Drug-induced sarcoidosis: an overview of the WHO pharmacovigilance database.

BACKGROUND: There is a documented association between drug exposure and sarcoidosis-like reactions. In this study, we used the largest pharmacovigilance database to describe drug-induced sarcoidosis. METHODS: Data were collected from the World Health Organization (WHO) pharmacovigilance database (VigiBase). We excluded steroids and vaccines from the analysis. The primary end-point was the lower end-point of the 95% credibility interval for the information component (IC025 ). RESULTS: A total of 127 reports had significant IC025 values for drug-induced sarcoidosis, and 110 were included in the final analysis, accounting for 2425 adverse drug reactions. Overall, 2074 (85.5%) reactions were considered 'serious' and 86 (3.5%) were fatal. Most of the drugs that led to sarcoidosis adverse reactions were TNF-alpha antagonists, interferon or peg-interferon therapeutics, and immune checkpoint inhibitors. Other biologic drugs were less frequently associated with sarcoidosis adverse events. Cancer-targeted therapies such as BRAF or MEK inhibitors were associated with sarcoidosis reactions in 37 cases. Pulmonary hypertension drugs were also reported for drug-induced sarcoidosis. Amongst the 55 drugs considered as potential sarcoidosis inducers, 25 (45.4%) were never reported in Medline as drug-induced sarcoidosis. CONCLUSIONS: We provide a detailed list of suspected drugs associated with drug-induced sarcoidosis that will improve the recognition of this drug-induced adverse event.

Evaluation of FDG PET combined with cardiac MRI for the diagnosis and therapeutic monitoring of cardiac sarcoidosis.

AIM: To compare combined 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-positron-emission tomography (PET) and cardiac magnetic resonance imaging (CMR) for the diagnosis and therapy monitoring of cardiac sarcoidosis (CS). MATERIALS AND METHODS: Eighty patients with sarcoidosis and a suspicion of CS who underwent PET and CMR were included retrospectively. PET was undertaken after a low-carbohydrate-high-fat diet in all patients using a combined 16-section PET/computed tomography (CT) camera. PET was considered positive (PET+) in cases of focal or multifocal FDG uptake. CMR was considered positive (CMR+) in cases of subepicardial late gadolinium enhancement (LGE). A subgroup of 50 patients (50/80) was monitored during therapy and classified as responders or non-responders. RESULTS: Eighty-two percent of patients with PET+ (9/11) also had CMR+ imaging, with good spatial agreement (kappa=0,79; 95% confidence interval [CI]: 0.65-0.94). Twenty-seven percent (22/80) had residual physiological FDG uptake, with a standardised uptake value (SUV) not significantly different compared to the SUV from pathological uptake (6.4 versus 6 respectively, p=0,92). The clinical response was more frequent in patients with baseline PET+ compared to baseline PET- (80% versus 45%, p=0.07). PET findings improved in all cases under treatment (7/7), whereas LGE improved in only 33% of patients (3/9). CONCLUSION: Due to high risk of false-positive or undetermined findings, PET might be performed as a second-line study in cases of LGE, to assess inflammatory load. In addition, PET seems suitable to predict and assess response under therapy.

Increase in both angiogenic and angiostatic mediators in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with a marked pulmonary vascular remodeling. The aim of this study was to investigate a potential imbalance between angiogenic and angiostatic factors in this disease. METHODS AND RESULTS: Sixty-four subjects with IPF and 10 healthy control subjects (60-70 years old) were prospectively included in this multicenter study. Plasma levels of vascular endothelial growth factor A (VEGF-A), thrombospondin-1 (TSP-1) and stem cell factor (SCF) were determined by Elisa. Comparisons between IPF and controls were made using the Mann-Whitney U test. We also analyzed these soluble mediators in relation with IPF severity (DLCO<40% or>40%) predicted or total lung capacity (TLC) and forced vital capacity (FVC) (both<55% or>55% predicted) using the same test. VEGF-A plasma levels were increased in IPF vs. controls (P=0.0008) as well as those of TSP-1 (P=0.008), irrespective of the severity of the disease as reflected by DLCO, TLC or FVC values. In contrast, SCF levels were similar in IPF and controls. CONCLUSIONS: Factors modulating angiogenic responses are dysregulated in patients with IPF with increases in VEGF-A and TSP-1. The serial assessment of VEGF-A and TSP-1 during the follow-up and the search for potential relationships with the outcome of the disease might give us hints to the clinical implication of these results.

[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

Lymphatic and blood microvasculature organisation in pulmonary sarcoid granulomas.

Pulmonary sarcoid granulomas are characterised by their elective distribution along collecting lymphatics. However, relationships between granulomas and intralobular lymphatics or blood microvascularisation have not been investigated. Therefore, we undertook a specific analysis of blood capillaries and lymphatics supplying sarcoid granulomas to identify additional clues to understanding the pathophysiogenesis of these lesions. Six pulmonary samples were immunolabelled with D2-40, anti-CD34 and anti-CD31 antibodies, paying particular attention to the relationships between lymphatics and granulomas, and the pattern of blood microvessels supplying sarcoid lesions. A morphometric study of granulomas included their distance to lymphatics and a three-dimensional reconstruction of a granuloma in its lymphatic context. Intralobular granulomas were closely associated with lymphatics; apart from a few granulomas, blood capillaries stopped at the outer border of the fibrous ring surrounding granulomas, and perigranuloma capillaries were particularly scarce. Our observations of the lymphatic and blood microvascular environment of intralobular pulmonary sarcoid granulomas provide evidence for the critical role of lymphatics in the emergence of these lesions. Moreover, pulmonary sarcoid lesions could be considered avascular structures, thereby providing new insights into the understanding of the granuloma physiology and the distribution of blood-borne therapeutic agents.

Stage IV sarcoidosis: comparison of survival with the general population and causes of death.

The objectives of this study were to compare the survival of sarcoid patients with pulmonary fibrosis with that of the general population and to determine the causes of death and the incidence of evolutive complications. This retrospective cohort included 142 sarcoid patients in radiographic stage IV (74 males; mean ± SD age 48.1 ± 12 yrs). Their survival was compared with that of the general French population, matched for the year and age at diagnosis of stage IV disease, sex and length of follow-up. Expected survival probabilities were calculated year-by-year on the basis of probabilities provided by official demographic data for France. Survival curves were based on the Kaplan-Meier method and compared using the log-rank test. During the follow-up period (7.1 ± 4.8 yrs), pulmonary hypertension (PH) was observed in 29.7% of cases and aspergilloma in 11.3%. Long-term oxygen therapy was required in 12%. Survival was 84.1% at 10 yrs, which was worse than for the general population (p = 0.013). 16 (11.3%) patients died from the following causes: refractory PH (n = 5), chronic respiratory insufficiency (n = 4), acute respiratory insufficiency (n = 2), haemoptysis due to aspergilloma (n = 1), heart sarcoidosis (n = 1), nocardiosis (n = 1) and unknown causes (n = 2). Survival is significantly decreased in stage IV patients. 75% of fatalities are directly attributable to respiratory causes.

[Is hypoxia a factor in the progression of pulmonary sarcoidosis?] / L'hypoxie est-elle un facteur impactant l'évolution de la sarcoïdose pulmonaire ?

Sarcoidosis is a systemic granulomatous disease that can reduce life expectancy mainly due to pulmonary fibrosis resulting from granulomatous inflammation The lack of vascularization within pulmonary granulomas suggests that macrophages localized in the center of these structures are hypoxic. Hypoxia signaling pathways are known to be pro-inflammatory and pro-fibrotic in various pathological conditions. Recent data suggest an involvement of the transcription factor hypoxia-inducible factor (HIF) in the pathogenesis of sarcoidosis. This could represent a new research approach for the understanding and therapeutic management of sarcoidosis.

[The effect of air pollution in diffuse interstitial lung disease]. / Rôle de la pollution au cours des pneumopathies interstitielles diffuses.

Few studies have examined the effects of air pollution in diffuse interstitial lung disease and they have focused on small numbers of patients. Most data are available in idiopathic pulmonary fibrosis and studies suggest that the level of exposure to pollutants may influence the development of acute exacerbations (ozone and NO2), their incidence (NO2), decline in respiratory function (PM10) and death (PM10 and PM2.5). Several studies show an increase in the incidence of rheumatoid arthritis in people living near busy roads. In systemic scleroderma, hypersensitivity pneumonitis and sarcoidosis although negative effects of pollution have been reported the data are insufficient to be conclusive. Nevertheless, the observed effects of air pollution are consistent with those described for other chronic respiratory diseases. Exposure to pollution induces oxidative stress, chronic inflammation and shortening of telomeres, which are all mechanisms described in fibrogenesis. New epidemiological studies are needed with individual measurements of exposure to outdoor and indoor pollution, as well as fundamental studies to clarify the effect of pollution on fibrogenesis.

Diagnosis issues in sarcoidosis.

Multiple problems may be encountered during the diagnosis of sarcoidosis: at first diagnose sarcoidosis in an appropriate clinical setting, secondly, identify any manifestation to be linked to sarcoidosis at diagnosis work-up and during evolution; thirdly, recognize "danger" in sarcoidosis and parasarcoidosis syndromes, and finally, diagnose sarcoidosis recovery. Diagnosis is often delayed as presentation may be diverse, non-specific, or atypical. Diagnosis of sarcoidosis is based on three criteria: a compatible presentation; evidence of non-caseating granulomas and exclusion of any alternative diagnosis. However, even when all criteria are fulfilled, the probability of sarcoidosis diagnosis varies from definite to only possible depending upon the presence of more or less characteristic radio-clinical and histopathological findings and on the epidemiological context. Bilateral hilar lymphadenopathy and/or diffuse lung micronodules mainly along lymphatics are the most frequent highly suggestive findings. Evidence of granulomas relies on superficial biopsies of clinically suspected lesion when present or most often by bronchial endoscopy. The diagnosis of sarcoidosis may be difficult in absence of thoracic or skin manifestations and may require the benefit of hindsight before being definitive. Differential diagnoses, mainly tuberculosis, must be considered. The diagnosis of events during evolution relies on serial clinical, pulmonary function, radiographic evaluation and on extrapulmonary manifestations work-up, including electrocardiogram and blood biology. Affected organs need to be related to sarcoidosis using an appropriate diagnostic assessment instrument. To declare the recovery of sarcoidosis, all manifestations must have disappeared spontaneously or after 3-5 years post-treatment without relapse.

[Diagnostic difficulties of chronic pulmonary berylliosis in France]. / Difficultés diagnostiques de la bérylliose pulmonaire chronique en France.

INTRODUCTION: The epidemiology of chronic beryllium disease (CBD) in France is poorly understood. The aim of this study was to determine the number of prevalent cases of CBD in France between 2010 and 2014. METHODS: We conducted a national survey using a specific questionnaire distributed by the professional pathology services. RESULTS: In total, 33 CBD cases were reported in France, with a diagnosis established between 1982 and 2014. 85% (28/33) of CBD cases resulted from professional exposure and mostly concerned foundry workers (39%). A definite diagnosis defined by the association of an abnormal beryllium lymphocyte proliferation test and of a granulomatous inflammatory response in the lung, was obtained in 29/33 cases (88%). The other cases were probable CBD, defined by a granulomatous lung disease with a beryllium exposure, but without evidence of beryllium sensitisation. The diagnosis of granulomatous disease was confirmed a mean of 4 years after the end of exposure. The median delay between diagnosis of a granulomatous disease and diagnosis of CBD was 2 years (range 0-38 years). A genetic predisposition was found in 14 of 17 tested patients (82%). CONCLUSION: In this study, we report 33 cases of CBD followed in France between 2010 and 2014. The poor understanding of CBD and the exposure leading to it, the late development after the end of exposure, the complexity of the diagnosis and the similarities with sarcoidosis may explain the small number of cases reported.

[Combined apical emphysema and basal fibrosis syndrome (emphysema/fibrosis syndrome): CT imaging features and pulmonary function tests]. / Syndrome emphysème des sommets et fibrose pulmonaire des bases combinés (syndrome emphysème/fibrose): aspects tomodensitométriques et fonctionnels.

PURPOSE: To describe the high resolution CT (HRCT) imaging and functional features of the emphysema/fibrosis syndrome. PATIENTS AND METHODS: A total of 61 patients were included based on HRCT. We have quantified the extent of fibrosis and emphysema lesions and a combined score was calculated. The scores were correlated to pulmonary function test parameters and specific HRCT features were described. RESULTS: The emphysema and fibrosis scores correlated with functional parameters of obstruction and restriction respectively. The combined score correlated with the reduction in DLCO and degree of pulmonary hypertension. Three HRCT patterns were identified: progressive transition (n=23, 38%) with diffuse emphysema (centrilobular and/or bullous) and zone of transition between bullae and honeycombing; paraseptal emphysema (n=13, 21%) with predominant subpleural bullae of enlarging size at the bases; separate processes (n=14, 23%) with independent areas of fibrosis and emphysema. Eleven patients (18%) could not be classified. The HRCT imaging features changed based on TLC (p=0.04) and FEV1/FVC (p=0.01). CONCLUSION: The emphysema/fibrosis syndrome may be associated with different patterns on HRCT corresponding to specific profiles on pulmonary function tests.

Combined pulmonary fibrosis and emphysema in systemic sclerosis: A syndrome associated with heavy morbidity and mortality.

BACKGROUND: The syndrome of combined pulmonary fibrosis and emphysema (CPFE) primarily due to tobacco smoking has been reported in connective tissue disease, but little is known about its characteristics in systemic sclerosis (SSc). METHODS: In this retrospective multi-center case-control study, we identified 36 SSc patients with CPFE, and compared them with 72 SSc controls with interstitial lung disease (ILD) without emphysema. RESULTS: Rate of CPFE in SSc patients with CT scan was 3.6%, and 7.6% among SSc patients with ILD. CPFE-SSc patients were more likely to be male (75 % vs 18%, p < 0.0001), smokers (83 % vs 33%, p < 0.0001), and to have limited cutaneous SSc (53 % vs 24% p < 0.01) than ILD-SSc controls. No specific autoantibody was significantly associated with CPFE. At diagnosis, CPFE-SSc patients had a greater decrease in carbon monoxide diffusing capacity (DLCO 39 ± 13 % vs 51 ± 12% of predicted value, p < 0.0001) when compared to SSc-ILD controls, whereas lung volumes (total lung capacity and forced vital capacity) were similar. During follow-up, CPFE-SSc patients more frequently developed precapillary pulmonary hypertension (PH) (44 % vs 11%, p < 10-4), experienced more frequent unscheduled hospitalizations (50 % vs 25%, p < 0.01), and had decreased survival (p < 0.02 by Kaplan-Meier survival analysis) as compared to ILD-SSc controls. CONCLUSIONS: The CPFE syndrome is a distinct pulmonary manifestation in SSc, with higher morbidity and mortality. Early diagnosis of CPFE by chest CT in SSc patients (especially smokers) may result in earlier smoking cessation, screening for PH, and appropriate management.

Anthracofibrosis attributed to mixed mineral dust exposure: report of three cases.

Anthracofibrosis, defined as bronchial luminal narrowing with black pigmentation of the overlying mucosa, has been attributed to tuberculosis. Three patients with anthracofibrosis without mycobacterial infection are described who had previous occupational exposure to mixed dusts. CT scans showed calcified hilar lymph nodes in two patients. Surgical biopsy in one patient and autopsy in another revealed fibrotic lymph nodes with black pigmentation. Mineralogical analysis by transmission electron microscopy of pulmonary, hilar and/or bronchial samples found high levels of particle retention, raised percentages of free crystalline silica and mica in two patients, and free crystalline silica, kaolin and other silicates in the third. No evidence of any other contributory factor was found, suggesting that mixed mineral dust was the most probable cause. These observations suggest that exposure to mixed mineral dust should be added to the aetiology of anthracofibrosis.

Interstitial lung disease and anti-Jo-1 antibodies: difference between acute and gradual onset.

AIM: A multicentre retrospective study was undertaken to examine patients with interstitial lung disease (ILD) with the initial clinical manifestation of an anti-synthetase syndrome (anti-Jo-1 antibodies), and to analyse the characteristics and long-term outcome of these patients according to their clinical presentation (acute or gradual onset), treatment and adverse events related to treatment. METHODS: 32 patients, 15 (47%) presenting with acute onset and associated respiratory insufficiency (group A) and 17 (53%) with gradual onset (group G) were examined. Myositis was diagnosed at admission in only 31% of cases and was observed during follow-up in 56% of cases, but the prevalence did not differ between the two groups. RESULTS: Fever and radiological patterns including diffuse patchy ground-glass opacities, basal irregular lines and consolidation on high-resolution CT scan were more frequent in group A than in group G. More patients in group G had neutrophils in the bronchoalveolar lavage fluid and autoantibodies other than anti-Jo-1 (rheumatoid factor, anti SSa/SSb) than in group A. The percentage of patients in whom the ILD improved at 3 months was significantly higher in group A than in group G (13/15 vs 9/17; p = 0.006). In contrast, after 12 months, most patients with ILD progression were in group A and were treated with corticosteroids alone. A combination of corticosteroids and an immunosuppressive drug was required in most cases (84%) at the end of the follow-up period. Severe adverse effects of treatment were observed and varicella zoster virus infection was frequent. CONCLUSIONS: Early testing for anti-synthetase antibodies, particularly anti-Jo-1, and creatine kinase determination are useful procedures in patients presenting with ILD. Treatment with corticosteroids and immunosuppressive drugs is required in most patients. At the end of the study, around two-thirds of patients had stable ILD while the other third had disease progression with respiratory insufficiency.

Short- and long-term response to corticosteroid therapy in chronic beryllium disease.

Chronic beryllium disease (CBD) is a granulomatous disorder that affects the lung after exposure to beryllium. The present study reports short- and long-term evolution of granulomatous and fibrotic components in eight patients with severe CBD receiving corticosteroid therapy. Eight patients with confirmed CBD were studied at baseline, after initial corticosteroid treatment (4-12 months), at relapse and at the final visit. Beryllium exposure, Glu(69) (HLA-DPB1 genes coding for glutamate at position beta69) polymorphism, symptoms, pulmonary function tests (PFT), serum angiotensin-converting enzyme (SACE) and high-resolution computed tomography (HRCT) quantification of pulmonary lesions were analysed. The CBD patients were observed for a median (range) of 69 (20-180) months. After stopping beryllium exposure, corticosteroids improved symptoms and PFT (vital capacity +26%, diffusing capacity of the lung for carbon monoxide +15%), and decreased SACE level and active lesion HRCT score. In total, 18 clinical relapses occurred after the treatment was tapered and these were associated with SACE and active lesion HRCT score impairment. At the final visit, corticosteroids had completely stabilised all parameters including both HRCT scores of active lesions and fibrotic lesions in six out of eight patients. Corticosteroids were beneficial in chronic beryllium disease. They were effective in suppressing granulomatosis lesions in all cases and in stopping the evolution to pulmonary fibrosis in six out of eight patients.

[Atypical sarcoidosis]. / Sarcoïdose à présentation atypique.

PURPOSE: Sarcoidosis is a granulomatous disease of unknown etiology. Lung and lymphatic system are the principal localisations. Clinical presentations are various depending on involved organs. Some presentations, which are easily diagnosed, are typical and frequent. Atypical forms have unusual presentations and/or are rare. Beside, in a multisystemic sarcoidosis, the affection of only one organ can be unusual. Rigorous diagnosis procedure could avoid errors. CURRENT KNOWLEDGE AND KEY POINTS: Twenty percent of sarcoidosis have atypical presentation. However, each of them are infrequent. Atypical features are wide and can concern pulmonary or extrapulmonary manifestations, general manifestations, blood testing or pathological pattern. FUTURE PROSPECTS AND PROJECTS: Describing atypical forms are necessary for their diagnosis. The diagnosis of atypical sarcoidosis is found on the knowledge of atypical forms previously described, presence of granulomas on specimen biopsy and excluding other granulomatous disease.

[Mediastinitis following endobronchial ultrasound-guided transbronchial needle aspiration]. / Médiastinite au décours d'une échoendoscopie bronchique (EEB) avec cyto-aspiration ganglionnaire.

INTRODUCTION: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure designed to explore mediastinal lymphadenopathy. Its use and indications have increased recently and severe, though rare, complications have been reported. CASE REPORT: EBUS-TBNA was performed in a 64-year-old patient presenting with mediastinal lymphadenopathy, probably due to sarcoidosis, but without histological proof. Within hours of the aspiration of subcarinal lymph nodes (station 7), the patient developed fever and dry cough associated with progressive dysphagia and dysphonia that persisted for four weeks. Mediastinitis was diagnosed after a CT-scan revealed a collection in the subcarinal space previously tapped using CT guidance. Intravenous antibiotics were started and both symptoms and the mediastinal collection resolved without need of a surgical procedure. The patient recovered fully. CONCLUSION: EBUS-TBNA is associated with a risk of mediastinitis that may manifest as an isolated fever arising within hours of the procedure. The pathogens responsible are usually contaminants from the oropharynx such as Streptococcus sp, probably inoculated directly into the mediastinum during transbronchial needle aspiration. Rapid diagnosis and treatment are necessary in order to reduce morbidity and mortality associated with mediastinitis.

[Interstitial lung disease in systemic sclerosis]. / Pneumopathie infiltrante diffuse de la sclérodermie systémique.

INTRODUCTION: Interstitial lung diseases (ILD) in systemic sclerosis (SSc) are mainly encountered in patients with diffuse disease although they may occur less frequently in patients with limited cutaneous disease. BACKGROUND: In SSc early detection of ILD should be achieved by high resolution computed tomography and pulmonary function tests, including measurement of DLCO. In total up to 75% of patients with SSc develop ILD but it is progressive in only a minority of patients. Unlike idiopathic ILD, SSc associated ILD corresponds to non-specific interstitial pneumonia rather than usual interstitial pneumonia in the majority of cases. This explains the better prognosis of SSc associated ILD compared with idiopathic ILD. Nevertheless ILD represents one of the two main causes of death in SSc. VIEWPOINT: The treatment of SSc associated ILD is not well established. Anti-fibrosing treatments have failed to demonstrate benefit and cyclophosphamide, which has been used for about 15 years in the treatment of this condition, has recently been evaluated in two prospective randomised studies which showed a significant but modest effect on respiratory function. CONCLUSION: A subgroup of patients with rapidly progressive ILD might benefit from pulsed intravenous cyclophosphamide combined with prednisone 15 mg daily, but this remains to be confirmed.