Peripheral and alveolar biomarkers of fibrotic hypersensitivity pneumonitis.

Fibrotic hypersensitivity pneumonitis (fHP) is a frequently misdiagnosed fibrosing interstitial pneumonia, which often remains undiagnosed due to the lack of uniformity of diagnostic criteria. Its features are similar to those of other ILDs, especially idiopathic pulmonary fibrosis (IPF), and biomarkers with potential clinical value have been proposed. We reviewed the recent literature on serum and BAL biomarkers, focusing on their clinical role in the diagnosis and management of fHP. We searched Medline/Pubmed results from 2005 until April 2020. The manuscripts of interest selected by our search were limited in number and proposed different clinical biomarkers in serum (IgG antibodies, macrophage inflammatory proteins-1, epithelial cell proteins) and BAL (lymphocytes, T-cell mediators). This is the first review to summarize all the serum and BAL biomarkers for fHP proposed in the literature. This review summarized the main biomarkers investigated in fibrotic hypersensitivity pneumonitis because an urgent aim of subsequent research will be to validate and standardize them for diagnostic purposes.

Spontaneous abdominal bleeding associated with SARS-CoV-2 infection: causality or coincidence?

Authors present 6 cases of abdominal bleeding associated with COVID-19, representing 1.35% of all hospitalized COVID-19 patients and hypothesize that there could be, although not very frequently, a relationship between SARS-CoV2 and bleeding. They excluded a side effect of the low molecular weight heparin therapy that all patients underwent during the course of the disease or other possible causes. Alterations of the coagulation state or a weakness of the vascular wall due toa presumed endotheliitis SARS-CoV-2 infection induced, are hypothesized by the authors. Investigation and follow-up for possible hemorrhagic problems in patients with COVID-19 is recommended. In particular, clinicians should be vigilant about retroperitoneal hemorrhage in COVID-19 patients. In addition to the fact that these patients are being treated with anticoagulants, anemia and abdominal pain are the signs that should lead us to suspect this type of haemorrhage. More studies are needed to understand if COVID-19 can be directly associated with bleeding. (www.actabiomedica.it)

Antithrombin III as predictive indicator of survival in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib: a preliminary study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease often managed with nintedanib, a tyrosine kinase inhibitor targeting several profibrotic pathways. Although clotting processes are involved in wound healing and repair in the lung, there are no data on the role of antithrombin III (ATIII) in IPF patients treated with nintedanib. A previous proteomic analysis of serum of IPF patients before and after 1 year of nintedanib treatment showed differential protein expression of ATIII. AIMS: Here we used quantitative methods to evaluate differential ATIII concentrations in IPF patients before and after 1 year of nintedanib treatment and to assess the potential of ATIII as a prognostic biomarker in IPF patients. METHODS: Serum levels of ATIII were measured by enzyme-linked immunosorbent assay in 14 IPF patients before and after 1 year of nintedanib treatment. RESULTS: A statistically significant inverse correlation was found between serum ATIII concentrations and pulmonary function test parameters in all patients at baseline and follow up. Baseline serum ATIII and bronchoalveolar lavage (BAL) neutrophils proved to be reliable predictors of poor prognosis. A baseline ATIII threshold of 126.5 µg/mL discriminated survivors from non-survivors. CONCLUSIONS: After 12 months of antifibrotic treatment, IPF patients with high serum ATIII concentrations and high BAL neutrophil percentages had a poor prognosis and increased survival risk. The results of this preliminary study suggest that ATIII has potential as a biomarker of IPF severity and in predicting response to nintedanib therapy. As a marker, ATIII showed several advantages over BAL neutrophil percentage.

Portable Pocket-Sized Ultrasound Scanner for the Evaluation of Lung Involvement in Coronavirus Disease 2019 Patients.

Ultrasound imaging of the lung (LUS) and associated tissues has demonstrated clinical utility in coronavirus disease 2019 (COVID-19) patients. The aim of the present study was to evaluate the possibilities of a portable pocket-sized ultrasound scanner in the evaluation of lung involvement in patients with COVID-19 pneumonia. We conducted 437 paired readings in 34 LUS evaluations of hospitalized individuals with COVID-19. The LUS scans were performed on the same day with a standard high-end ultrasound scanner (Venue GO, GE Healthcare, Chicago, IL, USA) and a pocket-sized ultrasound scanner (Butterfly iQ, Butterfly Network Inc., Guilford, CT, USA). Fourteen scans were performed on individuals with severe cases, 11 on individuals with moderate cases and nine on individuals with mild cases. No difference was observed between groups in days since onset of symptoms (23.29 ± 10.07, 22.91 ± 8.91 and 28.56 ± 11.13 d, respectively; p = 0.38). No significant differences were found between LUS scores obtained with the high-end and the portable pocket-sized ultrasound scanner. LUS scores in individuals with mild respiratory impairment were significantly lower than in those with moderate and severe cases. Our study confirms the possibilities of portable pocket-sized ultrasound imaging of the lung in COVID-19 patients. Portable pocket-sized ultrasound scanners are cheap, easy to handle and equivalent to standard scanners for non-invasive assessment of severity and dynamic observation of lung lesions in COVID-19 patients.

Lung transplant in patients with familial pulmonary fibrosis. / Transplante pulmonar em pacientes com fibrose pulmonar familiar.

Objective Familial pulmonary fibrosis (FPF) is defined as an idiopathic interstitial lung disease affecting two or more members of the same family; poor outcome with high risk of death and chronic lung allograft dysfunction (CLAD) after lung transplant has been reported in these patients. The present study aimed to compare the short- and long-term outcome of lung transplants in patients with FPF and patients transplanted because of other interstitial lung diseases. Method Clinical pre- and post-transplant data from 83 consecutive patients with pulmonary fibrosis who underwent lung transplant at our centre were collected retrospectively. Patients were divided into those with familial (n=9 FPF group) and those with non-familial pulmonary fibrosis (n=74 controls). Results The FPF group was composed of 4 females and 5 males; 44.5% were ex-smokers. The majority presented their CT scan and pathology evidence of usual interstitial pneumonia. Patients with FPF had significantly lower pre-transplant levels of haemoglobin and haematocrit. No other differences in pre- and post-transplant characteristics were observed concerning controls. The clinical post-operative course was similar in the two groups. No significant difference in one-year CLAD-free survival and overall survival was observed. Conclusion The post-transplant course of patients with FPF was similar to patients with non-familial pulmonary fibrosis, although more patients with FPF had pre-transplant anaemia. Short- and long-term outcome was comparable in both groups. Lung transplant proved to be a valid option for patients with FPF as it was for patients with other types of pulmonary fibrosis.

Krebs von den Lungen-6 as a biomarker for disease severity assessment in interstitial lung disease: a comprehensive review.

Aim: Interstitial lung diseases (ILD) are a group of lung disorders characterized by interstitial lung thickening. Krebs von den Lungen-6 (KL-6) is a molecule that is predominantly expressed by damaged alveolar type II cells and it has been proposed as a potential biomarker of different ILD. Materials & methods: A growing literature about KL-6 has been reviewed and selected to evaluate its role in the clinical management of ILD to predict disease diagnosis, activity, prognosis and treatment response. Results: KL-6 concentrations have been evaluated in fibrotic and granulomatous lung diseases and it was demonstrated to be a biomarker of disease severity useful for clinical follow-up of ILD patients. KL-6 levels differentiated between fibrotic ILD, such as idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis, and nonfibrotic lung disorders, including sarcoidosis and pulmonary alveolar proteinosis. Conclusion: KL-6 is predictive biomarker useful in the clinical management of ILD patients, in particular in patients with severe fibrotic lung disorders.

BAL and serum multiplex lipid profiling in idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis.

BACKGROUND: Differential diagnosis between IPF and fibrotic HP (fHP) can be challenging: these two ILDs share many common features but call for different therapeutic approaches. In the present study, differential lipid mediator profiles were analysed by a new method in BAL and serum from HP and IPF patients. MATERIALS AND METHODS: 76 patients were enrolled retrospectively in the study. Median age (IQR) was 67 years (51-74); 63% were males, 30 had fHP and 46 had IPF. Serum and BAL samples were collected at initial diagnosis. For quantification of serum and BAL lipid mediators was used bead-based multiplex LEGENDPlex™ analysis (Biolegend). RESULTS: Serum Apo A1 levels were significantly higher in IPF than fHP patients (p = 0.314); indeed, serum levels of CCL2 and Apo C3 were lower in HP than in IPF patients (p = 0.013 and p = 0.041, respectively). BAL concentrations of Apo A1, adipsin, Apo C3 and APN were significantly lower in IPF than in fHP patients (p < 0.0001, p < 0.0001, p = 0.007 and p = 0.023, respectively). In the logistic regression, IPF was tested as dependent variable. Serum levels of Apo A1, CCL2 and Apo C3 were tested as independent variables and ROC curve analysis of model performance showed AUC 93% (p < 0.0001); on the other hand, BAL concentrations of Apo A1, adipsin, Apo C3 and APN showed AUC 81% (p < 0.0001). DISCUSSION: Lipid biomarkers evaluated in BAL in our study confirm the hypothesis that fHP and IPF have different lung fibrosis phenotypes. The former is a post-inflammatory cell-regulated ILD and the second is more related to tissue remodeling and repair.

Serum KL-6 concentrations as a novel biomarker of severe COVID-19.

Severe acute respiratory syndrome coronavirus 2-induced direct cytopathic effects against type I and II pneumocytes mediate lung damage. Krebs von den Lungen-6 (KL-6) is mainly produced by damaged or regenerating alveolar type II pneumocytes. This preliminary study analyzed serum concentrations of KL-6 in patients with coronavirus disease (COVID-19) to verify its potential as a prognostic biomarker of severity. Twenty-two patients (median age [interquartile range] 63 [59-68] years, 16 males) with COVID-19 were enrolled prospectively. Patients were divided into mild-moderate and severe groups, according to respiratory impairment and clinical management. KL-6 serum concentrations and lymphocyte subset were obtained. Peripheral natural killer (NK) cells/µL were significantly higher in nonsevere patients than in the severe group (P = .0449) and the best cut-off value was 119 cells/µL. KL-6 serum concentrations were significantly higher in severe patients than the nonsevere group (P = .0118). Receiver operating characteristic analysis distinguished severe and nonsevere patients according to KL-6 serum levels and the best cut-off value was 406.5 U/mL. NK cell analysis and assay of KL-6 in serum can help identify severe COVID-19 patients. Increased KL-6 serum concentrations were observed in patients with severe pulmonary involvement, revealing a prognostic value and supporting the potential usefulness of KL-6 measurement to evaluate COVID-19 patients' prognosis.

Serum KL-6 levels in pulmonary Langerhans' cell histiocytosis.

BACKGROUND: Serum Krebs von den Lungen-6 (sKL-6) is an high-molecular-weight (200 kDa) glycoprotein predominantly expressed by damaged alveolar type II cells, and it has been proposed as a potential biomarker of different ILD. This is a prognostic biomarker for chronic hypersensitivity pneumonitis (cHP) and idiopathic pulmonary fibrosis (IPF), two diseases that share several clinical and radiological features. Little data are available on the potential role of KL-6 in granulomatous and cystic interstitial lung diseases, including the orphan disease known as pulmonary Langerhans cell histiocytosis (PLCH). METHODS: For the first time, sKL-6 concentrations were assayed and compared in 96 patients (17 PLCH, 22 IPF, 34 cHP) and 22 healthy controls. RESULTS: Serum KL-6 concentrations were significantly higher in PLCH (599 ± 594 U/mL), IPF (1645 ± 846 U/mL) and cHP patients (1691 ± 1643 U/mL) than in healthy controls (268 U/mL) (P = .037). Area-under-the-curve values of sKL-6 were 73.4% between PLCH and healthy controls, 84.5% between IPF and PLCH and 78% between cHP and PLCH. An indirect correlation between sKL-6 concentrations and peripheral CD1a-positive cells was demonstrated (r = -0.82; P = .034). CONCLUSION: Serum KL-6 concentrations were higher in PLCH patients than in controls, reflecting the alveolar damage typical of this rare interstitial lung disease.

Pirfenidone in chronic lung allograft dysfunction: a single cohort study.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is still the principal long-term cause of mortality after lung transplant. Animal studies and small case series have proposed pirfenidone, a potent antifibrotic agent registered for idiopathic pulmonary fibrosis (IPF), for treatment of CLAD. The aim of this study was to evaluate the safety profile and potential efficacy of pirfenidone in patients with CLAD. METHODS: The present study concerns a cohort of nine CLAD patients treated with pirfenidone. Pulmonary function tests were performed before and after beginning treatment. Side effects were recorded and survival was analyzed. All data were retrospectively collected. RESULTS: The duration of treatment was 408.5±534.8 days. Significant side effects occurred in one case. FEV1 decline reduced from -44.5±40.7 mL/month in the 6 months before therapy to -12.8±34.3 mL/month in the following 6 months. However, data was only available for three patients (three patients died before 6 months of therapy, two patients lacked lung function parameters, one discontinued therapy and one was still in the early months of therapy). Median survival was 686 days. No significant survival differences were observed in relation to CLAD phenotype (BOS, RAS and BOS/RAS). Median survival from the start of pirfenidone therapy was 221 days. CONCLUSIONS: Our CLAD patients treated with pirfenidone showed a good safety profile, similarly to that reported for IPF patients. The drug showed potential for stabilizing decline in respiratory function. Further studies are needed in order to draw conclusions about the effectiveness of this therapy.

Correction to: BAL biomarkers' panel for differential diagnosis of interstitial lung diseases.

The original version of this article unfortunately contained a mistake. First and last names of the authors were interchanged.

Bronchoalveolar lavage and serum KL-6 concentrations in chronic hypersensitivity pneumonitis: correlations with radiological and immunological features.

Chronic hypersensitivity pneumonitis (cHP) is a fibrotic interstitial lung disease (ILD) resulting from inhalation of different organic substances and chemical compounds determining an inflammatory and immunological response in sensitized individuals. KL-6, a human mucin protein expressed by type 2 pneumocytes, has been proposed as a prognostic biomarker of cHP. Assessment of usefulness KL-6 in ILD has been investigated primarily in Asiatic population. The aim of this study was to evaluate clinical utility of KL-6 in serum and bronchoalveolar lavage (BAL). In this study, we retrospectively analysed clinical, radiological and immunological data of a cohort of 42 patients affected by cHP: KL-6 concentrations were collected from serum and BAL. KL-6 clinical value was assessed through the analysis of association between KL-6 concentrations and clinical, functional, immunological and radiological features. KL-6 serum concentration results increased in 28/34 patients (82%). A positive direct correlation was observed between KL-6 concentrations in BAL and serum (r = 0.62, p < 0.05). In our study population we found that patients with extensive presence of ground glass opacities and centrilobular nodules at high-resolution computed tomography (HRCT) showed the highest concentrations of KL-6 in BAL and a predominantly CD3+ CD8+ BAL lymphocytosis. BAL lymphocytosis and KL-6 concentrations showed a direct correlation. BAL KL-6, a result of alveolar damage, caused in cHP by CD3+ CD8+ mediated flogosis and suggested by radiological evidence of ground-glass opacities and centrilobular nodules, can be considered a useful biomarker to assess, along with BAL cellular analysis and HRCT findings, disease activity.

BAL biomarkers' panel for differential diagnosis of interstitial lung diseases.

Bronchoalveolar lavage (BAL) is a useful procedure for differential diagnosis of interstitial lung diseases (ILDs) and for identification of granulomatous lung diseases. We investigated a panel of biomarkers from BAL fluid of ILD patients to evaluate their utility in differentiating ILDs. Bronchoscopy with BAL was performed in 100 consecutive patients with suspected ILD (41 sarcoidosis, 11 cHP and 24 other ILDs); the 24 patients negative for ILD diagnosis were included as control group. BAL phenotypes and cell profiles (CD4+/CD8+ ratio, NK and CD103+ cell counts, chitotriosidase and KL-6 levels in BAL) were determined by flow cytometry. A decision-tree statistical algorithm was applied. Sarcoidosis was discriminated by a higher BAL CD4+/CD8+ ratio (p = 5.8E-05), a lower BAL CD103+CD4+ count (p = 5.0E-02) and lower BAL NK percentages (p = 8.8E-03) than the other groups. BAL KL-6 concentrations were higher in sarcoidosis than in other ILDs (p = 1.5E-02) and were directly correlated with CD4+/CD8+ ratio. We used decision-tree statistical analysis to combine our biomarkers into two diagnostic algorithms for differential diagnosis of ILDs. A panel of BAL biomarkers for diagnosis of ILDs is proposed; CD4+/CD8+ ratio, KL-6 concentrations, and NK and CD103+CD4+ cell percentages in BAL could improve the identification and differential diagnosis of sarcoidosis.

Correction to: Chitotriosidase: a biomarker of activity and severity in patients with sarcoidosis.

After publication of our article [1] the authors have notified us that one of the names has been incorrectly tagged.

Chitotriosidase: a biomarker of activity and severity in patients with sarcoidosis.

BACKGROUND: Serum chitotriosidase is a promising biomarker that has shown high specificity and sensitivity in patients with sarcoidosis. The aim of this study was to investigate correlations between serum chitotriosidase, clinical phenotypes, disease localizations and different radiological lung involvement and to identify clinical features associated with over-expression of chitotriosidase in a large cohort of sarcoidosis patients. METHODS: Chitotriosidase activity was evaluated in a population of 694 consecutive patients (males 39%, age 55.8 ± 12.8 years). Clinical and respiratory functional characteristics, Clinical Outcome Scale (COS) classification, clinical phenotypes proposed by the GenPhenResA project, and radiological assessment, including CT scan, were collected. Serum sampling and clinical and functional assessments at follow-up were also included. RESULTS: Significantly higher chitotriosidase activity was observed in sarcoidosis patients than in healthy controls (p < 0.0001). Evidence of lung fibrosis with reticular abnormalities and traction bronchiectasis at High resolution CT, presence of multiple extrapulmonary sarcoid localizations and increased 24-h urinary excretion of calcium were associated with significantly higher chitotriosidase activity (p < 0.005). Patients with remitted or minimal disease had lower values of chitotriosidase than patients with persistent disease. At follow-up, patients who required an increase in steroid dose showed an increase in its activity. CONCLUSIONS: Chitotriosidase is a reliable biomarker of sarcoidosis. It is increased in patients with sarcoidosis correlating with disease activity, severity and multiorgan dissemination. Steroid therapy tended to reduce chitotriosidase expression, however it responded in cases of disease relapse.

Transplante pulmonar em pacientes com fibrose pulmonar familiar / Lung transplant in patients with familial pulmonary fibrosis

RESUMO Objetivo A fibrose pulmonar familiar (FPF) é definida como uma doença pulmonar intersticial idiopática que afeta dois ou mais membros da mesma família. Nesses pacientes, os resultados têm sido insatisfatórios, apresentando alto risco de morte e disfunção crônica do enxerto pulmonar (CLAD) após o transplante de pulmão. O objetivo do presente estudo foi comparar o resultado de curto e longo prazo do transplante de pulmão em pacientes com FPF e pacientes transplantados por outras doenças pulmonares intersticiais. Métodos Foram coletados retrospectivamente dados clínicos pré e pós-transplante de 83 pacientes com fibrose pulmonar submetidos a transplante de pulmão. Os pacientes foram divididos em aqueles com fibrose pulmonar familiar (n = 9, grupo FPF) e aqueles com fibrose pulmonar não familiar (n = 74, grupo controle). Resultados O grupo FPF foi composto de quatro mulheres e cinco homens, sendo 44,5% ex-fumantes. A maioria apresentou tomografia computadorizada e evidência patológica de pneumonia intersticial usual. Os pacientes com FPF tiveram níveis significativamente menores de hemoglobina e hematócrito. Não foram observadas outras diferenças nas características pré e pós-transplante em relação ao grupo controle. A evolução clínica pós-operatória foi semelhante nos dois grupos. Não foi constatada diferença significativa na sobrevida de um ano livre de CLAD e na sobrevida em geral. Conclusão A evolução pós-transplante de pacientes com FPF foi semelhante à dos pacientes com fibrose pulmonar não familiar, embora mais pacientes com FPF tivessem anemia pré-transplante. O resultado a curto e longo prazo foi comparável em ambos os grupos. O transplante de pulmão provou ser uma opção válida para pacientes com FPF, assim como para pacientes com outros tipos de fibrose pulmonar.

ABSTRACT Objective Familial pulmonary fibrosis (FPF) is defined as an idiopathic interstitial lung disease affecting two or more members of the same family; poor outcome with high risk of death and chronic lung allograft dysfunction (CLAD) after lung transplant has been reported in these patients. The present study aimed to compare the short- and long-term outcome of lung transplants in patients with FPF and patients transplanted because of other interstitial lung diseases. Method Clinical pre- and post-transplant data from 83 consecutive patients with pulmonary fibrosis who underwent lung transplant at our centre were collected retrospectively. Patients were divided into those with familial (n=9 FPF group) and those with non-familial pulmonary fibrosis (n=74 controls). Results The FPF group was composed of 4 females and 5 males; 44.5% were ex-smokers. The majority presented their CT scan and pathology evidence of usual interstitial pneumonia. Patients with FPF had significantly lower pre-transplant levels of haemoglobin and haematocrit. No other differences in pre- and post-transplant characteristics were observed concerning controls. The clinical post-operative course was similar in the two groups. No significant difference in one-year CLAD-free survival and overall survival was observed. Conclusion The post-transplant course of patients with FPF was similar to patients with non-familial pulmonary fibrosis, although more patients with FPF had pre-transplant anaemia. Short- and long-term outcome was comparable in both groups. Lung transplant proved to be a valid option for patients with FPF as it was for patients with other types of pulmonary fibrosis.