[Clinical diagnostic and organizational aspects of providing care to patients with pulmonary sarcoidosis in the Armed Forces].

The data on the epidemiology and aetiology of sarcoidosis, the current classifications are presented. The basic provisions of the legal framework of medical management of patients suffering from sarcoidosis are given. The authors provided an analysis of the characteristics of diagnosis and treatment of sarcoidosis in the military, based on which we propose an algorithm of examination of patients with respiratory sarcoidosis in military health care facilities the Russian Defence Ministry, the recommended treatment regimens and order dynamic observation of patients. Invited to provide skilled care to patients with respiratory sarcoidosis selection based on the Main Military Clinical Burdenko Hospital specialized centre (department with bunks for the treatment of patients with sarcoidosis).

Phenotyping sarcoidosis from a pulmonary perspective.

RATIONALE: Sarcoidosis is known as a disease with high heterogeneity in clinical severity and inflammatory activity. On the basis of radiologic criteria, John Guyette Scadding developed a classification system, which is widely used, but is insufficient for clinical decision making. Therefore, biomarkers and genetic markers that predict outcome are urgently needed. OBJECTIVES: To obtain a classification system based on clinical criteria to evaluate biomarker and genetic markers. METHODS: We developed a protocol for classification of various disease courses (sarcoid clinical activity classification [SCAC]) based on clinical criteria with three categories: (1) whether the disease was acute or nonacute in onset, (2) whether treatment was required, and (3) whether there was need for long-term treatment. MEASUREMENTS AND MAIN RESULTS: In total, we evaluated 225 patients with sarcoidosis, applying both classification protocols retrospectively. The described SCAC protocol based on clinical criteria was retrospectively able to stratify patients according to disease outcome. The classes of patients with chronic disease differed significantly regarding pulmonary function test parameters and bronchoalveolar lavage fluid cell composition. Most interestingly, concentrations of soluble IL-2 receptor and neopterin were particularly increased in patients with acute disease who required long-term treatment. A moderate but significant increase in soluble IL-2 receptor and neopterin was also observed in patients with nonacute disease who needed long-term treatment. In contrast to the clinical classification system, the system based on radiologic criteria separated the patients with the need for long-term therapy insufficiently, but identified patients with advanced fibrotic remodeling. CONCLUSIONS: The described SCAC protocol is practicable and gives additional information not yet acquired by radiologic typing and seems suitable for studies evaluating genetic influence and biomarkers.

[Testicular carcinoma and sarcoid-like necrotizing granulomatosis]. / Cancer testiculaire et granulomatose nécrosante sarcoid-like.

A 35-year-old man with a stage I non-seminomatous germ-cell tumor of the right testis was treated with a simple orchidectomy. Sixty-seven months later, the patient who was on clinical follow-up, has presented five bilateral lung nodules on computed-tomography scan. Additional staging showed no other abnormalities. Lung biopsy of two nodules was performed during a videothoracoscopy and the histologic examination revealed a sarcoidosis-like necrotizing granulomatosis. The coexistence of non-caseating granulomas and testis carcinoma showed an increase during the last two decades. The immunopathogenesis of sarcoid formation in malignant tumours is still unknown. During follow-up of patients with testicular carcinomas, the presence of lung nodules requires a histologic examination and sarcoidosis should be considered as differential diagnosis.

Enhanced CD8+ cytolytic T cell responses in the peripheral circulation of patients with sarcoidosis and non-Löfgren's disease.

BACKGROUND: The role of CD4+ T cells in the immunopathogenesis of pulmonary sarcoidosis is well-established, while less is known about the phenotype and function of CD8+ cytolytic T cells (CTLs). METHODS: CD8+ CTLs were explored in peripheral blood and bronchoalveolar lavage (BAL) samples obtained from up to 25 patients with sarcoidosis and 25 healthy controls. The proportion of CTLs was assessed by the expression of cytolytic effector molecules perforin, granzyme B and granulysin in CD8+ T cells, using flow cytometry. Cytolytic function in blood lymphocytes was assessed using a standard 51Cr-release assay. Patients with Löfgren´s syndrome (LS) and an acute disease onset, were compared to non-LS patients with an insidious onset. RESULTS: Higher proportions of peripheral CD8+ CTLs expressing perforin and granzyme B were observed in sarcoidosis compared to healthy controls. Blood CTLs from non-LS patients had significantly higher expression of perforin, granzyme B and granulysin compared to matched BAL, while LS patients maintained lower levels of effector molecules in both compartments. Mitogen-stimulated peripheral lymphocytes from sarcoidosis patients, particularly from the non-LS group, showed a higher target cell lysis compared to controls. CONCLUSION: These results demonstrated enhanced peripheral CD8+ CTL responses in sarcoidosis, especially in non-LS patients who have an increased risk of chronic disease. Further comprehensive clinical studies are warranted to increase our understanding of CD8+ CTL responses in sarcoidosis.

Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?

Tuberculosis and sarcoidosis are chronic systemic diseases that have similar pulmonary and extra-pulmonary manifestations. Multiple studies have found an epidemiological, molecular, and immunological link between the two. It has been suggested that mycobacterium tuberculosis could be a common pathophysiologic mechanism for tuberculosis and sarcoidosis, and that both clinical entities can trigger similar immunological response in patients. Due to this close association, together with possible coexistence in the same patient, the diagnosis of one disease from another may be difficult. In our paper, we suggest that tuberculosis and sarcoidosis are two ends of the same spectrum. Given the pathophysiological and clinical link between the two, we also propose a classification system for tuberculosis and sarcoidosis: Sarcoidosis (S); Sarcoid-Tuberculous (ST); Tuberculous Sarcoid (TS) and Tuberculosis (TB). More research and clinical trials should first be done to affirm the link between the two disease entities.

Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602-DRB1*150101.

Sarcoidosis is a multiorgan granulomatous disease of unknown etiology. Several lines of evidence suggest a genetic predisposition and associations have been demonstrated with HLA antigens. HLA-DQB1 has been proposed as one of the candidate genes. To investigate the relationship between DQB1 and sarcoidosis at the allele level, we typed 149 Dutch Caucasian sarcoidosis patients for DQB1 by sequence-based typing as the ultimate technique to identify all DQB1 alleles. Phenotype frequencies were compared with controls. Both groups were also typed for HLA-A, -B, and -DRB1 at the low-resolution level. To decide on the possible linkage with DR, all DRB1*15-positive patients were subsequently sequence-based typed. Results showed a statistically significant increase of DQB1*0602 in sarcoidosis patients. The increase was also proven for DRB1*150101. Because of the high linkage disequilibrium between DRB1*1501 and DQB1*0602 in Caucasians, it could not be decided which one was the primary association. The increase was most pronounced in patients with severe pulmonary sarcoidosis indicated by radiographic stages II-IV. Although not statistically significant, DRB1*03 and DQB1*0201 were increased in radiographic stage I compared with II-IV. This study provides evidence that the combination DQB1*0602/DRB1*150101 is a strong positive marker for severe pulmonary sarcoidosis.

Ocular and systemic features of sarcoidosis and correlation with the International Workshop for Ocular Sarcoidosis diagnostic criteria.

PURPOSE: To describe the ocular and systemic features in biopsy proven (definite) and non-biopsy proven (clinical) ocular sarcoidosis and to compare the ocular features with those proposed by the International Workshop for Ocular Sarcoidosis (IWOS). METHODS: Retrospective chart review of 83 patients who attended a tertiary referral uveitis clinic and were diagnosed with sarcoidosis. Patients were divided into two groups based on the type of diagnosis: those who had tissue biopsy confirmed diagnosis 'definite sarcoidosis' (n= 42; 50.60 %) and those who had 'clinical sarcoidosis' (n= 41; 49.40%). Ocular and systemic manifestations, including lung function tests and bronchoalveolar lavage findings were compared in the two groups. The ocular features were also compared with the categories laid down by the International Workshop on Ocular Sarcoidosis (IWOS). RESULTS: The mean age at presentation was 38.75 years (SD=12.33), 55.42% patients were female and mean follow-up was 24.35 months (SD=18.35). Trabecular meshwork nodules and/or tent-shaped PAS (category II of IWOS) were observed more frequently in patients with biopsy proven sarcoidosis (26.19 % v/s 9.76%; p=0.08). After logistic regression analysis, the predictor coefficient curve showed area under curve of 0.7262. Lymphocytosis (38.61% and 28.02%, p=0.93) and monocytosis (55.11% and 53.83%, p=0.56) on bronchoalveolar lavage analysis was present in both the groups, highlighting presence of granulomatous disease. CONCLUSION: This study suggests high reliability for the clinical diagnosis of ocular sarcoidosis in patients with signs recommended by IWOS and that our diagnostic criteria are consistent with that of the IWOS.

Early treatment of stage II sarcoidosis improves 5-year pulmonary function.

STUDY OBJECTIVE: To evaluate the 5-year prognosis of patients with stage I and stage II newly detected (< 3 months) pulmonary sarcoidosis treated immediately after diagnosis with prednisolone for 3 months followed by inhaled budesonide for 15 months. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study for 18 months. Thereafter, open follow-up without treatment. SETTING: Twenty pulmonary medicine departments in Finland. PATIENTS: One hundred eighty-nine adult patients, most of them with normal lung function, were randomized to treatment. One hundred forty-nine patients were followed up for 5 years: 79 patients with initial stage I disease and 70 patients with stage II disease. TREATMENT: Oral prednisolone for 3 months followed by inhaled budesonide for 15 months (800 microg bid), or placebo tablets followed by placebo inhaler therapy. Thereafter, treatment only on an individual basis in the case of clinical deterioration. MEASUREMENTS: Yearly follow-up visits with chest radiographs, lung function tests (FEV(1), FVC), diffusion capacity of the lung for carbon monoxide (DLCO), serum angiotensin-converting enzyme (SACE), and serum and urinary calcium measurements. RESULTS: No initial differences were observed in chest radiographic findings between the active-treatment and placebo-treatment groups, either in patients with initial stage I or stage II(-III) disease. However, after the 5-year follow-up, 18 steroid-treated patients (26%) and 30 placebo-treated patients (38%) still had remaining chest radiographic changes. Placebo-treated patients more frequently required treatment with corticosteroids during the 5-year follow-up (p < 0.05). Steroid-treated patients with initial stage II(-III) disease improved more in FVC and DLCO (p < 0.05). No differences in reported adverse events or in SACE, serum calcium, or urinary calcium values were seen. CONCLUSION: Immediate treatment of pulmonary stage II(-III) sarcoidosis-but not stage I disease-improved the 5-year prognosis with regard to lung function variables.

Mortality of intrathoracic sarcoidosis in referral vs population-based settings: influence of stage, ethnicity, and corticosteroid therapy.

STUDY OBJECTIVES: To compare the sarcoidosis mortality in referral settings (RS) and population-based settings (PS), and to identify the contribution of stage, ethnicity, and corticosteroid therapy (CST) to their disparate outcomes. DESIGN: All observational studies identified in a MEDLINE search and bibliographic review published in the English language since 1960 dealing with the course and prognosis of sarcoidosis in large, unsorted, adult, ambulatory RS and PS providing long-term follow-up were reviewed and subjected to meta-analysis. MEASUREMENTS AND RESULTS: Sarcoidosis mortality in RS (4.8%), in which 17% of patients had the most unfavorable prognosis as judged by stage (stage III), was 10-fold that reported in PS (0.5%), in which 11% of patients were identified at this stage. The magnitude of this disparity could not be accounted for solely by adverse selection, as indicated by stage or by ethnicity. Patients in RS received CST with sevenfold the frequency of PS, and its provision was highly correlated with stage-normalized mortality. CONCLUSION: The prognosis of patients with intrathoracic sarcoidosis in PS is far more favorable than that obtained in RS. Sarcoidosis mortality is largely independent of ethnicity. The possibility cannot be excluded that excessive employment of CST may unfavorably influence the long-term course of the disease in some individuals.

Flexible transbronchial needle aspiration in the diagnosis of sarcoidosis.

The histopathologic diagnosis of sarcoidosis requires the presence of noncaseating granulomas. Transbronchoscopic lung biopsy (TBLB) has been considered the procedure of choice when less invasive tissue samples are unavailable. A total of 51 consecutive patients suspected of having sarcoidosis underwent combined TBLB and flexible transbronchial needle aspirate (TBNA). In 18 of the 30 patients (60 percent) with stage I disease, the diagnosis was confirmed by TBLB and 16 (53 percent) were confirmed by TBNA. The combined use of both procedures increased the diagnostic yield to 83 percent. The remaining 21 patients with stage II disease had their diagnosis confirmed in 16 (76 percent) cases by TBLB and 10 (48 percent) by TBNA with a combined diagnostic yield of 86 percent. Seven (23 percent) patients with stage I disease and 2 (10 percent) with stage II disease had their conditions diagnosed by TBNA. We conclude that combining TBNA with TBLB increases the diagnostic yield in pulmonary sarcoidosis; TBNA should complement TBLB in the diagnosis of this disease.

Study of Clara cell 16, KL-6, and surfactant protein-D in serum as disease markers in pulmonary sarcoidosis.

STUDY OBJECTIVES: To determine the discriminative value of serum Clara cell 16 (CC16), KL-6, and surfactant protein (SP)-D as markers of interstitial lung diseases, and their ability to reflect pulmonary disease severity and prognosis in sarcoidosis. SUBJECTS: Seventy-nine patients with sarcoidosis and 38 control subjects. MEASUREMENTS: Serum CC16, KL-6, and SP-D concentrations at disease presentation were measured. Pulmonary function tests and chest radiographs were analyzed at presentation and 2-year follow-up. RESULTS: All markers co-correlated, and a significant difference was found between CC16, KL-6 (Krebs von den Lungen-6), and SP-D levels in patients with sarcoidosis and control subjects (p < 0.0001). Receiver operating characteristic curve analysis revealed largest area under the curve for KL-6. Significantly higher levels of CC16 and KL-6 were found in patients with parenchymal infiltration (stage II, III) compared to patients without parenchymal infiltration (stage I). In concordance, CC16 and KL-6 levels inversely correlated with diffusion capacity and total lung capacity, and KL-6 also with inspiratory vital capacity. Moreover, higher KL-6 levels were weakly but significantly associated with persistence or progression of parenchymal infiltrates at 2-year follow-up. CONCLUSION: In this study, KL-6 appears to be the best discriminative marker in differentiating patients with sarcoidosis from healthy control subjects; however, as it is not a specific marker for this condition, this quality is unlikely to be useful as a diagnostic tool. Both CC16 and KL-6 may be of value in reflecting disease severity, and KL-6 tends to associate with pulmonary disease outcome.

TNF-alpha and HLA-DR genotyping as potential prognostic markers in pulmonary sarcoidosis.

We have analyzed the HLA-DRB1 alleles and -308 TNF-alpha gene polymorphism in 78 sarcoidosis patients and 50 controls. The sarcoidosis group as a whole did not show any significant correlation with the TNF-A or the HLA-DR alleles compared to the control group. However, the patient subgroups of Löfgren and non-Löfgren sarcoidosis exhibited significant allele associations. In the Löfgren patient group, the TNF-A2 and the HLA-DR3 alleles were represented significantly higher, with a highly significant relative risk resulting from the presence of the TNF-A2 or the HLA-DR3 allele or both. In the non-Löfgren patient group, the phenotype expressing HLA-DR2 and lacking TNF-A2 was significantly higher than in the Löfgren patient group. Due to these significant genetic differences in the subgroups of Löfgren and non-Löfgren sarcoidosis patients, we conclude that the genotyping of these two loci (-308 TNF-alpha promoter polymorphism and HLA-DR) may be of prognostic value for the course of disease in sarcoidosis.

Pulmonary sarcoidosis: spirometric correlation with transbronchial biopsy.

We studied the relationship between the histopathology obtained by trans-bronchial lung biopsy (TBLB), and spirometric indices in 28 patients of pulmonary sarcoidosis in whom the diagnosis was confirmed. There was a rough correlation between FVC and the histologic granuloma load, interstitial inflammation and the overall histopathological score. Radiological features did not correlate with either spirometry or histopathology.

[Massive hemoptysis during sarcoidosis]. / Hémoptysies graves au cours de la sarcoïdose.

Hemoptysis is a rare but often severe event in sarcoidosis. It usually occurs in patients with advanced, fibrotic lung disease. We herein report the case of a 36-year old female patient with type II pulmonary sarcoidosis who presented with abundant hemoptysis very early during the course of her disease. Two attempts to embolize bronchial arteries remained unsuccessful and surgery was eventually required to stop the bleeding. Clinical, microbiological, radiological and pathological data indicate that haemoptysis was caused by systemic hypervascularization around sarcoidosis granuloma.

[Late recurrences of spontaneously resolved mediastinal-pulmonary sarcoidosis]. / Récidives à distance de sarcoïdose médiastino-pulmonaire spontanément résolutive.

Five cases of recurrent thoracic sarcoidosis which happened 5.5 years on the average after spontaneous resolution of the disease are reported. Initially, these patients were characterized by the frequency of the presence of a Löfgren's syndrome and the absence of extrathoracic sarcoid localizations. Recurrence of sarcoidosis was potentially severe essentially because of extrathoracic localization which needed oral corticosteroid treatment in 2 patients. Because recurrence of sarcoidosis is rarely observed, the diagnosis should be, in the absence of erythema nodosum, confirmed histologically in order to exclude a lymphoma or one of the various etiologies of diffuse interstitial lung disease. A sustained and regular surveillance of sarcoid patients after spontaneous resolution, particularly those with a Löfgren's syndrome, is suggested.

[Value of CT scanning in the investigation of thoracic sarcoidosis]. / Apport de la TDM dans l'exploration de la sarcoïdose thoracique.

INTRODUCTION: Sarcoidosis is a systemic disease of unknown aetiology that includes a pulmonary or mediastinal component in 90% of cases. The aim of this study is to clarify the contribution of thoracic CT scanning in the diagnosis and differential diagnosis of sarcoidosis and its role in the follow-up and the evaluation of the activity of the disease. METHODS: It is a retrospective study of 39 patients with histologically confirmed sarcoidosis. All patients had one or more thoracic CT scans. RESULTS: The most common parenchymatous lesions were lymphatic micronodules and peri-bronchovascular thickening. The right paratracheal chain and the hilar nodes were the most frequently involved. CONCLUSIONS: The CT scan is better than the chest x-ray at studying the parenchymal lesions and lymph node involvement in sarcoidosis. It helps in the differential diagnosis of sarcoidosis and other granulomatous disorders, especially tuberculosis. It also allows follow up of patients for the detection of complications, particularly fibrosis. Its role in the assessment of disease activity remains controversial.

[A radiographic classification for sarcoidosis based on the ILP/UC classification bacillus].

A scheme was devised for semiquantitative description of 79 cases with sarcoidosis using the graphic terminology of International Labour Office and Union International Contre Le Cancer (ILO/CU) for the pneumoconioses. Among 56 patients with stage II, "linear-irregular" categories s t u (50%) and "reticulonodular" categories x y z (28%) predominated while "rounded" categories p q r (22%) were unusual. Among 13 patients with stage III s t u and x y z opacities were found in 38% of patients while p q r only in 23%. The opacities in both stages of sarcoidosis were most severe in the bilateral lower lobes. It was concluded that the traditional method for classification of sarcoidosis was helpful to give the qualitative diagnosis of the disease, but it did not provide objective description of the type and degree of pulmonary involvement. ILO/UC classification was an important supplement of traditional method as ILO/UC could be used to grade the type (linear irregular, rounded and reticulonodular opacities), severity and location of opacities. Therefore, the two methods should be used in combination so as to judge the location, type and severity of intrathoricic sarcoidosis.

[Bronchoscopic classification in sarcoidosis].

Retrospective analysis in sixty-six patients with pulmonary sarcoidosis: thirty-two males and thirty-four females according to bronchoscopic finding was performed and classified five types in patients with sarcoidosis. Type 1: normal findings. Type 2: prominent vascular change of the mucosa, beyond the bronchial cartilage ring. Type 2 was further divided into two subtypes. 2a: simple increase vascularity. (mucosal vessels run parallel to cricoid cartilage. 2b: irregular vessels. Type 3: sarcoido nodular lesions. Type 4: plaque present. Type 5: deformity of bronchial walls. Eleven type 1 cases were observed (16.7%), and forty-two type 2 cases, including twenty-two type 2a cases (33.3%), twenty type 2b cases (30.3%), There were nineteen type 3 cases observed (28.8%), seven type 4 cases (10.6%), and seven type 5 cases (10.6%).

[Roentgenographic type and CT findings in pulmonary sarcoidosis].

There are five roentgenographic type of intratracic changes, Type 0 means no visible intratracic findings. Type I is bilateral hilar lymphadenopathy, Type II is bilateral hilar adenopathy accompanied by parenchymal infiltration. Type III is only parenchymal infiltration and type IV is advanced fibrosis. CT findings are peribroncho-vascular markings, diffuse small nodules, and large irregular nodules. Usually diffuse small nodules had tendency to improve, although peribronchial markings, atelectacis, pleural thickening, and bullae are irreversible and progressive. CT plays an important role in the diagnosis and prognostic value in pulmonary sarcoidosis.