Lung biopsy has traditionally played a fundamental role in addressing diagnostic uncertainty and guiding management of fibrotic interstitial lung disease (fILD). Multiple lung biopsy procedures are available for evaluating fILD, including bronchoscopic techniques such as transbronchial biopsy and transbronchial lung cryobiopsy, as well as surgical lung biopsy, which is now almost exclusively conducted using minimally invasive video-assisted thoracoscopic surgery. The various evolving -considerations for and against lung biopsy have led to substantial ambiguity regarding the optimal timing and choice of biopsy method. The rationale for performing a lung biopsy in fILD is multifaceted, shaped by its potential to enhance diagnostic confidence and inform therapeutic decisions, weighed against procedural risks, and further nuanced by patient values and preferences. The objective of this state-of-the-art document from a multidisciplinary group of experts and patient representatives is to summarize the rationale for and against lung biopsy in the evaluation and management of fILD. Amid ongoing technological innovations, we further emphasize that future research should prioritize the development and validation of minimally invasive and noninvasive modalities that may serve as either alternatives or adjuncts to biopsy in the diagnostic evaluation of fILD.

INTRODUCTION:Patients with immunosuppression due to severe B cell depletion, such as those with hypogammaglobulinemia or those treated with B-cell suppressive medications, may experience prolonged replication and shedding of SARS-CoV-2. Their inability to mount a sufficient antibody response to clear the virus places them at risk for developing persistent pulmonary COVID-19 (PPC). PPC has mainly been described in case reports and case series. An awareness gap exists among physicians as to the risk factors, clinical manifestations and means of diagnosis and treatment of the disease. This article presents five cases of immunocompromised patients who received at least two doses of COVID-19 vaccination and developed PPC, which is defined by the presence of respiratory and systemic symptoms for ≥14 days, typical imaging findings, and a positive COVID-19 PCR test from a nasal swab or bronchoalveolar lavage (BAL). The patients received convalescent plasma during hospitalization, and no adverse effects related to the plasma were documented. Three out of five patients experienced clinical improvement within a few days post-infusion, one showed gradual improvement, and the last patient required multiple doses of plasma in order to achieve a cure. In all cases, there was resolution of pulmonary opacities on imaging, along with a decrease in inflammatory markers. This case series strengthens the importance of awareness and knowledge of the syndrome, and further establishes the efficacy of treatment with convalescent plasma. Additionally, the article discusses indications for convalescent plasma in the treatment of persistent COVID-19 infection in immunosuppressed patients.

BACKGROUND:Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. The recommended approach for mediastinal staging is a combination of both positron emission tomography- computed tomography (PET-CT) and endobronchial ultrasound (EBUS). Data on the correlation of PET-CT uptake to EBUS cytology and surgical lymph node biopsy is scarce. PATIENTS AND METHODS:Of 379 patients diagnosed with NSCLC, 65 underwent preoperative PET-CT, EBUS, and surgical lymph node biopsies. The correlations between EBUS cytology, fluoro-deoxy glucose (FDG) uptake (SUVmax) by PET-CT, and surgical biopsy were analyzed. RESULTS:About 229 lymph nodes derived from 65 patients were sampled, of which 67 lymph nodes had data from EBUS, PET-CT, and surgical biopsy. 58 nodes were negative in all modalities; 6 were malignant on EBUS but negative on surgical biopsy; 2 were malignant for both modalities; and one was EBUS negative but malignant in surgical staging. EBUS sensitivity was 89% with a negative predictive value of 98%. Six patients were upstaged after surgery due to inaccessible lymph nodes (at stations 5 and intralobar) for EBUS. No malignant lymph nodes had maximum standardized uptake (SUVmax) lower than 2.9. CONCLUSION:EBUS has high sensitivity and specificity rates, however it misses intralobar and station 5 lymph nodes which might upstage the patient after surgery. In cases when there is a high suspicion for malignant lymph nodes inaccessible to EBUS, other invasive strategies or neoadjuvant treatment should be considered. PET-CT was shown to be accurate in ruling out but not ruling in lymph node involvement.

The correlation between PET-CT uptake to EBUS cytology and surgical lymph node biopsy, 3 main modalities used as part of lung cancer diagnosis, is understudied. We assessed this correlation in 229 lymph nodes derived from 65 patients that underwent preoperative PET-CT, EBUS, and surgical lymph node biopsies. We demonstrate that PET-CT is accurate in ruling out but not ruling in lymph node involvement in NSCLC. Moreover, EBUS has high sensitivity and specificity rates, however it misses intralobar and station 5 lymph nodes which might upstage the patient after surgery. In cases when there is a high suspicion for malignant lymph nodes inaccessible to EBUS, other invasive strategies or neoadjuvant treatment should be considered. Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. The recommended approach for mediastinal staging is a combination of both positron emission tomography- computed tomography (PET-CT) and endobronchial ultrasound (EBUS). Data on the correlation of PET-CT uptake to EBUS cytology and surgical lymph node biopsy is scarce. Patients and methods: Of 379 patients diagnosed with NSCLC, 65 underwent preoperative PET-CT, EBUS, and surgical lymph node biopsies. The correlations between EBUS cytology, fluoro-deoxy glucose (FDG) uptake (SUVmax) by PET-CT, and surgical biopsy were analyzed. Results: About 229 lymph nodes derived from 65 patients were sampled, of which 67 lymph nodes had data from EBUS, PET-CT, and surgical biopsy. 58 nodes were negative in all modalities; 6 were malignant on EBUS but negative on surgical biopsy; 2 were malignant for both modalities; and one was EBUS negative but malignant in surgical staging. EBUS sensitivity was 89% with a negative predictive value of 98%. Six patients were upstaged after surgery due to inaccessible lymph nodes (at stations 5 and intralobar) for EBUS. No malignant lymph nodes had maximum standardized uptake (SUVmax) lower than 2.9. Conclusion: EBUS has high sensitivity and specificity rates, however it misses intralobar and station 5 lymph nodes which might upstage the patient after surgery. In cases when there is a high suspicion for malignant lymph nodes inaccessible to EBUS, other invasive strategies or neoadjuvant treatment should be considered. PET-CT was shown to be accurate in ruling out but not ruling in lymph node involvement.

Introduction: Pulse oximetry is a widely used non-invasive method to measure arterial oxygen saturation (SpO2). However, haemoglobinopathies, including rare low-oxygen-affinity variants such as haemoglobin (Hb) Lansing can result in falsely low SpO2 readings due to alterations in the Hb oxygen dissociation curve and spectral properties. Recognising these conditions is crucial to avoid misdiagnosis and unnecessary interventions. Case description: A 50-year-old female with a history of chronic obstructive pulmonary disease (COPD), hypertension and compensated cirrhosis presented for pre-operative evaluation. Persistent hypoxia (SpO2 84%), unresponsive to oxygen supplementation, was noted during routine assessment. Diagnostic investigations excluded pulmonary or cardiac shunts, hepatopulmonary syndrome and common causes of methaemoglobinaemia or carboxyhaemoglobinemia. Arterial blood gas analysis using a CO-oximeter revealed a true oxygen saturation of 90%, highlighting a discrepancy with pulse oximetry. Hb electrophoresis demonstrated an abnormal haemoglobin fraction, and subsequent genetic testing identified a heterozygous mutation (HBA1: c.264C>G), confirming Hb Lansing. The patient was asymptomatic apart from mild exertional dyspnoea attributed to underlying COPD and safely underwent planned surgery. Discussion: Hb Lansing is a rare haemoglobinopathy characterised by low oxygen affinity and high p50, leading to falsely low SpO2 readings and minimal response to supplemental oxygen. Diagnosis relies on CO-oximetry, Hb electrophoresis and genetic analysis. No specific treatment is required for low-affinity haemoglobinopathies, which generally have a benign clinical course. Conclusion: Haemoglobinopathies should be considered in the differential diagnosis of unexplained hypoxia. Utilisation of targeted diagnostic tools enables clinicians to ensure accurate diagnosis and appropriate management.

BACKGROUND AND OBJECTIVE:The risk of bacteremia following bronchoscopy procedures is well studied but limited data exists on bacteremia following Endo-Bronchial Ultrasound (EBUS) Guided Trans-Bronchial Needle Aspiration (TBNA). This prospective study aimed to assess bacteremia incidence following EBUS-TBNA, compare the findings to other studies made for various bronchoscopy procedures and evaluate the necessity of antibiotic prophylaxis. METHODS:We prospectively collected blood cultures pre- and post-procedure from 100 patients who underwent EBUS-TBNA in a single large center. RESULTS:The study revealed a 3 % bacteremia following EBUS-TBNA with no correlation between bacteremia and lymph node location or size. CONCLUSION:The results align with prior bronchoscopy studies, suggesting bacteremia rates range between 2 % and 7 %, with no clear association with procedure type.

Background/Objectives: Chronic lung diseases (CLDs) constitute a major burden on healthcare systems, significantly impairing patients' quality of life. In advanced stages, long-term oxygen therapy (LTOT) is often indicated. While pulmonary function tests (PFTs) are routinely used in clinical evaluation, their role in predicting the need for LTOT remains inadequately defined. This study aimed to determine whether specific PFT parameters, particularly diffusing capacity for carbon monoxide (DLCO), can serve as reliable predictors of LTOT requirement in patients with CLD. Methods: A retrospective observational study was conducted, including 302 patients with CLD who underwent PFTs at Rambam Health Care Campus between December 2021 and December 2023. Patients were stratified into LTOT and non-LTOT groups. Demographic, clinical, and functional variables were analyzed using univariate and multivariate logistic regression models. Receiver operating characteristic (ROC) analysis was performed to assess the discriminative capacity of DLCO. Results: Of the 302 patients, 42 (13.9%) were prescribed LTOT. The LTOT group was older, predominantly male, and had a higher prevalence of COPD and interstitial lung disease. DLCO emerged as an independent and statistically significant predictor of LTOT (p = 0.029). A DLCO value below 39% predicted LTOT requirement with 90% probability, whereas a DLCO above 60% indicated a 90% likelihood of not requiring LTOT. The area under the ROC curve for DLCO was 0.855, indicating excellent discriminative performance. Conclusions: DLCO is a robust independent predictor for LTOT eligibility in patients with CLD. Integration of DLCO thresholds into routine assessment may enhance clinical decision-making. Validation through prospective multicenter studies is warranted.

BACKGROUND:Diagnostic test evaluation requires a reference standard. We describe an approach for creating a reference standard for acute infection using unrestricted adjudication and apply it to compare biomarker tools. METHODS:Adults and children with suspected acute infection enrolled in three prospective studies at emergency departments and urgent cares were included. Adjudicators, blinded to C-reactive protein, procalcitonin, and MeMed BV (MMBV), labeled each case (bacterial/viral/non-infectious/indeterminate). Initial adjudication involved 3 adjudicators. Reference standard cohorts were defined: Microbiologically confirmed (3/3 adjudicators concur with high confidence and a concordant microbiological finding), unanimous (3/3 adjudicators concur with high confidence), suspected (3/3 adjudicators concur with high/moderate confidence or 2/3 adjudicators concur with high confidence), and all-inclusive (remaining unlabeled cases were reviewed by up to 7 additional adjudicators until reaching a leading label). RESULTS:Among 1016 patients, 156 difficult-to-diagnose cases required over 3 adjudicators. The area under the receiver operating characteristic curve in the microbiologically confirmed (n = 427), unanimous (n = 565), suspected (n = 860), and all-inclusive (n = 1016) cohorts for MMBV were 0.98 (95% confidence interval .94-1.00), 0.98 (.95-1.00), 0.95 (.92-.98) and 0.90 (.87-.93), respectively, and for procalcitonin were 0.69 (.57-.81), 0.77 (.68-.86), 0.74 (.68-.80) and 0.70 (.65-.75), respectively. A delta in performance between MMBV and procalcitonin was maintained across the different cohorts. CONCLUSIONS:Creating a reference standard that includes difficult-to-diagnose cases demands an approach to addressing diagnostic uncertainty in acute infections. Tool performance depends on the reference standard applied and decreases as the difficulty to diagnose increases, highlighting the importance of using the same reference standard when comparing tools.

Background/Objectives: Asthma is a chronic inflammatory disorder of the airways affecting over 10% of the global population. It is characterized by airway inflammation, mucus hypersecretion, and bronchial hyperresponsiveness, driven predominantly by type 2 helper T cells (Th2) and type 2 innate lymphoid cells (ILC2s) in a subset of patients. However, a significant portion of asthmatic individuals present with “type 2-low” asthma that is often refractory to standard inhaled corticosteroid (ICS) therapy. Therefore, developing innovative therapeutic strategies has become essential. Recent studies have highlighted cannabidiol (CBD) as a promising anti-inflammatory agent capable of modulating immune responses. This study investigates the therapeutic potential of a high-CBD extract (CBD-X) in asthma. Methods: We evaluated the effects of CBD-X on cells involved in asthma pathogenesis using primary human Th2 cells, neutrophils, and asthma mouse model. Results: Our findings indicate that CBD-X extract inhibits Th2 differentiation and reduces the secretion of IL-5 and IL-13, which are crucial cytokines in asthma. Additionally, CBD-X significantly reduces pro-inflammatory cytokines IL-8 and IL-6 in neutrophils and impairs their migration, a critical step in airway inflammation. In a murine asthma model, CBD-X administration led to marked downregulation of IgE and pro-asthmatic cytokines, along with reduced leukocyte, eosinophil, and neutrophil infiltration in lung tissues. Conclusions: These results suggest that CBD-X extract could offer a novel and complementary approach to managing both type 2-high and type 2-low asthma by targeting key inflammatory pathways and modulating immune cell behavior.

Background Hospitalized hematological patients often require bronchoalveolar lavage (BAL). Paucity of evidence exists as to the potential risks in patients with very-severe thrombocytopenia (VST). Methods This retrospective-cohort study included adult hematological in-patients with VST, defined as platelets<20x103/μL, undergoing BAL during 2012-2021. Mechanically-ventilated patients or those with known active bleeding were excluded. Primary outcomes included major bleeding halting the BAL or deemed significant by the treating physician, need for any respiratory support other than low flow O2 or death within 24 hours. Any other bleeding were recorded as secondary outcomes. Results Of the 507 patients included in the final analysis, the 281 patients with VST had lower hemoglobin (Md=0.3, p=0.003), longer prothrombin-time (Md=0.7s, p=0.025), higher chances of preprocedural platelet transfusion (RR 3.68, 95%CI[2.86,4.73]), and only one primary-outcome event (death of septic shock 21h postprocedurally) - compared with 3 (1.3%) events (two bleedings halting procedure and one need for non-invasive-ventilation) in patients with platelets ≥20x103/μL (p=0.219). Risk of minor, spontaneously resolved bleeding was higher (RR=3.217, 95%CI[0.919,11.262]) in patients with VST (4.3% vs 1.3%, p=0.051). No association was found between any of the complications recorded and preprocedural platelets, age, aPTT, PT, hematological status, or platelet transfusion. Conclusions This data suggests BAL to be safe even when platelet counts are <20x103/μL.

Reversed halo sign (RHS) is a radiological feature described as a focal, rounded area of ground-glass opacity surrounded by a ring of consolidation. In this report we describe two unique radiological cases demonstrating diffuse bilateral infiltrates with multiple RHSs in chest CT scans. Both patients were ultimately diagnosed as having tuberculosis (TB) and had been exposed to silica in the past. This report presents for the first time an association between silica exposure and RHS on CT scans among TB patients. It highlights the importance of having a high index of suspicion for TB in similar scenarios.

Division of Pulmonary Medicine, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel Disclosure: There is no conflict of interest or other disclosures.

Background Concerns regarding positive-pressure-ventilation for the treatment of coronavirus disease 2019 (COVID-19) hypoxemia led the search for alternative oxygenation techniques. This study aimed to assess one such method, dual oxygenation, i.e., the addition of a reservoir mask (RM) on top of a high-flow nasal cannula (HFNC). Methods In this retrospective cohort study, the records of all patients hospitalized with COVID-19 during 2020–2022 were reviewed. Patients over the age of 18 years with hypoxemia necessitating HFNC were included. Exclusion criteria were positive-pressure-ventilation for any indication other than hypoxemic respiratory failure, transfer to another facility while still on HFNC and “do-not-intubate/resuscitate” orders. The primary outcome was mortality within 30 days from the first application of HFNC. Secondary outcomes were intubation and admission to the intensive care unit. Results Of 659 patients included in the final analysis, 316 were treated with dual oxygenation and 343 with HFNC alone. Propensity for treatment was estimated based on background diagnoses, laboratories and vital signs upon admission, gender and glucocorticoid dose. Inverse probability of treatment weighted regression including age, body mass index, Sequential Organ Failure Assessment (SOFA) score and respiratory rate oxygenation index showed treatment with dual oxygenation to be associated with lower 30-day mortality (adjusted hazard ratio, 0.615; 95% confidence interval, 0.469–0.809). Differences in the secondary outcomes did not reach statistical significance. Conclusions Our study suggests that the addition of RM on top of HFNC may be associated with decreased mortality in patients with severe COVID-19 hypoxemia.

We propose LungNet; a deep learning architecture for the diagnosis of respiratory pathologies using multi-dimensional representations of lung sounds. The model is comprised of two independent branches, denoted CNN and LSTM. We have worked on three independent databases and conducted two experiments to evaluate the performance of our model. In the first experiment, the databases were merged into a single dataset. In the second experiment, we studied the distribution shift between the databases by training the model on one database and testing it on the other two. Our model outperformed the two baselines for both experiments. Our results suggest that LungNet has the potential to be a valuable tool for diagnosing respiratory pathologies, and could be integrated into clinical practice.

Background: Concerns regarding positive-pressure-ventilation for the treatment of coronavirus disease 2019 (COVID-19) hypoxemia led the search for alternative oxygenation techniques. This study aimed to assess one such method, dual oxygenation, i.e., the addition of a reservoir mask (RM) on top of a high-flow nasal cannula (HFNC). Methods: In this retrospective cohort study, the records of all patients hospitalized with COVID-19 during 2020-2022 were reviewed. Patients over the age of 18 years with hypoxemia necessitating HFNC were included. Exclusion criteria were positive-pressure-ventilation for any indication other than hypoxemic respiratory failure, transfer to another facility while still on HFNC and "do-not-intubate/ resuscitate" orders. The primary outcome was mortality within 30 days from the first application of HFNC. Secondary outcomes were intubation and admission to the intensive care unit. Results: Of 659 patients included in the final analysis, 316 were treated with dual oxygenation and 343 with HFNC alone. Propensity for treatment was estimated based on background diagnoses, laboratories and vital signs upon admission, gender and glucocorticoid dose. Inverse probability of treatment weighted regression including age, body mass index, Sequential Organ Failure Assessment (SOFA) score and respiratory rate oxygenation index showed treatment with dual oxygenation to be associated with lower 30-day mortality (adjusted hazard ratio, 0.615; 95% confidence interval, 0.469-0.809). Differences in the secondary outcomes did not reach statistical significance. Conclusions: Our study suggests that the addition of RM on top of HFNC may be associated with decreased mortality in patients with severe COVID-19 hypoxemia.

Background The ability to accurately distinguish bacterial from viral infection would help clinicians better target antimicrobial therapy during suspected lower respiratory tract infections (LRTI). Although technological developments make it feasible to rapidly generate patient-specific microbiota profiles, evidence is required to show the clinical value of using microbiota data for infection diagnosis. In this study, we investigated whether adding nasal cavity microbiota profiles to readily available clinical information could improve machine learning classifiers to distinguish bacterial from viral infection in patients with LRTI. Results Various multi-parametric Random Forests classifiers were evaluated on the clinical and microbiota data of 293 LRTI patients for their prediction accuracies to differentiate bacterial from viral infection. The most predictive variable was C-reactive protein (CRP). We observed a marginal prediction improvement when 7 most prevalent nasal microbiota genera were added to the CRP model. In contrast, adding three clinical variables, absolute neutrophil count, consolidation on X-ray, and age group to the CRP model significantly improved the prediction. The best model correctly predicted 85% of the ‘bacterial’ patients and 82% of the ‘viral’ patients using 13 clinical and 3 nasal cavity microbiota genera (Staphylococcus, Moraxella, and Streptococcus). Conclusions We developed high-accuracy multi-parametric machine learning classifiers to differentiate bacterial from viral infections in LRTI patients of various ages. We demonstrated the predictive value of four easy-to-collect clinical variables which facilitate personalized and accurate clinical decision-making. We observed that nasal cavity microbiota correlate with the clinical variables and thus may not add significant value to diagnostic algorithms that aim to differentiate bacterial from viral infections.

BACKGROUND:Post mild COVID-19 dyspnea is poorly understood. We assessed physiologic limitations in these patients.METHODS:Patients with post mild COVID-19 dyspnea (group A) were compared (pulmonary function tests, 6-min walk test (6MWT), echocardiography and cardiopulmonary exercise test (CPET)) to post moderate/severe COVID-19 (group B) and to CPET and spirometry of patients with unexplained dyspnea (group C).RESULTS:The study included 36 patients (13 in A, 9 in B and 14 in C). Diffusion capacity was lower in group B compared to group A (64 ± 8 vs. 85 ± 9% predicted, p = 0.014). 6MWT was normal and similar in both patient groups. Oxygen uptake was higher in group A compared to groups B and C (108 ± 14 vs. 92 ± 13 and 91 ± 23% predicted, p = 0.013, 0.03, respectively). O2 pulse was normal in all three groups but significantly higher in the mild group compared to the control group. Breathing reserve was low/borderline in 2/13 patients in the mild group, 2/9 in the moderate/severe group and 3/14 in the control group (NS).CONCLUSIONS:Patients with post mild COVID-19 dyspnea had normal CPET, similar to patients with unexplained dyspnea. Other mechanisms should be investigated and the added value of CPET to patients with post mild COVID-19 dyspnea is questionable.

CASE PRESENTATION:A 38-year-old African American woman with a history of menometrorrhagia on previous estrogen therapy and a previously biopsied benign thyroid nodule with recent interval enlargement presented with symptoms of shortness of breath on exertion, an intermittent nonproductive cough, and right upper quadrant abdominal pain for 1 year. She denied wheezing, hemoptysis, fevers, night sweats, or unintentional weight loss. Socially, the patient was a lifelong nonsmoker and denied alcohol or drug use. Travel history was not significant, and she had no contributory occupational, environmental, or animal exposures. Recent cancer screening that included Papanicolaou smear and mammography were negative for neoplasia. Vital signs were normal, and ambulatory pulse oximetry did not demonstrate evidence of oxygen desaturation. Physical examination demonstrated normal respiratory effort, diffuse vesicular breath sounds, and a soft abdomen without hepatomegaly or right upper quadrant tenderness.