Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.

Sarcoidosis is a disease of unknown etiology characterized by noncaseating epithelioid granulomas, oligoclonal CD4(+) T cell infiltrates, and immune complex formation. To identify pathogenic antigens relevant to immune-mediated granulomatous inflammation in sarcoidosis, we used a limited proteomics approach to detect tissue antigens that were poorly soluble in neutral detergent and resistant to protease digestion, consistent with the known biochemical properties of granuloma-inducing sarcoidosis tissue extracts. Tissue antigens with these characteristics were detected with immunoglobulin (Ig)G or F(ab')(2) fragments from the sera of sarcoidosis patients in 9 of 12 (75%) sarcoidosis tissues (150-160, 80, or 60-64 kD) but only 3 of 22 (14%) control tissues (all 62-64 kD; P = 0.0006). Matrix-assisted laser desorption/ionization time of flight mass spectrometry identified Mycobacterium tuberculosis catalase-peroxidase (mKatG) as one of these tissue antigens. Protein immunoblotting using anti-mKatG monoclonal antibodies independently confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues but in none of 14 control tissues (P = 0.0037). IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 (48%) sarcoidosis patients compared with 0 of 11 (0%) purified protein derivative (PPD)(-) (P = 0.0059) and 4 of 10 (40%) PPD(+) (P = 0.7233) control subjects, suggesting that remnant mycobacterial catalase-peroxidase is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis.

"Sarcoid like" granulomatous pulmonary disease in World Trade Center disaster responders.

BACKGROUND: More than 20,000 responders have been examined through the World Trade Center (WTC) Medical Monitoring and Treatment Program since September 11, 2001. Studies on WTC firefighters have shown elevated rates of sarcoidosis. The main objective of this study was to report the incidence of "sarcoid like" granulomatous pulmonary disease in other WTC responders. METHODS: Cases of sarcoid like granulomatous pulmonary disease were identified by: patient self-report, physician report and ICD-9 codes. Each case was evaluated by three pulmonologists using the ACCESS criteria and only "definite" cases are reported. RESULTS: Thirty-eight patients were classified as "definite" cases. Six-year incidence was 192/100,000. The peak annual incidence of 54 per 100,000 person-years occurred between 9/11/2003 and 9/11/2004. Incidence in black responders was nearly double that of white responders. Low FVC was the most common spirometric abnormality. CONCLUSIONS: Sarcoid like granulomatous pulmonary disease is present among the WTC responders. While the incidence is lower than that reported among firefighters, it is higher than expected.

Pulmonary manifestations of light chain deposition disease.

Light chain deposition disease (LCDD) is a rare condition characterized by extracellular light chain deposition in tissues. Patients commonly have an underlying plasma cell dyscrasia, and produce excess levels of monoclonal light chains. Renal involvement is the most common clinical manifestation. Rarely, light chains are deposited in the lung. We present the pathologic and radiographic findings of three patients with biopsy-proven pulmonary light chain disease and a review of the literature.

Results of 188 whole-body fluorodeoxyglucose positron emission tomography scans in 137 patients with sarcoidosis.

BACKGROUND: To study the role of whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans in the identification of occult biopsy sites and reversible granulomatous disease in patients with sarcoidosis. METHODS: A retrospective review was undertaken of 188 FDG PET scans performed in 137 patients with proven sarcoidosis. All patients had given a complete medical history and undergone a physical examination, standard chest radiograph, spirometry, diffusing capacity determination, and measurement of serum angiotensin-converting enzymes levels. RESULTS: One hundred thirty-nine whole-body scans had positive findings. The most common positive sites were mediastinal lymph nodes (54 scans), extrathoracic lymph nodes (30 scans), and lung (24 scans). The standardized uptake value (SUV) ranged from 2.0 to 15.8. Twenty occult disease sites were identified. Eleven repeat scans exhibited decreased SUV with corticosteroid therapy. The positive pulmonary FDG PET scan findings occurred in two thirds of patients with radiographic stage II and III sarcoidosis. Negative pulmonary FDG PET scan findings were common in patients with radiographic stage 0, I, and IV sarcoidosis. CONCLUSIONS: Whole-body FDG PET scans are of value in identifying occult and reversible granulomas in patients with sarcoidosis. However, a positive FDG PET scan finding, by itself, is not an indication for treatment.

Comparison of sarcoidosis phenotypes among affected African-American siblings.

STUDY OBJECTIVE: To test the hypothesis that sibling pairs, who share genes and environmental exposures, might have similar phenotypic expressions of sarcoidosis beyond what would be expected by chance alone. DESIGN: Multicenter family study with study subjects recruited from 11 clinical centers. SUBJECTS: Subjects were African-American sibling pairs with sarcoidosis. Sarcoidosis and organ pattern involvement were defined according to specific criteria. Fifteen different organ systems were evaluated. RESULTS: For full-sibling pairs, ocular involvement was found in both siblings more often than expected by chance alone (p < 0.05), but the concordance was weak (kappa = 0.18). When analyzing full-sibling and half-sibling pairs, ocular and liver involvement showed a significant concordance between sibling pairs (p < 0.05), but again the agreement was poor (kappa = 0.16 for both). Concordance in pulmonary function change over time was also weak. Clinical outcomes of sibling pairs were not significantly correlated except for whether treatment was prescribed, and this level of agreement was poor (kappa = 0.14 for full-sibling and half-sibling pairs; kappa = 0.15 for full-sibling pairs only). Modeling phenotypic expression in sibling pairs using logistic regression did show that the presence of ocular and liver sarcoidosis in the first affected sibling conferred a statistically significant increased risk to the second affected sibling for having those organs involved (odds ratio [OR], 3; 95% confidence interval [CI], 1.7 to 5.4 for ocular; OR, 3.3; 95% CI, 1.5 to 7.4 for liver). CONCLUSIONS: The phenotypic features and clinical outcomes of sarcoidosis in sibling pairs show minimal concordance, with the possible exception that the presence of ocular or liver involvement in the first sibling with a diagnosis of sarcoidosis makes involvement of these organs more likely in other affected siblings.

Usefulness of programmed ventricular stimulation in predicting future arrhythmic events in patients with cardiac sarcoidosis.

The utility of programmed ventricular stimulation to predict future arrhythmic events in patients with cardiac sarcoidosis is unknown. Similarly, the long-term benefit of implantable cardioverter-defibrillators (ICDs) in cardiac sarcoidosis has not been established. Thirty-two consecutive patients with cardiac sarcoidosis underwent programmed ventricular stimulation. Patients with spontaneous or inducible sustained ventricular arrhythmias (n = 12) underwent ICD insertion. All study patients were followed for the combined arrhythmic event end point of appropriate ICD therapies or sudden death. Mean length of follow-up to sustained ventricular arrhythmia or sudden death was 32 +/- 30 months. Five of 6 patients (83%) with spontaneous sustained ventricular arrhythmias and 4 of 6 patients (67%) without spontaneous but with inducible sustained ventricular arrhythmias received appropriate ICD therapy. Two of 20 patients (10%) with neither spontaneous nor inducible sustained ventricular arrhythmias experienced sustained ventricular arrhythmias or sudden death. Programmed ventricular stimulation predicted subsequent arrhythmic events in the entire population (relative hazard 4.47, 95% confidence interval [CI] 1.30 to 15.39) and in patients who presented without spontaneous sustained ventricular arrhythmias (relative hazard 6.97, 95% CI 1.27 to 38.27). No patient with an ICD died of a primary arrhythmic event. In patients with spontaneous or inducible sustained ventricular arrhythmias, mean survival from first appropriate ICD therapy to death or cardiac transplant was 60 +/- 46 months, with only 2 patients dying or reaching transplant at study end. In conclusion, programmed ventricular stimulation identifies patients with cardiac sarcoidosis at high risk for future arrhythmic events. ICDs effectively terminate life-threatening arrhythmias in high-risk patients, with significant survival after first appropriate therapy.

Familial solitary fibrous tumor of the pleura: a case report.

This report describes the occurrence of solitary fibrous tumors of the pleura in a mother and her daughter. No other occurrence of this rare tumor in members of the same family has ever been reported.

Distinctive clinical, radiographic, and functional characteristics of patients with sarcoidosis-related pulmonary hypertension.

STUDY OBJECTIVE: To differentiate the clinical, radiographic, and physiologic profile in patients with sarcoidosis with and without pulmonary hypertension. DESIGN: Retrospective survey. SETTING: Tertiary care center. PATIENTS: One hundred six patients with sarcoidosis were classified by two-dimensional echocardiography into two groups: group 1, 54 patients with pulmonary hypertension; group 2, 52 patients without pulmonary hypertension. INTERVENTIONS: Patients underwent two-dimensional and Doppler echocardiography, chest radiography (CXR), pulmonary function testing, and arterial oxygen saturation determination, and the test results were compared between the two groups. Statistical analysis was performed using independent-sample t test and chi2 test, as appropriate; p < 0.05 was considered to be significant. RESULTS: Predicted spirometric values and lung diffusing capacity were significantly lower in patients in group 1 compared to patients in group 2: FVC, 54% vs 64% (p = 0.0065), FEV(1), 47% vs 61% (p = 0.0005), forced expiratory flow, midexpiratory phase, 35% vs 52% (p = 0.0363), and single-breath diffusing capacity of the lung for carbon monoxide (D(LCO)sb), 39% vs 54% (p = 0.0001). Sixty percent of patients in group 1 had radiographic Scadding stage 4 sarcoidosis, while no radiographic stage predominated in group 2. Arterial oxygen saturation, need for oxygen supplementation, and degree of desaturation after exercise did not differ between groups. CONCLUSIONS: The presence of pulmonary hypertension in patients with sarcoidosis is associated with higher prevalence of stage 4 sarcoidosis by CXR and lower predicted spirometric and D(LCO)sb measurements.

Pleural involvement in chronic sarcoidosis detected by thoracic CT scanning.

BACKGROUND AND AIM: 5-10% of patients with sarcoidosis exhibit pleural involvement by standard chest radiograph (CXR) usually associated with chronic advanced lung disease. The frequency of pleural disease in sarcoidosis by chest CT scan is unknown. This study compared pleural involvement by standard CXR with thoracic CT scan and assessed the impact of pleural involvement on pulmonary function tests (PFT) in patients. METHODS: The records of 61 consecutive patients seen in the Sarcoidosis Service at Mount Sinai Hospital who had thoracic CT scan, standard CXR, and recent PFT were reviewed. RESULTS: 25 of the 61 patients (41%) had pleural involvement by CT (20 thickening, 5 effusions), compared to 7 (11%) by standard CXR (3 thickening, 4 effusions). Bilateral pleural thickening was more commonly seen in patients with CT evidence of parenchymal fibrosis. On univariate analysis, CT evidence of parenchymal fibrosis and CT pleural thickening were significantly associated with an increased odds of restrictive PFTs, ORs of 7.49 (CI 1.7-31.8) and 4.1 (CI 1.32-12.7), respectively. The association between CT pleural thickening and restrictive PFTs lost significance when adjusted for the confounding effect of parenchymal fibrosis. Restrictive physiology was associated with CT evidence of parenchymal fibrosis even when adjusted for pleural thickening (OR = 5.35 CI = 1.18-24.2). CONCLUSION: Sarcoidal pleural involvement as detected by CT scan is much more common than by CXR and is associated with restrictive pulmonary dysfunction. Pleural thickening was also associated with CT evidence of pulmonary fibrosis but not restrictive physiology when adjusted for parenchymal scarring.

The spectrum of biopsy sites for the diagnosis of sarcoidosis.

BACKGROUND: The diagnosis of sarcoidosis is most secure when supported by a tissue biopsy exhibiting noncaseating epithelioid granulomas with absence of known granulomagenic agents in a patient with multi-organ disease. Clinicians must decide which site offers the best chance of achieving a diagnostic biopsy with the least patient risk and discomfort. METHODS: 736 cases were enrolled in the NHLBI supported A Case Controlled Etiologic Study of Sarcoidosis (ACCESS) from November 1996 to June 1999. All cases required diagnostic organ biopsy (Bx) exhibiting non-caseating epithelioid granulomas without identifiable granulomagenic agent, within six months of recruitment. Positive Kveim-Siltzbach test was accepted in patients with Löfgren's syndrome. Bx sites were correlated with demographic data, chest radiographic stages, symptoms, pulmonary function and associated organ involvement. RESULTS: Seven hundred and seventy-six diagnostic biopsies were performed. Five hundred and sixty-seven were intrathoracic, 198 extrathoracic. Eleven Kveim tests were positive. When cutaneous sarcoidosis or an enlarged extrathoracic lymph node was present, skin or lymph node Bx was the preferred procedure. Twenty-three different organs yielded diagnostic biopsies. CONCLUSIONS: Biopsy diagnosis in sarcoidosis is almost always easily obtained. As shown by ACCESS, sarcoidosis offers a wide spectrum of diagnostic biopsy sites. The choice for biopsy is influenced by the presenting clinical constellation of organ involvement and the ease and safety of the biopsy procedure.

A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study.

BACKGROUND: Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the United States of America, African Americans have a higher sarcoidosis incidence and suffer greater morbidity than Caucasians. METHODS: A sarcoidosis genetic linkage study consortium was established to recruit African-American affected sib pair (ASP) families to identify chromosomal regions that may harbor sarcoidosis susceptibility genes and to determine if environmental factors modify any genetic effects. RESULTS: We successfully met our goal of enrolling 359 ASPs using a multifaceted recruitment approach. In the total 559 sib pairs that were enrolled, genetic analyses revealed incorrectly specified relationships that required reclassification or removal from the analysis dataset of 10.4% of reported full and 1.4% of reported half sib pairs. The final study sample comprised 415 full and 104 half sib pairs with complete data. This included 338 ASPs. Within sib pairs, affection status was not associated with sex. Only 15 per cent of the 229 families had three or more affected sibs, but they contributed 42 per cent of the ASP total. CONCLUSIONS: The SAGA study experience should provide useful lessons and information to serve others in conducting genetic studies of complex diseases in African-American families.

Pulmonary and psychosocial findings at enrollment in the ACCESS study.

AIM: To assess lung involvement and the association of demographic and psychosocial factors with respiratory health in 736 persons with sarcoidosis at enrollment in A Case Control Etiologic Study of Sarcoidosis (ACCESS). METHODS: 736 patients with biopsy diagnosis of sarcoidosis within 6 months of enrollment were studied at 10 US centers. Lung involvement was evaluated by chest radiography, spirometry and dyspnea questionnaire. Demographics, number of involved extrathoracic organ systems, comorbidities, and health-related quality of life (HRQL) were assessed. RESULTS: 95% of patients had lung involvement. 8% were Scadding Stage 0, 40% I, 37% II, 10% III, and 5% IV 51% reported dyspnea. Increasing radiographic lung stage was associated with decreasing Forced Vital Capacity (FVC) (p < 0.01). Patients with higher stages had more airways obstruction and dyspnea. 46% of cases and 27% of controls had Center for Epidemiologic Studies Depression Scale (CES-D) scores of 9 or greater, (p < 0.001). Age > or = 40, African-American race, body mass index > or = 30kg/m2, and CES-D scores > 9 were associated with decreased FVC and greater dyspnea. Impaired spirometry and greater dyspnea were associated with poorer quality of life. CONCLUSION: A "global" approach to the sarcoidosis patient, including careful assessment of dyspnea and health related quality of life, as well as of lung function and radiographic changes, and any extrathoracic involvement, is important, not only in management of the individual patient, but should also prove beneficial in assessing outcomes in clinical trials in the future.

Job and industry classifications associated with sarcoidosis in A Case-Control Etiologic Study of Sarcoidosis (ACCESS).

OBJECTIVES: To determine whether specific occupations and industries may be associated with sarcoidosis. METHODS: A Case Control Etiologic Study of Sarcoidosis (ACCESS) obtained occupational and environmental histories on 706 newly diagnosed sarcoidosis cases and matched controls. We used Standard Industrial Classification (SIC) and Standard Occupational Classification (SOC) to assess occupational contributions to sarcoidosis risk. RESULTS: Univariable analysis identified elevated risk of sarcoidosis for workers with industrial organic dust exposures, especially in Caucasian workers. Workers for suppliers of building materials, hardware, and gardening materials were at an increased risk of sarcoidosis as were educators. Work providing childcare was negatively associated with sarcoidosis risk. Jobs with metal dust or metal fume exposures were negatively associated with sarcoidosis risk, especially in Caucasian workers. CONCLUSIONS: In this study, we found that exposures in particular occupational settings may contribute to sarcoidosis risk.

Recovery of cell wall-deficient organisms from blood does not distinguish between patients with sarcoidosis and control subjects.

STUDY OBJECTIVE: To determine if cell wall-deficient forms (CWDF) of mycobacteria can be grown in culture of blood from subjects with sarcoidosis. DESIGN: A special multicenter study of sarcoidosis (A Case Control Etiologic Study of Sarcoidosis), supported by the National Heart, Lung, and Blood Institute. PATIENTS AND CONTROL SUBJECTS: PATIENTS AND CONTROL SUBJECTS were recruited at 10 institutions in the United States. Control subjects (controls) were of the same gender and race, and within 5 years of age as matching patients with sarcoidosis (cases). RESULTS: Cultures were incubated from 347 blood specimens (197 cases, 150 controls). Two investigators trained to recognize CWDF mycobacteria examined material obtained from culture tubes after 3 weeks. Structures thought to be CWDF were seen with equal frequency in cases (38%) and controls (41%). Thirty-nine percent of cases and 37% of controls were read as negative for CWDF. CONCLUSION: This study fails to confirm earlier reports that CWDF mycobacteria can be grown from the blood of patients with sarcoidosis, but not from control subjects.

Thalidomide for chronic sarcoidosis.

STUDY OBJECTIVES: Thalidomide therapy has been shown to modify granulomatous diseases, such as tuberculosis and leprosy. Lupus pernio is a skin manifestation of sarcoidosis that does not remit spontaneously, and was used as a marker of efficacy of thalidomide for sarcoidosis. DESIGN: An open-label, dose-escalation trial of thalidomide. SETTING: Patients were seen at one of four specialized sarcoidosis clinics in the United States. PATIENTS: Fifteen patients with lupus pernio and other manifestations of sarcoidosis unresponsive to prior therapy were enrolled. INTERVENTIONS: Skin lesions were assessed with visual examination by the treating physician, and photographic evaluation by a blinded panel of physicians reviewing photographs of the lesions before and after therapy. MEASUREMENTS AND RESULTS: Fourteen patients completed 4 months of therapy. All patients experienced some improvement in their skin lesions subjectively, and 10 of 12 evaluable patients showed improvement using photograph scoring. Five patients were better after 1 month (treated with 50 mg/d of thalidomide), seven more patients improved after 2 months (treated with 100 mg/d of thalidomide in the second month), and two patients required an additional month of 200 mg of thalidomide to achieve a response. Patients reported increased somnolence (n = 9), numbness (n = 7), dizziness (n = 2), constipation (n = 6), rash (n = 1), and increasing shortness of breath (n = 1). One patient discontinued therapy because of new-onset dyspnea, due to probably unrelated new-onset congestive heart failure. CONCLUSION: Thalidomide was an effective form of treatment for chronic cutaneous sarcoidosis. The drug was well tolerated and may be a useful alternative to systemic corticosteroids.

The diagnostic pathway to sarcoidosis.

PURPOSE: To examine the time from the first physician visit to the diagnosis of sarcoidosis. HYPOTHESES: The time required to diagnose sarcoidosis is dependent on the initial symptoms, socioeconomic status, referral to a specialist, race, and severity of pulmonary involvement. METHODS: Patients were recruited from the Case Control Etiology of Sarcoidosis Study (ACCESS) and had biopsy-confirmed sarcoidosis. Subjects were asked to recall the date of onset of symptoms of sarcoidosis, their first physician visit, number of physician visits, and types of physicians seen. RESULTS: One hundred eighty-nine patients were enrolled. The diagnosis of sarcoidosis was made on the first physician visit in only 15.3% of cases. The presence of pulmonary symptoms was associated with prolonged time (> 6 months vs < or = 6 months, p = 0.02) until diagnosis, and the presence of skin symptoms with a shorter time (< or = 6 months vs > 6 months, p = 0.02) until diagnosis. Patients with pulmonary symptoms had more physician visits (mean +/- SEM) until the diagnosis was made compared to those without pulmonary symptoms (4.84 +/- 0.38 visits vs 3.15 +/- 0.24 visits, p = 0.0002). The mean baseline FEV(1) was greater in those diagnosed < or = 6 months from the first physician visit than those diagnosed > 6 months (87.3 +/- 1.52% predicted vs 81.2 +/- 2.5% predicted, p = 0.04). There was a significant delay in diagnosis (> 6 months vs < or = 6 months) from first physician visit with higher Scadding stages (stage 4 vs stage 2, or stage 3 vs stage 0 or 1, p = 0.04). CONCLUSIONS: The diagnosis of sarcoidosis is often delayed and seems to be more a factor of disease presentation than patient or physician characteristics. The presence of pulmonary symptoms or higher radiographic stages is associated with a prolonged time until diagnosis. The presence of skin symptoms is associated with less delay in diagnosis. It is likely that the delay in diagnosis of pulmonary sarcoidosis relates to the fact that pulmonary symptoms and parenchymal involvement are nonspecific and are often regarded as manifestations of other pulmonary diseases.

Donor-acquired sarcoidosis.

"Donor-acquired sarcoidosis" is defined as the development of sarcoidosis in presumably naïve (non-sarcoidosis) transplant recipients who have received tissues or organs from donors who were not known or suspected to have active sarcoidosis. In reviewing the literature up until September of 1999, we found four publications describing a total of eight organs or tissues donated by subjects with sarcoidosis. These are the basis for this review. We draw upon these cases to discuss etiologic considerations for sarcoidosis, and suggest that donor-acquired sarcoidosis strengthens the view that sarcoidosis is caused by a transmissible agent, perhaps of infectious origin. Since not all recipients of organs from donors with active sarcoidosis develop sarcoidosis, host factors also appear to be important in disease pathogenesis. Less credence is ultimately given to external or environmental factors. Issues underlying host tolerance as a possible explanation for the reported absence of mortality or loss of allograft function during the limited periods of observation are also discussed.