Extrapulmonary Organ Involvement Research Articles

Long-term survival outcomes of 'watch and wait' in patients with bronchus-associated lymphoid tissue lymphoma: a multicenter real-world data analysis in Korea.

Bronchus-associated lymphoid tissue (BALT) is a rare cause of extranodal marginal zone lymphoma (MZL). Although most patients with BALT lymphoma (BALToma) show an indolent clinical course and are monitored without treatment, there are limited real-world data on the long-term outcome of "watch-and-wait' strategy in comparison with other treatments.The survival outcomes of patients newly diagnosed with BALToma at three tertiary hospitals in Korea undergoing two treatment strategies were analyzed: group A, patients who were monitored without any treatment or received only radiotherapy after diagnosis; and group B, patients receiving any kind of systemic chemotherapy after diagnosis, regardless of their history of any local treatment such as surgery or radiotherapy.Of the 67 patients included in our analysis, the 10-year progression-free survival (PFS) and 10-year overall survival (OS) rates were 65.3% and 83.2%, respectively. The 10-year PFS rates for observation or localized treatment and systemic chemotherapy were 78.7% and 56.9%, respectively (p = 0.044). Ten-year OS rates for observation or localized treatment and systemic chemotherapy were 100% and 71.7%, respectively (p = 0.016). Multivariate analysis showed that bilateral lung (HR 2.462, p = 0.047) and extrapulmonary organ (HR 4.485, p = 0.004) involvement were the only significant factors associated with poor PFS. Prognostic factor analysis for OS did not yield significant results.Patients with BALToma show a favorable prognosis, suggesting that observation or localized therapy alone may be effective for patient management. However, patients with bilateral lung or extrapulmonary involvement may require careful monitoring for disease progression and more aggressive treatment approaches.

Delayed inflammatory pulmonary syndrome: A distinct clinical entity in the spectrum of inflammatory syndromes in COVID-19 infection?

During the second wave of the coronavirus disease 2019 (COVID-19) pandemic, a subset of critically ill patients developed delayed respiratory deterioration in the absence of new infection, fluid overload or extra-pulmonary organ dysfunction. To describe the clinical and laboratory characteristics, outcomes, and management of these patients, and to contrast this entity with other post COVID-19 immune dysregulation related inflammatory disorders. This was a retrospective observational study of adult patients admitted to the medical intensive care unit of a 2200-bed university affiliated teaching hospital, between May and August 2021, who fulfilled clearly defined inclusion and exclusion criteria. Outcome was assessed by a change in PaO2/FiO2 ratio and levels of inflammatory markers before and after immunomodulation, duration of mechanical ventilation after starting treatment, and survival to discharge. Five patients developed delayed respiratory deterioration in the absence of new infection, fluid overload or extra-pulmonary organ dysfunction at a median interquartile range (IQR) duration of 32 (23-35) d after the onset of symptoms. These patients had elevated inflammatory markers, required mechanical ventilation for 13 (IQR 10-23) d, and responded to glucocorticoids and/or intravenous immunoglobulin. One patient died (20%). This delayed respiratory worsening with elevated inflammatory markers and clinical response to immunomodulation appears to contrast the well described Multisystem Inflammatory Syndrome - Adults by the paucity of extrapulmonary organ involvement. The diagnosis can be considered in patients presenting with delayed respiratory worsening, that is not attributable to cardiac dysfunction, fluid overload or ongoing infections, and associated with an increase in systemic inflammatory markers like C-reactive protein, inteleukin-6 and ferritin. A good response to immunomodulation can be expected. This delayed inflammatory pulmonary syndrome may represent a distinct clinical entity in the spectrum of inflammatory syndromes in COVID-19 infection.

Novel biomarkers for the assessment of disease activity in patients with sarcoidosis: a case-control study.

The prognosis of sarcoidosis is challenging and largely depends on the persistence of disease activity and the degree of organ dysfunction. Various biomarkers have been evaluated for diagnosis, disease activity assessment, and prognosis. This study aimed to determine if the ratios of monocytes to high-density lipoprotein cholesterol (MHR), platelets to lymphocytes (PLR), neutrophils to lymphocytes (NLR), and lymphocytes to monocytes ratio (LMR) could be used as novel sarcoidosis activity markers. In a case-control study, 54 patients with biopsy-confirmed sarcoidosis were divided into two groups; group 1: consisted of 27 patients with active sarcoidosis who were newly diagnosed and treatment-naive, and group 2: consisted of 27 patients with inactive sarcoidosis who had been on treatment for at least 6 months. All patients were subjected to a comprehensive history, physical examination, laboratory tests, chest imaging, spirometry, and screening for extrapulmonary organ involvement by means of electrocardiogram and eye examination. The mean age of the patients was 44 ± 11 years (79.6% were females & 20.4% were males). MHR, NLR, and LMR were significantly higher in patients with active sarcoidosis than in an inactive disease with a cut-off value of 8.6, a sensitivity of 81.5%, and a specificity of 70.4% (P-value < 0.001), a cut-off value of 1.95, sensitivity of 74% and specificity of 66.7% (P-value 0.007) and a cut-off value of < 4, a sensitivity of 81.5%, and a specificity of 85.2% (P-value < 0.001), respectively. In contrast, PLR was not statistically significant between active and inactive sarcoidosis patients. The lymphocytes monocytes ratio is a highly sensitive and specific biomarker that could be used to assess the disease activity in sarcoidosis patients.

EGPA Phenotyping: Not Only ANCA, but Also Eosinophils

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a small-vessel necrotizing vasculitis. The anti-neutrophil cytoplasmic antibodies' (ANCA) role in defining clinical EGPA phenotypes is well established. Although the role of eosinophils in disease pathogenesis has been clearly demonstrated, the value of blood eosinophil count (BEC) as a biomarker of disease phenotypes is currently uncertain. We retrospectively analyzed EGPA patients referred to our Immunology Clinic. Demographic, laboratory and clinical features were retrieved from clinical records, and a Logistic Regression was fitted to evaluate the predictive power of all baseline clinical and laboratory features to define EGPA phenotypes. 168 patients were recruited. BEC ≤ 1500 cells/mL was predictive of a clinical involvement characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and lung opacities (OR 0.18, 95% CI 0.07-0.43; respiratory-limited phenotype); BEC > 3500/mL was predictive of extrapulmonary organ involvement (OR 3.5, 95% CI 1.7-7.1; systemic phenotype). BEC was also predictive of peripheral nervous system (PNS) involvement, with a positive trend with increasing BEC (<1500/mL: OR 0.17, 95%CI, 0.06-0.47; >3500/mL: OR 2.8, 95% CI, 1.5-5.28). ANCA positivity was also predictive of extrapulmonary involvement (OR 4.7, 95% CI 1.9-11.99). according to BEC and irrespective of the ANCA status, two EGPA phenotypes could be identified, named systemic and respiratory-limited phenotypes, with different organ involvement and possibly different prognoses.

90 A RETROSPECTIVE COHORT STUDY COMPARING THE CLINICAL CHARACTERISTICS, TREATMENT AND OUTCOMES OF BIOPSY-CONFIRMED SARCOIDOSIS IN LATE-ONSET AND YOUNGER-ONSET PATIENTS

Abstract Background Late-Onset Sarcoidosis (LOS) accounts for up to one-third of cases and is diagnostically challenging due to the difficulty in satisfactorily excluding malignancy and infection, often necessitating repeated investigations. Endobronchial Ultrasound (EBUS) is the gold standard for diagnosing pulmonary sarcoidosis. This study aims to compare the clinical presentation, treatment and outcomes in patients with biopsy confirmed sarcoidosis in older and younger patients Methods A retrospective cohort analysis was performed on all patients with EBUS-confirmed sarcoidosis at a tertiary referral centre between 2012 and 2019. Electronic healthcare records were reviewed to obtain information on clinical presentation, confirmatory investigations, treatment and outcomes. LOS was defined as patients aged &amp;gt;65 years Results In total, 247 patients were included, 68.8% were male. LOS accounted for 9.3% (n=23).Extra-pulmonary and systemic features were less common in LOS (26.1% vs 58%, p&amp;lt;0.002). There was no difference in systemic treatment between cohorts (84.6% vs 67.9%, p=0.21) and LOS patients experienced comparably high rates of satisfactory outcomes. At follow up, the majority of patients either improved or achieved clinical stability in both groups (92.3% vs 76.1%, p=0.18). Clinical and/or radiological progression occurred in 7% in both groups with no reported deaths. Confirmatory investigations were infrequent and EBUS was safe and well-tolerated in older patients. Conclusion LOS was lower than expected and extra-pulmonary involvement was uncommon suggesting a pre-selected population. Referral for EBUS should be considered as first line for older patients with unexplained thoracic adenopathy provided further diagnostic investigations are in line with their goals of care. Clinical outcomes were excellent with low rates of progression, extra-pulmonary organ involvement and systemic therapy initiation, differing from prior studies and may represent less severe disease at diagnosis, enhanced diagnostic certainty or referral bias.

Autoantibody profile in sarcoidosis, analysis from the GRADS sarcoidosis cohort.

BackgroundSarcoidosis, a multi-systemic granulomatous disease, is a predominantly T-cell disease but evidence for a role for humoral immunity in disease pathogenesis is growing. Utilizing samples from the Genomic Research in Alpha-1 anti-trypsin Deficiency and Sarcoidosis (GRADS) study, we examined the prevalence of autoantibodies in sarcoidosis patients with pulmonary-only and extra-pulmonary organ involvement compared to normal controls.Study design and methodsWe analyzed serum samples from sarcoidosis patients who participated in the GRADS study utilizing an autoantigen microarray platform for both IgM and IgG antibodies. The cohort included sarcoidosis patients with pulmonary-only disease (POS, n = 106), sarcoidosis patients with extra-pulmonary disease (EPS, n = 120) and a normal control cohort (NC, n = 101). Organ involvement was assessed following a standardized format across all GRADS participating centers.ResultsSarcoidosis patients overall had increased levels of IgM and IgG autoantibodies compared to normal controls. In addition, several autoantibodies were elevated in the POS and EPS cohorts compared to the NC cohort. Differences in autoantibody levels were also noted between the POS and the EPS cohorts. When comparing organ involvement with sarcoidosis, bone, spleen and ear, nose and throat involvement had higher IgM expression than other organs.ConclusionSarcoidosis patients have elevated IgM and IgG autoantibody levels compared to normal controls. In addition, individuals with pulmonary as well as additional organ involvement had higher IgM expression. Further research is needed focusing on specific organ-autoantibody pairs and role of autoantibodies in disease pathogenesis.

Diagnostic utility of 68Ga-citrate and 18FDG PET/CT in sarcoidosis patients.

Sarcoidosis is a chronic granulomatous disease of unknown etiology. The disease most commonly involves the lungs and the mediastinal lymph nodes while extrapulmonary organs such as the skin, eye, liver or spleen may also be comprised. Many imaging modalities have been used for the clinical evaluation of sarcoidosis patients but all have been found to have certain drawbacks for a reliable identification assessment due to the equivocal diagnostic results. This case series was designed to determine the clinical trenchancy of simultaneous 68Ga citrate PET/CT [Positron emission tomography with 68Ga citrate (68Ga citrate PET/CT)] and 18F-FDG PET/CT [Positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT)] imaging in sarcoidosis patients. The main goal of the study was to evaluate sarcoidosis with respect to disease activity and organ involvement. A total of eight sarcoidosis patients with a comorbid disease suspicion were included in the study. Conventional clinical parameters used for the diagnosis and the activity of sarcoidosis including CT [Computed tomography (CT)] were compared with the 68Ga-citrate PET/CT findings. Concurrent 18F-FDG PET/CT was performed to verify the granulomatous inflammation of sarcoidosis and to determine coexisting malignant or other inflammatory diseases. Our study results revealed that 68Ga citrate PET/CT imaging appears to be highly useful for the diagnosis, activity assessment and extrapulmonary organ involvement in sarcoidosis. Another crucial finding was the detection of extrapulmonary organ disease that are exceptionally involved, almost inaccessible by biopsy and that could not be otherwise displayed by other conventional imaging modalities. The third hallmark was the identification of a clinically asymptomatic and occult malignancy accompanying sarcoidosis that would not be revealed in any way if synchronous 18FDG PET/CT had not been performed. Simultaneous application of 68Ga citrate and 18FDG PET/CT may provide extremely useful data for the clinical evaluation of sarcoidosis patients in terms of the primary disease diagnosis, activity state, extrapulmonary organ involvement unachievable for biopsy and the clinically occult malignant disorders.

Kidney injury in COVID-19.

Coronavirus disease 2019 (COVID-19) continues to affect millions of people around the globe. As data emerge, it is becoming more evident that extrapulmonary organ involvement, particularly the kidneys, highly influence mortality. The incidence of acute kidney injury has been estimated to be 30% in COVID-19 non-survivors. Current evidence suggests four broad mechanisms of renal injury: Hypovolaemia, acute respiratory distress syndrome related, cytokine storm and direct viral invasion as seen on renal autopsy findings. We look to critically assess the epidemiology, pathophysiology and management of kidney injury in COVID-19.

The Role of Staging Evaluation at Initial Diagnosis of Adult Patients with Clinically Isolated Pulmonary Langerhans Cell Histiocytosis

Background: Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder that is now recognized as a neoplasm by the World Health Organization. It is generally classified based on the site and extent of disease involvement (single system or multisystem). Pulmonary LCH (pLCH), an uncommon interstitial lung disease associated with smoking, often presents as isolated pulmonary disease. It is unclear whether patients with clinically isolated pLCH have extra-pulmonary lesions at diagnosis or during the course of their disease. The role of [18F] fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) in the staging of pLCH remains unclear. Our study aims to better characterize the utility of radiographic staging studies at time of diagnosis and prevalence of extrapulmonary disease at follow up in pLCH. Methods: We conducted a retrospective study of patients presenting with clinical findings consistent with isolated pLCH seen at the Mayo Clinic from January 2000 to January 2020. All patients had a diagnosis of pLCH determined by chest imaging studies [computed tomography (CT) or high-resolution CT (HRCT)] or by histopathologic findings from surgical or transbronchial lung biopsy. Histopathologic findings for the diagnosis of pLCH required the presence of Langerhans cells (S100+/CD1a+/Langerin+). Patients were excluded if they had clinically apparent extra-pulmonary organ involvement at the time of diagnosis. BRAF V600E mutation was determined by immunohistochemistry (IHC) or cell-free DNA (cfDNA). Staging was defined as FDG-PET-CT or whole body CT imaging obtained within 3 months of diagnosis of pLCH. Extra-pulmonary LCH involvement was determined by imaging characteristics or by histopathologic findings. Descriptive statistics and overall survival (OS) were analyzed with JMP software, version 14 (SAS Institute Inc., Cary, NC). Results: A total of 112 patients with clinically isolated pLCH were identified. The median age at diagnosis was 45 years (range 21-73), and 48 (43%) were male. The majority (n=110, 99%) were former or current smokers with a median pack year of 25 (range 1-57). Three (3%) patients were noted to have occupational industrial exposure. Nine patients had a history of another cancer prior to their diagnosis and staging of pLCH [lung (n=4), breast (n=2), neuroendocrine (n=2), thyroid (n=1)]. Presenting symptoms included dyspnea on exertion 49 (44%), cough 18 (16%), chest pain 14 (13%), and 29 (28%) were incidentally discovered on imaging studies. On HRCT, the following characteristics were observed: 42 (38%) cystic, 32 (29%) cystic and nodular, 37 (33%) nodular, 1 (&amp;lt;1%) ground glass opacities. Seventy (63%) patients had lung biopsy confirmation, of which 11 (16%) patients underwent BRAF V600Emutation testing (7 by IHC, 4 by cfDNA). Six (55%) of these 11 patients were positive for BRAF V600E mutation. 34 (30%) patients underwent radiographic staging studies within 3 months of diagnosis of pLCH (25 FDG-PET-CT and 9 whole-body CT), and none of these imaging studies showed evidence of extra-pulmonary disease. Of the patients who had at least one year of follow-up (n=52), one (2%) developed extra-pulmonary disease. This patient did not undergo initial staging studies, developed headaches and was found to have a large calvarial lytic lesion within 2 months of pLCH diagnosis (BRAF V600E+). Among those who did not undergo staging at diagnosis (n=78), long term (&amp;gt;5 years) follow up data were available for 23 (29%), and none developed extra-pulmonary disease as determined by clinical notes or imaging studies. No patient had evidence of new extra-pulmonary involvement or second malignancy at the time of last known follow-up. After a median follow-up duration of 2.4 years (95% CI: 1.5-3.6, range: 0.1-17) ten (9%) patients died, of which 5 died of pLCH related complications. The median OS for entire cohort was 15 years (95% CI 9.1-not reached, Figure 1). Conclusion: Our study shows that adult patients with clinically isolated pLCH rarely present with extra-pulmonary manifestations at diagnosis or at follow up. These findings suggest a limited role of routine radiographic staging studies in pLCH unless clinically indicated. Studies on longer follow up of this cohort would provide further insights into the natural history of pLCH and are underway. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding. Shah:Dren Bio: Consultancy.

Clinical features and the prognostic significance of ocular sarcoidosis

The main objective of this study was to evaluate the clinical features of ocular sarcoidosis. The second aim was to assess the influence of eye involvement on the prognostic outcome, extrapulmonary organ, and endobronchial involvement in sarcoidosis patients.

Culture proven extra pulmonary tuberculosis: drug susceptibility and genetic profile analysis

Tuberculosis is seen generally in the lungs. Besides, all organs in the body can be affected by tuberculosis. Diagnosis of extra pulmonary tuberculosis (EPTB) is more difficult than pulmonary tuberculosis (PTB). Although, the isolation of Mycobacterium tuberculosis is gold standard of diagnosis of EPTB, the rate of bacteriologic isolation is low especially in EPTB. If M. tuberculosis is detected, it gives some information about the epidemiological features of the disease and drug susceptibility. In this study, extra pulmonary samples isolated M. tuberculosis in mycobacteriology laboratory were evaluated between 2009-2016. The identification of the genotype of isolated bacteria and drug sensitivity tests were conducted. Spoligotyping was accomplished using a standard technique as described previously. During the study period, M. tuberculosis were cultured in 171 extra pulmonary samples of 165 patients (75 male, 90 female, mean age: 53.35 ± 19.92). Initial direct microscopically examination was revealed M. tuberculosis in 44 patients. There were more than one extra pulmonary organ involvement in six patients. The most common EPTB forms were lymph node TB in 60 patients, pleural tuberculosis in 32 patients and bone tuberculosis in 25 patients. Immunosuppression was detected in 44 (%26.6) patients. Among these, seven patients were infected with HIV. In 21 of 175 samples, drug resistance was detected. Rifampicin resistance in 7 samples, high level isoniazid resistance in 11 samples and rifampicin plus isoniazid resistance (multiply drug resistance) in 6 samples were demonstrated. One hundred thirty-five clinical isolates were cultured from tuberculosis patient's different samples, of which the genetic profile was determined by using Spoligotyping. The major Spoligotypes were T (n= 62; 45.9%), LAM7-TUR (ST41) (n= 11; 8.1%) and H1 (n= 9; 6%) genotypes. The most common EPTB form was lymph node tuberculosis in culture proven patients. In these patients group, multiply drug resistance rate was low (3.6%). Spoligotypes T (45.9%) was detected as most common genetic profile.

Clinical and prognostic significance of muscle biopsy in sarcoidosis.

The main objective of this study was to evaluate the influence of muscle involvement on the clinical features, prognostic outcome, extrapulmonary organ, and endobronchial involvement in sarcoidosis patients. The second aim was to assess the diagnostic yield of muscle biopsy for the histopathologic identification of sarcoidosis. Fifty sarcoidosis patients participated in the study. The patients were classified into two groups according to the histopathologic presence of non-caseating granulomatous inflammatory pattern of the muscle biopsy samples and were evaluated retrospectively in regard to clinical features, prognosis, extrapulmonary, and endobronchial disease involvement. Pathologic examination of the muscle biopsy samples revealed non-caseating granulomas in eighteen and myositis in seven patients compatible with sarcoidosis. The diagnostic yield of muscle biopsy for demonstrating non-caseating granulomatous inflammation was fifty percent. Patients with muscle sarcoidosis showed a worse prognosis and a more severe extrapulmonary organ involvement than the patients without muscle disease. Muscle biopsy was not statistically significant to delineate diffuse endobronchial involvement while it was suggestive for endobronchial disease clinically. The results of our study reveal that muscle biopsy appears to be a useful diagnostic tool along with its safety and easy clinical applicability. It is a rewarding utility to predict the prognostic outcome and extrapulmonary involvement in sarcoidosis patients. Positive biopsy on the other hand confirms the identification of sarcoidosis in patients with single organ involvement carrying an equivocal diagnostic clinical pattern. Muscle biopsy may be considered as the initial step for the final diagnosis of sarcoidosis in such cases.

Gastric Sarcoidosis: An Atypical Presentation of a Rare Disease

Sarcoidosis is a multisystemic granulomatous disease characterised by the histologic evidence of granulomas in various organs. Clinically discernible gastric sarcoidosis is extremely rare, reported in less than 1% of the patients. We present a case of gastric sarcoidosis with atypicial manifestations and without current pulmonary disease. The patient was admitted for gastric fullness, anorexia, and weight loss. She had a history of migraine and nodular goiter. Family history revealed bladder carcinoma in the mother and gastric carcinoma in the uncle. Initial laboratory findings and chest x-ray were normal. Biopsies from the gastric mucosa revealed noncaseating granulomas with focal multinucleate giant cells. Six months after the patient was admitted for dry cough and fatigue. Chest x-ray and CT revealed diffuse nodules in the upper and middle lung zones. Transbronchial biopsy demonstrated noncaseiting granulomas compatible with sarcoidosis. The patient was started on mehtylprednisolone and had a significant improvement in her symptoms. This case is an unique paradigm for the exceptional presentation of sarcoidosis. Isolated extrapulmonary organ involvement without simultaneous lung disease may be the initial manifestation of sarcoidosis. Meticulous follow-up for sarcoidosis is required for patients presenting with atypical symptoms and noncaseiting granulomas in any extrapulmonary organ.

Resolution rate of pulmonary sarcoidosis and its related factors in a Japanese population.

A number of previous studies have reported on the rate of resolution of pulmonary sarcoidosis and its associated factors. However, most of the studies were conducted several decades ago and no similar surveys have been conducted in recent years. The aim of this study was to evaluate the rate of resolution of pulmonary sarcoidosis and its related factors in recently diagnosed patients, and to compare the results with those from previous studies. This study included 306 patients who had been newly diagnosed with pulmonary sarcoidosis between 2000 and 2009 in Sapporo, Japan. Chest radiographical findings were assessed at the initial visit and at the 2- or 5-year observation points. The rates of resolution on chest radiographs and the association with clinical manifestations were evaluated. The resolution rates were 17.9% at the 2-year and 29.9% at the 5-year observation point. These rates were lower than those reported in the earlier surveys. Younger subjects (aged <40 years) showed resolution more often (P < 0.05). The absence of extra-pulmonary organ involvement was associated with resolution at 5 years (P < 0.05). The clinical course of pulmonary sarcoidosis may be changing, showing a tendency not to resolve. At least in part, this may be due to the ageing of the Japanese population.

Clinical and Serological Features of Eosinophilic and Vasculitic Phases of Eosinophilic Granulomatosis with Poliangiitis: a Case Series of 15 Patients.

Eosinophilic granulomatosis with poliangiitis (EGPA) which was previously called Churg-Strauss Syndrome, is classified into eosinophilic and vasculitic phases. To characterize the eosinophilic and vasculitic phases of the disease in terms of clinical findings, serology, and treatment. We included 15 EGPA patients in the study. The clinical, serological, and therapeutic characteristics and the treatment responses of the patients were recorded. Thirteen patients were classified as being in the eosinophilic phase and two were classified as being in the vasculitic phase of EGPA. Initial symptoms were worsening asthma in all patients (n=15; 100%). All patients had rhinosinusitis, and 66.6% had hypersensitivity to nonsteroidal anti-inflammatory drugs. The two patients in the vasculitic phase did not have nasal polyposis. Pulmonary and nervous system involvement were the most common symptoms. The erythrocyte sedimentation rates (ESRs) of the two patients in the vasculitic phase were 65 mm/h and 55 mm/h, while ESR was normal in eosinophilic-phase patients. Antineutrophil cytoplasmic antibodies (ANCA) was detected in one patient (6.6%) who was in the vasculitic phase (Case 15). The disease was under control with higher doses of methylprednisolone in the vasculitic phase (Case 14: 12 mg/day, Case 15: 10 mg/day) than in the eosinophilic phase. Relapse was detected in the two patients in the vasculitic phase. Oral corticosteroid was not discontinued in any case, and no mortality was reported. Patients with eosinophilic phase or vasculitic phase EGPA had similar clinical onset. However, higher ESR, ANCA positivity, and extrapulmonary organ involvement were only found in patients in the vasculitic phase. Corticosteroid responsiveness was very good in all patients in the eosinophilic phase, and the disease could be controlled with a very low maintenance dose of a corticosteroid.

Sarcoidosis--a multisystem disorder with variable prognosis

Sarcoidosis is a pneumotropic granulomatous inflammatory multisystem disorder of unknown origin and heterogeneous outcome. In most cases the disease is self-limited, others progress or die from organ involvement, which is often associated with extensive pulmonary scarring or relevant extrapulmonary organ involvement. Therefore, patients with sarcoidosis must be staged for multiorgan involvement. Modern treatment strategies appraise a critical awareness for the effect to side-effect-ratio of long-term immunosuppressive medication.

Clinical Features and Prognostic Significance of Limited and Diffuse Endobronchial Sarcoidosis

Aims: Airway involvement is a common feature of sarcoidosis and mucosal abnormalities may be evident in the respiratory tract. However, firm data establishing the clinical features and prognosis of sarcoidosis in these patients is lacking although the incidence of endobronchial disease is high. The purpose of this study was to evaluate the clinical features of the patients with limited, diffuse and no endobronchial involvement. Another aim was to investigate the prognostic differences between these patients. Methods: We conducted a retrospective study to evaluate the clinical and laboratory findings of 48 patients with endobronchial sarcoidosis and 50 patients without endobronchial involvement seen at our institution. The patients fulfilled the clinical, radiologic or both features of sarcoidosis supported by the histopathologic evidence of noncaseiting granulomas. Six to ten bronchial biopsies were taken from each patient. The sample was considered positive if it demonstrated noncaseiting Original Research Article Tetikkurt et al.; BJMMR, 11(6): 1-7, 2016; Article no.BJMMR.20786 2 granulomas with negative fungal and mycobacterial cultures. The patients were classified into three groups according to the histopathologic biopsy results: 1) No endobronchial involvement, 2) Limited endobronchial involvement: One biopsy site positive and 3) Diffuse endobronchial involvement: Two or more biopsy sites positive for noncaseaiting granulomas. Results: Bronchial biopsy was positive in 82% of the abnormal appearing airways while it was diagnostic in 36% of the normal appearing mucosa. The most frequent bronchoscopic appearence was miliary infiltration. Nodular, erythematous lesions and edematous mucosal swelling were other bronchoscopic findings. There were no significant differences between the three groups for FEV1, FVC, TLC, DLCO/VA serum and 24 h urinary calcium levels. Serum ACE levels were significantly higher (p<0.001) in patients with limited and diffuse bronchial involvement compared to patients with no endobronchial disease. The extrapulmonary organ involvement (p<0.001) and progressive disease incidence was more frequent (p<0.001) in patients with limited and diffuse endobronchial disease. Conclusions: Endobronchial involvement in sarcoidosis appears to be a significant predictive risk factor for progressive disease. Patients with limited or diffuse endobronchial disease have more severe extrapulmonary organ involvement and a worse prognosis than patients without endobronchial disease. Bronchoscopy may identify such patients carrying a risk factor for progressive sarcoidosis.

Endobronchial Involvement in Sarcoidosis

Endobronchial involvement is a common feature of sarcoidosis. The mucosa may appear normal or there may be inflammatory changes with erythematous lesions, miliary nodules, and, rarely, mass-like lesions leading to obstruction. In patients with bronchial lesions, the bronchial biopsy may be positive in three-quarters of patients. On the other hand, granulomas may be identified in one-third of patients with a normal mucosa. Current data on endobronchial sarcoidosis is primarily associated with the treatment and prognosis of obstructive mass-like granulomas. Data relevant to clinical features of superficial endobronchial involvement and its implications on prognosis and extrapulmonary organ involvement is lacking. The results of our two previous studies reveal that clinical findings of endobronchial disease may be different. These studies also suggest that there is a great difference between patients with no endobronchial involvement, limited and diffuse endobronchial disease in regard to clinical features, and prognosis. The incidence of extrapulmonary organ involvement is also significantly different between the three groups. In this short review, the clinical findings of endobronchial sarcoidosis have been defined, the effects of superficial endobronchial involvement on prognosis, and extrapulmonary organ involvement.

Clinical Features and Prognostic Significance of Liver Involvement in Sarcoidosis

Background:Sarcoidosis is a systemic disease, characterised by non-caseating granulomas in various organs. Liver involvement is not an uncommon feature of sarcoidosis. However, firm data establishing the clinical features and prognosis in these patients are lacking, although the incidence of liver sarcoidosis is high. In this study, we aimed to investigate the features of liver involvement in patients with sarcoidosis. Another aim was to evaluate the prognostic significance of liver disease by comparing the differences between patients with no liver involvement, limited and diffuse liver involvement.Methods:We conducted a retrospective study to evaluate the clinical and laboratory findings of 271 sarcoidosis patients seen at our institution. Patients with liver sarcoidosis identified by liver biopsy were compared to patients without liver involvement for clinical features and prognosis. The biopsy sample was considered positive if it demonstrated non-caseaiting granulomas with negative fungal and mycobacterial cultures. The patients were classified into three groups according to the radiological and histopathological biopsyresults:no liver involvement; limited liverinvolvement:two sites positive; and diffuse liverinvolvement:three or more sites positive for granulomas.Results:Hepatic involvement was identified by biopsy in 81 (81/271, 29.8%) while 43 (43/271, 15.8%) patients had elevated liver function tests. Most of the patients (94.6%) had lung involvement. Other organs involved, in the order of frequency,were:lymph nodes, skin, eye, spleen and parotid gland. There was no significant difference between the three groups for forced expiratory volume in one second, forced vital capacity, total lung capacity, diffusing capacity of the lungs for carbon monoxide/alveolar volume, serum and 24-hour urinary calcium levels. Serum angiotensin-converting enzyme levels were significantly higher (p&lt;0.01) in patients with diffuse liver involvement than patients with no or limited liver disease. Progressive disease was more frequent (p&lt;0.01) in patients with diffuse liver disease. Extra-pulmonary organ involvement was significantly different between the three groups (p&lt;0.01).Conclusions:Diffuse liver involvement in sarcoidosis is a significant risk factor for progressive disease. Patients with diffuse liver disease have a worse prognosis than patients without or with limited liver involvement. Diffuse hepatic involvement in sarcoidosis is also associated with an increased incidence of extra-pulmonary organ involvement. Presence of diffuse liver disease may reveal a severe prognosis for sarcoidosis patients.

Granuloma genes in sarcoidosis

Nonnecrotizing granulomas in the affected organ are the hallmark of sarcoidosis. This review summarizes most recent genetic findings in sarcoidosis with a focus on genes that might influence granuloma formation or resolution. Specific results in multiple ethnic groups and certain clinical subphenotypes, such as extra-pulmonary organ involvement, are discussed. Associations of genetic variants in antigen-presenting molecules (HLA-DRB1) were shown to confer risk to sarcoidosis and certain disease phenotypes in populations of different ethnic origins. Specific DRB1 alleles, such as *0301 and *0302, appear to confer protection against chronic disease, but in an ethnic-specific manner illustrating the extensive genetic heterogeneity and complexity at this locus. Mechanistic studies of putative sarcoid antigens lend further credence to a role of HLA-DRB1 in disease pathogenesis. With relevance to granuloma formation, genes involved in apoptotic processes and immune cell activation were further confirmed (ANXA11 and BTNL2) in multiple ethnicities; others were newly identified (XAF1). Linking mechanism to clinical application, a TNF variant was shown to correlate with anti-TNF response in sarcoidosis patients. The investigation of known and novel risk variants for sarcoidosis and specific clinical phenotypes in various ethnicities highlights the genetic complexity of the disease. Detailed subanalysis of disease phenotypes revealed the potential for prediction of extra-pulmonary organ involvement and therapy response based on the patient's genotype.