Granulomatous Lung Diseases: A Practical Approach and Review of Common Entities.

Granulomas are frequently encountered by pathologists in all types of lung specimens and arise from diverse etiologies. They should always be reported as necrotizing or non-necrotizing, with microorganism stains performed to evaluate for infection. With attention to distribution, quality (poorly vs well-formed), associated features, and correlation with clinical, radiologic, and laboratory data, the differential diagnosis for granulomatous lung disease can usually be narrowed to a clinically helpful "short list." This review describes a practical approach to pulmonary granulomas and reviews the clinicopathological aspects of common entities, including infectious (mycobacteria, fungi) and noninfectious (hypersensitivity pneumonitis, sarcoid, and vasculitis) causes.

Increased proportions of circulating PD-1+ CD4+ memory T cells and PD-1+ regulatory T cells associate with good response to prednisone in pulmonary sarcoidosis.

BACKGROUND: The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4+ T cells are central in sarcoid pathogenesis and their phenotype in peripheral blood (PB) associates with disease course. We hypothesized that the phenotype of circulating T cells in patients with sarcoidosis may correlate with the response to prednisone treatment. Therefore, we aimed to correlate frequencies and phenotypes of circulating T cells at baseline with the pulmonary function response at 3 and 12 months during prednisone treatment in patients with pulmonary sarcoidosis. METHODS: We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients and 21 healthy controls (HCs). Pulmonary function tests at baseline, 3 and 12 months were used to measure treatment effect. RESULTS: Patients with sarcoidosis showed an absolute forced vital capacity (FVC) increase of 14.2% predicted (± 10.6, p < 0.0001) between baseline and 3 months. Good response to prednisone (defined as absolute FVC increase of ≥ 10% predicted) was observed in 12 patients. CD4+ memory T cells and regulatory T cells from patients with sarcoidosis displayed an aberrant phenotype at baseline, compared to HCs. Good responders at 3 months had significantly increased baseline proportions of PD-1+CD4+ memory T cells and PD-1+ regulatory T cells, compared to poor responders and HCs. Moreover, decreased fractions of CD25+ cells and increased fractions of PD-1+ cells within the CD4+ memory T cell population correlated with ≥ 10% FVC increase at 12 months. During treatment, the aberrantly activated phenotype of memory and regulatory T cells reversed. CONCLUSIONS: Increased proportions of circulating PD-1+CD4+ memory T cells and PD-1+ regulatory T cells and decreased proportions of CD25+CD4+ memory T cells associate with good FVC response to prednisone in pulmonary sarcoidosis, representing promising new blood biomarkers for prednisone efficacy. TRIAL REGISTRATION: NL44805.078.13.

Diagnostic Value of Imaging and Serological Biomarkers in Pulmonary Sarcoidosis.

Sarcoidosis is a multisystem granulomatous disease of an unknown aetiology. It can exist in many organs. Pulmonary and intrathoracic lymph nodes are most commonly involved. Lung sarcoidosis is uncommon in Asia. However, due to the large population of our country and the development of bronchoscopy, percutaneous lung puncture, and other medical technologies, the number of pulmonary sarcoidosis patients is on the rise. Pulmonary sarcoidosis patients have no obvious symptoms in the early stage, and the clinical manifestations in the later stage may vary from person to person. Eventually, the disease progresses to life-threatening pulmonary fibrosis. Therefore, patients with pulmonary sarcoidosis should receive a timely diagnosis. In recent years, the imaging features and serologic biomarkers of pulmonary sarcoidosis have been continuously studied. The diagnostic value of imaging and serologic biomarkers for pulmonary sarcoidosis is summarized below.

Decreased serpin C1 in extracellular vesicles predicts response to methotrexate treatment in patients with pulmonary sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown etiology primarily affecting the lungs. Treatment is needed when disease symptoms worsen and organ function deteriorates. In pulmonary sarcoidosis, prednisone and methotrexate (MTX) are the most common anti-inflammatory therapies. However, there is large inter-patient variability in response to treatment, and predictive response markers are currently lacking. OBJECTIVE: In this study, we investigated the predictive potential of biomarkers in extracellular vesicles (EVs) isolated from biobanked serum of patients with pulmonary sarcoidosis stored prior to start of therapy. METHODS: Protein concentrations of a four-protein test panel of inflammatory proteins were measured in a discovery (n = 16) and replication (n = 129) cohort of patients with sarcoidosis and 47 healthy controls. Response to therapy was defined as an improvement of the absolute score of > 5% forced vital capacity (FVC) and/or > 10% diffusion lung of carbon monoxide (DLCO) after 24 weeks compared to baseline (before treatment). RESULTS: Serum protein levels differed between EV fractions and serum, and between sarcoidosis cases and controls. Serpin C1 concentrations in the low density lipid particle EV fraction were lower at baseline in the group of patients with a good response to MTX treatment in both the discovery cohort (p = 0.059) and in the replication cohort (p = 0.032). EV Serpin C1 showed to be a significant predictor for response to treatment with MTX (OR 0.4; p = 0.032). CONCLUSION: This study shows that proteins isolated from EVs harbor a distinct signal and have potential as new predictive therapy response biomarkers in sarcoidosis.

Organ involvement in newly diagnosed sarcoidosis patients in the Netherlands: The first large European multicentre prospective study.

BACKGROUND: Clinical presentation and prevalence of organ involvement is highly variable in sarcoidosis and depends on ethnic, genetic and geographical factors. These data are not extensively studied in a Dutch population. AIM: To determine the prevalence of organ involvement and the indication for systemic immunosuppressive therapy in newly diagnosed sarcoidosis patients in the Netherlands. METHODS: Two large Dutch teaching hospitals participated in this prospective cohort study. All adult patients with newly diagnosed sarcoidosis were prospectively included and a standardized work-up was performed. Organ involvement was defined using the WASOG instrument. RESULTS: Between 2015 and 2020, a total of 330 patients were included, 55% were male, mean age was 46 (SD 14) years. Most of them were white (76%). Pulmonary involvement including thoracic lymph node enlargement was present in 316 patients (96%). Pulmonary parenchymal disease was present in 156 patients (47%). Ten patients (3%) had radiological signs of pulmonary fibrosis. Cutaneous sarcoidosis was present in 74 patients (23%). Routine ophthalmological screening revealed uveitis in 29 patients (12%, n = 256)). Cardiac and neurosarcoidosis were diagnosed in respectively five (2%) and six patients (2%). Renal involvement was observed in 11 (3%) patients. Hypercalcaemia and hypercalciuria were observed in 29 (10%) and 48 (26%, n = 182) patients, respectively. Hepatic involvement was found in 6 patients (2%). In 30% of the patients, systemic immunosuppressive treatment was started at diagnosis. CONCLUSIONS: High-risk organ involvement in sarcoidosis is uncommon at diagnosis. Indication for systemic immunosuppressive therapy was present in a minority of patients.

Sarcoidosis: Evaluation and Treatment.

Sarcoidosis is a multisystem granulomatous inflammatory disease of unknown etiology that can involve any organ. Ongoing dyspnea and dry cough in a young to middle-aged adult should increase the suspicion for sarcoidosis. Symptoms can present at any age and affect any organ system; however, pulmonary sarcoidosis is the most common. Extrapulmonary manifestations often involve cardiac, neurologic, ocular, and cutaneous systems. Patients with sarcoidosis can exhibit constitutional symptoms such as fever, unintentional weight loss, and fatigue. The early recognition and diagnosis of sarcoidosis are challenging because there is no diagnostic standard for testing, initial symptoms vary, and patients may be asymptomatic. Consensus guidelines recommend a holistic approach when diagnosing sarcoidosis that focuses on clinical presentation and radiographic findings, biopsy with evidence of noncaseating granulomas, involvement of more than one organ system, and elimination of other etiologies of granulomatous disease. Corticosteroids are the initial treatment for active disease, with refractory cases often requiring immunosuppressive or biologic therapies. Transplantation can be considered for advanced and end-stage disease depending on organ involvement.

Role of Bronchoscopy in Diagnosis of Sarcoidosis.

Sarcoidosis is a multisystem inflammatory disorder with unclear etiology and can often pose a diagnostic challenge. A tissue diagnosis is often necessary to illustrate the non-caseating granulomas on histopathology. This review aims to synthesize current evidence related to tissue diagnosis of sarcoidosis using various bronchoscopic techniques. We start by discussing standard bronchoscopic techniques which have remained the cornerstone of diagnostic workup such as bronchoalveolar lavage (BAL), endobronchial biopsy (EBB), conventional transbronchial needle aspiration (cTBNA) and transbronchial lung biopsy (TBLB) followed by newer modalities that incorporate real-time image guidance using endobronchial and endoscopic ultrasound. Although BAL, EBB, and TBLB have been employed as a diagnostic tool for several decades, their sensitivity and diagnostic yield is inferior to ultrasound-based endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). More recently, convincing evidence has also emerged to support the diagnostic accuracy and tissue yield of transbronchial lung cryobiopsy which will also be discussed in this review. These advances in bronchoscopic equipment and techniques over the last 2 decades have made it possible to obtain tissue samples using minimally invasive techniques thus avoiding invasive open lung biopsy and the risks that inherently follow. Up-to-date knowledge of these modalities is imperative for ensuring evidence-based medicine and improving patient-centric outcomes.

Monitoring of Sarcoidosis.

This article focuses on the monitoring of pulmonary sarcoidosis. The monitoring of sarcoidosis is, in part, focused on serial change in major organ involvement but also includes diagnostic re-evaluation and review of change in quality of life. Recent criteria for progression of fibrotic interstitial lung disease are adapted to pulmonary sarcoidosis. The frequency and nature of monitoring are discussed, integrating baseline risk stratification and strategic treatment goals. Individual variables used to identify changes in pulmonary disease severity are discussed with a focus on their flaws and the need for a multidimensional approach. Other key monitoring issues are covered briefly.

Clinical manifestations and associated factors of uveitis in patients with pulmonary sarcoidosis: a case control study.

Sarcoidosis, an idiopathic and inflammatory disease, affects various organs and can manifest as uveitis. Due to limited evidence, researchers investigated the risk factors associated with uveitis in patients with pulmonary sarcoidosis. A retrospective study was conducted on 71 pulmonary sarcoidosis patients, including 19 with uveitis and 52 without. Data on involved organs, imaging findings, spirometry, and analyses from blood and bronchoalveolar lavage fluid were collected. Logistic regression models were used for multivariate analysis. Among the 71 newly diagnosed pulmonary sarcoidosis patients, uveitis was observed in 19 patients (26.8%). No significant differences were found in clinical characteristics between patients with and without uveitis. Fewer patients with uveitis presented lung parenchymal lesions (P = 0.043). In multivariate analysis, skin lesions (aOR 7.619, 95% CI 1.277-45.472, P = 0.026) and ophthalmic symptoms (aOR 4.065, 95% CI 1.192-13.863, P = 0.025) were associated with uveitis. Absence of uveitis was related to lung parenchymal lesions (aOR 0.233, 95% CI 0.062-0.883, P = 0.032). Approximately one-quarter of patients with an initial diagnosis of pulmonary sarcoidosis were diagnosed with uveitis. Presence of skin lesions, ophthalmic symptoms, and absence of lung parenchymal lesions were related to uveitis. These results need to be clarified by further studies to confirm the clinical role of early ophthalmologic screening for pulmonary sarcoidosis patients with these factors.

The role of serum and bronchoalveolar lavage fluid chitotriosidase activity on diagnosis, disease characteristics and prognosis of sarcoidosis.

Introduction: Sarcoidosis is a multisystem granulomatous disease with an unpredictable clinical course. Chitotriosidase is a chitinase mainly expressed by activated macrophages. Increased chitotriosidase activity has been reported in serum and bronchoalveolar lavage (BAL) of sarcoidosis patients compared to healthy controls. This study aims to evaluate the role of serum and BAL chitotriosidase activity on diagnosis, disease characteristics, and prognosis of sarcoidosis. Materials and Methods: Patients referred with suspected sarcoidosis or other interstitial lung disease were prospectively included in the study. All patients underwent bronchoscopy with BAL. Serum and BAL chitotriosidase activity, BAL differential cell counts, and lymphocyte phenotypes were determined. Sarcoidosis patients were followed up regularly. Result: Forty-two sarcoidosis and 28 non-sarcoidosis patients were included in the study. Serum chitotriosidase activity was higher in sarcoidosis group 247.5 (2.78-461) vs 108 (2.78-272) nmol/h/mL (p< 0.001). BAL chitotriosidase activity tended to be higher in sarcoidosis group 11 (2-308) vs 6.95 (2.27-44) nmol/h/mg but was not found to be statistically significant (p= 0.11). Serum and BAL chitotriosidase activities were correlated with each other (p= 0.023, r= 0.355). No significant difference was found between the diagnostic performance of BAL CD4/CD8 ratio and serum chitotriosidase activity (p= 0.079). Serum chitotriosidase and ACE activities were correlated with each other (p= 0.004, r= 0.457). No significant difference was found between serum or BAL chitotriosidase activity and stage or extrapulmonary involvement. Serum chitotriosidase activity was higher in patients who needed systemic therapy at diagnosis (p= 0.046). However, no significant difference was found between serum or BAL chitotriosidase activities and disease progression (p= 0.395 and p= 0.723, respectively). Conclusions: Serum chitotriosidase activity can be helpful in the differential diagnosis of sarcoidosis with a similar diagnostic performance with BAL CD4/CD8 ratio. Although serum chitotriosidase activity at diagnosis does not predict progressive disease, it is associated with the need for systemic therapy at diagnosis. Serial chitotriosidase measurements may be useful in monitoring disease progression during follow-up.

REFRACTORY PULMONARY SARCOIDOSIS: INCIDENCE AFTER TREATMENT WITH METHYLPREDNISOLONE AND/OR METHOTREXATE IN PATIENTS WITH NEWLY DIAGNOSED DISEASE.

Pulmonary sarcoidosis is considered refractory if glucocorticoids (GCs) at a maintenance dose of at least 10 mg/day (prednisolone equivalent) and methotrexate (MTX), including their combined use, are not effective enough to achieve clinical remission. Aim - to study the rate of refractory pulmonary sarcoidosis after conventional treatment with methylprednisolone (MP) and/or MTX in patients with newly diagnosed disease. 250 patients with newly diagnosed pulmonary sarcoidosis (106 men and 144 women; mean age 44 years) were examined. Radiological stage II was established in 237 (94.8%) patients, stage III - in 13 (5.2%). GCs therapy was carried out using MP in 190 patients at an initial dose of 0.4 mg/kg/day for 4 weeks with a gradual decrease to a maintenance dose (0.1 mg/kg/day) by the end of the 6th month. In the presence of contraindications or serious adverse effects of MP (60 patients), MTX was used at a dose of 15 mg/week. Patients without contraindications and serious adverse effects of MP treated with MTX, in case of initial therapy failure, were prescribed combined therapy with MP (12 mg/day) and MTX (10 mg/week). Based on combination therapy outcomes, as well as taking into account the cases of MTX therapy failure in patients with contraindications or serious adverse effects of GCs therapy, refractory pulmonary sarcoidosis was diagnosed in 27 (10.8%) patients. Patients with refractory pulmonary sarcoidosis were more likely to have stage III disease (Pearson's χ2 test=5.766, p=0.018), as well as extrapulmonary lesions (χ2 test=4.672, p=0.031). The high rate of conventional therapy failure using first- and second-line medications in patients with newly diagnosed sarcoidosis determines the relevance of further study of the causes, development of risk criteria and new approaches to the treatment of refractory pulmonary sarcoidosis.

T-cell signature cytokines distinguish pulmonary sarcoidosis from pulmonary tuberculosis.

Sarcoidosis is a systemic inflammatory disorder characterized by tissue infiltration due to mononuclear phagocytes and lymphocytes and associated noncaseating granuloma formation. Pulmonary sarcoidosis (PS) shares a number of clinical, radiological, and histopathological characteristics with that of pulmonary tuberculosis (PTB). Due to this, clinicians face issues in differentiating between PS and PTB in a substantial number of cases. There is a lack of any specific biomarker that can diagnose PS distinctively from PTB. We compared T-cell-based signature cytokines in patients with PS and PTB. In this study, we proposed a serum biomarker panel consisting of cytokines from cells: T helper (Th) 1 [interferon-gamma (IFN-γ); tumor necrosis factor-alpha (TNF-α)], Th9 [interleukin (IL)-9], Th17 [IL-17], and T regulatory (Treg) [IL-10; transforming growth factor-beta (TGF-ß)]. We performed the principal component analysis that demonstrated that our serum cytokine panel has a significant predictive ability to differentiate PS from PTB. Our results could aid clinicians to improve the diagnostic workflow for patients with PS in TB endemic settings where the diagnosis between PS and PTB is often ambiguous.

Pulmonary Sarcoidosis: Experimental Models and Perspectives of Molecular Diagnostics Using Quantum Dots.

Sarcoidosis is a complex inflammatory multisystem disease of unknown etiology that is characterised by epithelioid cell granulomatous lesions affecting various organs, mainly the lungs. In general, sarcoidosis is asymptomatic, but some cases result in severe complications and organ failure. So far, no accurate and validated modelling for clinical and pathohistological manifestations of sarcoidosis is suggested. Moreover, knowledge about disease-specific diagnostic markers for sarcoidosis is scarce. For instance, pulmonary granulomatosis is associated with the upregulated production of proinflammatory molecules: TNF-α, IL-6, CXCL1, CCL2, CCL18, CD163, serum angiotensin-converting enzyme (sACE), lysozyme, neopterin, and serum amyloid A (SAA). Quantum dots (QDs) are widely applied for molecular diagnostics of various diseases. QDs are semiconductor nanoparticles of a few nanometres in size, made from ZnS, CdS, ZnSe, etc., with unique physical and chemical properties that are useful for the labelling and detection in biological experiments. QDs can conjugate with various antibodies or oligonucleotides, allowing for high-sensitivity detection of various targets in organs and cells. Our review describes existing experimental models for sarcoidosis (in vitro, in vivo, and in silico), their advantages and restrictions, as well as the physical properties of quantum dots and their potential applications in the molecular diagnostics of sarcoidosis. The most promising experimental models include mice with TSC2 deletion and an in silico multiscale computational model of sarcoidosis (SarcoidSim), developed using transcriptomics and flow cytometry of human sarcoid biopsies. Both models are most efficient to test different candidate drugs for sarcoidosis.

[Sarcoidosis]. / Sarkoidose.

Sarcoidosis is the most common granulomatous disease in northern Europe. A distinction is made between acute forms of sarcoidosis and chronic sarcoidosis. Chronic sarcoidosis can affect practically all organs but the lungs are affected in 90-95% of patients. The clinical appearance varies between asymptomatic and oligosymptomatic courses, which are diagnosed more by chance, to courses with acute organ failure. An extensive organ work-up is necessary at the time of the initial diagnosis in order to record the extent of organ involvement and to make appropriate treatment decisions. Asymptomatic courses with purely pulmonary sarcoidosis do not require treatment and can be observed over the course of the disease, whereas courses with extensive organ involvement or organ dysfunction require treatment. The treatment consists primarily of the administration of glucocorticoids. If the effect of the glucocorticoids is insufficient or if there are side effects, various immunosuppressive agents, including biologics can be added.

Clinical and Histopathologic Characteristics of Recurrent Sarcoidosis in Posttransplant Lungs: 25 Years of Experience.

Lung transplantation is the definitive therapy for end-stage pulmonary sarcoidosis. While recurrent sarcoidosis in allografts has been described in several case reports, the incidence and clinicopathologic characteristics remain unclear. In this study, we characterize the clinical and histopathologic features of recurrent sarcoidosis diagnosed in posttransplant lung surveillance transbronchial biopsies (TBBx). We identified 35 patients who underwent lung transplant for pulmonary sarcoidosis during the study period. Among them, 18 patients (51%) experienced recurrent sarcoidosis posttransplant. These included 7 females and 11 males with mean age at recurrence of 51.6 years. The average time interval from transplant to recurrence was 252 days (22 to 984 d). All TBBx contained >4 pieces of alveolated lung tissue with no evidence of International Society for Heart and Lung Transplantation (ISHLT) grade A2, A3, or A4 acute cellular rejection; chronic rejection; or antibody-mediated rejection. There were 33 surveillance TBBx that contained granulomatous inflammation with a mean of 3.6 well-formed granulomas per TBBx (range: 1 to >20). Multinucleated giant cells were identified in 11 TBBx (33.3%), with 1 case containing asteroid bodies. While most of the granulomas were "naked granulomas," 5 cases (15.2%) showed prominent lymphoid cuffing. Two cases showed evidence of fibrosis. One of the granulomas had focal necrosis; however, no infectious organisms were identified by special stains and clinical correlation suggested this case represented recurrent sarcoidosis. Biopsies of recurrent sarcoidosis usually show multiple well-formed granulomas with giant cells in more than half of the cases, while lymphoid cuffing, fibrosis, asteroid bodies, and necrotizing granulomas are uncommon findings. Pathologists should be aware of these features, as recurrence of sarcoidosis following lung transplant occurs in more than half of patients.

Dyspnoea in a patient with biopsy-proven pulmonary sarcoidosis: the challenges in diagnosing cardiac sarcoidosis.

A man in his 60s with biopsy-proven pulmonary sarcoidosis, not on treatment, presented with 6 weeks of dyspnea to the emergency department. ECG showed first-degree atrioventricular block and CT thorax demonstrated progressive pulmonary sarcoidosis with new multifocal consolidation. Antibiotics were initiated.A brain natriuretic peptide was elevated at 2024 ng/L and echocardiogram showed global left ventricular systolic dysfunction. Coronary angiogram revealed normal coronary arteries, and cardiac positron emission tomography and MRI demonstrated patterns compatible with cardiac sarcoidosis. The patient significantly improved with diuresis; he was started on prednisone, methotrexate and standard heart failure therapies.We outline the difficulties of attributing cardiac causes of dyspnoea in a patient with known pulmonary sarcoidosis given the rarity of cardiac involvement. We review proposed diagnostic criteria for cardiac sarcoidosis using enhanced imaging techniques without requiring invasive myocardial biopsy. This case discussion also highlights nuances in managing cardiac sarcoidosis based on the best available evidence and expert consensus.

Risk Indicators of Sarcoidosis Evolution-Unified Protocol (RISE-UP): protocol for a multi-centre, longitudinal, observational study to identify clinical features that are predictive of sarcoidosis progression.

INTRODUCTION: Sarcoidosis is a pulmonary and systemic granulomatous disease with a wide range of potential outcomes, from spontaneous resolution to end-stage organ damage and death. Currently, clinicians have no easy-to-use risk stratification tools for important clinical outcomes in sarcoidosis, such as progressive lung disease. This study will address two clinical practice needs: (1) development of a risk calculator that provides an estimate of the likelihood of pulmonary progression in sarcoidosis patients during the follow-up period and (2) determine the optimal interval for serial clinical monitoring (eg, 6, 12, 18 months) using these risk prediction tools. METHODS AND ANALYSIS: The Risk Indicators of Sarcoidosis Evolution-Unified Protocol study is a National Institutes of Health-sponsored, longitudinal observational study of adults with pulmonary sarcoidosis who will be enrolled at five US tertiary care centres. Participants will be evaluated at approximately 6-month intervals for up to 60 months with collection of lung function, blood samples and clinical data. The target sample size is 557 and the primary objective is to determine which clinical features measured during a routine clinic visit carry the most prognostic information for predicting clinical progression of pulmonary sarcoidosis over the follow-up period. The primary outcome measure will be quantified by a clinically meaningful change in forced vital capacity, forced expiratory volume in 1 s or diffusing capacity of the lung for carbon monoxide. The secondary objective is to determine if blood biomarkers measured during a routine clinic visit can improve the risk assessment modelling for progression of pulmonary sarcoidosis over the follow-up period. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Review Boards at each centre and the reliance Institutional Review Board overseeing the study (WCG, Protocol #20222400). Participants will provide informed consent prior to enrolment. Results will be disseminated via publication in a relevant peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05567133.