoglobulinemia and seven patients with mixed cryoglobulinemia. All of 10 patients were IgM isotype cryoglobulinemia. All type I patients were secondary to B-cell non-Hodgkin lymphoma. Four mixed patients were essential, and the remaining patients were secondary to infections (n = 2) and systemic lupus erythematosus (n = 1), respectively. Six patients had additional affected organs, including skin (60%), kidney (50%), peripheral nerves (30%), joints (20%), and heart (20%). The pulmonary symptoms included dyspnea (50%), dry cough (30%), chest tightness (30%), and hemoptysis (10%). Chest computed tomography (CT) showed diffuse ground-glass opacity (80%), nodules (40%), pleural effusions (30%), and reticulation (20%). Two patients experienced life-threatening diffuse alveolar hemorrhage. Five patients received corticosteroid-based regimens, and four received rituximab-based regimens. All patients on rituximab-based regimens achieved clinical remission. The estimated two-year overall survival (OS) was 40%. Patients with pulmonary involvement had significantly worse OS and progression-free survival than non-pulmonary involvement patients of cryoglobulinemia (P < 0.0001). CONCLUSIONS: A diagnosis of pulmonary involvement should be highly suspected for patients with cryoglobulinemia and chest CT-indicated infiltrates without other explanations. Patients with pulmonary involvement had a poor prognosis. Rituximab-based treatment may improve the outcome.

Time-dependent CT score-based model for identifying severe/critical COVID-19 at a fever clinic after the emergence of Omicron variant.

Rationale and objectives: The computed tomography (CT) score has been used to evaluate the severity of COVID-19 during the pandemic; however, most studies have overlooked the impact of infection duration on the CT score. This study aimed to determine the optimal cutoff CT score value for identifying severe/critical COVID-19 during different stages of infection and to construct corresponding predictive models using radiological characteristics and clinical factors. Materials and methods: This retrospective study collected consecutive baseline chest CT images of confirmed COVID-19 patients from a fever clinic at a tertiary referral hospital from November 28, 2022, to January 8, 2023. Cohorts were divided into three subcohorts according to the time interval from symptom onset to CT examination at the hospital: early phase (0-3 days), intermediate phase (4-7 days), and late phase (8-14 days). The binary endpoints were mild/moderate and severe/critical infection. The CT scores and qualitative CT features were manually evaluated. A logistic regression analysis was performed on the CT score as determined by a visual assessment to predict severe/critical infection. Receiver operating characteristic analysis was performed and the area under the curve (AUC) was calculated. The optimal cutoff value was determined by maximizing the Youden index in each subcohort. A radiology score and integrated models were then constructed by combining the qualitative CT features and clinical features, respectively, using multivariate logistic regression with stepwise elimination. Results: A total of 962 patients (aged, 61.7 ± 19.6 years; 490 men) were included; 179 (18.6%) were classified as severe/critical COVID-19, while 344 (35.8%) had a typical Radiological Society of North America (RSNA) COVID-19 appearance. The AUCs of the CT score models reached 0.91 (95% confidence interval (CI) 0.88-0.94), 0.82 (95% CI 0.76-0.87), and 0.83 (95% CI 0.77-0.89) during the early, intermediate, and late phases, respectively. The best cutoff values of the CT scores during each phase were 1.5, 4.5, and 5.5. The predictive accuracies associated with the time-dependent cutoff values reached 88% (vs.78%), 73% (vs. 63%), and 87% (vs. 57%), which were greater than those associated with universal cutoff value (all P < 0.001). The radiology score models reached AUCs of 0.96 (95% CI 0.94-0.98), 0.90 (95% CI 0.87-0.94), and 0.89 (95% CI 0.84-0.94) during the early, intermediate, and late phases, respectively. The integrated models including demographic and clinical risk factors greatly enhanced the AUC during the intermediate and late phases compared with the values obtained with the radiology score models; however, an improvement in accuracy was not observed. Conclusion: The time interval between symptom onset and CT examination should be tracked to determine the cutoff value for the CT score for identifying severe/critical COVID-19. The radiology score combining qualitative CT features and the CT score complements clinical factors for identifying severe/critical COVID-19 patients and facilitates timely hierarchical diagnoses and treatment.

Effectiveness of azvudine in reducing mortality of COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: Azvudine has been approved for the treatment of coronavirus disease 2019 (COVID-19) patients in China, and this meta-analysis aims to illustrate the safety of azvudine and its effectiveness in reducing mortality. METHODS: PubMed, Embase, Web of science, Cochrane Library and the Epistemonikos COVID-19 Living Overview of Evidence database (L.OVE) were searched to aggregate currently published studies. Cochrane risk of bias tool and ROBINS-I tool were used to assess the risk of bias of randomized controlled study and cohort study respectively. Odds radios (ORs) with 95% confidence interval (CIs) were combined for dichotomous variables. Publication bias was assessed by Egger's test and funnel plots. RESULTS: A total of 184 articles were retrieved from the included databases and 17 studies were included into the final analysis. Pooled analysis showed that azvudine significantly reduced mortality risk in COVID-19 patients compared with controls (OR: 0.41, 95%CI 0.31-0.54, p < 0.001). Besides, either mild to moderate or severe COVID-19 patients could benefit from azvudine administration. There was no significant difference in the incidence of ICU admission (OR: 0.90, 95%CI 0.47-1.72, p = 0.74) and invasive ventilation (OR: 0.94, 95%CI 0.54-1.62, p = 0.82) between azvudine and control group. The incidence of adverse events was similar between azvudine and control (OR: 1.26, 95%CI 0.59-2.70, p = 0.56). CONCLUSIONS: This meta-analysis suggests that azvudine could reduce the mortality risk of COVID-19 patients, and the safety of administration is acceptable. TRIAL REGISTRATION: PROSPERO; No.: CRD42023462988; URL: https://www.crd.york.ac.uk/prospero/ .

Risk factors associated with severe adverse events in patients with relapsing polychondritis undergoing flexible bronchoscopy.

BACKGROUND: Patients with relapsing polychondritis (RP) sometimes experience upper airway collapse or lower airway stenosis, and bronchoscopy may provide a valuable typical image to confirm the diagnosis. This study aimed to identify potential risk factors associated with severe adverse effects during bronchoscopy. METHODS: We performed a retrospective cohort study of 82 consecutive patients with RP hospitalized at Peking Union Medical College Hospital between January 1, 2012 and December 31, 2022. Clinical features and disease patterns were compared among patients with RP undergoing bronchoscopy with or without severe adverse effects. Binary logistic regression analysis was performed to identify the associated risk factors. RESULTS: For patients with RP undergoing bronchoscopy with severe adverse effects, the forced vital capacity (FVC), forced vital capacity percent predicted values (FVC%), and peak expiratory flow were significantly lower (P = 0.001, P = 0.001, and P = 0.021, respectively) than those in the non-severe adverse effect subgroup. Binary logistic regression analysis revealed that low FVC% (odds ratio, 0.930; 95% confidence interval, 0.880-0.982; P = 0.009) was an independent risk factor for severe adverse events in patients undergoing bronchoscopy. CONCLUSIONS: Low FVC or FVC% suggests a high risk of severe adverse effects in patients with RP undergoing bronchoscopy. Patients with such risk factors should be carefully evaluated before bronchoscopy and adequately prepared for emergency tracheal intubation or tracheostomy.

Efficacy and safety of azvudine in symptomatic adult COVID-19 participants who are at increased risk of progressing to critical illness: a study protocol for a multicentre randomized double-blind placebo-controlled phase III trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 will coexist with humans for a long time, and it is therefore important to develop effective treatments for coronavirus disease 2019 (COVID-19). Recent studies have demonstrated that antiviral therapy is a key factor in preventing patients from progressing to severe disease, even death. Effective and affordable antiviral medications are essential for disease treatment and are urgently needed. Azvudine, a nucleoside analogue, is a potential low-cost candidate with few drug interactions. However, validation of high-quality clinical studies is still limited. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled phase III clinical trial involving 1096 adult patients with mild-to-moderate symptoms of COVID-19 who are at high risk for progression to severe COVID-19. Patients will be randomized to (1) receive azvudine tablets 5 mg daily for a maximum of 7 days or (2) receive placebo five tablets daily. All participants will be permitted to use a standard treatment strategy except antiviral therapy beyond the investigational medications. The primary outcome will be the ratio of COVID-19-related critical illness and all-cause mortality among the two groups within 28 days. DISCUSSION: The purpose of this clinical trial is to determine whether azvudine can prevent patients at risk of severe disease from progressing to critical illness and death, and the results will identify whether azvudine is an effective and affordable antiviral treatment option for COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT05689034. Registered on 18 January 2023.

Burnout among radiology residents: a systematic review and meta-analysis.

OBJECTIVE: To analyze the prevalence of burnout among radiology residents. METHOD: Five databases (PubMed, Web of Science, Embase, PsycINFO, and Scopus) were searched for studies reporting burnout in radiology residents for the period up to November 7, 2022. RESULTS: A total of 423 studies were identified, and eventually, 16 studies were selected for the qualitative analysis, of which 11 studies were used in the meta-analysis. There was a total of 2164 radiology residents. Six studies reported the prevalence of burnout but the data could not be pooled due to their inconsistent definitions of burnout. The mean scores of three burnout subscales indicated a moderate to high degree of severity: emotional exhaustion = 25.2 (95% CI, 22.1-28.3; I2 = 94.4%), depersonalization = 10.2 (95% CI, 8.5-11.9; I2 = 93.0%), and low perception of personal accomplishment = 32.9 (95% CI, 30.5-35.4; I2 = 94.4%). The pooled prevalence of high-degree emotional exhaustion was 49.9% (95% CI, 43.6-56.1%; I2 = 55.7%), high-degree depersonalization was 45.1% (95% CI, 38.3-52.0%; I2 = 63.2%), and high-degree diminished personal accomplishment was 58.2% (95% CI, 36.0-77.6%; I2 = 84.9%). The impact of the COVID-19 pandemic on radiology residents was not investigated. In addition, there are inconsistent findings on the effects of female sex, seniority, and social support on burnout. CONCLUSIONS: About half of the radiology residents showed at least one of the three burnout manifestations (emotional exhaustion, depersonalization, and personal accomplishment), with a moderate to high degree of severity. CLINICAL RELEVANCE STATEMENT: Such a high prevalence and severity of burnout among radiology residents warrant the attention of residency program directors. KEY POINTS: • Burnout, not uncommon among radiology residents, has not been effectively analyzed. • Nearly half of the radiology residents experience at least one of the three manifestations of burnout to a moderate to high degree. • The high prevalence and severe degree of burnout among radiology residents warrant the attention of residency program directors.

Mutations in CFAP47, a previously reported MMAF causative gene, also contribute to the respiratory defects in patients with PCD.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic ciliopathy characterized by dysfunction of motile cilia. Currently, approximately 50 causative genes accounting for 60%-70% of all PCD cases have been identified in PCD-affected individuals, but the etiology in approximately 30%-40% of PCD cases remains unknown. METHODS: We analyzed the clinical and genetic data of two PCD individuals who were suspected of having PCD. Whole-exome sequencing and Sanger sequencing were performed to identify and verify the variants in CFAP47. We also evaluated the expression of CFAP47 by real-time quantitative PCR and immunofluorescence. Transmission electron microscopy in respiratory epithelial cells was also conducted to analyze ciliary function. RESULTS: Two hemizygous missense variants of X-linked CFAP47 in two unrelated PCD individuals were identified. The expression of CFAP47 in two PCD individuals was significantly reduced in vivo and in vitro assays. A reduction in the amount of epithelial ciliary cells and basal bodies from PCD individuals was also observed. CONCLUSIONS: We describe two hemizygous missense variants of X-linked CFAP47 in two unrelated PCD individuals and prove CFAP47 variants are related to a reduced number of epithelial ciliary cells. Therefore, we suggest that CFAP47 should be known as a novel pathogenic gene of human PCD.

GOLM1 Promotes Pulmonary Fibrosis through Upregulation of NEAT1.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.

Effects of COVID-19 infection in patients with autoimmune pulmonary alveolar proteinosis: a single-center study.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease. COVID-19 is associated with worse prognosis in previous lung diseases patients. But the prognosis of aPAP patients after infection with COVID-19 is unclear. In December 2022, China experienced a large-scale outbreak of Omicron variant of the SARS-CoV-2. In this study, we aim to explore the clinical outcomes of aPAP patients infected with COVID-19. RESULTS: A total of 39 aPAP patients were included in this study. 30.77% patients had a decrease in oxygen saturation after COVID-19 infection. We compared the two groups of patients with or without decreased oxygen saturation after COVID-19 infection and found that patients who had previous oxygen therapy (decreased oxygen saturation vs. non decreased oxygen saturation: 6/12 vs. 4/27, P = 0.043), with lower baseline arterial oxygen partial pressure (74.50 ± 13.61 mmHg vs. 86.49 ± 11.92 mmHg, P = 0.009), lower baseline DLCO/VA% [77.0 (74.3, 93.6) % vs. 89.5 (78.2, 97.4) %, P = 0.036], shorter baseline 6MWD [464 (406, 538) m vs. 532 (470, 575) m, P = 0.028], higher disease severity score (P = 0.017), were more likely to have decreased oxygen saturation after COVID-19 infection. CONCLUSION: aPAP patients with poor baseline respiration have a higher probability of hypoxia after COVID-19 infection, but fatal events were rare.

Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients.

Primary ciliary dyskinesia (PCD) is a highly heterogeneous recessive inherited disorder. FAP54, the homolog of CFAP54 in Chlamydomonas reinhardtii, was previously demonstrated as the C1d projection of the central microtubule apparatus of flagella. A Cfap54 knockout mouse model was then reported to have PCD-relevant phenotypes. Through whole-exome sequencing, compound heterozygous variants c.2649_2657delinC (p. E883Dfs*47) and c.7312_7313insCGCAGGCTGAATTCTTGG (p. T2438delinsTQAEFLA) in a new suspected PCD-relevant gene, CFAP54, were identified in an individual with PCD. Two missense variants, c.4112A>C (p. E1371A) and c.6559C>T (p. P2187S), in CFAP54 were detected in another unrelated patient. In this study, a minigene assay was conducted on the frameshift mutation showing a reduction in mRNA expression. In addition, a CFAP54 in-frame variant knock-in mouse model was established, which recapitulated the typical symptoms of PCD, including hydrocephalus, infertility, and mucus accumulation in nasal sinuses. Correspondingly, two missense variants were deleterious, with a dramatic reduction in mRNA abundance from bronchial tissue and sperm. The identification of PCD-causing variants of CFAP54 in two unrelated patients with PCD for the first time provides strong supportive evidence that CFAP54 is a new PCD-causing gene. This study further helps expand the disease-associated gene spectrum and improve genetic testing for PCD diagnosis in the future.

A multicenter prospective study of comprehensive metagenomic and transcriptomic signatures for predicting outcomes of patients with severe community-acquired pneumonia.

BACKGROUND: Severe community-acquired pneumonia (SCAP) results in high mortality as well as massive economic burden worldwide, yet limited knowledge of the bio-signatures related to prognosis has hindered the improvement of clinical outcomes. Pathogen, microbes and host are three vital elements in inflammations and infections. This study aims to discover the specific and sensitive biomarkers to predict outcomes of SCAP patients. METHODS: In this study, we applied a combined metagenomic and transcriptomic screening approach to clinical specimens gathered from 275 SCAP patients of a multicentre, prospective study. FINDINGS: We found that 30-day mortality might be independent of pathogen category or microbial diversity, while significant difference in host gene expression pattern presented between 30-day mortality group and the survival group. Twelve outcome-related clinical characteristics were identified in our study. The underlying host response was evaluated and enrichment of genes related to cell activation, immune modulation, inflammatory and metabolism were identified. Notably, omics data, clinical features and parameters were integrated to develop a model with six signatures for predicting 30-day mortality, showing an AUC of 0.953 (95% CI: 0.92-0.98). INTERPRETATION: In summary, our study linked clinical characteristics and underlying multi-omics bio-signatures to the differential outcomes of patients with SCAP. The establishment of a comprehensive predictive model will be helpful for future improvement of treatment strategies and prognosis with SCAP. FUNDING: National Natural Science Foundation of China (No. 82161138018), Shanghai Municipal Key Clinical Specialty (shslczdzk02202), Shanghai Top-Priority Clinical Key Disciplines Construction Project (2017ZZ02014), Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases (20dz2261100).

The prevalence of burnout among pulmonologists or respiratory therapists pre- and post-COVID-19: a systematic review and meta-analysis.

OBJECTIVES: The coronavirus disease-19 (COVID-19) increased the already heavy workload in the pulmonary and respiratory departments, which therefore possibly increased the prevalence of burnout among pulmonologists or respiratory therapists. We aimed to compare the differences in burnout among pulmonologists or respiratory therapists pre- and post-COVID-19 by doing a systematic review with meta-analysis. METHODS: We searched pulmonologist, or pulmonary, or respiratory, and burnout up to 29 January 2023 in six databases. We included studies investigating pulmonologists or respiratory therapists and reporting the prevalence of burnout among them. The risk of bias was assessed by a tool for prevalence studies. The overall prevalence of burnout was pooled. RESULTS: A total of 2859 records were identified and 16 studies were included in the final analysis. The included studies reported 3610 responding individuals and 2336 burnouts. The pooled prevalence of burnout was 61.7% (95% confidence interval (CI), 48.6-73.2%; I2 = 96.3%). The pooled prevalence of burnout during COVID-19 was significantly higher than it was prior to the outbreak (68.4% vs. 41.6%, p = .01). The result of the meta-regression revealed that COVID-19 coverage was significantly associated with the prevalence of burnout (p = .04). CONCLUSIONS: Burnout was widely prevalent among pulmonologists or respiratory therapists and increasingly perceived during COVID-19. Therefore, interventions were needed to reduce burnout in this specialty.KEY MESSASGESThe coronavirus disease-19 increased the already heavy workload in the pulmonary and respiratory departments.Burnout was widely prevalent among pulmonologists or respiratory therapists and increasingly perceived during COVID-19.

Analysis of cytokines in bronchoalveolar lavage fluid in patients with checkpoint inhibitor pneumonitis and pulmonary infection: A case-control study.

BACKGROUND: The discovery of immune checkpoint inhibitors (ICIs) is a breakthrough in the field of cancer therapy. However, ICIs may cause immune-related adverse reactions, including checkpoint inhibitor-related pneumonitis (CIP). The aim of this study was to investigate cytokines in bronchoalveolar lavage fluid (BALF) of patients with CIP compared with patients with pulmonary infection and patients with cancer. METHODS: We retrospectively analyzed 34 cytokine levels and T cell subsets in BALF supernatant samples from ICI-treated patients with CIP (n = 13), pulmonary infection (n = 10), and progressive cancer (n = 12). Cytokine levels and T cell subsets were compared among the three groups of patients. RESULTS: We observed significantly higher levels of IFN-γ-induced protein 10(IP-10) (p = 0.002), and percentage of CD3 + CD8 + T cells (p = 0.020) in BALF of patients with CIP compared with the other two groups. However, we found significantly lower levels of interleukin-21 (p = 0.008) in BALF of patients with progressive disease compared with the other two groups. CONCLUSIONS: Cytokine profile and character of cell subsets in BALF was helpful for the differential diagnosis of CIP. IP-10 may play an important role in pathophysiology for CIP and also be a potential therapeutic target.

Multiple Bone Destruction Secondary to Mycobacterium kansasii Pulmonary Disease: A Case Report.

Mycobacterium kansasii infections predominantly manifest in immunocompromised people and are primarily responsible for lung disease and systemic disseminated infection. Osteopathy is a rare consequence of M. kansasii infection. Here, we present imaging data from a 44-year-old immunocompetent Chinese woman diagnosed with multiple bone destruction, particularly of the spine, secondary to M. kansasii pulmonary disease, which is easily misdiagnosed. The patient underwent an emergency operation after experiencing unexpected incomplete paraplegia during hospitalization, indicating an aggravation of bone destruction. Preoperative sputum testing and next-generation sequencing of DNA and RNA of intraoperative samples confirmed the diagnosis of M. kansasii infection. Treatment with anti-tuberculosis therapy and the subsequent patient response supported our diagnosis. Given the rarity of osteopathy secondary to M. kansasii infection in immunocompetent individuals, our case offers some insight into this diagnosis.

Risk factors for mortality in patients with anti-MDA5 antibody-positive dermatomyositis: A meta-analysis and systematic review.

OBJECTIVES: To determine the prognostic factors of dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a rare disease and often complicated by life-threatening, rapidly progressive interstitial lung disease. METHODS: Herein, we searched the Medline, Embase, and Cochrane Library databases and extracted studies published before August 23, 2022. Pooled analysis of hazard ratios (HRs) or odds ratios was used to identify prognostic factors for mortality among patients with anti-MDA5 antibody-positive dermatomyositis (MDA5+ DM). RESULTS: Twenty-nine cohorts with 2,645 patients were included in this meta-analysis. Factors related to poor prognosis included old age (HR 1.54, 95% confidence interval (CI) 1.41-1.69, p < 0.01), male sex (HR 2.07, 95% CI 1.34-3.18, p < 0.01), rapidly progressive interstitial lung disease (RP-ILD) (HR 9.34, 95% CI 6.39-13.6, p < 0.01), high levels of ferritin (HR 1.05, 95% CI 1.01-1.08, p < 0.01), C-reactive protein (CRP) (HR 1.12, 95% CI 1.06-1.19, p < 0.01), creatine kinase (HR 1.05, 95% CI 1.03-1.07, p < 0.01), and lactate dehydrogenase (LDH) (HR 1.27, 95% CI 1.12-1.45, p < 0.01), whereas oxygen index (HR 0.990, 95% CI 0.988-0.992, p < 0.01), partial pressure of oxygen (HR 0.933, 95% CI 0.906-0.961, p < 0.01), forced vital capacity (HR 0.962, 95% CI 0.928-0.998, p = 0.038), and lymphocyte count (HR 0.421, 95% CI 0.282-0.629, p < 0.01) were associated with better outcomes. CONCLUSIONS: Old age, male sex, hypoxemia, low forced vital capacity, lymphocytopenia, and high levels of ferritin, CRP, creatine kinase, and LDH are risk factors for mortality in patients with MDA5+ DM. However, a cautious interpretation of these results and further quality investigation are warranted.

Association between one-session bilateral whole-lung lavage and periprocedural complications in patients with pulmonary alveolar proteinosis: a retrospective cohort study.

BACKGROUND: Whole lung lavage (WLL) has been recognized as the most effective therapy of severe pulmonary alveolar proteinosis (PAP). Most centers perform the lavage of each lung in two sessions under general anesthesia at an interval of several days to weeks. Compared with two-session WLL, one-session bilateral sequential WLL only requires general anesthesia once. However, the safety of one-session WLL in PAP patients has not been assessed by large cohort studies. In this study, we aimed to investigate the association between the mode of WLL procedure (one-session or two-session) and the risk of periprocedural complications in PAP patients. METHODS: In this single-center retrospective cohort study, we included adult patients who were diagnosed as PAP and had undergone WLL procedures under general anesthesia from 2000 to 2022. Patients requiring extra-corporeal oxygenation during WLL were excluded. Since some patients received multiple WLL procedures, we considered each procedure in one-session or two-session group as a unique unit in our analysis. The primary outcome was the occurrence of any complications during hospitalization, including termination of WLL procedure due to fluid leakage or refractory hypoxemia, bronchospasm, delayed endotracheal extubation, cardiovascular event, pneumothorax, and fever. RESULTS: We included a total of 175 WLL procedures (118 patients), with 48 in the two-session group and 127 in the one-session group. Periprocedural complications occurred in 17 (35.4%) and 39 (30.7%) procedures in the two-session and the one-session groups, respectively. The risk of periprocedural complications did not differ significantly between groups, after adjusting the unbalanced confounders in a multivariable model (odds ratio 0.95, 95% confidence interval 0.34 to 2.69, P 0.929) or by inverse probability of treatment weighting (odds ratio 0.70, 95% confidence interval 0.30 to 1.54, P 0.379). Compared with the two-session WLL group, the one-session WLL group had a shorter postprocedural length of hospitalization and comparable decrease in alveolar-arterial oxygen tension gradient from baseline. CONCLUSIONS: One-session bilateral WLL was not associated with an increased risk of periprocedural complications compared with two-session WLL in PAP patients. Experienced physicians may consider performing one-session WLL in view of the comparable safety and efficacy and potential advantages of saving time.

Updated severity and prognosis score of pulmonary alveolar proteinosis: A multi-center cohort study in China.

Background: The high-resolution computed tomography (HRCT) score is an important component of the severity and prognosis score of pulmonary alveolar proteinosis (SPSP). However, the HRCT score in SPSP only considers the extent of opacity, which is insufficient. Methods: We retrospectively evaluated HRCT scores for 231 patients with autoimmune pulmonary alveolar proteinosis (APAP) from three centers of the China Alliance for Rare Diseases. The SPSPII was created based on the overall density and extent, incorporating the SPSP. The severity of APAP patients was assessed using disease severity scores (DSS), SPSP, and SPSPII to determine the strengths and weaknesses of the different assessment methods. We then prospectively applied the SPSPII to patients before treatment, and the curative effect was assessed after 3 months. Results: The HRCT overall density and extent scores in our retrospective analysis were higher than the extent scores in all patients and every original extent score severity group, as well as higher related to arterial partial oxygen pressure (PaO2) than extent scores. The mild patients accounted for 61.9% based on DSS 1-2, 20.3% based on SPSP 1-3, and 20.8% based on SPSPII 1-3. Based on SPSP or SPSPII, the number of severe patients deteriorating was higher in the mild and moderate groups. When applied prospectively, arterial PaO2 differed between any two SPSPII severity groups. The alveolar-arterial gradient in PaO2 (P[A-a]O2), % predicted carbon monoxide diffusing capacity of the lung (DLCO), and HRCT score were higher in the severe group than in the mild and moderate groups. After diagnosis, mild patients received symptomatic treatment, moderate patients received pure whole lung lavage (WLL) or granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy, and severe patients received WLL and GM-CSF therapy. Importantly, the SPSPII in mild and severe groups were lower than baseline after 3 months. Conclusion: The HRCT density and extent scores of patients with APAP were better than the extent score. The SPSPII score system based on smoking status, symptoms, PaO2, predicted DLCO, and overall HRCT score was better than DSS and SPSP for assessing the severity and efficacy and predicting the prognosis. Trial registration: ClinicalTrial.gov, identifier: NCT04516577.

Determinants of Progression and Mortality in Lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mortality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined. RESEARCH QUESTION: Which factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis? STUDY DESIGN AND METHODS: The progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV1, and generalized linear models were used to identify variables affecting FEV1 decline. A Cox proportional hazards model was used to explore the association between clinical variables and the outcomes of death or lung transplantation in patients with lymphangioleiomyomatosis. RESULTS: VEGF-D levels and sirolimus treatment were associated with FEV1 changes and survival prognosis. Compared with patients with VEGF-D of < 800 pg/mL at baseline, patients with VEGF-D of ≥ 800 pg/mL lost FEV1 faster (SE, -38.86 mL/y; 95% CI, -73.90 to -3.82 mL/y; P = .031). The 8-year cumulative survival rates of patients with VEGF-D of ≥ 2,000 pg/mL and < 2,000 pg/mL were 82.9% and 95.1%, respectively (P = .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV1 by 65.56 mL/y (95% CI, 29.06-102.06 mL/y) in patients treated with sirolimus compared with those without sirolimus (P < .001). The 8-year risk of death was reduced by 85.1% (hazard ratio, 0.149; 95% CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV1 of 70% predicted or St. George's Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival. INTERPRETATION: Serum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03193892; URL: www. CLINICALTRIALS: gov.

Case report: Checkpoint inhibitor pneumonitis with positive anti-melanoma differentiation-associated gene 5 antibodies in a patient with lung cancer.

With the widespread use of immune checkpoint inhibitors to treat various cancers, pulmonary toxicity has become a topic of increasing concern. Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies are strongly associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis. However, anti-MDA5 antibody expression has not been reported in patients with immune-related adverse events. We present the case of a 74-year-old man with lung adenocarcinoma who developed RP-ILD after treatment with immune checkpoint inhibitors. Further investigation revealed multiple autoantibodies, including anti-MDA5 antibodies. He initially responded to systemic glucocorticoids, immunosuppressants, and tocilizumab but eventually died from worsening pneumomediastinum. This case is the first one to suggest that checkpoint inhibitor pneumonitis can present as RP-ILD with positive anti-MDA5 antibodies, which may be predictive of a poor prognosis.