Martina Vasakova

Bronchoalveolar lavage fluid cellular characteristics, functional parameters and cytokine and chemokine levels in interstitial lung diseases.

Idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP) and sarcoidosis belong to interstitial lung diseases (ILD) where an imbalance of regulatory, profibrotic and antifibrotic cytokines is hypothesized. The relationship of bronchoalveolar lavage (BAL) fluid (BALF) cytokines, BALF cell profile and ILD course is supposed. The aim of our study was to correlate BALF cytokine and chemokine levels with BALF cellular characteristics and lung function parameters in different ILD. Twenty‐two sarcoidosis, seven IPF and 11 HP patients underwent lung function tests and BAL. The BALF differential cell counts and superficial cell markers were characterized, and MCP‐1, MIP‐1α, MIP‐1β, RANTES, epithelial neutrophil‐activating protein (ENA)‐78, FGF, G‐CSF, GM‐CSF, IFN‐γ, interleukin (IL)‐1α, IL‐1RA, IL‐1β, ‐2β, ‐4β, ‐5β, ‐6β, ‐8β, ‐10β, ‐17β, tumour necrosis factor (TNF)‐α, thromobopoietin (Tpo) and vascular endothelial growth factor (VEGF) values measured. The BALF VEGF values were highest in sarcoidosis (P = 0.0526). IL‐1RA values were higher in IPF and HP compared with sarcoidosis (P = 0.0334). IL‐8/ENA‐78 ratio positively correlated with BALF neutrophil counts in IPF (r = 0.89, P = 0.04). Vital capacity and TLCO values positively correlated with VEGF and negatively with IL‐8 BALF levels in all ILDs but the correlations were most significant in sarcoidosis group. We suppose that VEGF plays a role in ILDs’ early phases and has rather angiogenic than profibrotic effect. On the contrary, IL‐8 is probably upregulated in advanced ILDs with prominent fibrosis and marked lung functions decline. We state that BALF VEGF, IL‐8 and ENA‐78 levels and IL‐8/ENA‐78 ratio could become useful markers of ILDs’ phase, activity and prognosis. They might also be helpful in treatment modality choice.

Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis

Procoagulant and antifibrinolytic activity has been associated with idiopathic pulmonary fibrosis (IPF); however, investigation of anticoagulant therapy in IPF has suggested deleterious effects. This post hoc analysis evaluated the effect of medically indicated anticoagulation on mortality and other clinical outcomes in IPF. Patients randomised to placebo (n=624) from three controlled trials in IPF were analysed by oral anticoagulant use. End-points included all-cause and IPF-related mortality, disease progression, hospitalisation, and adverse events, over 1 year. At baseline, 32 (5.1%) patients randomised to placebo were prescribed anticoagulants for non-IPF indications, 29 (90.6%) of whom received warfarin. Unadjusted analyses demonstrated significantly higher all-cause and IPF-related mortality at 1 year in baseline anticoagulant users versus nonusers (15.6% versus 6.3%, p=0.039 and 15.6% versus 3.9%, p=0.002, respectively). In multivariate analyses, baseline use of anticoagulants was an independent predictor of IPF-related mortality (hazard ratio 4.7, p=0.034), but not other end-points. Rates of bleeding and cardiac events did not differ significantly between groups. In an exploratory analysis, anticoagulant use at any time during the study was an independent predictor of all end-points. This post hoc analysis suggests that anticoagulants used for non-IPF indications may have unfavourable effects in IPF patients. Future studies are needed to explore this relationship further. Anticoagulant use for medically indicated comorbidities may have unfavourable effects in IPF http://ow.ly/XZC9j

Hypersensitivity Pneumonitis: Perspectives in Diagnosis and Management

Hypersensitivity Pneumonitis: Perspectives in Diagnosis and Management Martina Vasakova, Ferran Morell, Simon Walsh, Kevin Leslie, and Ganesh Raghu Department of Respiratory Medicine, First Faculty of Medicine of Charles University, Thomayer Hospital Prague, Prague, Czech Republic; Vall d’Hebron Institut de Recerca, Servei de Pneumologı́a, Hospital Universitari Vall d’Hebron, Departament de Medicina, Universitat Autonóma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Respiratoria, Barcelona, Catalonia, Spain; King’s College National Health Service Hospital Foundation Trust, Denmark Hill, London, United Kingdom; Mayo Clinic, Scottsdale, Arizona; and Center for Interstitial Lung Diseases, University of Washington Medical Center, Seattle, Washington

Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?

Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF.

Correlation of IL-1alpha and IL-4 Gene Polymorphisms and Clinical Parameters in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a serious disease characterized with progressive scarring of the lungs in which a genetic background is supposed. We have tested correlation of promotor regions of IL‐1alpha and IL‐4 gene polymorphisms with clinical parameters in IPF.

Pitfalls in diagnosis and management of hypersensitivity pneumonitis

Purpose of review Hypersensitivity pneumonitis is a complex syndrome characterized by a combination of inflammation and fibrosis located in both the airways and the lung parenchyma. Both diagnosis and treatment are a real challenge for physicians. This review will focus on recent developments in this emerging field; furthermore, we will emphasize major gaps in the current knowledge, to stimulate further research in this field. Recent findings The main diagnostic issue is not to miss the entity as the clinical presentation is extremely variable even as the nature of the causal antigen. This article provides an overview of current ways to uncover possible causes of hypersensitivity pneumonitis. A problem of another kind is treatment of this disorder. Crucial in treatment is antigen avoidance, often in combination with immunosuppressive agents. The treatment of acute forms is rather straightforward, but the biggest endeavour, however, is treatment of chronic forms of hypersensitivity pneumonitis, which not always respond to immunosuppressive agents. Therefore, new initiatives should be taken in order to help clinicians in making a proper diagnosis and develop more efficacious treatment especially for patients suffering from chronic hypersensitivity pneumonitis. Summary Diagnosis and treatment of hypersensitivity pneumonitis remain a real challenge; this article provides an overview of our current understanding and points out new opportunities for further research.

Diffuse parenchymal lung disease as first clinical manifestation of GATA-2 deficiency in childhood

BackgroundGATA-2 transcription factor deficiency has recently been described in patients with a propensity towards myeloid malignancy associated with other highly variable phenotypic features: chronic leukocytopenias (dendritic cell-, monocyto-, granulocyto-, lymphocytopenia), increased susceptibility to infections, lymphatic vasculature abnormalities, and sensorineural deafness. Patients often suffer from opportunistic respiratory infections; chronic pulmonary changes have been found in advanced disease.Case presentationWe present a case of a 17-year-old previously healthy Caucasian male who was admitted to the hospital with fever, malaise, headache, cough and dyspnea. A chest X-ray revealed bilateral interstitial infiltrates and pneumonia was diagnosed. Despite prompt clinical improvement under antibiotic therapy, interstitial changes remained stable. A high resolution computer tomography showed severe diffuse parenchymal lung disease, while the patient’s pulmonary function tests were normal and he was asymptomatic. Lung tissue biopsy revealed chronic reparative and resorptive reaction with organizing vasculitis. At the time of the initial presentation to the hospital, serological signs of acute infection with Epstein-Barr virus (EBV) were present; EBV viremia with atypical serological response persisted during two-year follow up. No other infectious agents were found. Marked monocytopenia combined with B-cell lymphopenia led to a suspicion of GATA-2 deficiency. Diagnosis was confirmed by detection of the previously published heterozygous mutation in GATA2 (c.1081 C > T, p.R361C). The patient’s brother and father were both carriers of the same genetic defect. The brother had no clinically relevant ailments despite leukocyte changes similar to the index patient. The father suffered from spondylarthritis, and apart from B-cell lymphopenia, no other changes within the leukocyte pool were seen.ConclusionWe conclude that a diagnosis of GATA-2 deficiency should be considered in all patients with diffuse parenchymal lung disease presenting together with leukocytopenia, namely monocyto-, dendritic cell- and B-lymphopenia, irrespective of severity of the clinical phenotype. Genetic counseling and screening for GATA2 mutations within the patient’s family should be provided as the phenotype is highly variable and carriers without apparent immunodeficiency are still in danger of developing myeloid malignancy. A prompt recognition of this rare condition helps to direct clinical treatment strategies and follow-up procedures.

IL-4 polymorphisms, HRCT score and lung tissue markers in idiopathic pulmonary fibrosis.

AIMS We studied the influence of IL-4 gene polymorphisms on the IPF phenotype, i.e., extent of radiological changes (HRCT interstitial (IS) and alveolar (AS) score) and histopathological markers from lung biopsies. PATIENTS AND METHODS 46 IPF patients underwent genotyping, 43 of them had HRCT and 14 patients had a surgical lung biopsy. The HRCT scans were evaluated for AS and IS. The histopathological evaluation comprised myofibroblast foci (MF), intensity of inflammation and fibrosis (Ashcroft score) and numbers of eosinophils and granulomas. For immunohistochemical evaluation primary antibodies against PAR-2, CD124, TGF beta, YY-1 and TSLP were used. The IL-4 and IL-4 R alpha gene polymorphisms were characterized. RESULTS We found a correlation between eosinophils in lung biopsies and AS. The Ashcroft score was higher in IL-4 HA 2 GCC and MF were more frequent in IL-4 HA 2 TCC carriers. A relationship was found between IL-4 (-1098) A2 T and PAR-2 expression and IL-4 (-590) A1 T, IL-4 HA1TTT and CD124 expression. AS was lower in IL-4 (-590) A1 C, in IL-4 HA1 TCC and in IL-4RA (+1902) A1 A carriers. CONCLUSIONS We suggest that the polymorphisms of IL-4 genes might influence the phenotype of IPF reflected by histopathological changes in lung biopsies and HRCT score.

No Evidence for Linkage between the Hereditary Angiooedema Clinical Phenotype and the BDKR1, BDKR2, ACE or MBL2 gene

Hereditary angiooedema (HAE) is a life‐threatening disease with poor clinical phenotype correlation with its causal mutation in the C1 inhibitor (SERPING1) gene. It is characterized by substantial symptom variability even in affected members of the same family. Therefore, it is likely that genetic factors outside the SERPING1 gene have an influence on disease manifestation. In this study, functional polymorphisms in genes with a possible disease‐modifying effect, B1 and B2 bradykinin receptors (BDKR1, BDKR2), angiotensin‐converting enzyme (ACE) and mannose‐binding lectin (MBL2), were analysed in 36 unrelated HAE patients. The same analysis was carried out in 69 HAE patients regardless of their familial relationship. No significant influence of the studied polymorphisms in the BDKR1, BDKR2, ACE and MBL2 genes on overall disease severity, localization and severity of particular attacks, frequency of oedema episodes or age of disease onset was detected in either group of patients. Other genetic and/or environmental factors should be considered to be responsible for HAE clinical variability in Caucasians.

Burden of serious fungal infections in the Czech Republic

We have estimated the number of serious fungal infections in the Czech Republic. All published epidemiology papers reporting Czech fungal infection rates were identified. Where no data existed, we used specific populations at risk and fungal infection frequencies in those populations. Population statistics were obtained from the 2011 Census data, prevalence and incidence data for at‐risk conditions were obtained from publicly accessible healthcare statistics and relevant surveys. We estimate that 152 840 Czech women suffer with recurrent vaginal thrush. Allergic bronchopulmonary aspergillosis is likely in 4739 adults and 6581 more have severe asthma with fungal sensitisation. Hypersensitivity pneumonitits secondary to fungi is estimated in 1050 cases and 365 people may have chronic pulmonary aspergillosis. Oesophageal candidiasis is estimated in 210 HIV‐positive people. There are 12 cases of Pneumocystis pneumonia in HIV population and 60 more cases in non‐HIV population. There are an estimated 526 cases of candidaemia, 79 cases of Candida peritonitis and 297 cases of invasive aspergillosis a year. About 176 000 (1.67%) Czech people suffer from severe fungal infections each year, predominantly from recurrent vaginitis and allergic respiratory conditions. Substantial uncertainty surrounds these estimates except for invasive aspergillosis in haematology and candidaemia in critical care.