Serum vitamin D levels may not reflect tissue-level vitamin D in sarcoidosis.

Hypercalcemia in sarcoidosis is due to three mechanistic reasons: (1) systemic conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the enzyme 1-α hydroxylase produced by activated monocyte/macrophage system, (2) production of parathormone-related peptide (PTHrP) by the sarcoid granuloma, (3) tissue-level conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by 1-αhydroxylase produced by local monocyte/macrophage system in the sarcoid granuloma. We report two cases of one proposed mechanism of hypercalcaemia in sarcoidosis (mechanism 3). Both individuals presented with sarcoidosis and 25-hydroxyvitamin D deficiency and developed symptomatic hypercalcaemia with vitamin D replacement. Given their low serum parathormone and parathormone-related peptide levels, low serum 25-hydroxy vitamin D and normal serum 1,25-dihydroxyvitamin D, the systemic 25-hydroxy vitamin D deficiency may not have reflected an increased activity of vitamin D at the local granulomatous tissue level.

Rapid diagnosis of Mycobacterium tuberculosis infection in children using interferon-gamma release assays (IGRAs).

Diagnosis of tuberculosis (TB) in children by the tuberculin skin test (TST) poses a diagnostic challenge for physicians due to its low specificity and cross-reactivity with nontuberculous mycobacteria and bacille Calmette-Guerin (BCG). Although interferon-gamma release assays (IGRAs) have been shown as novel TST alternatives for diagnosis of latent TB infection (LTBI) in adults, their effectiveness is less clear in children. The present study examined QuantiFERON-TB Gold (QFT-G) responses and IFN-gamma production capacity of TST-positive children, younger children ≤5 years. A total of 517 children of whom 434 were TST positive ranging in age from 1 month to 18 years were evaluated by the QFT-G. Of the 517 children, 434 (84%) were TST positive, 25 (5.8%) of whom were found to be QFT-G positive and 25 (5.4%) with an indeterminate response. Of the 517 children, 355 (68.7%) were previously BCG immunized and 310/355 (87.3%) were TST positive including 18/27 (66.7%) QFT-positive children. Adequate IFN-gamma production by purified TB peptides or mitogen was observed in 92.8% of children, 29.6% of whom were <5 years. This study shows that the QFT-G assay is useful for diagnosis of LTBI. The finding of 5.8% positive QFT-G in 434 TST-positive children underscores the superior specificity of the QFT-G than the TST and its greater cost effectiveness in preventing unnecessary and potentially toxic treatment in children. The study suggests that the majority of positive TST in children represent false-positive reactions and supports the use of IGRAs for diagnosis of LTBI in children, including those <5 years of age.

Sarcoidosis: can a murine model help define a role for silica?

Both genetic and environmental factors are thought to play a role in the etiology of sarcoidosis. An association of the condition with exposure to environmental microbes has been recognized for many years, and has become stronger in the last 10-15 years with the advent of newer investigative techniques. A body of literature now is accumulating suggesting that silica may be yet another trigger in genetically predisposed persons. Impressive support for an etiologic role of mycobacteria derives from earlier studies by several investigators in Japan and in Europe and more recently from the US in Baltimore and Nashville. Other investigators have produced evidence that propionibacteria and fungi can also act as environmental triggers in sarcoidosis patients. We propose that, in an animal model that has been previously sensitized to microbial antigens, the introduction of silica through the gastrointestinal route, or intravenously, may have a granuloma-worsening effect, if the strain of animals is already predisposed to develop granulomatous disease. Here the silica may add a "second hit" to the "first hit" given by the exposure to microbial antigens.

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.

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.

A case control etiologic study of sarcoidosis: environmental and occupational risk factors.

Past research suggests that environmental factors may be associated with sarcoidosis risk. We conducted a case control study to test a priori hypotheses that environmental and occupational exposures are associated with sarcoidosis. Ten centers recruited 706 newly diagnosed patients with sarcoidosis and an equal number of age-, race-, and sex-matched control subjects. Interviewers administered questionnaires containing questions regarding occupational and nonoccupational exposures that we assessed in univariable and multivariable analyses. We observed positive associations between sarcoidosis and specific occupations (e.g., agricultural employment, odds ratio [OR] 1.46, confidence interval [CI] 1.13-1.89), exposures (e.g., insecticides at work, OR 1.52, CI 1.14-2.04, and work environments with mold/mildew exposures [environments with possible exposures to microbial bioaerosols], OR 1.61, CI 1.13-2.31). A history of ever smoking cigarettes was less frequent among cases than control subjects (OR 0.62, CI 0.50-0.77). In multivariable modeling, we observed elevated ORs for work in areas with musty odors (OR 1.62, CI 1.24-2.11) and with occupational exposure to insecticides (OR 1.61, CI 1.13-2.28), and a decreased OR related to ever smoking cigarettes (OR 0.65, CI 0.51-0.82). The study did not identify a single, predominant cause of sarcoidosis. We identified several exposures associated with sarcoidosis risk, including insecticides, agricultural employment, and microbial bioaerosols.

Two year prognosis of sarcoidosis: the ACCESS experience.

A cohort of 215 sarcoidosis patients from the ACCESS study underwent a clinical evaluation at study enrollment and two years later. Approximately 80% of subjects had an improved or stable FVC, FEV1, chest radiograph determined by Scadding stage, and dyspnea scale. African-Americans had less improvement in FVC than Caucasians (p = 0.04). Patients with erythema nodosum at presentation were more likely to have improvement in the chest radiograph at two-year follow-up (p = 0.007). Patients with a lower annual family income were more likely to worsen with respect to dyspnea (p = 0.01) and more likely to have new organ involvement at two-year follow-up (p = 0.045). The development of new organ involvement over the two year follow-up period was more common in African-Americans compared to Caucasians (p = 0.002) and more likely in those with extrapulmonary involvement at study entry (p = 0.003). There was an excellent concordance between changes in FVC and FEV1 over the two-year period. However, changes in FVC alone were inadequate to describe the change in pulmonary status of the patients, as changes in chest radiographic findings or the level of dyspnea did often but not always move in the same direction as FVC. In conclusion, data from this heterogeneous United States sarcoidosis population indicate that sarcoidosis tends to improve or remain stable over two years in the majority of patients. Several factors associated with improved or worse outcome over two years were identified.

Clinical bronchiectasis complicating pulmonary sarcoidosis: case series of seven patients.

BACKGROUND AND AIM OF WORK: It has been known for years that pathological changes of bronchiectasis may be seen on tissue examination of the lungs in pulmonary sarcoidosis. However, the clinical picture that may develop as a result of these changes has been under-appreciated. METHODS: We report seven patients with advanced stage IV pulmonary sarcoidosis in whom clinical bronchiectasis developed, seen in our university based pulmonary clinic between 1978 and 1999. RESULTS: These patients frequently exhibited symptoms and signs that are uncommon in sarcoidosis - hemoptysis, recurrent infection, lung crackles and digital clubbing. The clinical course was worse than similar stage nonbronchiectatic sarcoidosis, with more frequent infections and a higher mortality rate. CONCLUSIONS: Recognition of this subset of patients may improve management when complications arise. Therapy directed at bronchiectasis rather than aimed at suppressing putative continued sarcoidosis activity appears to be more important at this late stage of disease.