Genetic and geographic influence on phenotypic variation in European sarcoidosis patients.

Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.

Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

[Combined pulmonary fibrosis and emphysema syndrome]. / Sindrom plucne fibroze udruzene s emfizemom.

CPFE-combined pulmonary fibrosis and emphysema is a new term for a syndrome whose main characteristic is fibrosis in lower pulmonary lobes with simultaneous emphysema in upper pulmonary lobes. CPFE patients have well preserved pulmonary test values for unexpectedly long period, but extremely lowered carbon monoxide diffusion capacity and significant arterial hypertension. All CPFE studies indicate that CPFE occurs predominately in older male population. Smoking is considered main cause in developing CPFE. Reduced survival rate is linked with arterial hypertension extent, and mortality rate is greater than that for patients with isolated pulmonary fibrosis or emphysema. This study is focused on characteristics of twelve CPFE patients. This paper describes cases of 12 patients with the syndrome of pulmonary fibrosis associated with emphysema. All patients were male, mean age of 68 years. At the certain period of life they all were smokers, but most of them were also exposed to air pollution due to their profession. Shortness of breath on exertion was present in all patients. All patients had neat pulmonary function tests with significantly reduced diffusing capacity for carbon mon- oxide (average 39%). Pulmonary arterial hypertension (PAH) averaged 56 mmHg (range 25-75 mmHg) was present in 75% of patients. Four patients died during the period of four months, of which three patients had PAH greater than 70 mmHg. The fourth patient died of lung cancer.

WHOQOL-bREF questionnaire as a measure of quality of life in sarcoidosis.

The aim of this study was to evaluate the usefulness of a short form of the WHOQOL questionnaire, the WHOQOL-BREF, which consists of 24 questions, in evaluating quality of life (QOL) in sarcoidosis patients. A group of 97 sarcoidosis patients and a matched group of 97 healthy controls took part in the study. Their QOL was examined by means of the WHOQOL-BREF, and the respiratory functions were measured in sarcoidosis patients. The WHOQOL-BREF revealed significantly poorer QOL of sarcoidosis patients in the domains of Physical and Psychological Health in comparison to healthy controls. In contrast, sarcoidosis patients perceived their QOL significantly better than healthy controls in the domains of Social Relations and Environment. Differences between sarcoidosis patients and healthy controls were found in several items from the WHOQOL-BREF and some of them were modified by gender. However, the WHOQOL-BREF did not prove to be a sensitive measure of fatigue, which is the most common symptom in sarcoidosis patients.

Morphometric and DNA image analysis of bronchoalveolar lavage fluid macrophages nuclei in interstitial lung diseases with lymphocytic alveolitis.

Lymphocytic alveolitis is a characteristic of diverse interstitial lung diseases (ILD-s), but macrophages are often more numerous cell population in bronchoalveolar lavage fluid (BALF). Aim of this study is to analyze morphometric characteristics of macrophages nuclei in BALF in patients with ILD-s and to detect possible differences allowing distinguishing sarcoidosis from other lymphocytic alveolitis ILD-s. Thirty-one patient with interstitial lung disease who had lymphocytic alveolitis in BALF cell count (17 sarcoidosis and 14 other ILD-s) and nine controls were included in the study. The following patients data were numbered: age, lymphocyte percentage and CD4/CD8 ratio in BALE Investigated morphometric parameters of macrophages nuclei were: area, outline, maximal radius, minimal radius, length, breadth, form factor (FF), elongation factor (EF) and DNA image cytometry ploidy status determined with Van Velthoven method. Predicted classifications in classification matrix (forward step-wise method in multivariate discriminant function analysis) based on macrophages nuclei length mean, minimum and maximum, breadth SD, FF mean and lymphocyte % were 100% (9/9) correct for control group, 88.235% (15/17) correct for sarcoidosis, and 92.857% (13/14) correct for other lymphocytic alveolitis ILD group. In total, 92.5% (37/40) of the examinees were correctly classified in particular group upon the observed variables.

Lung lavage cell profiles in diffuse lung disease.

The standard armamentarium of tests that are used by pulmonologist are laboratory tests, pulmonary function tests, different radiological techniques (conventional chest-X rays, HRCT scans, etc) and pathohistological analyses of biopsies. The minimally invasive bronchoalveolar lavage (BAL) procedure, in addition to methods earlier mentioned, is an important diagnostic instrument that can facilitate the diagnosis of various diffuse lung diseases (DLD). BAL fluid white blood cell profiles are analyzed, malignant cells looked for, and in certain circumstances particular stains are performed to detect yet other cell types. Additionally, BAL can play a very important role in the diagnosis of respiratory tract infections. All these analyses are usually readily performed in a moderately equipped cytological laboratory.

Diffuse pulmonary ossification: an unusual interstitial lung disease.

PURPOSE OF REVIEW: Diffuse pulmonary ossification is a rare disease characterized by diffuse small bone fragments in the lung tissue. It can be idiopathic or associated with underlying chronic pulmonary or heart diseases. The majority of cases had been diagnosed on autopsy. This review collects present knowledge of diffuse pulmonary ossification with the purpose of understanding and considering the entity in the differential diagnosis of interstitial lung diseases better. RECENT FINDINGS: Diffuse pulmonary ossification is the result of multiple factors that interact enhancing each other. Tissue injury is the most important provoking factor that, in an alkaline environment, initiates precipitation of calcium salts, enables alkaline phosphatase activity, and activates profibrogenic cytokines. Alveolar bleeding is responsible for interstitial metallic deposition that attracts calcium salts and multinucleated giant cells. High-resolution computed tomography scan in the mediastinal window facilitates the detection of bone density lesions and provides diagnosis by using low-invasive method. Reports on the efficacy of bisphosphonates and warfarin in the management of heterotopic ossification encourage further investigation. SUMMARY: Diffuse pulmonary ossification is still underrecognized during life. Its relevance concerning the increasing age of population and longer survival of patients with chronic diseases is underrated. A timely diagnosis will enable a better understanding of pathogenesis and natural course of disease thus paving the way to new therapeutic strategies.

[Diffuse lung disease--advances in patient management]. / Difuzne bolesti pluca--napredak u skrbi bolesnika.

Diffuse lung diseases (DLD), known as interstitial lung diseases or diffuse parenchymal lung diseases, are a large group of disorders of diverse etiology and causes, however, sharing similar clinical, radiological and pathophysiological characteristics. In the last fifteen years, DLD have attracted considerable interest of medical society. During that period, a consensus of the British Thoracic Society on the Diffuse Parenchymal Lung Disease and Statement of the American Thoracic Society (ATS) and European Respiratory Society (ERS) on idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias and sarcoidosis have helped precisely define certain phenotypes. The newly developed technique of high resolution computed tomography, which can show finest details of lung parenchyma, has also helped precisely define diverse entities, which have aroused interest among molecular biologists and genetic researchers with a goal to define the etiology, pathogenesis and progression of these diseases. The renaissance of interest in this scientific field has also stimulated pharmaceutical industry to enhance its activity, which has resulted in intensified research of potentially new drugs, especially for fibrotic lung processes such as idiopathic pulmonary fibrosis. The disease outcome is very difficult to estimate in these, most often chronic diseases; however, it is very important to achieve the best possible if not the same quality of life as before the disease onset. Different questionnaires have been used and the results were not always as expected; for instance, worsened lung function tests were not most important in defining the quality of life. These vivacious activities have stimulated us to present to the patient and diligent reader recent advances in the management of DLD patient; the article is mostly dedicated to recent advances made in diagnostic procedures, hoping for a comparable success to be achieved in therapeutic approach.

Hypereosinophilic syndrome: diagnosis and treatment.

PURPOSE OF REVIEW: Hypereosinophilic syndrome is increasingly recognized as a heterogeneous group of disorders, in some cases with precisely defined pathogenesis, which has led to changes in diagnostic approaches and therapeutic strategies. An update on causes and modern therapy is presented here. RECENT FINDINGS: Clonal eosinophilias belong to the group of myeloid malignancies. Karyotypically occult FIP1L1- platelet-derived growth factor receptor alpha and beta rearranged eosinophilic disorders respond to imatinib mesylate with almost 100% efficacy. If standard therapies fail, the FIP1L1- platelet-derived growth factor receptor-negative cases of hypereosinophilic syndrome should also be considered for treatment with imatinib. The recognition of acquired resistance to imatinib has aroused interest in developing new tyrosine kinase inhibitors. Other subgroups of clonal eosinophilias have been molecularly defined, but the curative verification of pathogenetic relevance has not been certified. Hypereosinophilic syndrome patients with abnormal T-cell populations have benefited from treatment with anti IL-5 monoclonal antibodies. SUMMARY: The FIP1L1- platelet-derived growth factor receptor alpha and beta-positive patients, and those with abnormal T-cell populations are currently the only clearly defined treatable subgroups of hypereosinophilic syndrome. The FIP1L1- platelet-derived growth factor receptor alpha-negative responders to imatinib pose a question as to the existence of subentities with unrecognized tyrosine kinases-based mutation. The search for such cases and other treatable subgroups of hypereosinophilic syndrome has already begun.

Relationship between symptoms and quality of life in a sarcoidosis population.

BACKGROUND: As sarcoidosis is a multisytemic disorder, patients may suffer from various symptoms. The relationship between frequently reported symptoms and quality of life (QOL) has not yet been studied. OBJECTIVES: The aim of the present cross-sectional study was to examine the predictive value of the most frequently reported subjective symptoms on QOL after controlling for demographic variables and clinical parameters. METHODS: A cross-sectional study was conducted at an outpatient pulmonary clinic in Zagreb, Croatia. One hundred and fifty outpatients with sarcoidosis were seen between January 2002 and May 2004. Symptoms were assessed with a symptom inventory questionnaire, and QOL was measured using the World Health Organization Quality of Life Assessment Instrument. Clinical parameters were derived from the patients' medical files. Regression analyses were performed to examine the predictive value of symptoms on QOL. RESULTS: The four most frequently mentioned symptoms were fatigue, breathlessness, reduced exercise capacity and arthralgia. In various combinations, being female, using corticosteroids and fatigue predicted the QOL domains physical and psychological health as well as level of independence. CONCLUSIONS: Fatigue appeared to be the most important symptom in predicting various QOL domains after controlling for demographics, disease stage and clinical parameters. Therefore, considering improvement in the patients' QOL, it is recommended to focus not only on objective health parameters, but also on fatigue in the management of sarcoidosis.

Epidemiological characteristics of sarcoidosis patients hospitalized in the Uuniversity Hospital for Lung Diseases "Jordanovac" (Zagreb, Croatia) in the 1997-2002 period.

The aim of our study was to explore the characteristics of hospitalized patients with sarcoidosis concerning age, gender, clinical forms and staging, seasonality, geographical distribution, smoking habit and profession, familial clustering and mortality. We included 476 biopsy-proven sarcoidosis patients who were diagnosed at the University Hospital for Lung Diseases "Jordanovac" in the period from 1997-2002. Most of the patients (44%) were in the group of age between 20 and 40 years. The ratio of women to men was 1.4:1. The onset of the disease usually appeared in spring and summer, especially in the patients presenting with erythema nodosum, with majority of patients hospitalized in the period from May to August (51%). More patients came from urban, than from rural areas (1.5:1), and they were mostly nonsmokers (3.3:1). In 2% of sarcoidosis patients we found familial clustering. Although these data are biased regarding the selection of patients they give new insights into characteristics of sarcoidosis patients in Croatia.

Fatigue is associated with quality of life in sarcoidosis patients.

BACKGROUND: Fatigue is one of the core symptoms of sarcoidosis patients. Although it is known that fatigue affects quality of life (QOL) in other patient groups, this relationship has never been studied in sarcoidosis patients using a reliable and valid fatigue scale and a multidimensional QOL instrument. The present cross-sectional study among sarcoidosis patients attempts to gain more insight into this relationship. METHODS: One hundred forty-five sarcoidosis patients of an outpatient pulmonary clinic in Zagreb, Croatia, completed the Fatigue Assessment Scale (FAS) and QOL scale (World Health Organization Quality of Life Assessment Instrument-100) between January 2002 and May 2004. Clinical parameters were derived from the patients' medical files. RESULTS: Tired patients reported a worse QOL in all domains and fatigue negatively predicted all QOL domains by means of multivariate regression analyses (beta values ranging from - 0.31 to - 0.64, all p < 0.001). Corticosteroid use was not a predictor of QOL. Diffusion capacity of the lung for carbon monoxide was the only clinical parameter associated with a QOL domain, namely level of independence. CONCLUSIONS: Fatigue was related to all QOL domains. Furthermore, standard clinical parameters were not associated with fatigue or QOL, except for level of independence. If these results were to be replicated in a prospective study, fatigue as measured by the FAS could be a good indicator of QOL in sarcoidosis patients.

Psychometric qualities of the Fatigue Assessment Scale in Croatian sarcoidosis patients.

BACKGROUND AND AIM: Fatigue is an unspecific symptom, but a major problem in sarcoidosis patients. There is a need for a reliable and valid way to measure fatigue. The Fatigue Assessment Scale (FAS) has good psychometric properties in healthy and sarcoidosis samples in the Netherlands, but nothing is known about the psychometric qualities of the FAS in sarcoidosis samples from other countries. Therefore, we examined the reliability, construct, and content validity in Croatian sarcoidosis patients. METHODS: Croatian sarcoidosis patients from a pulmonary outpatient clinic completed the FAS and a symptom inventory questionnaire. RESULTS: The internal consistency of the FAS was 0.91. Using exploratory factor analysis and Mokken scale analysis, the scale was unidimensional. A dichotomous fatigue item distinguished between individuals who scored high or low on the FAS. Concerning discriminant validity, individuals reporting health complaints were more tired. The FAS correlated moderately with a number of neurological and psychological problems. Females and lower educated individuals reported more fatigue. CONCLUSIONS: The Croatian translation of the FAS has good reliability and validity in a sarcoidosis sample. Future research is needed to explore the psychometric qualities (i) of the Croatian FAS in healthy individuals and (ii) of the FAS in other languages.

Multiple primary intrathoracic neoplasms: case report and a review of the literature.

This is a case report of a patient diagnosed with three distinct primary intrathoracic tumors (mesothelioma, carcinoid and B-cell lymphoma). The patient had previously had mycosis fungoides. The occurrence of multiple neoplasms in a single patient, synchronous or metasynchronous, is not a rare phenomenon; the incidence varies from 1-11% of all neoplasms. They can be hereditary, or connected with some environmental agents or previous therapies. The incidence of multiple neoplasms increases with age. We report an extremely rare case of multiple intrathoracic neoplasms in a 71-year-old man. A left upper lobectomy was performed, followed by 6 courses of chemotherapy and irradiation of the sternum. The patient was stable two years later.

Prevalence of hospitalized patients with sarcoidosis in Croatia.

The aim of this study was to investigate the prevalence of hospitalized patients of sarcoidosis in the Republic of Croatia, its distribution in relation to sex and age as well as its geographical distribution. The data on sarcoidosis patients hospitalized in Croatia in the last six years, from 1997 to 2002, were analyzed retrospectively. The prevalence of sarcoidosis patients hospitalised in the Republic of Croatia is 4.1/100,000. The prevalence among women is 4.7 and among men 3.5 per 100,000 persons, with a ratio of 1.4:1. The disease more frequently occurs in the regions with a continental climate than in the Mediterranean zone. The ratio of sarcoidosis patients in the continental zone to the Mediterranean zone is 1.5:1. It occurs predominantly among the adults. Over the investigated period, in our country we have not registered any case of sarcoidosis among children. It occurs more frequently at a younger age and therefore 44.5% of the patients with sarcoidosis were between 20 and 39 years of age, 40.1% were between 40 and 59 years of age and 15.3% were more than 60 years old.

[Bronchoalveolar lavage]. / Bronhoalveolarna lavaza.

Bronchoalveolar lavage (BAL) is a bronchoscopic technique that reveals specific insight in the distal parts of lung parenchyma. During the past twenty years, research of cellular and extracellular bronchoalveolar profiles gave important information on pathogenesis of some pulmonary disorders, promoting this technique as a diagnostic tool in pulmonary infections and interstitial lung diseases. Bronchoalveolar lavage is a safe, well-tolerated and suitable diagnostic procedure in immunocompromised patients. The patients with alveolar proteinosis gain therapeutic benefit of bronchoalveolar lavage. In this article we described technical notes, sampling, storage, cellular and noncellular analyses of bronchoalveolar lavage, including interpretation of results and significance in pulmonary diseases.

The role of transbronchial lung biopsy in the diagnosis of solitary pulmonary nodule.

Transbronchial lung biopsy (TBLB) is a well-recognized diagnostic technique in diffuse interstitial lung diseases, but it is not considered to be the first choice in investigation of solitary pulmonary nodules (SPN). The main idea of this study was to increase the sensitivity of bronchoscopy using multiple techniques, especially TBLB, thus to avoid more aggressive diagnostic procedures. The objective of this prospective study was to evaluate the efficacy and safety of TBLB in the diagnosis of SPN, in comparison with other bronchoscopic techniques. Fifty patients with chest x-ray finding consistent with SPN underwent bronchoscopy with bronchial washing, brushing, bronchoalveolar lavage (BAL) and TBLB were included in this study. Thirty-one patients suffered from malignant tumors, while 19 patients had nonmalignant lesions. TBLB achieved overall diagnostic sensitivity of 62%, BAL of 29%, bronchial brushing of 16% and washing of 6%. Combining all techniques together, bronchoscopy had overall sensitivity of 86%. Concerning malignant lesions, TBLB had a sensitivity of 65%, specificity of 100%, and accuracy of 82%. TBLB had a significantly better yield for lesions with a diameter > or = 25 mm than for lesions of < 25 mm (sensitivity of 82% and 53% respectively, p < 0.05). Diagnostic yield improved significantly with the increasing number of specimens (less than 3 specimens: sensitivity 59%, 3 or more specimens: sensitivity 87%, p < 0.05). Complications of TBLB occurred in 2 (4%) patients: 1 incomplete pneumothorax and 1 hemorrhage. According to the results, we conclude that TBLB is an accurate and safe technique for the diagnosis of pulmonary solitary nodule with a diameter equal or greater than 25 mm.

[BOOP-bronchiolitis obliterans organizing pneumonia]. / BOOP--bronhiolitis obliterans s organiziranom pneumonijom.

Bronchiolitis obliterans organizing pneumonia (BOOP) is increasingly recognized in "Jordanovac" Clinical hospital for lung diseases. The characteristic pathohistologic finding is the granulated tissue plugs within the lumen of small airways which extend into the alveolar ducts and alveoli. Numerous conditions and diseases show such histologic picture but the clinician by means of clinical, radiologic and laboratory findings establishes the final diagnosis. By eliminating the known causes and conditions of this syndrome the diagnosis of idiopathic BOOP is established. Idiopathic BOOP is unequivocal clinicopathologic entity which is in typical cases recognized as a pulmonary infiltrate accompanied by febrile illness of a few weeks' duration that is not responsive to a typical course of antibiotics. Corticosteroid therapy causes the complete disappearance of pulmonary infiltrates in 65% to 85% of cases but relapses are common. The therapy of secondary BOOP is less efficient. The aim of this review is to acquaint the readers with the BOOP so it could be incorporated in the differential diagnosis of febrile noninfective diseases that resemble pneumonia.

[Early recognition of Churg-Strauss syndrome]. / Rano prepoznavanje Churg-Straussova sindroma.

We present a patient with Churg-Strauss syndrome which appeared with asthma, chronic sinuitis, peripheral and tissue oeosinophilia, migratory pulmonary infiltrates and polyneuropathy but without histologically proven granuloma or vasculitis. The patient successfully recovered under corticosteroid therapy. The aim of this presentation is early recognition of Churg-Strauss syndrome in order to timely diagnose and treat these patients.