Characterization of chronic fatigue in patients with sarcoidosis in clinical remission.

BACKGROUND: Patients with sarcoidosis frequently complain of fatigue, even when sarcoidosis has come into clinical remission. The primary aim of this study was to assess the severity of fatigue in patients with sarcoidosis in clinical remission and to characterize it according to the international criteria for chronic fatigue syndrome (CFS). Furthermore, we evaluated whether fatigue is associated with depression and anxiety, health status, and patient-reported sleep quality, and we recorded physical activity levels and muscle strength as objective assessments of fatigue. METHODS: Data on 75 patients with sarcoidosis in clinical remission were obtained by questionnaires (Checklist Individual Strength [CIS], Symptom Checklist-90, Beck Depression Inventory for primary care, Medical Outcomes Study 36-Item Short-Form Health Survey), standardized interview (CFS criteria), sleep diary, accelerometer, and muscle strength tests. RESULTS: Fatigue severity mean score in patients with sarcoidosis in clinical remission was high (CIS fatigue severity 30.5 ± 15.5), and criteria for CFS were met in 47% of fatigued participants. Median time since diagnosis was 9 years. Fatigue was associated with depression (P = .01), anxiety (P = .013), and reduced health status (P < .001). Scores on sleep quality were normal. Physical activity levels were reduced in fatigued participants. Muscle strength, particularly handgrip (P = .006) and quadriceps strength (P < .001), was significantly associated with fatigue. CONCLUSIONS: Fatigue in patients with sarcoidosis in clinical remission is a frequent symptom and can be characterized as a severe and long-lasting problem, symptomatically similar to CFS. Psychologic distress and reduced health status are associated with fatigue. Interestingly, we observed significantly reduced physical activity and muscle weakness in fatigued patients.

Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis.

BACKGROUND: The chitinase-like protein YKL-40 is a serum biomarker in diseases with fibrosis, inflammation and tissue remodelling. Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that is hallmarked by these processes. The aim of this study was to investigate the potential of YKL-40 as a prognostic biomarker for survival in IPF patients. METHODS: Serum and bronchoalveolar lavage fluid (BALF) levels of YKL-40 at the time of diagnosis and a promoter polymorphism in CHI3L1, the gene encoding YKL-40, were determined in 85 IPF patients and 126 controls. The relationship between YKL-40 levels and clinical parameters was evaluated. Kaplan-Meier and Cox regression analyses were used to examine the association between YKL-40 levels and survival. RESULTS: Serum and BALF YKL-40 levels were significantly higher in patients than in healthy controls (p < 0.001). The - 329 A/G polymorphism had a significant influence on BALF YKL-40 levels and the influence on serum YKL-40 levels showed a trend towards significance in IPF patients. IPF patients with high (> 79 ng/ml) serum or high BALF YKL-40 (> 17 ng/ml) levels had significantly shorter survival than those with low YKL-40 levels in serum or BALF. In patients with both low serum and low BALF YKL-40 levels no IPF related mortality was observed. Cox regression modelling showed that there were no confounding factors. CONCLUSIONS: The - 329 polymorphism was associated with serum and BALF YKL-40 levels in IPF patients. High serum and BALF YKL-40 levels are associated with poor survival in IPF patients and could be useful prognostic markers for survival in IPF.

Pulmonary embolism and pulmonary infarction after lung transplantation.

Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a common occurrence in patients undergoing surgery and is a potentially fatal complication. Especially after lung transplantation, vascular complications can compromise the function of the allograft and limit survival. Typically, the risk of pulmonary infarction after PE in lung transplant recipients is high because the absence or poor development of the collateral bronchial circulation may predispose lung transplant recipients to pulmonary infarction. This article reports 2 cases of PE with associated pulmonary infarction after lung transplantation with significant morbidity.

Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort.

RATIONALE: Familial clustering of adult idiopathic interstitial pneumonias (IIP) suggests that genetic factors might play an important role in disease development. Mutations in the gene encoding surfactant protein C (SFTPC) have been found in children and families with idiopathic pneumonias, whereas cocarriage of a mutation in ATP-binding cassette subfamily A member 3 (ABCA3) was postulated to have a disease-modifying effect. OBJECTIVES: To investigate the contribution of SFTPC mutations to adult familial pulmonary fibrosis (FPF) and the disease-modifying effect of mutations in ABCA3 within their families. METHODS: Twenty-two unrelated patients with FPF (10%) were identified within our single-center cohort of 229 patients with IIP. SFTPC was sequenced in 20 patients with FPF and 20 patients with sporadic IIP. In patients with an SFTPC mutation, sequencing of ABCA3 was performed. Discovered variants were typed in more than 100 control subjects and 121 additional patients with sporadic IIP. MEASUREMENTS AND MAIN RESULTS: In 5/20 unrelated patients with FPF (25%; confidence interval, 10-49) a mutation in SFTPC was detected: M71V, IVS4+2, and three times I73T. No mutations were detected in the sporadic or control cohort. Patients with SFTPC mutations presented with a histopathological pattern of usual interstitial pneumonia and nodular septa thickening and multiple lung cysts in combination with ground glass or diffuse lung involvement on chest high-resolution computed tomography. Two variants in ABCA3 were found in adult patients with FPF but not in affected children. CONCLUSIONS: Mutations in SFTPC are a frequent cause of FPF in adult patients in our cohort. Nonclassifiable radiological patterns with cystic changes and histopathological patterns of usual interstitial pneumonia are characteristics of adult SFTPC mutation carriers.

Systemic and exhaled cytokine and chemokine profiles are associated with the development of bronchiolitis obliterans syndrome.

BACKGROUND: The mechanisms that lead to the fibrotic obliteration in bronchiolitis obliterans syndrome (BOS) may involve the interactions between T-helper (Th)1 and Th2 cytokines. The aim of this study is to determine the Th1 and Th2 cytokine and chemokine profiles in serum and exhaled breath condensate (EBC) in lung transplant recipients and to assess their usefulness as biomarkers to predict the development of BOS. METHODS: Serum and EBC from 10 patients with BOS (BOS(pos)) and 10 patients without BOS (BOS(neg)), matched for clinical and demographic variables, were analyzed with a multiplex immunoassay to measure a panel of 27 cytokines and chemokines. RESULTS: The pro-inflammatory cytokines in serum were elevated in lung transplant recipients compared with controls. BOS(pos) patients had significantly lower concentrations of interleukin (IL)-4, IL-13, and vascular endothelial growth factor (VEGF) compared with BOS(neg) patients. The concentration of IL-5, however, was significantly higher in BOS(pos) patients. Levels of IL-4 and IL-5 were hardly detectable in EBC. IL-13 and VEGF, both decreased in serum in BOS(pos) patients, were also decreased in EBC in BOS(pos) patients compared with BOS(neg) patients. Longitudinal analysis of cytokines and chemokines in serum and EBC from the time of lung transplantation onwards did not reveal significant trends in cytokines and chemokines that preceded the diagnosis of BOS. CONCLUSIONS: Levels of pro-inflammatory cytokines were increased in lung transplant recipients compared with controls. From the moment of transplantation onwards, there is a different pattern of Th2 cytokines in serum in BOS(pos) patients than in BOS(neg) patients.

[Idiopathic pulmonary fibrosis; description of a Dutch cohort]. / Idiopathische pulmonale fibrose; beschrijving van een Nederlands cohort.

OBJECTIVE: To describe the clinical presentation, diagnosis, and prognosis of a cohort of Dutch patients with idiopathic pulmonary fibrosis (IPF), a serious and rapidly progressive lung disease belonging to the idiopathic interstitial pneumonias. DESIGN: Retrospective study of patient records. METHOD: The data from the clinical presentation, diagnosis, treatment and survival of all patients with IPF, diagnosed in the St. Antonius Hospital in Nieuwegein and University Medical Center Utrecht (UMCU), both in the Netherlands, during the period 1998-2007 were investigated. For the diagnosis, the criteria of the American Thoracic Society and the European Respiratory Society from 2002 were adhered to. RESULTS: The records of 113 patients satisfied the inclusion criteria. Mean age at the time of presentation was 61.9 (SD: 12.7) years and a strong male predominance was observed (90 men vs. 23 women). The most common complaints and symptoms at presentation were dyspnoea, cough, basal crepitations and clubbing of the nails. Lung function tests revealed restrictive lung function impairment and a reduced diffusing capacity. In 72% of cases the diagnosis IPF was histologically confirmed by open lung biopsy, which revealed a pattern of usual interstitial pneumonia (UIP). In 17% of patients it concerned a familial form of the disease with diagnosis at a younger age (average 52 years; SD: 14.8). The medical treatment mostly consisted of corticosteroids, which for half of the patients were administered in combination with an immunosuppressant such as azathioprine or cyclophosphamide. After screening, 28 patients were eligible for lung transplantation. Of these, 12 patients underwent a lung transplantation in the study period, 9 died and 7 are still on the waiting list. The median survival period was 3.9 years. CONCLUSION: In the cohort studied, IPF presented as a rapidly progressive disease with only a marginal response to medical treatment and a poor prognosis. It is important to differentiate IPF from other fibrotic interstitial lung diseases and to refer to a specialist centre, especially in the case of patients who could be eligible for a lung transplant or for participation in trials with new drugs.

MUC1 568 A/G genotype-dependent cancer antigen 15-3 levels in breast cancer patients.

OBJECTIVES: CA 15-3 is a widely used tumor marker for breast cancer. We have investigated whether the MUC1 568 A/G polymorphism can influence CA 15-3 levels in healthy women and patients with breast tumors. DESIGN AND METHODS: CA 15-3 was measured in 208 healthy women, in 67 with benign disease, and in 162 women with breast cancer. All subjects were genotyped for the MUC1 568 A/G polymorphism. RESULTS: Significant differences were observed between mean CA 15-3 levels of control subjects grouped according to the MUC1 568 genotype (mean+/-SD): AA (10.3+/-3.8), AG (15.9+/-5.0) and GG (19.0+/-5.6) U/mL, p<0.0001. Similar (median) results were observed in women with benign breast disease: AA (10.2), AG (14.2) and GG (16.6) U/mL, p<0.0001, and those with breast cancer: AA (10.4), AG (17.1) and GG (23.9) U/mL, p<0.0001. CONCLUSIONS: The MUC1 568 A/G polymorphism strongly influences CA 15-3 levels in healthy women and women with either benign or malignant breast tumors.

Imaging of fibrogenesis in patients with idiopathic pulmonary fibrosis with cis-4-[(18)F]-Fluoro-L: -proline PET.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease for which no single diagnostic modality is able to evaluate the activity of the disease process. Cis-4-(18)F-fluoro-L: -proline ((18)F-proline) was shown in animal studies to be a reliable marker for fibrosis formation. We tested this candidate radioligand for imaging of fibrogenesis in patients with IPF. METHODS: Five patients with IPF proven by lung biopsy and computed tomography were included. Furthermore, we also included one patient with non-specific interstitial pneumonia (NSIP) and scleroderma and one with NSIP and organising pneumonia. Positron emission tomography (PET) acquisition was performed 1, 2 and 3h after injection of 400MBq (18)F-proline. We scored (18)F-proline activity visually and quantitatively by calculating the activity in the regions of interest over lung, liver and mediastinum. RESULTS: We found low uptake of (18)F-proline in the lungs of all patients with IPF. The highest uptake was seen at 2h post-injection, with a decline at 3h past injection. The differences in lung uptake between patients were small, except for one patient with NSIP and organising pneumonia who had a slightly higher (18)F-proline uptake. No significant correlations between (18)F-proline uptake and clinical parameters were found. CONCLUSIONS: Due to the low pulmonary uptake of (18)F-proline in patients with IPF, (18)F-proline does not seem to be a suitable radioligand to evaluate the activity of fibrosis formation in patients with IPF. The low uptake in the lungs of patients with interstitial fibrosis may be explained by the slow nature of fibrogenesis or to the relatively low dose of proline that can be used.

Soluble CD30 measured after lung transplantation does not predict bronchiolitis obliterans syndrome in a tacrolimus/mycophenolate mofetil-based immunosuppressive regimen.

BACKGROUND: The purpose of this study was to determine the utility of post-transplant serum soluble CD30 levels as a biomarker for the development of the bronchiolitis obliterans syndrome (BOS) after lung transplantation during a tacrolimus/mycophenolate mofetil-based regimen. METHODS: Soluble CD30 (sCD30) concentrations were measured prior to transplantation and in 175 samples taken after transplantation in 7 patients developing BOS and 7 non-BOS patients closely matched for age, underlying diseases, follow-up and gender. RESULTS: High pre-transplant sCD30 levels dropped significantly after lung transplantation, but in the post-transplant samples no differences could be detected between patients developing BOS or not, and no changes were found prior to or during the development of BOS. CONCLUSIONS: After transplantation, sCD30 levels are consistently suppressed, but BOS is not prevented, indicating that sCD30 cannot be used as a biomarker to predict BOS after transplantation in the regimen employed.

Increased expression of CD16, CD69, and very late antigen-1 on blood monocytes in active sarcoidosis.

BACKGROUND: Different types of immune cells are involved in the formation of granulomas, a hallmark of pulmonary sarcoidosis. Proinflammatory monocytes are activated circulating monocytes thought to be related to the initial events of granuloma formation. We tested the hypothesis that peripheral blood monocytes in patients with active pulmonary sarcoidosis have an activated phenotype and, secondly, that measuring this activation status can provide a new tool for monitoring disease activity. METHODS: Blood was collected of 23 steroid-naive patients presenting with pulmonary sarcoidosis and 10 healthy control subjects. Expression of CD16 (Fc-gamma type III receptor), CD69 (a general activation marker of cells of the hematopoietic lineage), and the integrin very late antigen (VLA)-1 (on interaction with extracellular matrix compounds mediates cell adhesion) was measured by flow cytometry. RESULTS: Percentages of monocytes expressing CD16, CD69, and VLA-1 in patients vs control subjects were 56.2 +/- 4.1% vs 12.2 +/- 2.4% (p < 0.0001), 87.3 +/- 2.1% vs 8.6 +/- 3.3% (p < 0.0001), and 66.5 +/- 3.6% vs 11.2 +/- 2.3% (p < 0.0001), respectively. Moreover, the CD69+VLA-1+ monocyte subset, abundantly present at disease presentation, was found to decrease to normal levels during follow-up with disease remission. CONCLUSIONS: Peripheral blood monocytes from patients with pulmonary sarcoidosis show a highly activated phenotype. Phenotyping circulating monocytes might be a promising tool for monitoring sarcoidosis disease activity but needs further investigation.

Identification of non-HLA target antigens recognized after lung transplantation.

BACKGROUND: It has become evident that, besides cellular allogeneic immune responses against airway epithelial cells (AEC), humoral responses also contribute significantly to the pathogenesis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Antibody responses against transplanted lungs are directed against HLA and non-HLA antigens, but the identity of the latter antigens is presently unknown. METHODS: The main purpose of this study is to identify non-HLA target antigens on donor lungs recognized by patients' antibodies after LTx. Serum samples were taken before and 6 months after lung transplantation from 11 patients (4 men and 6 women, median age 44 years, range 18 to 63 years). Protein expression libraries were made from the luminal side containing AEC of discarded the donor bronchus, which was snap frozen in liquid N(2) during the organ harvesting procedure. Subsequently, all sera were analyzed for reactivity against library-encoded antigens by serologic analysis of recombinant cDNA expression libraries (SEREX). Recognized gene products were sequenced and analyzed by the NCBI/BLAST server. RESULTS: From a total of +/-3 x 10(4) gene products analyzed, six different non-HLA antigens were recognized by individual patient sera. Gene analysis indicated that they consisted of both polymorphic (PSMC4, F3, LOC284058, PLUNC, ZNF33A) and non-polymorphic (XP_931864) antigens. Cross-sectional analysis indicated that some antigens were recognized by 4 of 10 patient sera tested. CONCLUSIONS: Antibodies directed against non-HLA antigens are present after LTx, and can be identified using the SEREX technique. Identification of target antigens recognized after LTx will improve our understanding of the pathogenesis of BOS. Monitoring of the antibody response may be used to predict BOS.

High-dose acetylcysteine in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis. METHODS: We conducted a double-blind, randomized, placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine (600 mg three times daily) added to standard therapy with prednisone plus azathioprine. The primary end points were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity (DL(CO)). RESULTS: A total of 182 patients were randomly assigned to treatment (92 to acetylcysteine and 90 to placebo). Of these patients, 155 (80 assigned to acetylcysteine and 75 to placebo) had usual interstitial pneumonia, as confirmed by high-resolution computed tomography and histologic findings reviewed by expert committees, and did not withdraw consent before the start of treatment. Fifty-seven of the 80 patients taking acetylcysteine (71 percent) and 51 of the 75 patients taking placebo (68 percent) completed one year of treatment. Acetylcysteine slowed the deterioration of vital capacity and DL(CO): at 12 months, the absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 liter (95 percent confidence interval, 0.03 to 0.32), or a relative difference of 9 percent, for vital capacity (P=0.02), and 0.75 mmol per minute per kilopascal (95 percent confidence interval, 0.27 to 1.23), or 24 percent, for DL(CO) (P=0.003). Mortality during the study was 9 percent among patients taking acetylcysteine and 11 percent among those taking placebo (P=0.69). There were no significant differences in the type or severity of adverse events between patients taking acetylcysteine and those taking placebo, except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine (P=0.03). CONCLUSIONS: Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DL(CO) in patients with idiopathic pulmonary fibrosis better than does standard therapy alone.

Primary pulmonary malignant meningioma.

Primary pulmonary meningiomas are relatively rare and mostly benign. To exclude pulmonary metastasis of an intracranial meningioma, imaging studies of the brain should be performed. We believe that only one primary pulmonary malignant meningioma in which a metastasis from the brain was excluded has been reported. In this report we describe a second case with malignant features.

Analysis of KL-6 and SP-D as disease markers in bird fancier's lung.

BACKGROUND AND AIM: KL-6 and SP-D are potential serum markers in interstitial lung diseases. Their discriminative value, and ability to reflect pulmonary disease activity and prognosis in bird fancier's lung were analyzed. METHODS: We studied 49 patients, 38 unexposed and 9 exposed controls. Serum KL-6 and SP-D concentrations were measured at presentation and a second sample, taken after antigen avoidance, was available in 17 patients. Pulmonary function tests were analyzed at presentation and 2-year follow-up. RESULTS: KL-6 and SP-D were significantly elevated in patients compared to controls (p < 0.0001). ROC curve analysis revealed that both are equally useful in discriminating patients from controls. Analysis of their value as activity markers showed that both correlated with pulmonary function impairment; however, KL-6 correlated best with diffusing capacity. Evaluation of their predictive value showed that higher levels at onset were associated with improvement of diffusing capacity during follow-up. Further, it was noted that KL-6 and SP-D levels decreased after more than one month of allergen avoidance. CONCLUSIONS: KL-6 and SP-D appear useful serum markers in bird fancier's lung. Since higher levels are associated with more severe lung function impairment at presentation, and better recovery over time, we postulate that in this disease they are especially markers of disease activity.

Surgical treatment of Pancoast tumours.

Due to its localisation in the apex of the lung with invasion of the lower part of the brachial plexus, first ribs, vertebrae, subclavian vessels or stellate ganglion, a superior sulcus tumour causes characteristic symptoms, like arm or shoulder pain or Horner's syndrome. If rib invasion is the only feature, lysis of the rib must be evident on the chest radiograph; otherwise the tumour cannot be defined as a Pancoast tumour. It is important to adequately stage the tumour, because staging significantly influences survival. Survival is better for T3 than T4 tumours and mediastinal lymph node involvement has been found to be a negative prognostic factor. Also Horner's syndrome and incompleteness of resection worsen survival. The management of superior sulcus tumours has evolved over the past 50 years. Before 1950 it was considered to be inoperable and uniformly fatal. Shaw and Paulson introduced combined modality treatment and for many years, this combination of radiotherapy and surgery was the treatment of choice with a mean 5-year survival of approximately 30%. Postoperative radiotherapy or brachytherapy does not improve survival in patients with complete or incomplete resection. The tumour can be resected through the classic posterior Shaw-Paulson approach or the newer anterior transcervical approach, introduced by Dartevelle. This method facilitates better exposure of the extreme apex of the lung, brachial plexus and subclavian vessels. Regarding the extent of pulmonary resection, en bloc resection of the involved ribs with a lobectomy is recommended. Recent multimodality studies, involving chemoradiotherapy and surgical resection, show promising results regarding completeness of resection, local recurrence and survival, provided that appropriate staging has been carried out. However, careful patient selection and adequate perioperative management with protection of the bronchial stump or anastomosis are important to achieve reasonable rates of morbidity and mortality. As brain metastases remain one of the most common forms of relapse, further studies are needed to examine the role of prophylactic cranial irradiation in patients with complete resection. Also the addition of other chemotherapy agents or biologic agents such as angiogenesis inhibitors or tyrosine kinase inhibitors gives a new perspective in the treatment of Pancoast tumours.

Results of surgical treatment of T4 non-small cell lung cancer.

OBJECTIVE: Because of location and invasion of surrounding structures, the role of surgical treatment for T4 tumors remains unclear. Extended resections carry a high mortality and should be restricted for selected patients. This study clarifies the selection process in non-small cell T4 tumors with invasion of the mediastinum, recurrent nerve, heart, great vessels, trachea, esophagus, vertebral body, and carina, or with malignant pleural effusion. METHODS: From 1977 through 1993, 89 patients underwent resection for primary non-small cell T4 carcinomas. Resection was regarded as complete in 34 patients (38.2%) and incomplete in 55 patients (61.8%). Actuarial survival time was calculated and risk factors for late death were identified. RESULTS: Overall hospital mortality was 19.1% (n=17). Mean 5-year survival was 23.6% for all hospital survivors, 46.2% for patients with complete resection and 10.9% for patients with incomplete resection (P=0.0009). In patients with complete resection, mean 5-year survival for patients with invasion of great vessels was 35.7%, whereas mean 5-year survival for invasion of other structures was 58.3% (P=0.05). Age, mediastinal lymph node involvement, type of operative procedure, and postoperative radiotherapy did not significantly influence survival. CONCLUSION: In certain T4 tumors complete resection is possible, resulting in good mean 5-year survival especially for tumors with invasion of the trachea or carina. High hospital mortality makes careful patient selection imperative.

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.

Analysis of IL6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis.

BACKGROUND: Proinflammatory cytokines are a major determinant in the inflammatory events leading to sarcoidosis. Genetic variations in the genes encoding these cytokines might contribute to sarcoidosis susceptibility, disease severity and outcome. METHODS: In the present study we genotyped two clinically well-defined cohorts of Caucasian sarcoidosis patients from different European countries (each with their own controls) for the following polymorphisms using SSP-PCR: IL6 -174(G/C), IL6 intron 4(A/G) and IL1A-889(C/T). In total, 516 individuals were studied (147 UK + 102 Dutch patients, 101 UK + 166 Dutch controls). Disease severity data at presentation included chest radiographic stage, FVC, DL(CO), and extrapulmonary manifestations. Disease progression was evaluated on follow-up chest radiographs and sequential lung function measurements (2, 4 years). RESULTS: No differences in genotype, carriage and allele frequencies of the investigated polymorphisms were found in either of the populations. Analysis of genotype data in relation to disease severity data, however, showed a slightly increased carrier frequency of the rarer-174C allele in patients with Stage IV sarcoidosis (p = 0.03, Pc = 0.09). Pulmonary function progression analysis did not reveal significant associations. CONCLUSIONS: Although the investigated polymorphisms are unlikely to contribute to sarcoidosis susceptibility, the IL6-174C allele might have a role in the genetics underlying sarcoidosis severity or the progression towards pulmonary fibrosis in a particular subgroup.