UNUSUAL CLINICAL COURSE OF NEUROSARCOIDOSIS MANIFESTED WITH ACUTE HYDROCEPHALUS.

Approximately 5% to 15% of patients with systemic sarcoidosis develop neurological complications. However, the actual prevalence of subclinical disease may be higher. Symptoms are not specific, and may resemble those of other neurological diseases. Hydrocephalus occurs in 6% of patients with neurosarcoidosis. Acute hydrocephalus is extremely rare and when it occurs, it is usually difficult to diagnose, thus leading to possible complications. We present a patient who developed acute hydrocephalus due to neurosarcoidosis, for which he had to be operated on; soon after the operation, cranial infection developed that required definitive drainage system and ventriculoperitoneal shunt had to be implanted. In further complicated clinical course, after four years on corticosteroid therapy (corticosteroid dependent sarcoidosis), he had to be urgently operated on because of significant ventricular catheter adhesions, but several days after the operation he died in coma because of progressive brain edema not responding to treatment. As hydrocephalus due to neurosarcoidosis has high morbidity and mortality, early diagnosis and proper treatment are of utmost importance.

Associations of lipoprotein subclasses and oxidative stress status in pulmonary and pulmonary plus extrapulmonary sarcoidosis.

Background: Sarcoidosis is an inflammatory disease with pulmonary and extrapulmonary manifestations. In such pathologic conditions, increased oxidative stress and rearrangement of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) may occur. Objective: This study evaluated association of oxidative stress and lipoprotein subclasses in severe forms of pulmonary and pulmonary plus extrapulmonary sarcoidosis. Methods: Lipid parameters, LDL and HDL subclass distributions, high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), paraoxonase 1 (PON1), malondialdehyde (MDA), total-oxidant status (TOS), sulfhydryl (SH) groups, pro-oxidant anti-oxidant balance (PAB) were determined in 77 patients (53 isolated pulmonary and 24 pulmonary plus extrapulmonary) and 139 controls. Results: Both pulmonary and extrapulmonary sarcoidosis patients had significantly higher levels of triglycerides and TOS (P<0.05) and more LDL II, LDL III, LDL IVA particles (P<0.01), but lower HDL size, SH groups (P<0.001), PON1 activity and less LDL I subclasses (P<0.05) than controls. In isolated pulmonary disease, HDL-cholesterol (P<0.01) was significantly lower whereas proportions of HDL 3a and PAB were significantly higher (P<0.05) when compared with the control group. PON1 was significantly higher in pulmonary than in combined pulmonary-extrapulmonary disease (P<0.05). In pulmonary sarcoidosis, TOS and PON1 correlated significantly with small-sized HDL particles (P<0.05). Conclusions: Both patient groups were characterized by adverse lipoprotein profile and elevated oxidative stress. In isolated pulmonary group significant associations of oxidative stress and HDL particles distribution was demonstrated. Pulmonary sarcoidosis was associated with higher PON1 activity and rearrangement of LDL particles did not depend on disease localization. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 198-205).

SOLITAIRE-IV: A Randomized, Double-Blind, Multicenter Study Comparing the Efficacy and Safety of Intravenous-to-Oral Solithromycin to Intravenous-to-Oral Moxifloxacin for Treatment of Community-Acquired Bacterial Pneumonia.

BACKGROUND: Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. METHODS: A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. RESULTS: In the ITT population, 79.3% of solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the solithromycin group. Other adverse events were comparable between treatment groups. CONCLUSIONS: Intravenous-to-oral solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. CLINICAL TRIALS REGISTRATION: NCT01968733.

Association of serum amyloid A and oxidative stress with paraoxonase 1 in sarcoidosis patients.

BACKGROUND: It has been reported that high-density lipoprotein (HDL) particles have anti-inflammatory and antioxidant roles thanks to different enzymes such as paraoxonase 1 (PON1). Under inflammatory and oxidative stress conditions, HDL particles may lose their protective properties. Sarcoidosis is an inflammatory disease characterized by excessive oxidative stress. Serum amyloid A (SAA) is produced in liver and in granulomas, and its concentration increases in inflammatory conditions contributing to increased catabolism of HDL particles. The aim of our study was to determine PON1 activity, SAA concentration and their associations in patients with sarcoidosis. MATERIALS AND METHODS: Inflammatory [high-sensitive C-reactive protein (hsCRP), angiotensin-converting enzyme (ACE), SAA], lipid [total cholesterol (TC), HDL-cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG)] oxidative stress status parameters [total oxidant status (TOS), malondialdehyde (MDA), pro-oxidant-antioxidant balance (PAB), sulfhydryl (SH) groups] and PON1 activities were determined in serum of 72 patients with sarcoidosis and 62 healthy subjects. RESULTS: HsCRP (P < 0·05), TC, LDL-c, TG, SAA, TOS, MDA and PAB (P < 0·001) were significantly higher, whereas HDL-c, SH groups and PON1 activity (P < 0·001) were significantly lower in patients with sarcoidosis when compared with controls. PON1 showed significant association with SAA, MDA and PAB. It was shown that 71% of decrease in PON1 activity may be explained by increase in TOS, PAB and SAA concentration. CONCLUSIONS: We found decreased PON1 activity and increased SAA concentration in patients with sarcoidosis. Inflammatory condition presented by high SAA was implicated in impaired HDL functionality evident through dysregulated PON1 activity. Excessive oxidative stress was also involved in dysregulation of PON1 activity.

Distribution of low-density lipoprotein and high-density lipoprotein subclasses in patients with sarcoidosis.

CONTEXT: Systemic inflammatory diseases are associated with proatherogenic lipoprotein profile, but there is a lack of information regarding overall distributions of lipoprotein subclasses in sarcoidosis. OBJECTIVE: To investigate whether patients with sarcoidosis have altered distributions of plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. DESIGN: Seventy-seven patients with biopsy-proven sarcoidosis (29 with acute and 48 with chronic sarcoidosis) treated with corticosteroids and 77 age- and sex-matched controls were included in the study. Low-density lipoprotein and HDL subclasses were determined by gradient gel electrophoresis, while inflammatory markers and lipid parameters were measured by standard laboratory methods. RESULTS: Compared to controls, patients had fewer LDL I subclasses (P < .001), but more LDL II and III (P < .001) subclasses. This pattern was evident in both acute and chronic disease groups. Patients also had smaller HDL size (P < .001) and higher proportions of HDL 2a (P = .006) and 3a particles (P = .004). Patients with chronic sarcoidosis had smaller LDL size than those with acute disease (P = .02) and higher proportions of HDL 3a subclasses (P = .04) than controls. In acute sarcoidosis, relative proportions of LDL and HDL particles were associated with levels of inflammatory markers, whereas in chronic disease an association with concentrations of serum lipid parameters was found. CONCLUSIONS: The obtained results demonstrate adverse lipoprotein subfraction profile in sarcoidosis with sustained alterations during disease course. Evaluation of LDL and HDL particles may be helpful in identifying patients with higher cardiovascular risk, at least for prolonged corticosteroid therapy due to chronic disease course.

Responsiveness of FDG PET/CT to treatment of patients with active chronic sarcoidosis.

PURPOSE: This study aimed to compare baseline to follow-up 18F-FDG PET/CT findings after treatment for active chronic sarcoidosis and to correlate changes on 18F-FDG PET/CT with changes in clinical status. PATIENTS AND METHODS: The sample included 66 patients with chronic sarcoidosis and evidence of active inflammation on baseline F-FDG PET/CT for which they received therapy. Of these 66 patients, 30 returned for the follow-up 18F-FDG PET/CT after 12 (5) months to evaluate response to treatment. They were also asked to indicate changes in clinical status. Baseline characteristics of patients who did and did not return for the follow-up were compared to assess selection bias. RESULTS: SUVmax was significantly decreased at the follow-up compared with baseline 18F-FDG PET/CT (8.46 [3.52] vs 4.90 [0.96]; P = 0.006), primarily in the mediastinum. Inflammatory activity appeared absent in 9 patients, decreased in 12 patients, and increased in 9 patients, with the corresponding changes in SUVmax of -80%, -41%, and +54%, respectively. The changes on 18F-FDG PET/CT were in agreement with self-perceived changes in clinical symptoms (P = 0.019). The angiotensin-converting enzyme at the follow-up was not significantly different from baseline (49.80 [19.25] vs 46.35 [25.58], P = 0.522). There was no difference in baseline characteristics of patients who did and did not return for the follow-up. CONCLUSIONS: 18F-FDG PET/CT is able to detect clinically meaningful changes in magnitude and extent of inflammatory activity in patients receiving treatment for active chronic sarcoidosis. Thus, 18F-FDG PET/CT is a valuable adjunct to clinical evaluation for monitoring the response to treatment in these patients.

The utility of 18F-FDG PET/CT for diagnosis and adjustment of therapy in patients with active chronic sarcoidosis.

UNLABELLED: The purpose of this study was to assess the utility of (18)F-FDG PET/CT for detection of inflammation in granulomatous sites and management of patients with chronic sarcoidosis. The 3 specific aims were to assess differences between (18)F-FDG PET/CT and multidetector CT (MDCT) findings, to compare (18)F-FDG PET/CT results with serum levels of angiotensin-converting enzyme (ACE), and to determine whether (18)F-FDG PET/CT findings are associated with the decision to change therapy. METHODS: We studied 90 sarcoidosis patients (mean age ± SD, 47 ± 12 y; 32 men and 58 women) with persistent symptoms who were referred for (18)F-FDG PET/CT evaluation to assess the extent of inflammation. They also underwent MDCT and measurement of serum ACE level. After the follow-up (12 ± 5 mo after (18)F-FDG PET/CT), the clinical status and changes in therapy were analyzed. RESULTS: (18)F-FDG PET/CT detected inflammation in 74 patients (82%) (maximum standardized uptake value, 8.1 ± 3.9). MDCT was positive for sarcoidosis in 6 additional patients (80, 89%). The difference between the 2 methods was not significant (P = 0.238, McNemar test), and their agreement was fair (κ = 0.198). Although ACE levels were significantly higher in patients with positive than negative (18)F-FDG PET/CT results (P = 0.002, Mann-Whitney test), 38 patients (51%) with positive (18)F-FDG PET/CT results had normal ACE levels. The therapy was initiated or changed in 73 out of 90 patients (81%). Both univariate and multivariate logistic regression analyses indicated that positive (18)F-FDG PET/CT results were significantly (P < 0.001) associated with changes in therapy, with no contribution from age, sex, ACE level, CT results, or previous therapy. CONCLUSION: Our results indicate that (18)F-FDG PET/CT is a useful adjunct to other diagnostic methods for detecting active inflammatory sites in chronic sarcoidosis patients with persistent symptoms, especially those with normal ACE levels. (18)F-FDG PET/CT proved advantageous for determining the spread of active disease throughout the body and influenced the decision to adjust the therapy.

Dyslipidemia and oxidative stress in sarcoidosis patients.

OBJECTIVES: Sarcoidosis is an inflammatory disease characterised by enhanced production of reactive oxygen species and alterations in the circulating lipid profile. Both attributes are thought to play a role in its pathogenesis. However, current knowledge regarding the significance of blood oxidative stress/anti-oxidant defence as well as alterations in lipid status parameters in sarcoidosis is scarce. The aim of our study was to assess these parameters and their inter-relationships, as well as their potential for patient-control discrimination. DESIGN AND METHODS: Oxidative stress status and anti-oxidant defence parameters were determined in serum and erythrocytes and lipid status parameters were assessed in the serum of 213 treated sarcoidosis patients and 90 controls. RESULTS: Malondialdehyde, superoxide anion, total oxidant status, prooxidant-antioxidant balance and triglycerides were significantly higher whereas total anti-oxidant status, superoxide dismutase activity and HDL-cholesterol were significantly lower in sarcoidosis patients compared with controls. Total sulfhydryl group content was higher in patients compared with controls. Serum and erythrocyte malondialdehyde exhibited the strongest ability to predict disease presence. Elevated oxidative stress was characterised by higher clinical accuracy compared with lipid status abnormality. Some oxidative stress and lipid status markers were significantly associated in sarcoidosis. CONCLUSIONS: Sarcoidosis is characterised by increased oxidative stress, diminished overall anti-oxidative protection and alterations in the circulating lipid profile. Both oxidative stress and lipid status parameters demonstrated the potential to discriminate sarcoidosis from controls which was particularly evident from the point of view of oxidative stress status parameters. Association between these parameters may indicate an increased risk for atherosclerosis development.

Evaluation of the role of pathology in the diagnosis and differential diagnosis of pulmonary and extrapulmonary sarcoidosis.

UNLABELLED: INTRODUCTION; Sarcoidosis is a multisystem, granulomatous disease of unknown etiology. Sarcoid granulomas appear as immunological response to a particular but still unknown agent of the human body. OBJECTIVE: The main purpose of this study was to point out the important fact that the exact diagnosis of sarcoidosis must be estimated by clinical and pathological correlation, and team cooperation between the clinician and the pathologist. METHODS: Of 751 patients referred with the suspected diagnosis of sarcoidosis, from 1995 to 1999, 663 (431 female and 232 male) were analyzed and confirmed as having sarcoidosis stage I-III based on biopsy findings obtained by bronchoscopy, open lung biopsy, skin biopsy, liver biopsy or splenectomy. RESULTS: Diagnosis of sarcoidosis was made in 663 patients, 431 females and 232 males (ratio 1.9:1). The average age of patients varied from 16 to 67 years, with those below age 50 years being predominant (78.4%). The highest number of patients was diagnosed in stage I of lung sarcoidosis (81.7%). Sarcoidosis was the most common cause of hilar and mediastinal lymphadenopathy (72.2%). CONCLUSION: Biopsy is a necessary diagnostic procedure for pathological diagnosis of sarcoid granuloma before treatment even in patients where clinical, radiological, biochemical and immunological tests imply the diagnosis of sarcoidosis.

[The impact of resistant strains of Mycobacterium tuberculosis on relapse of tuberculosis].

INTRODUCTION: Relapses of tuberculosis are fairly rare nowdays and they represent the onset of tuberculosis two, or more than two years after completion of previous treatment. MATERIAL AND METHODS: In the previous period, relapses of tuberculosis occurred in 141 patients (87 male and 54 female). Their mean age was 46.2 years. RESULTS: Relapses of tuberculosis occurred after 11.3 years, on average. All patients presented with pulmonary tuberculosis, and two patients also had pulmonary and extrapulmonary tuberculosis (bones). Resistance was one of the statistically significant factors for relapse of tuberculosis. Resistance to one antituberculotic agent was most common--8 patients, resistance to two drugs--4 patients, resistance to three drugs--4 patients, resistance to four drugs in 5 patients. Due to these findings on resistant strains of mycobacterium tuberculosis, a huge number of patients with relapses of tuberculosis had full recovery and completed the treatment. CONCLUSION: The importance of resistant strains of mycobacterium tuberculosis is really huge in our conditions. The findings of these resistant strains of mycobacterium tuberculosis and adequate medical treatment are obligatory nowadays.

[The role of vitamin D in the formation of granuloma and in calcium metabolism].

INTRODUCTION: Affection of the abdominal organs with sarcoidosis is a part of the generalized granulomatous diseases with clinical manifestations that vary depending on the affected organ. IMMUNOPATHOGENESIS OF GRANULOMA AND THE ROLE OF VITAMIN D: Formation of granuloma represents a response of the host immune system to different antigen stimuli and it represents an attempt of the host to block the endogenous or exogenous irritant. The active form of vitamin D-1,25-dihydroxyvitamin-D (1,25-D) has an important function in formation of granuloma. HEPATOMEGALY AND SPLENOMEGALY: As for the abdominal region, sarcoidosis is most frequently clinically manifested by liver and/or spleen enlargement (20-30% of the affected patients). However, granulomatous infiltrations may also be present along with normal sized organs. Other abdominal localizations are significantly less frequent. THE ROLE OF VITAMIN D IN CALCIUM METABOLISM: Calcium metabolism disorder represents a significant problem in patients affected with sarcoidosis, particularly in extrapulmonary, chronic forms of the disease. It develops as a result of complex metabolic processes consequential to increased level of 1,25-D and it is considered to be a parameter of granuloma activity (physiological blood value is up to 45 pq/ml). An increased level of provitamin D initiates osteoclast activity that causes bone resorption, which represents a factor of osteoporosis that results in hypercalcemia and hypercalciuria. RENAL CALCULOSIS AS A SIGN OF SARCOIDOSIS ACTIVITY: Increased calcium release into blood results in production of calcium deposits in the soft tissues and certain organs and thus calculosis develops. It is clinically most frequently manifested as renal calculosis, which is approximately 20 times more frequent in patients affected with sarcoidosis in comparison to general population. CONCLUSION: Examinations of abdominal organ involvement should be a standard procedure in each patient affected with sarcoidosis.

[The importance of hypercalciuria in assessing the clinical course and treatment modalities of sarcoidosis].

INTRODUCTION: In patients with sarcoidosis high levels of Ca2+ in blood serum accompanied by increased 24-hour urinary calcium are of great diagnostic and prognostic value. High levels of these two important parameters may point to hyperparathyroidism and/or chronic sarcoidosis. It is necessary to exclude kidney insufficiency by kidney ultrasound. MATERIAL AND METHODS: During the previous four years (1999-2003), urinary Ca was significantly higher than the physiological level in 25 patients, whereas the blood serun Ca was normal. 18 patients received corticosteroid therapy (40 mg for two months, and 35 mg later on). Patients with acute sarcoidosis received prednisone for 11.8 months, while patients with chronic sarcoidosis received it for 13.6 months. One patient with chronic sarcoidosis received methotrexate, as alternative therapy. RESULTS: 4 months later, after normalization of urinary Ca excretion, the follow-up of patients revealed only one patient with increased urinary Ca excretion associated with increased ACE and radiographic progression of the disease.

[The role of EQ5D self-classifier in assessing quality of life in patients with sarcoidosis].

INTRODUCTION: In medicine, quality of life is a very important issue. Nowdays, in our circumstances, it is an important part of diagnostic and therapeutic procedures. The aim of this study was to analyze the role of EQ5D questionnaire in patients with sarcoidosis. MATERIAL AND METHODS: EQ5D self-questionnaire was used in patients with sarcoidosis and we analyzed the obtained data. RESULTS: The analysis included patients with previously proved sarcoidosis--pulnmonary and extrapulmonary (bronchoscopy and other biopsies). All patients were treated at the Institute of Tuberculosis and Lung Diseases. We analyzed a group of 84 (19 male and 65 female) patients with average age of 45 years. Most patients had a chronic state of disease and were nonsmokers. In regard to the radiographic stage of pulmonary sarcoidosis, levels of disease activity (acute, chronic and relapse), levels of sACE, levels of sIgE, smokers--non smokers, and in regard to obtained scores, no statistically significant difference was found in examined groups, except in the group of patients with low level sIgE (score 0.276). CONCLUSION: EQ5D questionnaire is a good tool for analyzing the health status of patients with sarcoidosis, but still a more specific questionnaire should be designed for this multisystem disease.