Increased Vascular Endothelial Growth Factor Serum Level and the Role of +936C/T Gene Polymorphism in Chronic Obstructive Pulmonary Disease.

Background and Objectives: Chronic obstructive pulmonary disease (COPD) represents a debilitating disease, with rising morbidity and mortality. Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis, vascular permeability, and airway remodeling. The purpose of this study was to investigate the relationship between VEGF serum levels and VEGF +936 C/T gene polymorphism (rs3025039) with COPD, for the first time in a Romanian population. Materials and Methods: In total, 120 participants from Transylvania were included in this case-control study. Serum levels of VEGF were determined using an enzyme-linked immune-sorbent assay and rs3025039 was investigated by high molecular weight genomic deoxyribonucleic acid (DNA). Spirometric values, arterial blood gas analysis, and the Six Minute Walk Test (6MWT) outcome were also determined. Results: The serum level of VEGF was higher in the COPD group versus controls (p < 0.001), with a positive correlation with the 6MWT outcome. No significant difference was observed in the VEGF serum levels between VEGF +936C/T genotypes. There was no difference in the VEGF +936C/T genotype between COPD patients and healthy subjects (chi2 test p = 0.92, OR = 1.04, 95%CI = 0.41-2.62), but the presence of the T allele was significantly linked to the presence of COPD (chi2 test p = 0.02, OR = 2.36, 95%CI = 1.12-4.97). Conclusions: Higher VEGF serum levels were found in moderate and severe COPD and were positively correlated with the distance in the 6MWT. No significant difference was found between CC, CT, and TT genotypes of rs3025039 and the presence of COPD. The presence of the T allele was found to be linked to COPD and also to the degree of airway obstruction.

Alveolar proteinosis - an underdiagnosed condition in young people.

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by an abnormal intra-alveolar accumulation of surfactant derived lipoproteinaceous compounds, leading to dyspnea and, in severe cases, to respiratory failure. The most common form of PAP is the auto-immune one. Secondary PAP has been recognized in myeloid leukemia, non-hematological neoplasms, lung infections or environmental exposure to noxious particles. Mutations in several genes (such as MARS, SFTPB, TTF1) are responsible for the alteration of surfactant production. Diagnosis tools include high-resolution computed tomography, bronchoalveolar lavage. Although over the past 20 years the pathophysiology of PAP has become more clear, the therapeutic strategies still need improvement. A national programme for patients with PAP might be useful in Romania.

Correlations between neutrophil to lymphocyte ratio, blood eosinophils and clinical characteristics in chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death worldwide, with increasing mortality and morbidity. The neutrophil to lymphocyte ratio (NLR) and blood eosinophils level (EOS) represent biomarkers of inflammation in various diseases, with current research in the field of COPD. The aim of this study was to determine correlations of NLR and EOS with certain characteristics of COPD in a group of patients without major comorbidities. METHODS: We conducted an observational study on COPD patients admitted to the Clinical Hospital of Pneumology in Cluj-Napoca, Romania. The smoking history, body mass index (BMI), NLR, EOS, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and the arterial partial pressure of oxygen (PaO2) were determined. Functional assessment consisted of spirometric and BODE index determinations. The duration of hospitalization was expressed as the length of stay (LOS). The patients were divided into 3 subgroups: active smokers (AS), former smokers (FS) and never smokers (NS). RESULTS: No significant differences between AS and FS were found when age, airway obstruction, BODE index, PaO2, ESR and CRP were considered. The NLR was higher in AS versus FS (p=0.035), while EOS was lower in AS group (p=0.061). COPD patients with ≥300 EOS/µL had lower CRP, ESR levels and NLR compared to those with eosinophilia <300/µL (p=0.020, p=0.009 and p=0.007, respectively). With a threshold of 3.5 for NLR, patients with lower NLR had lower CRP values (p=0.05). COPD patients with higher NLR had significant lower EOS levels (p=0.018). Overall, the NLR and EOS were not correlated with the investigated characteristics (p>0.05), but intragroup analysis (based on smoking status) revealed correlations with ESR (p=0.0001), CRP (p=0.053), BODE index (p=0.029) and LOS (p=0.042). CONCLUSIONS: AS have higher NLR and lower EOS levels versus FS. COPD patients with higher EOS level have lower CRP, ESR and NLR. In AS, EOS level is positively correlated with BODE index and negatively correlated with NLR.

CD4+ regulatory T cells and CD4+ activated T cells in new active and relapse tuberculosis.

The aim of the present study was to examine characteristics of tuberculosis (TB) patients with different clinical forms and to study the frequency of Regulatory T cells (Treg cells) and Activated T cells in patients with new active and relapse TB. Forty-five pulmonary TB patients and a control group of 15 healthy individuals were enrolled in this study. Of the 45 TB patients, 15 were new cases with drug-susceptible active TB and 30 were relapsed cases (15 drug-susceptible and 15 multidrug resistant-TB). The age of study participants ranged from 21 to 68 years old. According to sex presentation, males were appreciably highly affected than females with a sex ratio of 2. The patients reported a mean recent weight loss of 8.9 kg. The Erythrocyte Sedimentation Rate was high in TB group, far exceeding the normal value. The results revealed that the number of CD3+ CD4+ T-cells significantly decreased whereas the level of blood Treg cells and expression of activation markers CD38 and HLA-DR on CD4+ T-cells significantly increased in TB group compared with the control group (p<0.05). The frequency of Treg cells was significantly higher in the TB group than the control group. Both the patients with new active TB and relapse TB demonstrated significantly higher levels of CD4+FoxP3+ Treg compared to healthy subjects (p<0.05). A high and significant percentage of Treg cells were found in patients with DS active TB than patients with MDR relapse TB. Interestingly, the frequency of CD4+FoxP3+ cells also differs according to the sputum smear microscopy status. The presence of high numbers of Treg cells and corresponding high immune activation may be an unfavourable factor that can predispose individuals to different clinical forms of TB, including relapse TB.

Fatal hypersensitivity pneumonitis after chemical occupational exposure.

Hypersensitivity pneumonitis (HP; extrinsic allergic alveolitis) is a rare non-immunoglobulin E (IgE)-mediated inflammatory lung disease caused by inhalation exposure (occupational, recreational or ordinary home exposure). A 36-year-old female patient, without significant medical history, is referred to an outpatient pulmonology clinic for dry cough, shortness of breath, fever, fatigue and weight loss. Chest high-resolution computed tomography (HRCT) was performed, and significant lung fibrosis (especially centrilobular and interlobular in bilateral "thick lines"), traction bronchiectasis and alveolitis in both superior lobes are described. Lung function tests showed severe restrictive dysfunction. Transfer factor of the lung for carbon monoxide (TLCO) being very low, the flexible bronchoscopy was contraindicated. Surgical lung biopsy was performed. Histopathological examination showed characteristic lesions of chronic bilateral hypersensitivity pneumonitis. The patient died four days after the surgical intervention due to post-operative complications. Exposure to various chemical substances can form bonds with human proteins molecules and induce an exaggerated immune response in susceptible individuals. A high index of suspicion of occupational exposure can determine an early diagnosis with a better outcome.

MRI as indicator of pulmonary tuberculosis activity: from morphological to molecular level assessment - a case report.

We present the case of an adult patient with active post-primary pulmonary tuberculosis (TB) and discuss specific morphological and textural aspects found at high-field magnetic resonance imaging (MRI) of the lung. The 42-year-old man, heavy smoker, undertook a routine employment medical examination and was admitted to a referral pulmonology and TB center due to the abnormal findings seen on his chest radiography. The patient presented nonspecific symptoms, bilateral bronchial breath at pulmonary auscultation, inflammatory syndrome on the laboratory blood tests and positive sputum smears for acid-fast bacilli, which together with the typical aspect on the chest radiography lead to a diagnosis of post-primary pulmonary TB and administration of specific medication. To exclude a possible lung cancer and to reevaluate the extent of the disease, computed tomography and magnetic resonance imaging of the lung were performed. The magnetic resonance examination showed, with an accuracy similar to that of computed tomography, the morphology of active post-primary parenchymal TB lesions, as depicted on the T2-weighted acquisition. Moreover, the T1-weighted sequence using iterative decomposition allowed the assessment of both lipid and caseous pneumonia. To the best of our knowledge, this is the first reported case to assess post-primary pulmonary TB using high field MRI equipment, with an analysis from a morphological to a molecular level. By using a fast two-sequence protocol, both morphological, through T2-weighted acquisition, and textural information such as fat content, using dedicated T1-weighted sequence, can be obtained.

Texture analysis using proton density and T2 relaxation in patients with histological usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP).

OBJECTIVES: The purpose of our study was to assess proton density (PD) and T2 relaxation time of usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP) and to evaluate their utility in differentiating the two patterns. Furthermore, we aim to investigate whether these two parameters could help differentiate active-inflammatory and stable-fibrotic lesions in NSIP. METHODS: 32 patients (mean age: 69 years; M:F, 1:1) with pathologically proven disease (UIP:NSIP, 1:1), underwent thoracic thin-section multislice CT scan and 1.5T MRI. A total of 437 regions-of-interest (ROIs) were classified at CT as advanced, moderate or mild alterations. Based on multi-echo single-shot TSE sequence acquired at five echo times, with breath-holding at end-expiration and ECG-triggering, entire lung T2 and PD maps were generated from each subject. The T2 relaxation time and the respective signal intensity were quantified by performing a ROI measurement on the T2 and PD maps in the corresponding CT selected areas of the lung. RESULTS: UIP and NSIP regional patterns could not be differentiated by T2 relaxation times or PD values alone. Overall, a strong positive correlation was found between T2 relaxation and PD in NSIP, r = 0.64, p<0.001; however, this correlation was weak in UIP, r = 0.20, p = 0.01. T2 relaxation showed significant statistical difference between active-inflammatory and stable-fibrotic NSIP regions at all levels, p<0.05, while for the analysis of ventral lesions PD proved no statistical difference, p>0.05. CONCLUSIONS: T2 relaxation times and PD values may provide helpful quantitative information for differentiating NSIP from UIP pattern. These parameters have the potential to differentiate active-inflammatory and stable-fibrotic lesions in NSIP.

Morbidity by tuberculosis in the Jiu Valley: relation with diagnostic practice and the impact on therapeutic results.

BACKGROUND AND AIM: In the last two and a half decades the dynamics of tuberculosis has been modelled by social and economic conditions, with consequences on the life style, and effects on the onset and evolution of the disease. The Jiu Valley is an area with social problems: mining, mines closing down and ceasing activity, poverty. We looked for a relationship between changes of life style in the Jiu Valley and the dynamics of tuberculosis. METHODS: We studied 528 patients who asked for medical services in different hospitals in the Jiu Valley between 2010-2013. We structurally characterized this group, we identified the characteristics of life style, and we assessed the health state, in particular the relation with tuberculosis. RESULTS: We found out that the quality of life was influenced by the health state, especially by tuberculous disease. Quality of life was influenced by the life style, professional factors and their long term consequences. The study evidenced a strong relationship between apparently very different factors such as life style, professional factors on one side and those characterizing tuberculosis. CONCLUSIONS: We report the first detailed epidemiological data on tuberculosis in an economically poor area, the Jiu Valley.

A case control study of risk factors associated with pulmonary tuberculosis in romania: experience at a clinical hospital of pneumology.

BACKGROUND AND AIM: Tuberculosis (TB) remains a major public health issue in Romania. The aim of the present study was to evaluate the potential demographic, socioeconomic and behavioral risk factors for TB among hospitalized patients in Romania. METHODS: This is a case-control study conducted between March 1st 2014 and March 30th 2015 at Leon Daniello Clinical Hospital of Pneumology, Cluj Napoca. A total of 150 TB patients defined as "cases" were matched for age, sex and county of residence to 150 controls selected from patients attending the same hospital with respiratory diseases other than TB. Data collection was obtained through patient interviews using a structured questionnaire. Factors potentially associated with TB infection were analyzed using univariate and multivariate logistic regression. RESULTS: Factors independently associated with TB were illiteracy (OR=2.42, 95% CI 1.09-5.37), unemployment (OR=2.08, 95% CI 1.23-3.53), low household income (OR=4.12, 95% CI 2.53-6.71), smoking (more than 20 cigarettes per day) (OR=2.12, 95% CI 1.20-3.74), poor knowledge of TB (OR=3.46, 95% CI 1.97-6.07), presence of TB patient in household (OR=4.35, 95% CI 1.42-13.36), prior TB treatment (OR=2.2, 95% CI 1.93-2.5) and diabetes (OR=3.32, 95% CI 1.36-8.08). CONCLUSION: This study provided useful information that might help to develop and adapt effective policies for TB control in Romania.

The impact of immune disturbances on the failure of antituberculosis treatment.

BACKGROUND AND AIM: Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex, with an evolution and treatment outcome determined by the interaction between the mycobacterial and human genotypes. Various deficiencies of innate immune response starting from the first encounter of M. tuberculosis with lung cells endanger host infection control due to decreased triggering of cellular immune resistance and disturbed humoral immunity. Disturbed cell mediated immunity, known as the basic immune response in tuberculous infection, contributes to the deficient generation of central necrosis granuloma, consequently being responsible for severe clinical aspects and low final outcome. The tuberculosis patient's immune assessment is important before treatment initiation, for establishing the risk reduction measures and increasing success rate. MATERIAL AND METHODS: The immune study was conducted on 54 new pulmonary tuberculosis cases with treatment failure, 34 new pulmonary tuberculosis cases that successfully ended the treatment and 50 healthy group individuals. Immune assays performed were: blastic transformation of lymphocytes induced by different antigens, quantitatitve assessment of cellular immunity through CD4+ T cell and CD8+ T cell phenotyping, humoral immunity - through immunoglobulin isotyping, innate resistance - through phagocyte activity of neutrophils, the titter of anti-tuberculosis antibodies and the serum level of circulating immune complexes. Investigations were performed at the onset the treatment and at the end of intensive phase of the standard anti-tuberculosis treatment. RESULTS: Immune disturbances evidenced in patients with treatment failure were: important deficiencies of cellular immunity, hyperactivity of humoral immunity and deficiencies of innate immunity. High predictive value for treatment failure showed the indices: deficiency of T lymphocytes count (OR=62.5) and T helper count (OR=12.5), high level of circulating immune complexes (OR=9.801), deficiency of innate resistance (decreased phagocytating index OR=2.875). CONCLUSIONS: For increasing the treatment success rate, the study of immune disturbances must be performed before of antituberculosis treatment initiation, especially of cellular immunity for the early start of immune adaptive treatment.

The role of exogenous risk factors of antituberculosis treatment failure.

BACKGROUND AND AIM: The Republic of Moldova reports the highest incidence of tuberculosis and the lowest treatment success rate among European region countries. In most of the patients the antituberculosis treatment failure is correlated with social risk factors (low socio-economical state, epidemiological danger characteristics) and biological factors (young age, male sex, physiological conditions, associated diseases). Clinical factors (advanced forms of tuberculosis, chronic evolution, immune disturbances), therapeutic factors (treatment errors and interruptions, individualized regimens) and administrative factors (drug interruption in supply, suboptimal treatment quality) prevail in regions with defficient in health care delivery. The association of risk factors has a higher impact than the severity of one risk factor. The risk factor assessment is very important before initiation of the treatment, for establishing the plan of risk reduction measures for increasing the success rate. The aim of the study was to determine the impact of exogenous risk factors on antituberculosis treatment failure. METHODS: The study was conducted on 201 patients with pulmonary tuberculosis and treatment failure and 105 patients with pulmonary tuberculosis who successfully finished the antituberculosis treatment. Selected cases were investigated according national standards. RESULTS: The treatment failure occurred in patients belonging to socially disadvantaged groups, patients with harmful habits (alcohol abuse, drug use, active smoking), patients from infectious clusters. Migration, homelessness and detention releasing imperil the quality of treatment, thus predisposing to the treatment failure. Social, educational support and the substitutive therapy and withdrawal techniques (tobacco, alcohol, psycho-active substances) must be implemented in the high risk groups in order to diminish the risk of treatment failure and to increase the treatment success rate. CONCLUSIONS: The study of exogenous risk factors in vulnerable groups will contribute to the precocious detection of patients predisposed to failing the tuberculosis treatment and will permit the initiation of measures centered on patient that will favor the increase of treatment quality and success rate.

State of the art in the diagnosis and management of interstitial lung disease.

The interstitial lung diseases (ILDs) are a diverse group of disorders characterized by a varying combination of inflammation and fibrosis of the pulmonary parenchyma. Treatment and prognosis of ILD typically depend on the underlying ILD subtype, highlighting the importance of accurate classification and diagnosis. Besides a thorough history and clinical examination, the protocol should include a 6-minute walk test, chest radiography, high-resolution computed tomography, biochemical analysis, pulmonary function tests, blood gas analysis, bronchoalveolar lavage, and, when necessary, a lung biopsy. The final diagnosis of ILD entities requires dynamic interaction between clinicians, radiologists and pathologists to reach a clinico-radiologic-pathologic diagnosis, the gold standard no longer being the histology but rather a multidisciplinary approach.

T2 mapping of CT remodelling patterns in interstitial lung disease.

OBJECTIVES: To evaluate lung T2 mapping for quantitative characterization and differentiation of ground-glass opacity (GGO), reticulation (RE) and honeycombing (HC) in usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). METHODS: Twelve patients with stable UIP or NSIP underwent thin-section multislice CT and 1.5-T MRI of the lung. A total of 188 regions were classified at CT into normal (n = 29) and pathological areas, including GGO (n = 48), RE (n = 60) and HC (n = 51) predominant lesions. Entire lung T2 maps based on multi-echo single shot TSE sequence (TE: 20, 40, 79, 140, 179 ms) were generated from each subject with breath-holds at end-expiration and ECG-triggering. RESULTS: The median T2 relaxation of GGO was 67 ms (range 60-72 ms). RE predominant lesions had a median relaxation of 74 ms (range 69-79 ms), while for HC pattern this was 79 ms (range 74-89 ms). The median T2 relaxation for normal lung areas was 41 ms (ranged 38-49 ms), and showed significant difference to pathological areas (p < 0.001). A statistical difference was found between the T2 relaxation of GGO, RE and HC (p < 0.05). CONCLUSIONS: The proposed method provides quantitative information for pattern differentiation, potentially allowing for monitoring of progression and response to treatment, in interstitial lung disease. KEY POINTS: • Multi-echo single shot TSE sequence allows for entire lung T2 mapping. • Lung remodelling patterns in ILD show different T2 relaxation. • Quantitative T2 mapping may provide information for monitoring of ILD.

Lung response after subchronic glass fiber intratracheal instillation: an experimental study on rats.

The aim of the study was to identify the effects on the lung after subchronic glass fiber intratracheal instillation study on rats. We evaluated the toxicological effects on the lung: persistent inflammatory reaction, cell proliferation, and pulmonary fibrosis on histopathological examination. We performed a glass fiber intratracheal instillation study on total 32 Wistar rats. The animals were divided into four groups: three test groups exposed to different doses of glass fiber and one control group. One week after the end of the exposure period, all animals were euthanized. The histopathological examination of the lung performed in this study followed both distribution of the lesions through the multilevel biopsies that were taken and the inflammatory profile using both hematoxilin-eozin and Sirius red staining. The inflammatory lesions described for the first group were minimal/slight (grade I) and the total score was between 0 and 10 points (mean value = 3). For the second group, the inflammatory lesions were moderate/marked (grade II) with discrete collagen proliferation and discrete fibrosis and the total score ranged between 11 and 20 points (mean value = 11,250). For the third group, the described inflammatory lesions were massive with total score ranging between 21 and 30 points with collagen deposition, pulmonary and pleural fibrosis, and lung emphysema (mean value = 21,750) and no lesion in control group (with statistically significant difference P ≤ .001). This study of fiber glass intratracheal instillation of three different doses demonstrates that exposure to fiber glass is responsible for the development of persistent inflammatory response and a large range of hystopathological lesions which correlate to the administered dose.

[Primary pleural-pulmonary non-Hodgkin lymphoma]. / Limfom non-Hodgkin primar pleuro-pulmonar.

Primary pleuro-pulmonary non-Hodgkin lymphomas are very rare tumors, possibly under diagnosed, with a very long, frequently asymptomatic evolution. The authors present the diagnostic difficulties of such pathology, in a particular case, which was diagnosed only by open biopsy and immunohistochemical analysis of tissue fragments. Chemotherapy and radiotherapy determined a favorable course of the disease.