Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis.

Rationale: Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown. Objectives: To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods: Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo. The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. Measurements and Main Results: We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease. Conclusions: Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.

Pulmonary Emphysema Regional Distribution and Extent Assessed by Chest Computed Tomography Is Associated With Pulmonary Function Impairment in Patients With COPD.

Objective: This study aimed to evaluate how emphysema extent and its regional distribution quantified by chest CT are associated with clinical and functional severity in patients with chronic obstructive pulmonary disease (COPD). Methods/Design: Patients with a post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) < 0.70, without any other obstructive airway disease, who presented radiological evidence of emphysema on visual CT inspection were retrospectively enrolled. A Quantitative Lung Imaging (QUALI) system automatically quantified the volume of pulmonary emphysema and adjusted this volume to the measured (EmphCTLV) or predicted total lung volume (TLV) (EmphPLV) and assessed its regional distribution based on an artificial neural network (ANN) trained for this purpose. Additionally, the percentage of lung volume occupied by low-attenuation areas (LAA) was computed by dividing the total volume of regions with attenuation lower or equal to -950 Hounsfield units (HU) by the predicted [LAA (%PLV)] or measured CT lung volume [LAA (%CTLV)]. The LAA was then compared with the QUALI emphysema estimations. The association between emphysema extension and its regional distribution with pulmonary function impairment was then assessed. Results: In this study, 86 patients fulfilled the inclusion criteria. Both EmphCTLV and EmphPLV were significantly lower than the LAA indices independently of emphysema severity. CT-derived TLV significantly increased with emphysema severity (from 6,143 ± 1,295 up to 7,659 ± 1,264 ml from mild to very severe emphysema, p < 0.005) and thus, both EmphCTLV and LAA significantly underestimated emphysema extent when compared with those values adjusted to the predicted lung volume. All CT-derived emphysema indices presented moderate to strong correlations with residual volume (RV) (with correlations ranging from 0.61 to 0.66), total lung capacity (TLC) (from 0.51 to 0.59), and FEV1 (~0.6) and diffusing capacity for carbon monoxide DLCO (~0.6). The values of FEV1 and DLCO were significantly lower, and RV (p < 0.001) and TLC (p < 0.001) were significantly higher with the increasing emphysema extent and when emphysematous areas homogeneously affected the lungs. Conclusions: Emphysema volume must be referred to the predicted and not to the measured lung volume when assessing the CT-derived emphysema extension. Pulmonary function impairment was greater in patients with higher emphysema volumes and with a more homogeneous emphysema distribution. Further studies are still necessary to assess the significance of CTpLV in the clinical and research fields.

Management of Coronavirus Disease 2019 Patients With Lung Cancer: Experience From a Thoracic Oncology Center.

BACKGROUND: Cancer patients appear to be at a higher risk of complications from coronavirus disease 2019 (COVID-19). Specific data related to lung cancer (LC) patient management, active treatment, and/or recent diagnosis are still very limited. Here, we aimed to investigate the clinical presentation, baseline features, and clinical outcomes of LC patients with COVID-19. METHODS: A retrospective case study was performed at Centro Hospitalar Universitário de São Joao, a tertiary hospital in the North of Portugal. Data from LC patients diagnosed with COVID-19 were collected during the first 10 months of the COVID-19 pandemic (March 2020-January 2021). RESULTS: Twenty-eight patients with active LC were diagnosed with COVID-19, being adenocarcinoma the most common histological type present (n = 13, 46.4%). Sixteen patients had metastatic stage IV LC (61.5%). Twenty-five patients (89.3%) had relevant comorbidities including hypertension (39.3%) and chronic obstructive pulmonary disease (32.1%). For patients undergoing antineoplastic treatment, the median time from the last chemotherapy administration to COVID-19 diagnosis was of 16 days (interquartile range = 13-41 days). Half of patients were previously on corticosteroid therapy. Twenty patients (71.4%) needed hospitalization, 18 received oxygen therapy (64.3%), 3 (10.7%) of them received high-flow nasal cannula with good tolerability, and 1 (3.6%) needed non-invasive ventilation. Hydroxychloroquine and antibiotics were given to 4 (14.3%) and 12 (42.9%) patients, respectively. Seven patients (25%) died at a median time of 5 days following COVID-19 diagnosis. CONCLUSION: This is one of the first studies reporting the adverse outcomes associated with COVID-19 in LC patients at same time that adds evidence regarding the need to create protocols and guidelines to reduce the infection risk in such patients.

Heterogeneous Streptomycin Resistance Level Among Mycobacterium tuberculosis Strains From the Same Transmission Cluster.

Widespread and frequent resistance to the second-line tuberculosis (TB) medicine streptomycin, suggests ongoing transmission of low fitness cost streptomycin resistance mutations. To investigate this hypothesis, we studied a cohort of 681 individuals from a TB epidemic in Portugal. Whole-genome sequencing (WGS) analyses were combined with phenotypic growth studies in culture media and in mouse bone marrow derived macrophages. Streptomycin resistance was the most frequent resistance in the cohort accounting for 82.7% (n = 67) of the resistant Mycobacterium tuberculosis isolates. WGS of 149 clinical isolates identified 13 transmission clusters, including three clusters containing only streptomycin resistant isolates. The biggest cluster was formed by eight streptomycin resistant isolates with a maximum of five pairwise single nucleotide polymorphisms of difference. Interestingly, despite their genetic similarity, these isolates displayed different resistance levels to streptomycin, as measured both in culture media and in infected mouse bone marrow derived macrophages. The genetic bases underlying this phenotype are a combination of mutations in gid and other genes. This study suggests that specific streptomycin resistance mutations were transmitted in the cohort, with the resistant isolates evolving at the cluster level to allow low-to-high streptomycin resistance levels without a significative fitness cost. This is relevant not only to better understand transmission of streptomycin resistance in a clinical setting dominated by Lineage 4 M. tuberculosis infections, but mainly because it opens new prospects for the investigation of selection and spread of drug resistance in general.

Insights on chronic hypersensitivity pneumonitis' treatment: Factors associated with a favourable response to azathioprine.

BACKGROUND: The use of immunosuppressive and antifibrotic agents for the treatment of chronic hypersensitivity pneumonitis (CHP) appears promising, but there is still no evidence supporting the clinical decision regarding the implementation of each specific pharmacological strategy. METHODS: Patients diagnosed with CHP and treated with azathioprine (AZA) were retrospectively selected from a single centre for Interstitial Lung Diseases. Baseline clinical data, as well as functional, imaging, bronchoalveolar lavage (BAL) and histology features were assessed. Longitudinal data on functional parameters were collected and comparatively analysed with patients' characteristics. RESULTS: In this cohort of 80 patients, of those who reached 12 months of treatment, 78.3% presented a preserved forced vital capacity, with 59 being eligible to be classified as AZA responders (n = 36) or non-responders (n = 23). BAL lymphocytosis was associated with a favourable response to AZA treatment (OR 1.051; 95% CI 1.015-1.089), although it didn't identify all responders. CONCLUSIONS: AZA revealed to be effective in disease stabilisation in most patients, while ineffective for a subset. BAL lymphocytosis appears as a potentially valuable strategy to identify AZA responders, although with limited accuracy. Further studies are needed to clarify other response markers to immunosuppressive agents, in order to optimize the therapeutic options for this condition.

Correction: A Prediction Rule to Stratify Mortality Risk of Patients with Pulmonary Tuberculosis.

[This corrects the article DOI: 10.1371/journal.pone.0162797.].

Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1ß production.

Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1ß is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1ß production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.

Diagnostic yield and safety of transbronchial cryobiopsy in sarcoidosis.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is an endoscopic technique proven to be useful in diagnostic approach to interstitial lung disease (ILD), but its role in sarcoidosis is not fully established. The aim of the present study was to assess the diagnostic yield of TBLC in sarcoidosis and its safety profile. METHODS: Retrospective analysis of patients, evaluated in a tertiary hospital ILD outpatient clinic, who underwent TBLC in the diagnostic work-up. TBLC was performed in accordance with the 2018 expert statement from the Cryobiopsy Working Group. RESULTS: 32 patients were included (mean±sd age 47.7±12.6 years, 59.4% male) and divided into three groups: highly likely sarcoidosis (n=21), possible sarcoidosis (n=6) and unlikely sarcoidosis (n=5). A mean of 2.8±0.8 TBLCs were performed. The definitive diagnosis was established by TBLC in 20 out of 27 patients with suspected sarcoidosis. Two patients were diagnosed with sarcoidosis by other methods performed afterwards. TBLC leaded to other diagnosis as well, such as fungal infection (n=1), hypersensitivity pneumonitis (n=1) and silicosis (n=3), making the diagnostic yield for suspected sarcoidosis of TBLC of 92.6%. TBLC was also able to show compatible histological features in five patients whom sarcoidosis was not previously considered. The complications reported overall were pneumothorax in five (15.6%) patients and moderate bleeding in one (3.1%) case. CONCLUSION: In this cohort, TBLC was a safe, reliable and useful procedure in sarcoidosis diagnosis. These results suggest that TBLC can be used successfully in those cases where a definitive diagnosis could not be reached with the usual and less-invasive diagnostic tools.

The Troika Host-Pathogen-Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes.

The already enormous burden caused by tuberculosis (TB) will be further aggravated by the association of this disease with modern epidemics, as human immunodeficiency virus and diabetes. Furthermore, the increasingly aging population and the wider use of suppressive immune therapies hold the potential to enhance the incidence of TB. New preventive and therapeutic strategies based on recent advances on our understanding of TB are thus needed. In particular, understanding the intricate network of events modulating inflammation in TB will help to build more effective vaccines and host-directed therapies to stop TB. This review integrates the impact of host, pathogen, and extrinsic factors on inflammation and the almost scientifically unexplored complexity emerging from the interactions between these three factors. We highlight the exciting data showing a contribution of this troika for the clinical outcome of TB and the need of incorporating it when developing novel strategies to rewire the immune response in TB.

A Prediction Rule to Stratify Mortality Risk of Patients with Pulmonary Tuberculosis.

Tuberculosis imposes high human and economic tolls, including in Europe. This study was conducted to develop a severity assessment tool for stratifying mortality risk in pulmonary tuberculosis (PTB) patients. A derivation cohort of 681 PTB cases was retrospectively reviewed to generate a model based on multiple logistic regression analysis of prognostic variables with 6-month mortality as the outcome measure. A clinical scoring system was developed and tested against a validation cohort of 103 patients. Five risk features were selected for the prediction model: hypoxemic respiratory failure (OR 4.7, 95% CI 2.8-7.9), age ≥50 years (OR 2.9, 95% CI 1.7-4.8), bilateral lung involvement (OR 2.5, 95% CI 1.4-4.4), ≥1 significant comorbidity-HIV infection, diabetes mellitus, liver failure or cirrhosis, congestive heart failure and chronic respiratory disease-(OR 2.3, 95% CI 1.3-3.8), and hemoglobin <12 g/dL (OR 1.8, 95% CI 1.1-3.1). A tuberculosis risk assessment tool (TReAT) was developed, stratifying patients with low (score ≤2), moderate (score 3-5) and high (score ≥6) mortality risk. The mortality associated with each group was 2.9%, 22.9% and 53.9%, respectively. The model performed equally well in the validation cohort. We provide a new, easy-to-use clinical scoring system to identify PTB patients with high-mortality risk in settings with good healthcare access, helping clinicians to decide which patients are in need of closer medical care during treatment.

Randomised short-term trial of high-span versus low-span APAP for treating sleep apnoea.

PURPOSE: Auto-titrating continuous positive airway pressure (APAP) devices were developed to improve treatment efficacy and compliance in patients with obstructive sleep apnoea syndrome (OSAS). Since there are insufficient data on the optimal pressure range setting, we aimed to compare the adherence, efficacy and tolerability of treatment with high-span versus low-span APAP. METHODS: Seventy-six newly diagnosed OSAS patients fulfilling the treatment criteria were randomised to receive high-span (HS, range 4-15cmH2O, n = 38) or low-span (LS, range 8-12cmH2O, n = 38) APAP. Patients were assessed at 1 and 3 months. RESULTS: Median Epworth sleepiness scale (ESS) was 13 (IQR, 6-16) and median apnoea-hypopnoea index (AHI) was 35.9 (IQR, 27.6-56.3). There were no significant differences in baseline demographic and clinical characteristics between groups. Overall, no significant differences were found at the first month assessment. After 3 months of therapy, we found again no differences in residual AHI or ESS. However, the group HS proved less adherent than group LS, respectively, with median 87 % (IQR, 60.5-97.5) versus 94 % (IQR, 80.0-98.3) of the nights using ≥4 h (P = 0.014) and mean (±SD) usage 5.7 ± 1.6 versus 6.4 ± 1.2 h/night (P = 0.049). The group HS reported more frequently nasal congestion, excessive oronasal dryness and nocturnal awakenings of at least moderate intensity, the latter with statistical significance (P = 0.005). CONCLUSIONS: Both pressure ranges appear to be equally effective to correct AHI and to improve symptoms. Though, patients with high-span APAP were less compliant to treatment, raising issues about the tolerability of wide pressure range settings of these devices.

Influence of emphysema distribution on pulmonary function parameters in COPD patients / Influência da distribuição do enfisema nos parâmetros de função pulmonar em pacientes com DPOC

ABSTRACT OBJECTIVE: To evaluate the impact that the distribution of emphysema has on clinical and functional severity in patients with COPD. METHODS: The distribution of the emphysema was analyzed in COPD patients, who were classified according to a 5-point visual classification system of lung CT findings. We assessed the influence of emphysema distribution type on the clinical and functional presentation of COPD. We also evaluated hypoxemia after the six-minute walk test (6MWT) and determined the six-minute walk distance (6MWD). RESULTS: Eighty-six patients were included. The mean age was 65.2 ± 12.2 years, 91.9% were male, and all but one were smokers (mean smoking history, 62.7 ± 38.4 pack-years). The emphysema distribution was categorized as obviously upper lung-predominant (type 1), in 36.0% of the patients; slightly upper lung-predominant (type 2), in 25.6%; homogeneous between the upper and lower lung (type 3), in 16.3%; and slightly lower lung-predominant (type 4), in 22.1%. Type 2 emphysema distribution was associated with lower FEV1, FVC, FEV1/FVC ratio, and DLCO. In comparison with the type 1 patients, the type 4 patients were more likely to have an FEV1 < 65% of the predicted value (OR = 6.91, 95% CI: 1.43-33.45; p = 0.016), a 6MWD < 350 m (OR = 6.36, 95% CI: 1.26-32.18; p = 0.025), and post-6MWT hypoxemia (OR = 32.66, 95% CI: 3.26-326.84; p = 0.003). The type 3 patients had a higher RV/TLC ratio, although the difference was not significant. CONCLUSIONS: The severity of COPD appears to be greater in type 4 patients, and type 3 patients tend to have greater hyperinflation. The distribution of emphysema could have a major impact on functional parameters and should be considered in the evaluation of COPD patients.

RESUMO OBJETIVO: Avaliar o impacto que a distribuição do enfisema tem na gravidade clínica e funcional em pacientes com DPOC. MÉTODOS: A distribuição do enfisema foi analisada em pacientes com DPOC, que foram classificados de acordo com um sistema de classificação visual de cinco pontos a partir de achados de TC de tórax. Avaliou-se a influência do tipo de distribuição do enfisema na apresentação funcional e clínica da DPOC. Hipoxemia após o teste da caminhada de seis minutos (TC6) foi também avaliada e a distância percorrida (DTC6) foi determinada. RESULTADOS: Foram incluídos 86 pacientes. A média de idade foi de 65,2 ± 12,2 anos, 91,9% eram homens, e todos menos um eram fumantes (média de carga tabágica, 62,7 ± 38,4 anos-maço). A distribuição do enfisema foi categorizada como obviamente predominante no pulmão superior (tipo 1), em 36,0% dos pacientes; levemente predominante no pulmão superior (tipo 2), em 25,6%; homogêneo entre o pulmão superior e inferior (tipo 3), em 16,3%; e levemente predominante no pulmão inferior (tipo 4), em 22,1%. A distribuição do enfisema do tipo 2 foi associada a menores valores de VEF1, CVF, relação VEF1/CVF e DLCO. Em comparação com os pacientes do tipo 1, os do tipo 4 apresentaram maior probabilidade de ter VEF1 < 65% do previsto (OR = 6,91, IC95%: 1,43-33,45; p = 0,016), DTC6 < 350 m (OR = 6,36, IC95%: 1,26-32,18; p = 0,025),e hipoxemia após o TC6 (OR = 32,66, IC95%: 3,26-326,84; p = 0,003). Os pacientes do tipo 3 tiveram uma relação VR/CPT maior, embora sem diferença significativa. CONCLUSÕES: A gravidade da DPOC parece ser maior nos pacientes do tipo 4, e os do tipo 3 tendem a apresentar maior hiperinsuflação. A distribuição do enfisema pode ter um impacto importante nos parâmetros funcionais e deve ser considerada na avaliação de pacientes com DPOC.

Influence of emphysema distribution on pulmonary function parameters in COPD patients.

OBJECTIVE: To evaluate the impact that the distribution of emphysema has on clinical and functional severity in patients with COPD. METHODS: The distribution of the emphysema was analyzed in COPD patients, who were classified according to a 5-point visual classification system of lung CT findings. We assessed the influence of emphysema distribution type on the clinical and functional presentation of COPD. We also evaluated hypoxemia after the six-minute walk test (6MWT) and determined the six-minute walk distance (6MWD). RESULTS: Eighty-six patients were included. The mean age was 65.2 ± 12.2 years, 91.9% were male, and all but one were smokers (mean smoking history, 62.7 ± 38.4 pack-years). The emphysema distribution was categorized as obviously upper lung-predominant (type 1), in 36.0% of the patients; slightly upper lung-predominant (type 2), in 25.6%; homogeneous between the upper and lower lung (type 3), in 16.3%; and slightly lower lung-predominant (type 4), in 22.1%. Type 2 emphysema distribution was associated with lower FEV1, FVC, FEV1/FVC ratio, and DLCO. In comparison with the type 1 patients, the type 4 patients were more likely to have an FEV1 < 65% of the predicted value (OR = 6.91, 95% CI: 1.43-33.45; p = 0.016), a 6MWD < 350 m (OR = 6.36, 95% CI: 1.26-32.18; p = 0.025), and post-6MWT hypoxemia (OR = 32.66, 95% CI: 3.26-326.84; p = 0.003). The type 3 patients had a higher RV/TLC ratio, although the difference was not significant. CONCLUSIONS: The severity of COPD appears to be greater in type 4 patients, and type 3 patients tend to have greater hyperinflation. The distribution of emphysema could have a major impact on functional parameters and should be considered in the evaluation of COPD patients.

Association of polymorphisms in genes of the homologous recombination DNA repair pathway and thyroid cancer risk.

BACKGROUND: Ionizing radiation exposure has been pointed out as a risk factor for thyroid cancer. The double-strand breaks induced by this carcinogen are usually repaired by homologous recombination repair pathway, a pathway that includes several polymorphic genes. Since there is a scarcity of data about the involvement of these gene polymorphisms in thyroid cancer susceptibility, we carried out a case-control study in a Caucasian Portuguese population. METHODS: We genotyped 109 patients and 217 controls for the XRCC3 T241M, XRCC2 R188H, NBS1 E185Q, and RAD51 Ex1-59G>T polymorphisms to evaluate their potential main effects on risk for this pathology. RESULTS: The results obtained showed that for the RAD51 Ex1-59G>T polymorphism, the homozigosity for the variant allele was associated with an almost significant increase of the odds ratio (OR) (adjusted OR = 1.9; confidence interval 95%: 1.0-3.5; p = 0.057). Additionaly, when the XRCC3 T241M data were analyzed concerning the presence of at least one wild-type allele, we observed that individuals homozygous for the variant allele had a higher risk for thyroid cancer (adjusted OR = 2.0; confidence interval 95%: 1.1-3.6; p = 0.026). When the data were analyzed according to the number of RAD51 Ex1-59G>T and XRCC3 T241M variant alleles, the coexistence of three or more variant alleles in either gene was associated to a significant higher risk (three variant alleles: adjusted OR = 2.9, p = 0.036; four variant alleles: adjusted OR = 8.0, p = 0.006). CONCLUSIONS: Since XRCC3 is involved in the assembly and stabilization of RAD51 protein multimers at double-strand break sites, we cannot exclude that the interaction of both polymorphisms can lead to a decreased DNA repair capacity and consequently increased risk for thyroid cancer.