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The pathophysiology of high-altitude pulmonary edema is currently attributed to exacerbated heterogeneous hypoxic pulmonary vasoconstriction. However, although other cellular mechanisms have been hypothesized, they are still poorly understood. In this review, we focused on cells of the pulmonary acinus, the distal unit for gas exchange, known to be responders to acute hypoxia, notably through many humoral or tissue factors that connect this intercellular network constituting the alveolo-capillary barrier. Hypoxia could drive alveolar edema by: 1) damaging the fluid reabsorption capacity of alveolar epithelial cells, 2) increasing the endothelial and epithelial permeability, especially by alteration of occluding junctions, 3) triggering the inflammation mainly led by alveolar macrophages, 4) increasing interstitial water accumulation by disruption of extracellular matrix architecture and tight junctions, 5) inducing pulmonary vasoconstriction through an orchestrated response of pulmonary arterial endothelial and smooth muscle cells. Hypoxia may also alter the function of fibroblasts and pericytes that contribute to the interconnection of the cells of the alveolar-capillary barrier. Due to its complex intercellular network and delicate pressure gradient equilibrium, the alveolar-capillary barrier is simultaneously affected by acute hypoxia in all its components, leading to rapid accumulation of water in the alveoli.
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Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.
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Exposição Ocupacional , Sarcoidose , Adulto , Criança , Poeira , Exposição Ambiental/efeitos adversos , Humanos , Exposição Ocupacional/efeitos adversos , Ocupações , TalcoRESUMO
PURPOSE OF REVIEW: Sarcoidosis remains a mysterious disease that presents many challenges both in pathogenetic understanding and in the management of patients. This review presents experimental models for sarcoidosis developed since 2016 and discusses their strengths and weaknesses and how they have contributed to the understanding and therapeutic approaches in this disease. In addition, future directions are proposed to overcome the limitations of current models. RECENT FINDINGS: New cellular models using infectious antigen as trigger, and transgenic models in mice have recently been developed to study signaling pathways potentially implicated in the pathogenesis of sarcoidosis. SUMMARY: No model fully reproduces sarcoidosis, but most of them generate data supporting key concepts and some open up therapeutic perspectives, like mTOR inhibition or IL-1ß blocking. However, there are still many limitations to these models, largely related to the complexity of sarcoidosis, which might be overcome with new technologies, such as mathematical modeling.
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Modelos Animais de Doenças , Técnicas In Vitro , Sarcoidose/imunologia , Animais , Humanos , Camundongos , Camundongos Transgênicos , Modelos Teóricos , Terapia de Alvo Molecular , Sarcoidose/tratamento farmacológico , Transdução de SinaisRESUMO
PURPOSE OF REVIEW: To describe the current knowledge on indications for sarcoidosis treatment. RECENT FINDINGS: Despite the lack of evidence-based recommendations, the sarcoidosis community has adopted the concept of starting systemic anti-inflammatory treatment because of potential danger (risk of severe dysfunction on major organs or death) or unacceptable impaired quality of life (QoL). On the contrary, while QoL and functionality are patients' priorities, few studies have evaluated treatment effect on patient-reported outcomes. The awareness of long-term corticosteroids toxicities and consequences on QoL and the emergence of novel drugs have changed therapeutic management. Second-line therapy, mainly methotrexate and azathioprine, are indicated for corticosteroids sparing or corticosteroids-resistant sarcoidosis. TNF-α inhibitors are a useful third-line therapy in chronic refractory disease. In addition to organ-targeted treatment, efforts should also be taken for treating nonorgan-specific symptoms, such as physical training for fatigue, and various disease complications. SUMMARY: Clinicians should offer a tailored treatment for each patient and ensure a holistic multidisciplinary approach, including pharmacological and nonpharmacological interventions. Patient-centered communication is critical to drive shared decisions, in particular for the tricky situation of isolated impaired QoL as the unique therapeutic indication. Once treatment is decided, clinicians should define a clear therapeutic plan, including goals and instruments to assess response.
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Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Qualidade de Vida , Sarcoidose/tratamento farmacológico , HumanosRESUMO
Sarcoidosis. Sarcoidosis is a rare, systemic granulomatosis disease of unknown cause. In almost all cases sarcoidosis affects the lung and the lymphatic system. Diagnosis and treatment can be difficult because of highly variable clinicals and evolutions presentations. Clinician must track organ dysfunctions that may be life-threatening (pulmonary, cardiac involment) or that impact functional prognosis (neurological, ophthalmic, renal) and qualified as «dangerous¼. It is important also to evaluate and take care of persistent signs of discomfort, which can severely affect patients' quality of life. The treatment of sarcoidosis is not systematic, but if necessary, corticosteroids, with notable side effects are the first intention treatment. Second- and third-line treatments are immunosuppressants and TNF antagonists, respectively.
Sarcoïdose. La sarcoïdose est une maladie rare, de type granulomatose systémique de cause inconnue touchant presque constamment le poumon et le système lymphatique. Le diagnostic et la prise en charge thérapeutique peuvent être difficiles du fait de la diversité de ses présentations cliniques, du retentissement et de l'évolution de la maladie. Les objectifs du clinicien sont de ne pas manquer les formes avec dysfonction d'un organe pouvant mettre en jeu le pronostic vital (atteinte pulmonaire, cardiaque) ou fonctionnel (formes neurologique, ophtalmique, rénale), qualifiées de « dangereuses ¼ mais aussi d'évaluer et prendre en charge les signes d'inconfort persistants, qui peuvent retentir sévèrement sur la qualité de vie des patients. Le traitement de la sarcoïdose n'est pas systématique mais, si nécessaire, les corticoïdes, aux effets indésirables notables, sont à donner en première intention. Les traitements de deuxième et de troisième ligne sont respectivement les immunosuppresseurs et les anti-tumor necrosis factor alpha.
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Sarcoidose Pulmonar , Sarcoidose , Humanos , Imunossupressores/uso terapêutico , Prognóstico , Qualidade de Vida , Sarcoidose/diagnóstico , Sarcoidose Pulmonar/diagnósticoRESUMO
Distal lung diseases, such as pulmonary fibrosis or acute lung injury, are commonly associated with local alveolar hypoxia that may be deleterious through the stimulation of alveolar epithelial cell (AEC) apoptosis. In various murine models of alveolar injury, administration of allogenic human mesenchymal stem cells (hMSCs) exerts an overall protective paracrine effect, limiting lung inflammation and fibrosis. However, the precise mechanisms on lung cells themselves remain poorly understood. Here, we investigated whether hMSC-conditioned medium (hMSC-CM) would protect AECs from hypoxia-induced apoptosis and explored the mechanisms involved in this cytoprotective effect. Exposure of rat primary AECs to hypoxia (1.5% O2 for 24 h) resulted in hypoxia-inducible factor (HIF)-1α protein stabilization, partly dependent on reactive oxygen species (ROS) accumulation, and in a twofold increase in AEC apoptosis that was prevented by the HIF inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl-indazole and the antioxidant drug N-acetyl cysteine. Incubation of AECs with hMSC-CM significantly reduced hypoxia-induced apoptosis. hMSC-CM decreased HIF-1α protein expression, as well as ROS accumulation through an increase in antioxidant enzyme activities. Expression of Bnip3 and CHOP, two proapoptotic targets of HIF-1α and ROS pathways, respectively, was suppressed by hMSC-CM, while Bcl-2 expression was restored. The paracrine protective effect of hMSC was partly dependent on keratinocyte growth factor and hepatocyte growth factor secretion, preventing ROS and HIF-1α accumulation.
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Células Epiteliais Alveolares/citologia , Apoptose , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/fisiopatologia , Células-Tronco Mesenquimais/citologia , Alvéolos Pulmonares/citologia , Espécies Reativas de Oxigênio/metabolismo , Células Epiteliais Alveolares/fisiologia , Animais , Células Cultivadas , Humanos , Masculino , Células-Tronco Mesenquimais/fisiologia , Alvéolos Pulmonares/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
BACKGROUND: Sarcoidosis is a systemic disease characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Exaggerated granulomatous reaction might be triggered in response to unidentified antigens in individuals with genetic susceptibility. The present study aimed to determine the genetic variants implicated in a familial case of sarcoidosis. METHODS: Sarcoidosis presentation and history, NOD2 profile, NF-κB and cytokine production in blood monocytes/macrophages were evaluated in individuals from a family with late appearance of sarcoidosis. RESULTS: In the present study, we report a case of familial sarcoidosis with typical thoracic sarcoidosis and carrying the NOD2 2722G > C variant. This variant is associated with the presence of three additional SNPs for the IL17RA, KALRN and EPHA2 genes, which discriminate patients expressing the disease from others. Despite a decrease in NF-κB activity, IL-8 and TNF-A mRNA levels were increased at baseline and in stimulated conditions. CONCLUSIONS: Combination of polymorphisms in the NOD2, IL17RA, EPHA2 and KALRN genes could play a significant role in the development of sarcoidosis by maintaining a chronic pro-inflammatory status in macrophages.
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Predisposição Genética para Doença/genética , Variação Genética/genética , Proteína Adaptadora de Sinalização NOD2/genética , Sarcoidose/diagnóstico , Sarcoidose/genética , Idoso de 80 Anos ou mais , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Chronic pulmonary aspergillosis (CPA) complicating sarcoidosis (SA) is associated with high mortality, and there is a lack of clarity regarding the relative contributions of SA or CPA.This was a retrospective single-centre study on CPA-SA.In total, 65 patients (44 men), aged 41.4±13.5 and 48.3±11.9â years at the time of SA and CPA diagnoses, respectively, were included between 1980 and 2015. Of these, 64 had fibrocystic SA, most often advanced, with composite physiological index (CPI) >40 (65% of patients) and pulmonary hypertension (PH) (31%), and 41 patients (63%) were treated for SA (corticosteroids or immunosuppressive drugs). Chronic cavitary pulmonary aspergillosis (CCPA) was the most frequent CPA pattern. Regarding treatment, 55 patients required long-term antifungals, 14 interventional radiology, 11 resection surgery and two transplantation. Nearly half of the patients (27; 41.5%) died (mean age 55.8â years); 73% of the patients achieved 5-year survival and 61% 10-year survival. Death most often resulted from advanced SA and rarely from haemoptysis. CPI, fibrosis extent and PH predicted survival. Comparison with paired healthy controls without CPA did not show any difference in survival, but a higher percentage of patients had high-risk mould exposure.CPA occurs in advanced pulmonary SA. CPA-SA is associated with high mortality due to the underlying advanced SA rather than to the CPA. CPI, fibrosis extent and PH best predict outcome.
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Antifúngicos/uso terapêutico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Pneumonectomia , Aspergilose Pulmonar , Sarcoidose Pulmonar , Adulto , Feminino , França/epidemiologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Transplante de Pulmão/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Pneumonectomia/métodos , Pneumonectomia/estatística & dados numéricos , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/diagnóstico , Aspergilose Pulmonar/fisiopatologia , Aspergilose Pulmonar/terapia , Sarcoidose Pulmonar/complicações , Sarcoidose Pulmonar/microbiologia , Sarcoidose Pulmonar/mortalidade , Sarcoidose Pulmonar/terapia , Análise de SobrevidaRESUMO
In common variable immunodeficiency, lung manifestations are related to different mechanisms: recurrent pneumonias due to encapsulated bacteria responsible for diffuse bronchiectasis, diffuse infiltrative pneumonia with various patterns, and lymphomas, mostly B cell extranodal non-Hodgkin type. The diagnosis relies on significant serum Ig deficiency and the exclusion of any primary or secondary cause. Histopathology may be needed. Immunoglobulin (IgG) replacement is crucial to prevent infections and bronchiectasis. IgG4-related respiratory disease, often associated with extrapulmonary localizations, presents with solitary nodules or masses, diffuse interstitial lung diseases, bronchiolitis, lymphadenopathy, and pleural or pericardial involvement. Diagnosis relies on international criteria including serum IgG4 dosage and significantly increased IgG4/IgG plasma cells ratio in pathologically suggestive biopsy. Respiratory amyloidosis presents with tracheobronchial, nodular, and cystic or diffuse interstitial lung infiltration. Usually of AL (amyloid light chain) subtype, it may be localized or systemic, primary or secondary to a lymphoproliferative process. Very rare other diseases due to nonamyloid IgG deposits are described. Among the various lung manifestations of dysregulated states of humoral immunity, this article covers only those associated with the common variable immunodeficiency, IgG4-related disease, amyloidosis, and pulmonary light-chain deposition disease. Autoimmune connective-vascular tissue diseases or lymphoproliferative disorders are addressed in other chapters of this issue.
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Amiloidose/complicações , Imunodeficiência de Variável Comum/complicações , Pneumopatias/etiologia , Pulmão/imunologia , Humanos , Imunidade HumoralRESUMO
PURPOSE OF REVIEW: Sarcoidosis is a disease caused by a complex combination of genetic susceptibility, immune networks and infectious and/or environmental agents. The onset and phenotypic variability of sarcoidosis remain poorly elucidated, not only due to the lack of clearly identified causes, but also because it is widely considered that no reliable model of this disease is available. In this review, we discuss the various models of granulomatous diseases in order to challenge this assertion. RECENT FINDINGS: A large number of models of granulomatous diseases are available, both cellular models used to study the natural history of granulomas and experimental animal models mostly developed in rodents. SUMMARY: Although none of the available models fully reproduces sarcoidosis, most of them generate various data supporting key concepts. Selected models with a high level of confidence among those already published may provide various pieces of the sarcoidosis jigsaw puzzle, whereas clinical data can provide other elements. A 'systems biology' approach for modelling may be a way of piecing together the various pieces of the puzzle. Finally, experimental models and a systemic approach should be considered to be tools for preclinical evaluation of the efficacy of drugs prior to testing in clinical trials.
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Modelos Biológicos , Sarcoidose , Animais , Modelos Animais de Doenças , Humanos , Técnicas In Vitro , Sarcoidose/etiologiaRESUMO
In this review, the infectious complications observed in sarcoidosis are considered from a practical point of view to help the clinician not to overlook them in a difficult context, as pulmonary sarcoidosis makes the recognition of superinfections more difficult. An increased incidence of community-acquired pneumonia and of opportunistic pneumonia has been reported, especially in immunosuppressed patients. Pulmonary destructive lesions of advanced sarcoidosis increase the incidence of chronic pulmonary aspergillosis and infection by other agents. Screening and treatment of latent tuberculosis infection are crucial to prevent severe tuberculosis. Severity in COVID-19 appears to be increased by comorbidities rather than by sarcoidosis per se. The diagnosis of infectious complications can be challenging and should be considered as a potential differential diagnosis when the exacerbation of sarcoidosis is suspected. These complications not only increase the need for hospitalizations, but also increase the risk of death. This aspect must be carefully considered when assessing the overall health burden associated with sarcoidosis. The impact of immune dysregulation on infectious risk is unclear except in exceptional cases. In the absence of evidence-based studies on immunosuppressants in the specific context of pulmonary sarcoidosis, it is recommended to apply guidelines used in areas outside sarcoidosis. Preventive measures are essential, beginning with an appropriate use of immunosuppressants and the avoidance of unjustified treatments and doses. This approach should take into account the risk of tuberculosis, especially in highly endemic countries. Additionally, parallel emphasis should be placed on vaccinations, especially against COVID-19.
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Fibrotic pulmonary sarcoidosis (fPS) affects about 20% of patients. fPS carries a significant morbidity and mortality. However, its prognosis is highly variable, depending mainly on fibrosis extent, functional impairment severity, and the development of pulmonary hypertension. Moreover, fPS outcomes are also influenced by several other complications, including acute exacerbations, and infections. fPS natural history is unknown, in particular regarding the risk of progressive self-sustaining fibrosis. The management of fPS is challenging, including anti-inflammatory treatment if granulomatous activity persists, rehabilitation, and in highly selected patients antifibrotic treatment and lung transplantation.
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Hipertensão Pulmonar , Transplante de Pulmão , Fibrose Pulmonar , Sarcoidose Pulmonar , Sarcoidose , Humanos , Sarcoidose Pulmonar/complicações , Sarcoidose Pulmonar/terapia , Fibrose Pulmonar/terapia , Fibrose Pulmonar/complicações , Hipertensão Pulmonar/terapia , Hipertensão Pulmonar/complicações , Transplante de Pulmão/efeitos adversos , Prognóstico , Sarcoidose/complicaçõesRESUMO
BACKGROUND: The Sarcoidosis Diagnostic Score (SDS) system has been established for sarcoidosis patients based on the WASOG organ involvement criteria. We evaluated modifications of the SDS system to determine if they improved its the diagnostic accuracy. METHODS: Biopsy-confirmed patients with sarcoidosis seen during a 7-month period at 9 sarcoidosis centers across the world. Patients with non-sarcoidosis seen at the same sites were served as control patients. Comparing the SDS-biopsy and SDS-clinical values of five groups: duration of symptoms prior to evaluation (≤1 years vs.>1 years, ≤2 years vs.>2 years), organ involvement (lung, eye, or cardiac), race, and sex. RESULTS: A total of 990 patients with sarcoidosis and 1011 controls were included in this study. The SDS-clinical was significantly more discriminating for those undergoing assessment with symptoms for more than one year (z-statistic=2.570, p = 0.0102) or two years (z-statistic=2.546, p = 0.0109). However, the addition of two points for both >1 years and >2 years since onset of symptoms did not increase sensitivity and specificity of diagnosis with the SDS system. The SDS-clinical cut-off for patients with ocular or cardiac disease was two points higher than that for lung disease. There was no difference in SDS-clinical or biopsy AUC values based on gender or race. CONCLUSIONS: The longer the duration of symptoms prior to diagnosis, the more likely the diagnosis of sarcoidosis was correct. For patients presenting with ocular or cardiac symptoms, evidence of multi-organ involved can improve the diagnostic accuracy of the SDS-clinical.
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Sarcoidosis is a multisystemic granulomatous disease of unknown origin. It has been argued that the skin is one of the entry doors of the possible antigen that causes sarcoidosis and after entering the skin, the causal agent may progress to the underlying bone. We report four cases with development of sarcoidosis in old scars located on the forehead, and contiguous bone involvement of the frontal bone. In most cases scar sarcoidosis was the first manifestation of the disease, and in most cases it was asymptomatic. Two patients never required treatment, and in all cases the frontal problem improved or remained stable spontaneously or under sarcoidosis treatment. Scar sarcoidosis in the frontal area may have contiguous bone damage. This bone involvement does not seem to be associated with neurological extension.
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Intimal granulomatous angiitis is a facet of pulmonary sarcoidosis vasculitis that has almost been forgotten. Its observation may offer new understanding of the various patterns of pulmonary hypertension associated with sarcoidosis. https://bit.ly/3g6Ms76.
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Sarcoidosis is an independent risk factor for venous thromboembolism (VTE). However, the characteristics and clinical evolution of sarcoidosis patients presenting a VTE (sarcoidosis/VTE group) in the course of their disease are not known. Consequently, if VTE occurrence is associated with a more severe disease is still pending. We conducted a retrospective case-control study of sarcoidosis/VTE patients compared to matched sarcoidosis controls without VTE in two French tertiary centers, analysed and compared the clinical, biological, functional, imaging and evolutive profiles of the two groups. Sixty-one patients were included with at least one episode of VTE during course of sarcoidosis. At sarcoidosis onset (before/at the time of VTE occurrence) the number of affected organs, radiological stages and pulmonary functional tests were not significantly different between the two groups. In contrast, we found that sarcoidosis/VTE patients required more frequently a systemic immunosuppressive therapy (corticosteroids and/or immunosuppressors, 79% versus 58%; p = 0.008). The functional course was also poorer in sarcoidosis/VTE patients with a more frequent decrease in functional vital capacity (33% versus 18% in sarcoidosis/VTE patients and controls, respectively, p = 0.008). Finally, sarcoidosis/VTE patients presented more frequently with pulmonary hypertension (10% versus 1% in patients and controls, respectively, p = 0.006), and their survival was significantly worse (log-rank p <0.001). The occurrence of VTE during sarcoidosis is associated with a more severe disease and a poorer prognosis. The occurrence of VTE during sarcoidosis might signal a more inflammatory and/or evolutive disease in sarcoidosis/VTE patients and should be taken in consideration when designing therapeutic strategies for them.
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Sarcoidose , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Estudos Retrospectivos , Prognóstico , Estudos de Casos e Controles , Sarcoidose/complicações , Sarcoidose/diagnóstico , Sarcoidose/epidemiologiaRESUMO
Diagnosing pulmonary sarcoidosis raises challenges due to both the absence of a specific diagnostic criterion and the varied presentations capable of mimicking many other conditions. The aim of this review is to help non-sarcoidosis experts establish optimal differential-diagnosis strategies tailored to each situation. Alternative granulomatous diseases that must be ruled out include infections (notably tuberculosis, nontuberculous mycobacterial infections, and histoplasmosis), chronic beryllium disease, hypersensitivity pneumonitis, granulomatous talcosis, drug-induced granulomatosis (notably due to TNF-a antagonists, immune checkpoint inhibitors, targeted therapies, and interferons), immune deficiencies, genetic disorders (Blau syndrome), Crohn's disease, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and malignancy-associated granulomatosis. Ruling out lymphoproliferative disorders may also be very challenging before obtaining typical biopsy specimen. The first step is an assessment of epidemiological factors, notably the incidence of sarcoidosis and of alternative diagnoses; exposure to risk factors (e.g., infectious, occupational, and environmental agents); and exposure to drugs taken for therapeutic or recreational purposes. The clinical history, physical examination and, above all, chest computed tomography indicate which differential diagnoses are most likely, thereby guiding the choice of subsequent investigations (e.g., microbiological investigations, lymphocyte proliferation tests with metals, autoantibody assays, and genetic tests). The goal is to rule out all diagnoses other than sarcoidosis that are consistent with the clinical situation. Chest computed tomography findings, from common to rare and from typical to atypical, are described for sarcoidosis and the alternatives. The pathology of granulomas and associated lesions is discussed and diagnostically helpful stains specified. In some patients, the definite diagnosis may require the continuous gathering of information during follow-up. Diseases that often closely mimic sarcoidosis include chronic beryllium disease and drug-induced granulomatosis. Tuberculosis rarely resembles sarcoidosis but is a leading differential diagnosis in regions of high tuberculosis endemicity.
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Rationale: The Sarcoidosis Diagnostic Score (SDS) has been established to quantitate the clinical features consistent with sarcoidosis in a monocentric study. Objectives: We aimed to confirm the diagnostic value of SDS in a large, multicontinental study and to assess the utility of SDS in differentiating sarcoidosis from alternative diagnoses, including infectious and noninfectious granulomatous diseases. Methods: We included patients with biopsy-confirmed sarcoidosis at nine centers across the world. Patients without sarcoidosis seen at the same sites served as control patients. Using a modified World Association of Sarcoidosis and Other Granulomatous Disorders organ assessment instrument, we scored all patients for the presence of granuloma on biopsy, highly probable symptoms, and least probable symptoms for each area. Two sarcoidosis scores were generated: SDS Biopsy (with biopsy) and SDS Clinical (without biopsy). SDS Clinical and Biopsy were calculated for all patients. We calculated and compared the area under the curve (AUC) for SDS Clinical and Biopsy according to different diagnosis scenarios. Results: A total of 1,041 patients with sarcoidosis and 1,035 without sarcoidosis were included. The results for SDS Clinical (AUC, 0.888; 95% confidence interval [CI], 0.874-0.902) and SDS Biopsy (AUC, 0.979; 95% CI, 0.973-0.985) according to AUC were good to excellent for differentiating sarcoidosis from alternative diagnosis. SDS Clinical was less discriminatory in males (P = 0.01) and in high tuberculosis prevalence centers (P < 0.001). However, SDS Clinical (AUC, 0.684; 95% CI, 0.602-0.766) and SDS Biopsy (AUC, 0.754; 95% CI, 0.673-0.835) were not sufficiently discriminative for noninfectious granulomatous diseases, but both SDSs could differentiate sarcoidosis from infectious granulomatous diseases. Algorithms were proposed for the SDS Clinical and SDS Biopsy to assist the clinician in the diagnostic process, and cutoff values were proposed for the SDS Clinical and SDS Biopsy, allowing the diagnosis of sarcoidosis to be safely confirmed or rejected in most cases except for noninfectious granulomatous disease. Conclusions: This multicontinental study confirms that both SDS Clinical and SDS Biopsy have good to excellent performance in discriminating sarcoidosis from alternative diagnoses. Differences in the AUC were seen for high tuberculosis prevalence versus low tuberculosis prevalence centers and for males versus females. Both SDSs had good discriminatory function for infectious granulomatous disease but failed in cases of noninfectious granulomatous disease such as berylliosis.