Search

Competing Interests: FB reports consulting fees and speaker honoraria from Boehringer Ingelheim, Bristol Myers Squibb, F Hoffmann– La Roche, Galapagos, and Savara Pharmaceuticals outside of the submitted work. All other authors declare no competing interests.

Background: Fatigue is a major and disabling problem in sarcoidosis. Knowledge concerning correlates of the development of fatigue and possible interrelationships is lacking., Objective: A conceptual model of fatigue was developed and tested., Methods: Sarcoidosis outpatients (n = 292) of Maastricht University Medical Center completed questionnaires regarding trait anxiety, depressive symptoms, cognitive failure, dyspnea, social support, and small fiber neuropathy (SFN) at baseline. Fatigue was assessed at 6 and 12 months. Sex, age, and time since diagnosis were taken from medical records. Pathways were estimated by means of path analyses in AMOS., Results: Everyday cognitive failure, depressive symptoms, symptoms suggestive of SFN, and dyspnea were positive predictors of fatigue. Fit indices of the model were good., Conclusions: The model validly explains variation in fatigue. Everyday cognitive failure and depressive symptoms were the most important predictors of fatigue. In addition to physical functioning, cognitive and psychological aspects should be included in the management of sarcoidosis patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Sarcoidosis patients often are troubled by dyspnea, exercise limitation, and fatigue. Many patients (up to 50-81%) suffer from sarcoidosis-associated fatigue. The etiology of fatigue in sarcoidosis is still unclear., Objective: The aim of this study was to assess the relationship between fatigue and both exercise capacity and clinical characteristics in sarcoidosis patients. Additionally, we studied the predictive value of exercise test results and other relevant clinical characteristics for the independent variable of fatigue., Methods: From November 2012 to September 2014, 201 sarcoidosis outpatients were referred to the Dutch ILD care foundation expertise team, 146 of whom were included in this retrospective cohort study. All patients completed the Fatigue Assessment Scale (FAS). Exercise capacity was assessed by the 6-min walking distance (6MWD) and steep ramp test (SRT) result. Clinical data were gathered from the medical records., Results: Exercise capacity only showed a weak correlation with fatigue (r = 0.25, p = 0.002 for 6MWD % of predicted; r = 0.24, p = 0.003 for SRT). Fatigue was not correlated with the demographic variables of age, body mass index, or time since diagnosis. Inflammatory markers, lung function tests, and hand grip strength showed no significant correlations with fatigue. Backward multiple regression analysis showed that only female sex (t = -2,614, p = 0.01) and 6MWD % of predicted (t = -2.773, p = 0.006) were independent predictors of fatigue. However, the r(2) indicated that these two variables together explained only 11% of the FAS score., Conclusions: These results show that exercise capacity partly predicts patients' fatigue scores. Fatigue was not explained by lung function test results, inflammatory markers, or other clinical parameters., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Tumor necrosis factor-alpha (TNF-α) inhibitors are regarded as the third-line therapy in sarcoidosis, the first choice generally being infliximab. To date, data regarding response to adalimumab in sarcoidosis patients intolerant to infliximab are lacking. The objective of this retrospective observational study was to establish if adalimumab could achieve stabilization or improvement of the disease in refractory sarcoidosis patients who developed intolerance to infliximab., Material and Methods: Sarcoidosis patients referred to St Antonius Interstitial Lung Diseases Center of Excellence, Nieuwegein, The Netherlands, between January 2008 and April 2015 who switched from infliximab to adalimumab were included. Changes in organ function, inflammatory biomarker levels, and adverse events were retrieved from medical records., Results: Out of 142 infliximab treated patients, 18 (13%) had to discontinue treatment due to antibody formation or severe adverse events and switched to adalimumab therapy. Organ function improved in 7 patients (39%), was stable in 6 patients (33%), and worsened in 5 patients (28%) after 12 months of treatment or after 6 months if evaluation after 12 months was not available (n = 4). In none of the patients biomarker levels of soluble interleukin-2 receptor (sIL-2R) deteriorated. Median decrease in sIL-2R was 3614 pg/mL. Most reported adverse event was infection (n = 10)., Conclusions: Adalimumab is an effective alternative for patients intolerant to infliximab. The switch to adalimumab achieved clinical improvement in 39% and stabilization in 33% of patients intolerant to infliximab. Further research is needed to develop guidelines on how to use adalimumab for sarcoidosis in terms of dosing regimen., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Assessing inflammatory activity is useful in the management of persistent symptomatic sarcoidosis patients. (18)F-FDG PET (PET) has been shown to be a sensitive technique to assess inflammatory activity in sarcoidosis. The aim of this study was to evaluate whether the severity of pulmonary involvement is associated with PET activity in persistent symptomatic sarcoidosis patients., Methods: Over a 5-year period, relevant clinical data including laboratory and lung function test results were gathered from the medical records of 95 sarcoidosis patients with persistent disabling symptoms who underwent both a PET and HRCT. HRCT scans were classified using a semiquantitative scoring system and PET findings as positive or negative, respectively., Results: PET was positive in 77/95 patients, of whom 56 demonstrated pulmonary PET-positivity. HRCT scores were high (7.1 ± 3.6) in patients with positive pulmonary PET findings (n = 56) compared to patients with negative pulmonary PET findings (n = 39; 3.0 ± 2.9; p < 0.001). DLCO (65 ± 20% predicted) and FVC (85 ± 24% predicted) were low in patients with pulmonary PET-positivity versus those with negative pulmonary PET findings (79 ± 16% predicted; p = 0.001 and 96 ± 22% predicted; p = 0.044, respectively). Interestingly, out of the 26 patients with fibrotic changes, 22 (85%) had positive pulmonary PET findings, of whom 18/22 (82%) showed extrathoracic PET-positive lesions and 16/22 (73%) showed signs of serological inflammation., Conclusions: The severity of the pulmonary involvement, assessed by HRCT features and lung function parameters, appeared to be associated with PET activity in sarcoidosis. The majority of patients with fibrotic changes demonstrated inflammatory activity at pulmonary and extrathoracic sites., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The objective of this study was to investigate the relation between growth hormone (GH) and attentional electro-cortical responses to task-relevant stimuli (N2b), target detections, speed of responding, P300 latencies, and performance on neuropsychological tests in 19 patients who received external beam radiation therapy for brain tumors in adulthood. In addition, we studied the association between IGF-I and activation of the motor cortex responses (lateralized readiness potential, LRP). Brain function was assessed using event-related potentials (ERPs) during a go/no go selective-attention task, including N2b, P300 and selective motor preparation as reflected in the LRP. Correlations were calculated between peak GH levels after a standardized growth hormone-releasing hormone (GHRH)-arginine test, plasma IGF-I, and cognitive functions. We separately studied four patients who were diagnosed with GHD according to the GHRH-arginine test. Performance on WAIS digit span backward and the Rey-Osterrieth complex figure test correlated positively with GH peak. GHD patients performed worse than non-GHD patients on Stroop interference, trail making B/A attentional shifting and Rey-Osterrieth complex figure test. At trend-level significance, trails A performance was better in patients with lower GH levels and higher radiation doses, and GHD participants detected fewer targets in the go/no go selective attention task. N2b was not significantly altered by GH status. Furthermore, plasma IGF-I was positively correlated with the sum of digit span forward and backward. No relations with P300 were observed. In this study only 21% (4/19) of the patients who received fractionated radiotherapy for a non-endocrine brain tumor were diagnosed with GHD. GHD in these patients was associated with impaired interference control, attentional shifting, and visual long-term memory. The results for interference control and attentional shifting suggest an additional effect of the radiation history., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Establishing inflammatory activity in sarcoidosis patients with persistent disabling symptoms is important. Whole body F(18)-FDG PET/CT (PET) appeared to be a sensitive method to detect inflammatory activity in newly diagnosed symptomatic sarcoidosis. The aim was to assess the presence of inflammatory activity using PET in sarcoidosis patients with unexplained persistent disabling symptoms and the association between PET findings and serological inflammatory markers., Methods: Sarcoidosis patients who underwent a PET between June 2005 and June 2010 (n = 89), were retrospectively included. All PET scans were examined and positive findings were classified as thoracic and/or extrathoracic. As serological markers of inflammatory activity angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), and neopterin were considered., Results: In 65/89 (73%) of the studied patients PET was positive, 52 of them (80%) had serological signs of inflammatory activity. In 14/15 patients with a Chest X-ray stage IV PET was positive. In 80% of the PET positive patients extrathoracic inflammatory activity was found. Sensitivity of combined serological inflammatory markers for the presence of inflammatory activity as detected by PET was 80%, specificity 100%, positive predictive value 100%, negative predictive value 65%., Conclusions: The majority of sarcoidosis patients with persistent disabling symptoms, even those with radiological stage IV, had PET positive findings with remarkably 80% extrathoracic lesions. In 20% PET was positive without signs of serological inflammatory activity. PET appeared to be of additional value to assess inflammatory activity in patients with persistent symptoms in the absence of signs of serological inflammatory activity and to detect extrathoracic lesions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The usefulness of any questionnaire in clinical management and research trials depends on its ability to indicate a likelihood of treatment success during follow-up. The Minimal Clinically Important Difference (MCID) reflects a clinically relevant change score. The aim of this study was to estimate the MCID for the Fatigue Assessment Scale (FAS) in patients with sarcoidosis., Methods: Outpatients (n = 321) of the ild care team of the Department of Respiratory Medicine of the Maastricht University Medical Centre, The Netherlands, participated in this prospective follow-up study. Anchor-based and distribution-based methods were used to estimate the MCID. Based on the anchor Physical Quality of Life, a Receiver Operating Characteristic (ROC) was obtained. The distribution-based methods consisted of the Effect Size and Standard Error Measurement (SEM)., Results: The anchor-based MCID found with ROC was 3.5. The distribution-based methods showed that the corresponding change scores in the FAS for a small effect was 4.2. The SEM criterion was 3.6 points change in the FAS., Conclusions: Based on the anchor-based and distribution-based methods, the MCID is a 4-point difference on the FAS. This MCID can be used in the follow-up of fatigue (FAS) in clinical trials and in the management of individual sarcoidosis cases., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background & Aims: Oxidative stress and low antioxidant levels are implicated in the aetiology of sarcoidosis, an inflammatory disease. Quercetin is a potent dietary antioxidant that also displays anti-inflammatory activities. Consequently, the aim is to examine the effect of quercetin supplementation on markers of oxidative stress and inflammation in sarcoidosis., Methods: A double-blind intervention study has been conducted with two groups of non-smoking, un-treated sarcoidosis patients, matched for age and gender. One group was given 4x500 mg quercetin (n = 12) orally within 24 h, the other one placebo (n = 6). Plasma malondialdehyde levels were used as marker of oxidative damage, plasma ratios of TNFα/IL-10 and IL-8/IL-10 as pro-inflammatory markers., Results: Quercetin supplementation improved the antioxidant defence, indicated by the increased total plasma antioxidant capacity. Moreover, quercetin supplementation also reduced markers of oxidative stress and inflammation in the blood of sarcoidosis patients. The effects of quercetin supplementation appeared to be more pronounced when the levels of the oxidative stress and inflammation markers were higher at baseline., Conclusions: Sarcoidosis patients might benefit from the use of antioxidants, such as quercetin, to reduce the occurring oxidative stress as well as inflammation. The effects of long-term use of antioxidant supplementation in sarcoidosis, using e.g. quercetin, on improvement of lung function remain to be investigated. (www.clinicaltrials.gov; NCT-00402623)., (Copyright © 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Small fiber neuropathy (SFN) appears to be relatively common in sarcoidosis patients. However, there is no golden standard to establish SFN and diagnostic tests for SFN are not widely available. There is a need for an easy to administer SFN screening instrument for clinical assessment, research or therapeutic trials. The aim of the present study was to develop a screening list to identify sarcoidosis patients with SFN in general clinical practice., Methods: We studied 139 sarcoidosis patients. The first consecutive 84 patients (Group 1) underwent temperature threshold testing (TTT) and completed an extensive SFN-symptoms-questionnaire. Based on data from Group 1 and using distribution measures and discriminant analyses, a screening list for SFN in sarcoidosis consisting of 21 questions was constructed: the Small Fiber Neuropathy Screening List (SFNSL). Subsequently, this SFNSL was crossvalidated in the next 55 consecutive patients (Group 2)., Results: The same cut-off scores as found for Group 1 were appropriate in Group 2. The SFNSL was found to have high levels of internal consistency (Cronbach's alpha 0.90) and exploratory factor analysis showed that it measures only one underlying factor. Convergent validity seems good., Conclusion: To assess the presence of SFN in clinical practice the SFNSL, a brief and easy to administer questionaire, was developed in a sarcoidosis population. The results of the present study support the idea that SFN is a serious problem in chronic sarcoidosis. Future studies are needed to establish the broad usefulness of this SFN screening list and expand knowledge on the psychometric properties., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: The best method to interpret the chest roentgenogram and its sensitivity to detect effect of treatment for sarcoidosis remains unclear. In a double-blind, randomized trial of infliximab for chronic pulmonary sarcoidosis, changes in serial chest roentgenograms were examined by radiologists, blinded to order or treatment., Methods: Chest roentgenograms were obtained at 0, 6, and 24 weeks of therapy with either placebo, 3 mg/kg infliximab, or 5 mg/kg infliximab. Films were reviewed in random order by two independent radiologists, unaware of treatment. The films were compared using two methods: the prespecified objective assessment, a scoring system previously proposed by Muers; and the post hoc assessment, a 5-point Likert scale global assessment between two films., Results: Of 138 patients enrolled in the study, chest roentgenograms for all studies were available on 130 patients. There was only fair agreement between the two radiologists in the original stage of the chest roentgenogram (weighted kappa = 0.43; 95% confidence interval [CI], 0.32 to 0.54). For the Likert scale of global assessment of change, there was good agreement between the two readers (weighted kappa = 0.61; 95% CI, 0.51 to 0.71). There was good correlation between the two readers for the various components of the Muers score, especially the reticulonodular (R) score (R = 0.578; p < 0.05). The initial R score was positively correlated with improvement in FVC with infliximab therapy (R = 0.239; p < 0.05)., Conclusion: Global assessment and the Muers scoring system were associated with good agreement between two expert readers. Improvement in both scores correlated with improvement in FVC., Trial Registration: ClinicalTrials.gov Identifier: NCT00073437.

Rationale: Enhanced production of reactive oxygen species (ROS), capable of reducing endogenous defense levels and enhancing inflammation, is suggested to play a role in sarcoidosis. Antioxidant supplementation might offer protection against such ROS-mediated damage. A promising candidate for antioxidant supplementation is the flavonoid quercetin., Aim: To determine the antioxidant and inflammatory status in sarcoidosis. Furthermore, the potential of quercetin to mitigate the occurring inflammation will be assessed., Methods: Non-smoking sarcoidosis patients and healthy controls matched for age, gender and dietary behavior were enrolled (NCT-00512967). Measurements included assessment of total plasma antioxidant capacity, vitamin C, uric acid, glutathione, basal and LPS-induced levels of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-8 and -10 as well as the effect of quercetin on these levels., Results: Compared to their controls, the sarcoidosis patients displayed significantly lower total plasma antioxidant capacity, decreased levels of vitamin C, uric acid and glutathione and increased levels of basal TNFalpha and IL-8. Quercetin significantly decreased ex vivo LPS-induced TNFalpha- and IL-8 production in a concentration-dependent manner in both groups. Interestingly, this quercetin effect was more pronounced in sarcoidosis patients., Discussion: The endogenous antioxidant defense was significantly reduced in sarcoidosis, indicating that oxidative stress underlies the pathology of this disease. Furthermore, the inflammatory status was significantly enhanced in sarcoidosis. Finally, our results regarding the effect of quercetin on cytokine production imply that sarcoidosis patients might benefit from antioxidant supplementation not only by empowering the relatively low protection against ROS but also by reducing inflammation.

Several commercial DNA isolation kits are available for extracting the genomic DNA from the ethylene diamine tetra-acetic acid (EDTA) whole blood samples. To obtain DNA from whole blood these DNA isolation procedures require quite some hands on time and are rather expensive. An alternative technique could be dried blood spot (DBS) sampling, with which DNA isolation is faster, cheaper and logistics are easier. We have developed a non-commercial DBS method and examined its performance in practice. DNA isolation from EDTA blood samples and made blood spots on filter paper from 106 renal transplant recipients were compared. Additionally, DNA isolation with a column method and two different DBS method was performed for 10 healthy volunteers and compared. Also DNA isolation with only capillary blood using both DBS methods from another 100 healthy volunteers has been investigated. Real-time PCR FRET assays for the CYP3A4 A-392G, CYP3A5 A6986G, ABCB1 C1236T, G2677T/A and C3435T polymorphisms were used and the melting curves of both DNA isolation methods were compared. In all cases DNA extracted with the column method corresponded completely with the results of the DNA isolated with the DBS procedure. Hence, DNA isolation from filter paper appears to be a useful alternative for the commercially available DNA isolation kits.

Background: The aim of this study was to evaluate the uptake and -washout of I-123 meta-iodobenzylguanidine (MIBG), reflecting norepinephrine metabolism, in the lungs in patients with sarcoidosis., Methods: Lung I-123 MIBG kinetics was assessed in 43 patients with sarcoidosis. The range of disease duration was 1-16 years (median: 3 years). Thirteen patients had radiographic stage 0-I, 30 patients had radiographic stage II-IV. Serological clinical parameters and small fibre neuropathy, as assessed by temperature threshold testing (TTT) were measured in 39/43 patients. 31/39 patients had an abnormal TTT. Eleven healthy controls participated in this study. Both dual head planar and dual headed SPECT images of the thoracic regions were made. The uptake of I-123 MIBG and the washout percentage were calculated in sarcoidosis patients and compared with the healthy persons., Results: Lung I-123 MIBG uptake in patients with sarcoidosis did not differ from controls. The lung washout of I-123 MIBG was significantly (p

Background: Sarcoidosis is a multi-systemic inflammatory disorder, which affects the lungs in 90% of the cases. The main pathologic feature is chronic inflammation resulting in non-caseating granuloma formation. Until now there is no satisfying biomarker for diagnosis or prognosis of sarcoidosis. This study is focused on the detection of potential biomarkers in serum for the diagnosis of sarcoidosis using surface-enhanced laser desorption ionization-time of flight-mass spectrometry (SELDI-TOF-MS)., Methods: For detection of potential biomarkers, protein profiles of anion exchange fractionated serum of 35 sarcoidosis patients and 35 healthy controls were compared using SELDI-TOF-MS. Sensitivities and specificities of the potential biomarkers obtained with SELDI-TOF-MS, generated with decision tree algorithm, were compared to the conventional markers angiotensin converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R)., Results: Optimal classification was achieved with metal affinity binding arrays. A single marker with a mass-to-charge (m/z) value of 11,955 resulted in a sensitivity and specificity of 86% and 63%, respectively. A multimarker approach of two peaks, m/z values of 11,734 and 17,377, resulted in a sensitivity and specificity of 74% and 71%, respectively. These sensitivities and specificities were higher compared to measurements of ACE and sIL-2R. Identification of the peak at m/z 17,377 resulted in the alpha-2chain of haptoglobin., Conclusions: This study acts as a proof-of-principle for the use of SELDI-TOF-MS in the detection of new biomarkers for sarcoidosis. The peak of the multimarker at m/z 17,377 was identified as the alpha-2chain of haptoglobin.

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.

Objective: Insulin-like growth factor I (IGF-I) levels and cognitive functioning decrease with aging. Several studies report positive correlations between IGF-I levels and cognitive functioning in healthy elderly. However, because of controversial data no definitive conclusions can be drawn concerning the relation between IGF-I and cognition. Therefore, we carried out a meta-analysis on studies that report on the relation between IGF-I and cognition in healthy elderly., Design: We searched the electronic databases for articles about IGF-I and cognition. Studies from 1985 to January 2005 are included. Two reviewers independently extracted data on study design and cognitive outcomes. Thirteen studies on IGF-I and cognition in elderly, with a total number of 1981 subjects, met the inclusion criteria. On the data from these studies meta-analyses were carried out by means of the program Comprehensive Meta-analysis using a random effects model., Results: Pooled effects show that IGF-I levels in healthy elderly have a positive correlation with cognitive functioning, which appeared to be mainly measured with the mini mental state examination (MMSE). The effect size is 0.6, which indicates the presence of a large positive relationship between IGF and cognition in healthy elderly., Conclusion: These meta-analyses showed an overall relationship between IGF-I levels and cognitive functioning in healthy elderly. Further studies should be performed to clarify the role of IGF-I substitution in preserving cognitive functions with aging.

Objective: The influence of growth hormone (GH) replacement on patient-reported outcomes (i.e., quality of life, health status and well-being) and cognitive functioning in GH-deficient adults is controversial., Design: We carried out a meta-analysis of clinical trials concerning the influence of GH substitution on patient-reported outcomes and cognitive functions (studies were selected from 1985 to 2004). The results of individual studies were combined in a series of meta-analyses using a random effects model. Effects of GH replacement in GH-deficient adults were compared to baseline and/or placebo., Results: Fifteen studies on GH and patient-reported outcomes were included (830 patients, follow-up 3-50 months). Four of these studies also provided data on cognitive functions (85 patients, follow-up 6-12 months). Relative to baseline, GH treatment is found to have a large effect on patient-reported outcomes at 3 months, a medium effect at 6 months and a small effect at 12 months. With respect to the median treatment duration of 6 months placebo appears to be as effective as GH substitution. Cognitive functioning does not improve after 6 months of GH substitution, relative to baseline., Conclusion: This meta-analysis provides no evidence that GH improves patient-reported outcomes in GH-deficient patients. As the amount of cognitive data was too limited to allow for comparisons with placebo, from the present meta-analysis no conclusions can be drawn with respect to the impact of GH treatment on cognition.

Small fiber neuropathy (SFN) is a neuropathy selectively involving small diameter myelinated and unmyelinated nerve fibers. Interest in this disorder has considerably increased during the past few years. It is often idiopathic and typically presents with peripheral pain and/or symptoms of autonomic dysfunction. Diagnosis is made on the basis of the clinical features, normal nerve conduction studies (NCS) and abnormal specialized tests of small nerve fibers. Among others, these tests include assessment of epidermal nerve fiber density, temperature sensation tests for sensory fibers and sudomotor and cardiovagal testing (QSART) for autonomic fibers. Unless an underlying disease is identified, treatment is usually symptomatic and directed towards alleviation of neuropathic pain.

Objective: A substantial number of sarcoidosis patients report apparently non-specific symptoms such as pain, for which no organic substrate has yet been found. Recently we observed symptoms suggestive of small-fibre neuropathy in a group of sarcoidosis patients. The aim of the present study was to verify this observation using various electrophysiological tests., Methods: In 74 sarcoidosis patients complaining of symptoms suggestive of small-fibre neuropathy, thresholds for warm (WS) and cold sensation (CS) as well as for heat pain were determined at the thenar eminence and the foot dorsum. Furthermore, sympathetic skin responses (SSR), nerve conduction studies and concentric needle electromyography were performed. In 31 patients, cardiovascular autonomic testing was carried out., Results: Thermal threshold testing (TTT) revealed abnormalities in 51 of the 74 patients. Abnormalities showed an asymmetrical distribution. WS was affected more often than CS and feet more often than hands. Nerve conduction studies in the legs showed slightly abnormal results in 6 patients; all of these had abnormal TTT results. The SSR was absent at the foot in 7 patients. Cardiovascular autonomic testing was abnormal in only a single patient., Conclusions: In a subgroup of sarcoidosis patients we found TTT abnormalities suggestive of small-fibre neuropathy. SSR and cardiovascular autonomic testing appeared to be of little diagnostic value. Small-fibre neuropathy may be the cause of a number of hitherto unexplained symptoms in sarcoidosis.

Some patients with sarcoidosis have unexplained pain and dysaesthesia. We did quantitative sensory testing in 31 sarcoidosis patients with pain or autonomic dysfunction. 25 patients had reduced warmth sensitivity, cold sensitivity, or both. Intraepidermal nerve fibre density (IENFD) was measured in punch biopsy skin samples in seven consecutive patients. All seven patients had reduced IENFD compared with controls, which confirmed the presence of small fibre neuropathy in these patients. Some patients with sarcoidosis may have small fibre neuropathy with autonomic involvement.

Recently we developed a validated computer program based on polychotomous logistic regression analysis using bronchoalveolar avage fluid (BALF) results to distinguish between the three most common interstitial lung diseases (ILD): sarcoidosis, idiopathic pulmonary fibrosis (IPF) and extrinsic allergic alveolitis (EAA) or drug-induced pneumonitis. One of the limitations of this program was that it was not useful in discriminating between infectious disorders and non-infectious disorders. Therefore, we added BALF samples obtained from patients with a confirmed bacterial pulmonary infection based on culture results > or = 10(4) cfum l(-1) (group I: n=31) to the study population mentioned above (group II: n=272). Notably, just one variable, i.e. the percentage of polymorphonuclear neutrophils, allowed us to distinguish between infectious and non-infectious disorders. The agreement of predicted with the actual diagnostic group membership was 99.67% (groups I and II). Additionally, 91.2% of the cases with ILD were correctly classified. In conclusion, this updated Windows version 2000 of the validated computer program provides a very reliable prediction of the correct diagnosis for an arbitrary patient with suspected pneumonia or with ILD given information obtained from BALF analysis results, and is thought to improve the diagnostic power of BALF analysis.

Study Objective: In the present study, we evaluated the leukocyte esterase (LE) area of a reagent strip designed for urinalysis for the semiquantitative measurement of the percentage of polymorphonuclear neutrophils (PMNs) in BAL fluid., Design: Prospective. The relative PMN counts (obtained by conventional microscopy and expressed as a percentage of a 500 cell count) of consecutive BAL fluid samples were compared with the corresponding LE categories as read with a urine chemistry reader. LE categories were graded as follows: negative, trace, +, + +, and + + +., Results: A total of 153 BAL fluid samples were included. The mean PMN counts of the negative LE category (4.1 +/- 4.3%; n = 43) and the + + + category (81.8 +/- 16.3%; n = 37) differed significantly from each other and from the mean PMN counts of the other categories. Within the trace, +, and + + categories, a considerable overlap of PMN counts was noted. Assignment of a BAL fluid to the negative LE category consistently predicted a PMN count < 20%. At a threshold value of 50% PMNs, the + + + LE category predicted the BAL fluid samples to the correct group (PMNs > 50% vs < 50%) with a sensitivity of 70.8% and a specificity of 97.1%., Conclusions: The reagent strips proved to be useful as a rapid test for semiquantitative measurement of the relative PMN counts in BAL fluid. However, the low predictive value for the exclusion of a high PMN count may limit their application.

It is assumed that sarcoidosis is caused by inhalation of air borne agents in susceptible persons triggering the inflammatory reaction. The association of metallic dust exposure, such as beryllium and aluminium, and sarcoidlike pulmonary disorders is well known. The ability of man-made mineral fibres (MMMF) to cause granulomatous lung disease has not been appreciated until now. Recently, we observed the association of sarcoidlike granulomatous reaction and occupational history of glass fibre exposure. We hypothesized that there might be a relationship between MMMF exposure and the development of sarcoidlike granulomas. Therefore, the records of 50 sarcoidosis patients-who visited our outpatient clinic between 1996 and 1999 were reviewed. This revealed that 14 cases recalled a history of exposure to either glass fibres or rock wool, both MMMF fibres. The available obtained tissue specimens (n = 12) were reviewed. In six cases electron microscopy qualitative analysis of small fragments of the tissue revealed among others silica, aluminium and sometimes titanium. A distinct relation between fibre deposits fibre deposits and granulomas was found. These findings indicate that in susceptible people MMMF exposure might be related to a chronic granulomatous disease similar to chronic beryllium disease.

Many studies conducted on the health status and quality of life (QOL) of patients with certain chronic diseases have demonstrated that their disease had an impact on their lives. However, less is known about the QOL and health status of patients suffering from idiopathic pulmonary fibrosis (IPF). In the present study, three focus groups of IPF patients (n=10) were run to identify the aspects of QOL or health status that are relevant to this population and to establish which measure is preferable to assess these aspects. The patients completed and discussed the St. George's Respiratory Questionnaire (SGRQ) and the World Health Organization Quality of Life assessment instrument (WHOQOL-100). Results indicated that hobbies/leisure activities, mobility, transport, social relationships, working capacity, energy and doing things slower were aspects relevant to IPF patients' QOL. The WHOQOL-100, with an additional social support questionnaire, appeared to be preferable.

The present study investigated the usefulness of bronchoalveolar (BAL) fluid cytology in the identification of non-infectious pulmonary conditions in patients hospitalized in the intensive care unit (ICU) and suspected of pneumonia. A total of 182 BAL fluid samples obtained during a 27-month period from 130 ICU patients with suspected pneumonia were quantitatively cultured and investigated for opportunistic pathogens. Cytocentrifuged preparations stained with the May-Grünwald Giemsa and Perls's methods were reviewed. A non-infectious aetiology was considered when cultures yielded micro-organisms in quantities < 10(3) colony-forming units (CFU) per ml, in the absence of any other pathogen and in conjunction with one or more of the following cytological findings: > 20% haemosiderin macrophages, > 10% lymphocytes, the presence of activated lymphocytes, plasma cells, > 5% eosinophils, a preponderance of foamy macrophages, reactive type II pneumocytes or malignant cells. Patients' clinical records were reviewed to identify a clinical diagnosis for these episodes. In thirty-five (19.2%) BAL fluid samples from 26 patients, the cytological findings pointed to a non-infectious origin. An alternative diagnosis was ascertained in 20 of 26 patients. Diagnoses included: drug-induced pneumonitis (n = 7), aspiration of gastric contents (n = 2), pulmonary emboli (n = 3), adult respiratory distress syndrome (n = 4), lung contusion (n = 1), cardiogenic pulmonary oedema (n = 1), and carcinomatous lymphangitis (n = 2). The BAL fluid cytological findings were readily discernable and proved to be useful in the diagnostic work-up of samples obtained from ICU patients with suspected pneumonia.

Health-related quality of life (QOL) has become an important topic in health care. However, hardly any attention has been paid to QOL in sarcoidosis. Therefore, the aim of this study was to assess the impact of sarcoidosis on QOL. Sixty-four sarcoidosis patients completed the World Health Organization Quality of Life assessment instrument (WHOQOL-100) and the Beck Depression Inventory (BDI). For the WHOQOL-100 a matched group of healthy controls was selected. Patients were divided into two groups: group I (n = 37) consisted of patients with actual symptoms, group II (n = 27) consisted of asymptomatic patients. The WHOQOL-100 revealed a number of areas in which sarcoidosis patients, especially those with current symptoms, experienced problems. A major symptom in both groups of sarcoidosis patients was fatigue. No association between the facet fatigue and the domain psychological health was found. Depressive symptoms (BDI) were associated with psychological function (WHOQOL-100). No association between pulmonary function tests and QOL was found. In conclusion, this study shows that sarcoidosis has a considerable impact on the QOL of patients. The WHOQOL-100 appeared to be a sensitive instrument to measure fatigue--one of the most common symptoms in sarcoidosis--which otherwise is difficult to assess objectively.

An inflammatory response has been observed in lung cancer both locally and systemically. The aim of the present study was to investigate whether the alveolar compartment was involved in the inflammatory response in non-small cell lung carcinoma (NSCLC). Both inflammatory mediators in bronchoalveolar lavage fluid (BALF) and cytokines produced by alveolar macrophages (AM) were investigated. Twenty patients with newly detected NSCLC and nine control subjects were studied. The patients had not been treated with chemotherapy, radiotherapy or with systemic or inhaled corticosteroids. All patients and control subjects were current smokers or stopped smoking recently. BAL was performed in the affected lung as well as in the contralateral lung of NSCLC patients, and only unilaterally in control subjects. Comparable results were demonstrated for the levels of the of the inflammatory mediators TNF-a, Interleukin (IL)-6, IL-8, both soluble TNF receptors and the soluble adhesion molecules E-selectin and intercellular adhesion molecule (ICAM)-1 between the affected lung and the contralateral lung in the NSCLC population as well as between the NSCLC population and the control subjects. Moreover, no significant differences in cytokine profiles of AM were found between AM obtained from the affected lung and from the contralateral lung. Although BAL is a useful tool in the diagnostic procedure for NSCLC, the present findings suggest that BAL does not reflect the enhanced inflammatory state, as reported in plasma and in the interstitial compartment around the tumour cells in NSCLC.

Serum lactate dehydrogenase (LDH) activity, a marker of cell damage, is increased in several pulmonary disorders, especially when fibrosis is involved. In rats exposed to silica, high levels of LDH activity were found. A rise of serum LDH3 has been associated with lung tissue injury. The aim of this study was to investigate the serum LDH isoenzyme pattern after coal-dust exposure and the possible relation to pulmonary function tests. Ex-coalminers (n = 201), with a history of coal-dust exposure more than 20 yr ago, were admitted to the authors' hospital for a medical check-up and were included in the study. The serum LDH activity was found to be elevated in 79.1% of the ex-coalminers (634 +/- 245 U I-1). Moreover, in 196 of the 201 cases (97.5%), a high LDH3 level (31 +/- 4%) was demonstrated. A moderate negative relation was found between the forced expiratory volume in 1 s (FEV1) and the LDH activity (r = -0.26; P < 0.001), as well as between FEV1 and LDH3 activity (r = -0.23; P < 0.001), even in the subgroup (n = 42) with a normal LDH. All other liver function tests were within normal limits. These results suggest that coal-dust, even many years after the actual exposure, causes an increase in the total serum LDH activity and changes in the LDH-isoenzyme pattern, mainly characterized by a high LDH3 activity.

Four case histories are reported in which the initial signs and symptoms were those of pulmonary infiltration and in which subsequently a diagnosis of myelodysplasia was made. The analysis of bronchoalveolar lavage fluid--demonstrating predominantly neutrophils and lymphocytes, and, occasionally blast cells as well as plasma cells--indicated that the pulmonary infiltration was related to the myelodysplastic process. As no other causes of pulmonary infiltration could be found, it seems that a pulmonary infiltrate can be the presenting symptom of a myelodysplastic syndrome. Although pleuropulmonary infiltrates most often are caused by infections, these cases illustrate that myelodysplasia related infiltrates should also be considered.

The aim of this study was to identify characteristic features in bronchoalveolar lavage fluid (BALF) samples of patients with tuberculosis, non-Hodgkin's or Hodgkin's disease and to investigate whether these differences facilitate the distinction of those disorders from sarcoidosis presenting with a similar clinical picture. Nonsmoker patients with histologically verified sarcoidosis (n = 29), tuberculosis (n = 6) proven by positive culture, non-Hodgkin's disease, (n = 6) or Hodgkin's disease (n = 7), both histologically verified, were investigated by BAL. A control group consisted of subjects without any pulmonary history. The presence of CD4+ and CD8+ T lymphocytes, as well as the CD4/CD8 ratio in BALF, aided in the differentiation between the various groups. Patients with malignant lymphomas had the lowest CD4/CD8 ratio in BALF, as well as in peripheral blood, and occasionally, plasma cells were present in BALF samples. The most important feature of BALF analysis in tuberculosis was detection of the causal microbial agent. In conclusion, although malignant lymphomas and tuberculosis require histologic evaluation and a positive culture, respectively, for diagnosis, BALF analysis may be of additional value in distinguishing those disorders from sarcoidosis.

One hundred patients with histologically verified sarcoidosis were studied. They were divided into three groups, based on their clinical presentation and smoking status. Group A consisted of patients whose disease was detected by routine chest x-ray film, without symptoms; group B included those with respiratory and general constitutional symptoms; and group C included patients with erythema nodosum and/or arthralgia and hilar lymphadenopathy. Group A showed an increased CD4/CD8 ratio of 4.7 +/- 1.1; group B, 8.0 +/- 1.2; and group C counted for the highest ratio of 10.7 +/- 1.5. Cigarette smoking modifies the immunologic bronchoalveolar lavage (BAL) fluid sample profile, since alveolitis was less pronounced in smokers. In addition, BAL fluid samples obtained from sarcoidosis patients with hilar lymphadenopathy showed the most characteristic features of alveolitis, suggesting a disseminated instead of a local immune response. Therefore, the clinical presentation of sarcoidosis and the smoking status of a sarcoidosis patient are crucial for interpreting individual lavage analysis results.

The aim of this study was to investigate whether the demonstration of plasma cells (PC), which are normally absent in bronchoalveolar lavage (BAL) fluid, facilitates differentiation among pulmonary disorders. Initial BAL fluid samples of 1,260 patients were analyzed. In 83 of these, PC were found. Of these 83, 47 were obtained from individuals suffering from extrinsic allergic alveolitis (EAA). The number of PC in BAL fluid from EAA patients was found related to the time between antigen exposure and BAL. Drug-induced pneumonitis appeared to be another disorder with a high percentage of cases with PC in the BAL fluid (35.7 percent). Therefore, we conclude that determination of PC in BAL fluid has differential diagnostic value in discriminating among interstitial lung diseases of various origins. However, the exact role of BAL fluid and PC and the link to clinical manifestations of these diseases needs further investigation.

Two patients are described with severe MVS, pulmonary venous hypertension and enlarged mediastinal, pulmonary and hilar lymph nodes. These enlargements were diagnosed on a preoperative chest CT. After MV replacement these enlarged lymph nodes nearly all resolved. The lymphadenopathy should be considered to be secondary to MVS with pulmonary venous hypertension.