Genome-wide search for sarcoidosis susceptibility genes in African Americans.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman-Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

Clinical characteristics of patients in a case control study of sarcoidosis.

Sarcoidosis may be affected by sex, race, and age. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled 736 patients with sarcoidosis within 6 mo of diagnosis from 10 clinical centers in the United States. Using the ACCESS sarcoidosis assessment system, we determined organ involvement for the whole group and for subgroups differentiated by sex, race, and age (less than 40 yr or 40 yr and older). The study population was heterogeneous in terms of race (53% white, 44% black), sex (64% female, 36% male), and age (46% < 40 yr old, 54% > or = 40 yr old). Women were more likely to have eye and neurologic involvement (chi(2) = 4.74, p < 0.05 and chi(2) = 4.60, p < 0.05 respectively), have erythema nodosum (chi(2) = 7.28, p < 0.01), and to be age 40 yr or over (chi(2) = 6.07, p < 0.02) whereas men were more likely to be hypercalcemic (chi(2) = 7.38, p < 0.01). Black subjects were more likely to have skin involvement other than erythema nodosum (chi(2) = 5.47, p < 0.05), and eye (chi(2) = 13.8, p < 0.0001), liver (chi(2) = 23.3, p < 0.0001), bone marrow (chi(2) = 18.8, p < 0.001), and extrathoracic lymph node involvement (chi(2) = 7.21, p < 0.01). We conclude that the initial presentation of sarcoidosis is related to sex, race, and age.

Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).

Despite reports of familial clustering of sarcoidosis, little empirical evidence exists that disease risk in family members of sarcoidosis cases is greater than that in the general population. To address this question, we estimated sarcoidosis familial relative risk using data on disease occurrence in 10,862 first- and 17,047 second-degree relatives of 706 age, sex, race, and geographically matched cases and controls who participated in the multicenter ACCESS (A Case-Control Etiology Study of Sarcoidosis) study from 1996 to 1999. Familial relative risk estimates were calculated using a logistic regression technique that accounted for the dependence between relatives. Sibs had the highest relative risk (odds ratio [OR] = 5.8; 95% confidence interval [CI] = 2.1-15.9), followed by avuncular relationships (OR = 5.7; 95% CI = 1.6-20.7), grandparents (OR = 5.2; 95% CI = 1.5-18.0), and then parents (OR = 3.8; 95% CI = 1.2-11.3). In a multivariate model fit to the parents and sibs data, the familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7 (95% CI = 2.3-9.7). White cases had a markedly higher familial relative risk compared with African-American cases (18.0 versus 2.8; p = 0.098). In summary, a significant elevated risk of sarcoidosis was observed among first- and second-degree relatives of sarcoidosis cases compared with relatives of matched control subjects.

Bronchiolitis obliterans in a patient with ulcerative colitis receiving mesalamine.

An 18-year-old woman with ulcerative colitis (UC) developed diffuse pulmonary infiltrates and hypoxemia three months after reinstitution of oral mesalamine. Lung biopsy revealed bronchiolitis obliterans with interstitial pneumonitis. Clinical and radiographic abnormalities improved upon discontinuation of mesalamine and treatment with corticosteroids. This patient presented the problem of differential diagnosis of pulmonary disease associated with inflammatory bowel disease (IBD), including lesions believed to result from lung involvement secondary to IBD, as well as adverse reactions to medications. We present and analyze evidence associating mesalamine with pulmonary toxicity in this patient, but emphasize that the distinction between adverse drug reaction and extraintestinal manifestations of IBD is difficult.

Pulmonary complications in cardiac transplant recipients.

BACKGROUND: The incidence of pulmonary complications in heart transplant recipients has not been extensively studied. We report pulmonary complications in 159 consecutive adult orthotopic heart transplantations (OHTs) performed in 157 patients. MATERIALS AND METHODS: Retrospective review of medical records. RESULTS: Forty-seven of 159 recipients (29.9%) had 81 pulmonary complications. Pneumonia was the most common (n = 27), followed by bronchitis (n = 15), pleural effusion (n = 10), pneumothorax (n = 7), prolonged respiratory failure requiring tracheotomy (n = 7), and obstructive sleep apnea syndrome (n = 6). All patients with late-onset (> 6 months after transplantation) community-acquired bacterial pneumonia presented with fever, cough, and a new lobar consolidation on the chest radiograph, and responded promptly to empiric antibiotics without undergoing an invasive diagnostic procedure. In contrast, early-onset nosocomial bacterial pneumonias carried a 33.3% mortality rate. A positive tuberculin skin test result was associated with a significantly higher rate of pulmonary complications (62.5% vs 26.8%, p = 0.007). Lung cancer and posttransplant lymphoproliferative disorder (PTLD) developed exclusively in 6 of the 61 patients (8.1%) who received induction immunosuppression with murine monoclonal antibody (OKT3). CONCLUSION: Pulmonary complications are common following heart transplantation, occurring in 29.9% of recipients, and are attributed to pneumonia of primarily bacterial origin in one half of cases. Late-onset community-acquired pneumonia carried an excellent prognosis following empiric antibiotic therapy, suggesting that in the appropriate clinical setting invasive diagnostic procedures are unnecessary. Analogous to reports in other solid-organ transplant recipients, induction therapy with OKT3 was associated with an increased incidence of lung cancer and PTLD. Overall, the development of pulmonary complications after OHT has prognostic significance given the higher mortality in this subset of patients.

Recurrent pulmonary sarcoidosis in HIV-infected patients receiving highly active antiretroviral therapy.

HIV infection and sarcoidosis occur in the same age group, but there are only a few reports of the coexistence of the two disorders in the same individual. This infrequent occurrence has been attributed to the paucity of functioning CD4(+) lymphocytes required for granuloma formation in patients with HIV infection. We report two patients with a history of remote sarcoidosis who later in life contracted HIV infection and developed recurrent, progressive pulmonary sarcoidosis while receiving highly active antiretroviral therapy (HAART). Progressive pulmonary sarcoidosis should be added to the differential diagnosis in patients receiving HAART for HIV infection who develop diffuse lung disease with recovery of CD4(+) lymphocyte population.

Depression in sarcoidosis.

Sarcoidosis, a chronic, multisystem disease, impacts quality of life and may increase depression risk. No previous study has reported the depression prevalence among U.S. sarcoid patients. This cross-sectional study examined sociodemographic and disease morbidity factors associated with depression. Patients diagnosed for > or = 1 yr and treated at one of six centers were eligible (n = 176); 154 completed a questionnaire of demographics, treatment, access to medical care, and a short-form Center for Epidemiologic Studies- Depression Scale (CES-D). The primary outcome variable was a CES-D score of > or = 9, indicating clinical depression. The prevalence of depression was 60%. Gender, income, access to medical care, dyspnea on exertion, and number of systems involved were associated with depression. Female sex, decreased access to medical care, and increased dyspnea predicted depression (odds ratio [OR] = 3.33, 11.64, and 2.78, respectively) after adjusting for race, income, and steroid therapy. Despite tertiary care access, patients reported medical care limitation. Health care providers must be sensitive to multiple barriers faced by chronic sarcoid patients; acknowledging depression risk and improving access to medical care will promote better overall health among sarcoid patients. Future studies of sarcoidosis will need to address depression diagnosis and treatment.

Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. ACCESS Research Group. A Case Control Etiologic Study of Sarcoidosis.

BACKGROUND: Sarcoidosis is a multiorgan granulomatous disease of unknown cause. Lack of an objective system for assessment of sarcoidosis to evaluate disease course and effectiveness of therapy is a major problem. METHODS: The sarcoidosis assessment instrument was developed by the Steering Committee of A Case Control Etiologic Study of Sarcoidosis (ACCESS) which included investigators at the ten ACCESS Clinical Centers, the Clinical Coordinating Center, and representatives of the National Heart, Blood, and Lung Institute. This system was developed to assess sarcoidosis organ involvement in ACCESS patients who would be followed over a two-year period. The system represents a consensus of opinions of members of the Steering Committee based on review of their experience and the medical literature. RESULTS: Criteria for involvement in patients with biopsy-confirmed sarcoidosis are presented for organs and systems that are commonly involved (lung, skin, eyes, liver, calcium metabolism), unusual but clinically important (nervous system, kidney, heart) and other sites (non-thoracic lymph nodes, bone marrow, spleen, bone/joint, ear/nose/throat, parotid/salivary glands, muscles). CONCLUSION: The proposed instrument is partially subjective in that it depends upon the clinician's diligence in pursuing evidence for sarcoidosis involvement of various organs. It is hoped that this instrument will lead to increased standardization in the definition of sarcoidosis organ involvement to help clinicians and researchers better characterize patients with sarcoidosis.

Metachronous cancers or late recurrences after resection of stage I lung cancer.

In 2 patients with stage I lung cancer, tumors recurred at their resection lines 10 years after the original surgical resections. These cases suggest that the prognosis of late cancer occurrences after resected primary lung malignancies might be related to the interval of time between primary and subsequent cancers rather than to their categorization as recurrent or metachronous cancers.

Kveim antigen: what does it tell us about causation of sarcoidosis?

This article explores the role of the Kveim-Siltzbach (KS) test in finding the cause of sarcoidosis. Experimental granulomas are formed by a T-cell mediated immunologic response to particulate agents which resist degradation and persist in tissues for prolonged periods. There is no animal model for human sarcoidosis. However, the KS test is an in vivo model of sarcoidosis. KS homogenates incite a tissue response in patients with sarcoidosis histologically identical to disease-caused granulomas. The suspensions are particulate and maintain activity when exposed to a variety of chemical and physical stresses. Studies of the monocyte and T-cell host response confirm that KS reagent provokes a sarcoidosis-like antigen driven granuloma. KS suspensions contain an antigen(s) that incite a granuloma identical with that occurring in sarcoidosis. Identification of the active principle in KS suspensions should aid in the search for the cause of sarcoidosis.

Effectiveness of cisplatin, paclitaxel, and suramin against human malignant mesothelioma xenografts in athymic nude mice.

BACKGROUND AND OBJECTIVES: Malignant mesothelioma has a poor prognosis and is refractory to many agents. The antitumor effectiveness of cisplatin, paclitaxel, and suramin as single agents and in combination was evaluated in vivo against four lines of human pleural malignant mesothelioma xenografts in athymic nude mice, including one epithelial type and three fibrosarcomatous. METHODS: After growth of tumors occurred by day 54 or 55, mice were randomized in groups of four each to receive either cisplatin 4 mg/kg intraperitoneally weekly x5, or paclitaxel (Taxol) 12.5 mg/kg subcutaneously daily 5 days/week for 3 consecutive weeks, or suramin 60 mg/kg intraperitoneally daily x4,versus controls treated with normal saline. RESULTS: Cisplatin was very effective against one line and also to a lesser degree against another line. Paclitaxel showed antitumor effects similar to cisplatin, being very effective in one line, and also showed good activity in another line. Suramin was basically inactive in all four lines. Following the results obtained with these single agents, it was decided to evaluate the combination of cisplatin and paclitaxel, which resulted in more pronounced antitumor effect in all four cell lines. CONCLUSIONS: These results indicate that the combination of cisplatin and paclitaxel is superior to each agent alone in this model, and that it deserves to be evaluated in patients with malignant mesothelioma.

Sarcoidosis and transplantation.

BACKGROUND AND AIM OF WORK: Organ transplantation is an accepted treatment for patients with end-stage organ failure. There is limited information about transplantation in patients with sarcoidosis. While there has been no systematic study of transplantation in sarcoidosis, there have been several reports of patients with sarcoidosis undergoing organ transplantation. The purpose of this review is to analyze the available literature. METHODS: We reviewed the literature regarding transplantation of kidney, liver, heart, heart-lung and lung in patients with sarcoidosis with attention to survival, complications and the incidence of recurrence of sarcoidosis in the transplanted organ and at distant sites. RESULTS: Survival and complication rates are similar to those of patients undergoing transplantation for other indications. Recurrence of pulmonary sarcoidosis has been estimated to be 47% following lung transplantation. The published cases represent a fraction of the patients reported to the International Registry maintained by the United Network of Organ Sharing (UNOS). CONCLUSIONS: Transplantation can be carried out safely in patients with sarcoidosis. Recurrence is frequent, often asymptomatic, and does not compromise graft function or patient survival. Radiographic abnormalities or symptoms associated with recurrence are responsive to increased adrenocorticosteroid therapy. Exacerbation of sarcoidosis in transplant recipients occurs in the setting of intense immunosuppression.

Sarcoidosis mythology.

BACKGROUND: Sarcoidosis continues to be shrouded by anecdotal misinformation which has gained credence by repetition. These myths have been developing for the past 50 years and continue to accumulate, despite remedial data. Among the most egregious myths are that sarcoidosis is a disease of Blacks, that the chest radiography is diagnostic of sarcoidosis, and has chronologic significance, that serum angiotensin converting enzyme and bronchoalveolar lavage are diagnostic of sarcoidosis and serve as guides to therapy, that the Kveim-Siltzbach test is not a reliable diagnostic test for sarcoidosis, that sarcoidosis is difficult to diagnose, and that sarcoidosis is tuberculosis. METHODS AND RESULTS: The literature regarding these myths has been reviewed and supported by the experience with more than 10,000 patients with sarcoidosis who have been treated at Mount Sinai Medical Center, New York. CONCLUSIONS: Sarcoidosis occurs with varying frequency among all races. The chest radiograph typical of sarcoidosis can be mimicked by other granulomatous and neoplastic diseases. The classic radiographic stages, from 0 to 111, do not reflect the time course of sarcoidosis can be made relatively easily in most patients, but its etiology is still unknown.

Sarcoidosis presenting as heart disease.

It is unusual for sarcoidosis to present with isolated cardiac involvement. We report 3 patients in whom conduction disturbances preceded other clinical or radiographic evidence of sarcoidosis, in 2 cases by several years. The literature of sarcoidosis manifesting solely with cardiac disease is reviewed. Our report is intended to emphasize consideration of sarcoidosis in the diagnostic evaluation of cardiac disease without another obvious cause, particularly in young patients with conduction disturbances, arrhythmias, or cardiomyopathy. We suggest diagnostic strategies and a therapeutic approach.

Excessive thoracic computed tomographic scanning in sarcoidosis.

BACKGROUND: The clinical value of computed tomographic (CT) scanning of the chest in the initial assessment of sarcoidosis was investigated. METHODS: One hundred consecutive patients referred to the sarcoidosis outpatient services of the Mount Sinai Medical Center, New York from 1990 to 1992 with a presumptive diagnosis of sarcoidosis were studied. The diagnosis was subsequently confirmed in all by a positive tissue biopsy sample or the Kveim-Siltzbach test. Clinical and laboratory data of each patient were reviewed. Chest radiographs were classified according to the classical stages of sarcoidosis. Thirty five of the 100 patients had a CT scan of the chest performed before presentation. The CT scans were compared with the presenting clinical data and standard chest radiographs in order to determine if they yielded useful additional information regarding diagnosis or treatment. RESULTS: The chest CT scan revealed no additional clinically relevant information compared with conventional chest radiographs in any of the 35 studies performed. In two patients mediastinal adenopathy was detected by CT scan which was not seen on standard radiographs. Two patients thought to exhibit hilar adenopathy and pulmonary infiltrations by standard radiography had no parenchymal disease on the CT scan. Bilateral parenchymal infiltrates were seen in one patient which were interpreted as unilateral infiltrates by standard radiographs. The variance between conventional radiographs and CT scans in these five patients was not clinically valuable. CONCLUSIONS: CT scans of the chest do not add clinically useful information to the standard chest radiographs in the initial assessment of sarcoidosis in patients presenting with the typical standard radiological patterns. CT scanning of the thorax is indicated in patients with proven or suspected sarcoidosis when the standard chest radiographs are normal or not typical of sarcoidosis, when signs or symptoms of upper airway obstruction are present, when the patient has haemoptysis, if there is a suspicion of a complicating second intrathoracic disease, or the patient is a candidate for lung transplantation.

Selection of oligoclonal V beta-specific T cells in the intradermal response to Kveim-Siltzbach reagent in individuals with sarcoidosis.

Sarcoidosis is a multiorgan granulomatous disorder of unknown etiology characterized by noncaseating granulomas in involved tissues. A positive Kveim-Siltzbach reaction is a granulomatous response to an intradermal injection of a suspension of sarcoid tissue extract in individuals with sarcoidosis. The protracted time course and granulomatous features of this reaction have a striking resemblance to the Mitsuda reaction in tuberculous leprosy, which suggests that the Kveim-Siltzbach reaction is a response to an unknown Ag(s). To evaluate whether this reaction is Ag-driven, an analysis of the TCR V beta repertoire in 15 Kveim-Siltzbach reaction sites was performed using a PCR technique and primers specific for 20 V beta gene families. Results of this analysis demonstrated a pattern of V beta expression dominated by expression of V beta 2, V beta 3, V beta 6, or V beta 8 to levels > 20% of total V beta gene expression in nine of 15 individuals. Analysis of paired biopsy and blood specimens revealed a preferential expression of specific V beta genes, such as V beta 3, V beta 5, and V beta 8, at sites of Kveim-Siltzbach reactions to levels four to seven times that of the corresponding peripheral blood. Sequence analysis demonstrated that preferential expression of specific V beta genes at Kveim-Siltzbach reaction sites is oligoclonal. Furthermore, the dominant V beta 8 sequence present at one of the reaction sites contained a sequence motif in the variable-diversity-joining junctional region previously identified in sarcoid lung and blood T cell populations. These results suggest that the Kveim-Siltzbach reaction is characterized by a limited TCR beta-chain repertoire consistent with an Ag-driven T cell immune response.

Cardiorespiratory responses to incremental exercise in sarcoidosis patients with normal spirometry.

Patients with sarcoidosis are known to have histologic pulmonary abnormalities despite normal lung fields or conventional pulmonary function or both. These patients permit a useful assessment of the alleged greater sensitivity of the various measurements made during incremental cardiorespiratory exercise testing. Abnormal responses on such testing may provide insight into such complaints as dyspnea in these patients. Incremental exercise testing was performed on 30 patients with biopsy-proven sarcoidosis who had normal spirometry; 13 had clear lung fields radiographically. Of these patients, the 21 who had normal single-breath diffusing capacity for carbon monoxide (Dsb; [group A]) were compared with the 9 who had decreased Dsb (group B). Half of the group A patients had excessive ventilation and 38% had increased dead space to tidal volume ratio (Vd/Vt), but frequencies of these abnormalities were greater in group B, 89 and 78%, respectively. Ventilatory response, as minute ventilation to oxygen consumption ratios ventilatory equivalents, and deadspace to tidal volume ratio (Vd/Vt) ratios were higher in group B. Widened alveolar-arterial oxygen pressure differences were seen in 7 of 9 group B patients but only 1 of 17 group A patients. This study supports the clinical impression that occult pulmonary impairment may be present in patients (in this case, sarcoidosis patients) with normal pulmonary function, and corroborates the utility of exercise testing in demonstrating such impairment. Reduction in Dsb predicted greater frequency of abnormal exercise responses, especially in oxygenation.