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Sarcoidosis is a systemic disease with heterogenous clinical phenotypes characterized by non-necrotizing granuloma formation in affected organs. Most disease either remits spontaneously or responds to corticosteroids and second-line disease-modifying therapies. These medications are associated with numerous toxicities that can significantly impact patient quality-of-life and often limit their long-term use. Additionally, a minority of patients experience chronic, progressive disease that proves refractory to standard treatments. To date, there are limited data to guide the selection of alternative third-line medications for these patients. This review will outline the pathobiological rationale behind current and emerging therapeutic agents for refractory or drug-intolerant sarcoidosis and summarize the existing clinical evidence in support of their use. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate detection and characterization of groundglass and fibrosis-like opacities imaged by non-contrast 0.55 Tesla MRI, and versus clinically-acquired chest CT images, in a cohort of post-Covid patients.Materials and Methods: 64 individuals (26 women, mean age 53 ± 14 years, range 19-85) with history of Covid-19 pneumonia were recruited through a survivorship registry, with 106 non-contrast low-field 0.55 T cardiopulmonary MRI exams acquired from 9/8/2020-9/28/2021. MRI exams were obtained at an average interval of 9.5 ± 4.5 months from initial symptom report (range 1-18 months). Of these, 20 participants with 22 MRI exams had corresponding clinically-acquired CT chest imaging obtained within 30 days of MRI (average interval 18 ± 9 days, range 0-30). MR and CT images were reviewed and scored by two thoracic radiologists, for presence and extent of lung opacity by quadrant, opacity distribution, and presence versus absence of fibrosis-like subpleural reticulation and subpleural lines. Scoring was performed for each of four lung quadrants: right upper and middle lobe, right lower lobe, left upper lobe and lingula, and left lower lobe. Agreement between readers and modalities was assessed with simple and linear weighted Cohen's kappa (k) coefficients.Results: Inter-reader concordance on CT for opacity presence, opacity extent, opacity distribution, and presence of subpleural lines and reticulation was 99%, 78%, 97%, 99%, and 94% (k 0.96, 0.86, 0.94, 0.97, 0.89), respectively. Inter-reader concordance on MR, among all 106 exams, for opacity presence, opacity extent, opacity distribution, and presence of subpleural lines and reticulation was 85%, 48%, 70%, 86%, and 76% (k 0.57, 0.32, 0.46, 0.47, 0.37), respectively. Inter-modality agreement between CT and MRI for opacity presence, opacity extent, opacity distribution, and presence subpleural lines and reticulation was 86%, 52%, 79%, 93%, and 76% (k 0.43, 0.63, 0.65, 0.80, 0.52).Conclusion: Low-field 0.55 T non-contrast MRI demonstrates fair to moderate inter-reader concordance, and moderate to substantial inter-modality agreement with CT, for detection and characterization of groundglass and fibrosis-like opacities. [ABSTRACT FROM AUTHOR]

Background: Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-γ1b (rIFN-γb) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance. Methodology/Principal Findings: We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-γ1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1β, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-c1b group from baseline to week 16. Both rIFN-γ1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-γ1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFNγ1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-γ1b versus DOTS alone. Conclusion: Recombinant interferon-γ1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms. Trial Registration: ClinicalTrials.gov NCT00201123. [ABSTRACT FROM AUTHOR]

The article investigates whether linezolid is safe and well tolerated in the treatment of extensively drug-resistant tuberculosis (XDR-TB). Results reveal that the linezolid-containing regimen resulted in sustained negative conversion of sputum cultures and radiographic improvement in all patients. In most patients, long-term therapy was well tolerated. Although neutropenia occurred in three patients and peripheral neuropathy in two patients, these conditions can be adequately managed.

Study Objectives: Aerosol interferon-gamma (IFN-gamma) is a potential immunomodulator in the treatment of pulmonary tuberculosis (TB). Previous investigations demonstrated conversion of sputum smears in five patients with multidrug-resistant TB after 12 treatments over 1 month, and induction of signaling molecules in 10 of 11 drug-sensitive TB patients using BAL. The objective of the current study was to evaluate particle size and deposition pattern in patients with TB receiving aerosol IFN-gamma treatment.Design: Particle size was determined with a cascade impactor, and deposition of IFN-gamma mixed with (99m)Tc-labeled human serum albumin was assessed using a gamma camera. Local levels of IFN-gamma were measured in BAL using enzyme-linked immunosorbent assays. Study patients/intervention: Fourteen patients with pulmonary TB received IFN-gamma aerosol (500 micro g) for 12 treatments in addition to antimycobacterial therapy with BAL before and after IFN-gamma aerosol treatment. Eight patients with minimal-to-moderate parenchymal involvement underwent deposition studies. Deposited (99m)Tc-labeled IFN-gamma aerosol was partitioned between upper airways and lungs using attenuation correction measurements. (133)Xe equilibrium scanning, (133)Xe washout, and (99m)Tc- macroaggregate injection defined regional lung volume, ventilation, and perfusion.Results: Upper airway deposition was significant often exceeding lung deposition (53.9 +/- 7.09 micro g vs 35.8 +/- 2.73 micro g, respectively [mean +/- SE]). IFN-gamma levels measured in BAL fluid were significantly increased with aerosol treatment (0.83 +/- 0.43 micro g before vs 24.76 +/- 8.71 micro g after, p Conclusions: Aerosol therapy with IFN-gamma in patients with pulmonary TB is widely distributed and results in significant enhancement of IFN-gamma levels in the lower respiratory tract. In patients without lung destruction, IFN-gamma aerosol may be an adjuvant to enhance the local immune response. [ABSTRACT FROM AUTHOR]

Study objectives: Aerosol interferon-γ (IFN-γ) is a potential immunomodulator in the treatment of pulmonary tuberculosis (TB). Previous investigations demonstrated conversion of sputum smears in five patients with multidrug-resistant TB after 12 treatments over 1 month, and induction of signaling molecules in 10 of 11 drug-sensitive TB patients using BAL. The objective of the current study was to evaluate particle size and deposition pattern in patients with TB receiving aerosol IFN-γ treatment. Design: Particle size was determined with a cascade impactor, and deposition of IFN-γ mixed with 99mTc-labeled human serum albumin was assessed using a gamma camera. Local levels of IFN-γ were measured in BAL using enzyme-linked immunosorbent assays. Study patients/intervention: Fourteen patients with pulmonary TB received IFN-γ aerosol (500 µg) for 12 treatments in addition to antimycobacterial therapy with BAL before and after IFN-γ aerosol treatment. Eight patients with minimal-to-moderate parenchymal involvement underwent deposition studies. Deposited 99mTc-labeled IFN-γ aerosol was partitioned between upper airways and lungs using attenuation correction measurements. 133Xe equilibrium scanning, 133Xe washout, and 99mTc- macroaggregate injection defined regional lung volume, ventilation, and perfusion. Results: Upper airway deposition was significant often exceeding lung deposition (53.9 ± 7.09 µg vs 35.8 _ 2.73 µg, respectively [mean ± SE]). IFN-γ levels measured in BAL fluid were significantly increased with aerosol treatment (0.83 ± 0.43 µg before vs 24.76 ± 8.71 µg after, p < 0.017), and IFN-γ levels correlated with regional deposition of IFN-γ aerosol (r = 0.823). Four-quadrant analysis of regional lung deposition best correlated with regional perfusion (r = 0.422, p = 0.013) with penetration of aerosol into areas of obvious radiographic infiltration on chest radiograph. Conclusions: Aerosol therapy with IFN-γ in patients with pulmonary TB is widely distributed and results in significant enhancement of IFN-γ levels in the lower respiratory tract. In patients without lung destruction, IFN-γ aerosol may be an adjuvant to enhance the local immune response. [ABSTRACT FROM AUTHOR]

Presents a study investigating the role of a blood-based PCR assay for diagnosis of pulmonary tuberculosis in a clinical setting. The need for a rapid diagnosis of the disease; Methods; Findings and interpretation; Conclusion and discussion.

Looks at an investigation of the safety and tolerability of aerosolized interferon-gamma in patients with multidrug-resistant tuberculosis, and assessed its efficacy in terms of sputum-smear grades. Methods; Findings; Interpretation.

Examines peripheral blood with the polymerase chain reaction (PCR). Methods used for analyzing PCR products; PCR assays on DNA; Diagnosis of active pulmonary tuberculosis; Amplification of mycobacterial DNA.

Parenteral IFN-γ was unsuccessful as a treatment for pulmonary fibrosis. Inhaled IFN-γ targeted to the lungs may be more effective. Our patient, a 56-year-old male with biopsy proven usual interstitial pneumonia (UIP) and declining pulmonary function tests (PFTs) was initially diagnosed with idiopathic pulmonary fibrosis (IPF). He enrolled in a 2-year research protocol and was treated with inhaled IFN-γ (100 μg, Actimmune, Horizon Pharma, Deerfield, IL) 3 times per week. After completion of the protocol, he was able to secure the drug and continued therapy for a total of 7 years. He felt better, returning to work. His only complaint was transient cough during inhalation. PFTs improved (e.g., DLCO, 58% at baseline, 81% at 2 years, 69% currently). Clinical monitoring showed preserved exercise tolerance and stable CT scans. He was ultimately diagnosed (year 5) with scleroderma-like connective tissue disease after he developed sclerodactyly and a positive antinuclear antibody. Inhaled IFN-γ was well tolerated for 7 years and may stabilize fibrotic lung disease. [ABSTRACT FROM AUTHOR]

• COVID-19 prevalence in people with CF in NYC first wave was 1.6%. • COVD-19 delayed care and increased anxiety for people with CF. People with cystic fibrosis (pwCF) may be at risk of complications from COVID-19 but the impact of COVID-19 on pwCF remains unknown. We conducted a multicenter retrospective cohort study to assess the impact of the COVID-19 pandemic first wave on pwCF in the New York metropolitan area (NY) from March 1, 2020 to August 31, 2020. Objectives were to determine (1) the prevalence of COVID-19 by PCR and IgG antibody testing, (2) the clinical characteristics of COVID-19, (3) delay in routine outpatient care, and (4) the effect on anxiety and depression in pwCF. There were 26 COVID-19 cases diagnosed by PCR or antibody testing among the study cohort of 810 pwCF. The prevalence of COVID-19 by PCR (1.6%) and IgG antibody (12.2%) testing was low. 58% of cases were asymptomatic and 82% were managed at home. 8% were hospitalized and 1 person died. 89% of pwCF experienced delay in care. The prevalence of anxiety increased from 43% baseline to 58% during the pandemic (P <0.01). In post-hoc analysis, the proportion of patients with diabetes (38% versus 16%, P <0.01) and pancreatic insufficiency (96% versus 66%, P <0.01) were higher while CFTR modulator use was lower (46% versus 65%, P = 0.05) in pwCF who tested positive for COVID-19. The prevalence of COVID-19 among pwCF in NY during the pandemic first wave was low and most cases were managed at home. CFTR modulators may be protective. PwCF experienced delay in routine care and increased anxiety. [ABSTRACT FROM AUTHOR]

Background: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes.Methods: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient case mix by adjusting for known predictors of each outcome. We assessed whether site-level heterogeneity existed for each patient-level outcome, and if so, we investigated potential drivers of the heterogeneity.Results: All 27 sites that enrolled ≥ 10 patients returned the questionnaire. Most sites were actively following > 100 patients with IPF (70.4%), had a lung transplant program (66.7%), and had a dedicated ILD nurse leader (77.8%). Substantial heterogeneity was observed in the event rates of clinically relevant outcomes across the sites. After controlling for patient case mix, there were no outcomes for which the site variance component was significantly different from 0, but the p-value for hospitalization was 0.052. Starting/completing an ILD-related quality improvement project in the previous 2 years was associated with a lower risk of hospitalization (HR 0.60 [95% CI 0.44, 0.82]; p = 0.001).Conclusions: Analyses of data from patients with IPF managed at sites across the US found no site-specific characteristics or practices that were significantly associated with clinically relevant outcomes after adjusting for patient case mix. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511. [ABSTRACT FROM AUTHOR]

Background: Hospitalizations are common among patients with idiopathic pulmonary fibrosis (IPF). We investigated the impact of hospitalizations on outcomes in patients with IPF.Methods: The IPF-PRO Registry is an observational US registry that enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Associations between patient characteristics and hospitalization, and between hospitalization and mortality, were analyzed using Cox regression models.Results: A total of 1002 patients with IPF were enrolled into the IPF-PRO Registry. Over a median follow-up time of 23.7 months (maximum: 67.0 months), 568 patients (56.7%) had at least one hospitalization. Of these patients, 319 (56.2%) had at least one respiratory-related hospitalization and 120 (21.1%) had at least one hospitalization with ventilatory support. Younger age (HR 0.68 [95% CI 0.55, 0.84] per 5-year increase for patients < 62 years), lower BMI (0.96 [0.93, 0.98] per 1-point increase), lower FVC % predicted (0.90 [0.83, 0.97] per 10% increase), oxygen use at rest (2.85 [2.18, 3.72]) and history of pulmonary hypertension (2.02 [1.37, 2.96]) at enrollment were associated with an increased risk of respiratory-related hospitalization during follow-up. In a multivariable model, there was an eightfold increase in the risk of mortality during hospitalization or within 90 days of discharge compared with outside of this period. The risk of mortality associated with a respiratory hospitalization or a hospitalization with ventilatory support was even greater.Conclusions: Data from the IPF-PRO Registry demonstrate that hospitalizations are common among patients with IPF. The risk of mortality during hospitalization or within 90 days of discharge was high, particularly among patients who were hospitalized for a respiratory cause or received ventilatory support. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511. [ABSTRACT FROM AUTHOR]

Purpose: Idiopathic Pulmonary Fibrosis is a progressive and fatal interstitial lung disease (ILD) characterized by a typical radiographic or histologic usual interstitial pneumonia (UIP) pattern. In 2018, diagnostic categories of UIP based on computed tomography patterns were revised by the Fleischner Society. The study aimed to describe differences in comorbidities and spirometry in ILD patients that were characterized by high-resolution computed tomography (HRCT) images as having a typical, probable, indeterminate, and alternative diagnosis of UIP. Methods: We retrospectively studied 80 ILD patients from 2017 to 2019. Typical UIP was defined using the Fleischner Society diagnostic criteria for IPF. Atypical UIP was reached by consensus after a multidisciplinary clinical–radiological–pathological review of patient data. Baseline characteristics, comorbidities, and spirometry were compared among the four subgroups. Results: Among 80 patients, 59% were male, 61% had a history of smoking, and the mean age was 67.7 ± 10 years (SD). A typical UIP pattern was more frequently observed among patients with chronic obstructive pulmonary disease (COPD) (p < 0.001) and pulmonary hypertension (p = 0.03). Of 30 patients with COPD, 14 had emphysema, while 10 had IPF. After adjusting for forced expiratory volume in one second (FEV1) in liters, change of FEV1% from baseline to 6–12 months, age, and sex, only COPD remained significantly associated with typical UIP (p = 0.018). Tobacco use was not significantly associated with any radiographic type (p = 0.199). Conclusion: Typical UIP was prevalent among COPD/emphysema patients. Although smoking has a strong association with IPF, we did not find a significant association with smoking and typical UIP in our cohort. [ABSTRACT FROM AUTHOR]

Progressive fibrosing interstitial lung disease (PF-ILD) has been redefined as a new clinical syndrome that shares similar genetics, pathophysiology, and natural history to idiopathic pulmonary fibrosis (IPF). IPF is the most common form of idiopathic interstitial pneumonias, which is progressive in nature and is associated with significant mortality. Therapies targeting an inflammatory and/or immune response have not been consistently effective or well tolerated in patients with IPF. The two antifibrotic drugs approved for IPF treatment, nintedanib and pirfenidone, have been shown to reduce lung function decline in PF-ILD. Novel uses of antifibrotic therapy are emerging due to a paucity of evidence-based treatments for multiple ILD subtypes. In this review, we describe the current body of knowledge on antifibrotic therapy and immunomodulators in PF-ILD, drawing from experience in IPF where appropriate. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) causes 1.45 million deaths annually world wide, the majority of which occur in the developing world. Active TB disease represents immune failure to control latent infection from airborne spread. Acid-fast bacillus (AFB) seen on sputum smear is a biomarker for contagiousness. Methods: We enrolled 73 tuberculosis patients with extensive infiltrates into a research study using bronchoalveolar lavage (BAL) to sample lung immune cells and assay BAL cell cytokine production. All patients had sputum culture demonstrating Mycobacterium tuberculosis and 59/73 (81%) had AFB identified by microscopy of the sputum. Compared with smear negative patients, smear positive patients at presentation had a higher proportion with smoking history, a higher proportion with temperature >38.50 C, higher BAL cells/ml, lower percent lymphocytes in BAL, higher IL-4 and IL-12p40 in BAL cell supernatants. There was no correlation between AFB smear and other BAL or serum cytokines. Increasing IL-4 was associated with BAL PMN and negatively associated with BAL lymphocytes. Each 10-fold increase in BAL IL-4 and IL-12p40 increased the odds of AFB smear positivity by 7.4 and 2.2-fold, respectively, in a multi-variable logistic model. Conclusion: Increasing IL-4 and IL-12p40 production by BAL cells are biomarkers for AFB in sputum of patients who present with radiographically advanced TB. They likely reflect less effective immune control of pathways for controlling TB, leading to patients with increased infectiousness. [ABSTRACT FROM AUTHOR]

Abstract: Quality assurance (QA) is essential for data accuracy and proper evaluation of study objectives in clinical trials. The Tuberculosis Trials Consortium (TBTC)–a collaboration of 28 clinical sites and the Centers for Disease Control and Prevention–has developed a comprehensive QA program that provides quantitative assessments of performance based on clearly defined standards that are communicated to data collectors through a feedback process. The Implementation and Quality Committee of the TBTC developed a Site Evaluation Report (SER) that assesses performance measures (PMs) critical to the accomplishment of study objectives. PMs are defined, quantified, and evaluated, and goals and minimum acceptable scores are specified. Sites not meeting a PM minimum must provide an explanation and develop a plan to meet the goal. Site-specific and system-wide problems can be readily identified through this process. The SER is used prospectively for all TBTC treatment trials, and a Web site has been developed to maximize the availability and usefulness of performance data. The TBTC''s comprehensive QA program is an example of a successful method for ensuring high quality, evaluable data. [Copyright &y& Elsevier]

Study objectives: To investigate the characteristics of tuberculosis infection in diabetic patients at Bellevue Hospital. Design: We conducted a case-control study retrospectively reviewing the records of patients at Bellevue Hospital Center from 1987 to 1997 with a discharge diagnosis of tuberculosis and diabetes mellitus. Setting: Bellevue Hospital Center is a 1,200-bed, inner-city municipal hospital located in the Lower East Side of New York City. Patients: Fifty-three identified patients had verified tuberculosis infection and diabetes; of these, 50 charts were available for review. One hundred five control cases were selected from nondiabetic patients with a discharge diagnosis of tuberculosis during the same time period. Measurements and results: Thirty-six percent (18 cases) of the patients with diabetes and tuberculosis had multidrug-resistant tuberculosis (MDR-TB) compared to only 10% (10 cases) in the control group (p < 0.01) Controlling for homelessness, HIV status, and directly observed therapy, the relative risk of MDR-TB was calculated to be 8.6 (confidence interval, 3.1 to 23.6) in the diabetic group compared to the control group. Conclusions: There was a significant association between diabetes and MDR-TB. Diabetes continues to be a risk factor for tuberculosis and was associated with MDR-TB in our patients. [ABSTRACT FROM AUTHOR]

In this study, we assessed changes in spirometry among patients with typical, probable, indeterminate, and consistent with non-IPF UIP patterns based on chest high resolution computed tomography (HRCT) images, in an effort to reveal prognostic factors. Eleven patients had typical UIP, 7 had probable UIP, 12 with indeterminate UIP and 15 with non-IPF UIP patterns. [Extracted from the article]

The aims of this study were to examine typical, probable, indeterminate, and consistent with non-IPF UIP patterns based on chest high resolution computed tomography (HRCT) images in patients with and without chronic obstructive pulmonary disease (COPD). A typical UIP pattern was more frequently observed among patients with COPD compared to those without COPD (47.37%, n = 9 vs. 4.55%, n = 2 respectively; p=0.001). B CONCLUSIONS: b In our study cohort, a typical UIP pattern was the predominant radiologic pattern observed among patients with COPD and PH. [Extracted from the article]

An abstract of the article "The Effect of Inhaled IFNγ on the Cytokine Profile in the Alveolar Space in Idiopathic Pulmonary Fibrosis (IPF)" by Stephanie Lau and colleagues is presented.