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The ultrastructural features of developing Kveim test granulomas.

The Kveim test provides a useful model for the ultrastructural study of developing epithelioid cell granulomas in man. We present a controlled prospective study in which 140 patients with possible sarcoidosis had two simultaneous Kveim tests, one being biopsed at a varying interval and the other at the usual 28 days: 52 patients showed a positive test. Controls were provided by the 88 negative tests, Kveim biopsis from 12 healthy subjects, and biopsies of normal spleen injection sites in a further 12 sarcoid patients. In all three groups the initial response (3 to 5 days) was macrophage influx. From 8 to 10 days, in developing positive tests only, mononuclear cells with abundant rough endoplasmic reticulum appeared. Mature epithelioid cells were seen at 12 to 14 days, when lymphocyte numbers and lymphocyte-histiocyte interactions were at a maximum. Epithelioid cells showed marked secretory activity; the ultrastructural features of the developing epithelioid cell vacuoles are identical to those seen in exocrine cells. Mast cells are not involved in the development of granulomas.

Granuloma

Kveim-test in patients suspected of sarcoidosis and in leprosy patients in a geographical area not yea investigated.

The Kveim-test was studied in a geographical area (São Paulo, Brazil) not yet investigated, and leprosy patients were also tested. One hundred and forty seven patients from a general hospital who had had the possibility of sarcoidosis, as a differential diagnosis, were tested with Kveim suspension. Another group of 13 patients with clinical and histological diagnosis of leprosy (10 with tuberculoid leprosy lepromin-positive and 3 with indetermined leprosy) was also tested with Kveim suspension. Sixteen Kveim-tests (10 per cent) with sarcoid granulomatous reaction revealed histologically were considered positive. Three patients with sarcoidosis for more than 3 years gave negative Kveim-test. Four patients with positive Kveim-test had respectively lymphosarcoma, Crohn's disease, lung fibrosis and concurrent tuberculosis infection. Nine positive Kveim-tests (5.6 per cent) were coincident with sarcoidosis. Thirteen leprosy patients (ten tuberculoid) gave negative Kveim-test.

Adolescent

The Kveim test: analysis of results of tests using colindale (K 12) materials.

Results of an analysis are presented of the salient clinical, pathological, and Kveim-test data of importance in the diagnostic assessment of 839 patients in whom a Kveim test was made as part of their routine clinical investigation. From these analyses the following significant observations can be made: 1) The age distribution and negative tuberculin results in patients with sarcoidosis were in keeping with the diagnosis of sarcoidosis, whereas for those in whom a diagnosis other than sarcoidosis was made, they were not. 2) The findings of 64% positive tuberculin results in cases of confirmed sarcoidosis of less than 2 yr known duration and only 39% in those of greater than 2 yr duration are closely similar to those found in international Kveim-test studies reported by Siltzbach in 1966 and Hurley and Bartholomeusz in 1971. 3) The use of the material was helpful in confirming a diagnosis of sarcoidosis in patients with extrathoracic lesions, for positive results were obtained in 33% of those with uveitis 40% of those with erythema nodosum only (findings which are in keeping with those of other studies in the United Kingdom, and 60% among 27 patients presenting with lesions in various sites, including 2 with cranial nerve lesions and one with cardiac arrhythmia. 4) We found only 2 positive reactions (less than 1%) among 221 patients in whom a diagnosis other than sarcoidosis was reached. Clearly these findings show that the Kveim test material. Lots 19 and 22, of spleen K 12 exhibited not only a high degree of reactivity and selectivity for sarcoidosis, but also that they were of considerable practical value as an aid to diagnosis. The finding of only 2(0.9%) positive Kveim tests among 221 patients with diseases other than sarcoidosis is of special interest. Of the different diseases that were ultimately diagnosed only 6 patients tested had lymphoma, only 11 had either pulmonary or lymphatic tuberculosis, and only one had Crohn's disease. Although these numbers are small, it is relevant to compare the Kveim-test data of Lots 19 and 22 of K 12 with those of Lot 5 and of Lot 14 of the same spleen. In validation studies Lot 5 yielded the expected proportion of positive reactions at different stages of sarcoidosis and a negligible proportion of positive reactions with active or quiescent pulmonary tuberculosis or among healthy subjects. However, in subsequent studies in special groups of patients, those with Crohn's disease, ulcerative colitis, or lymphatic tuberculosis, a proportion of the Kveim tests performed with these lots were positive. Within the context of the present field study, the results of these analyses confirm that the last lots of K 12 material exhibited a high degree of selectivity for sarcoidosis and that they emphasize again the practical value of the Kveim tests with suspensions that have undergone careful validation.

Adolescent

Leukocyte migration agarose test (LMAT) in sarcoidosis using Kveim test material.

The two-stage leukocyte migration agarose test (indirect LMAT), shown to be a sensitive in vitro assay for cell-mediated immunity, was used to study Kveim reactivity in vitro in patients with sarcoidosis. No Kveim-induced inhibition of leukocyte migration in agarose or Kveim-induced lymphocyte transformation in vitro was found in 23 patients with sarcoidosis, suggesting that the Kveim reaction is not an expression of cell-mediated immunity.

Adult

Counts of S-100 positive epidermal dendritic cells in Kveim test skin biopsies.

S-100 positive epidermal dendritic cells were counted in skin biopsies from 48 Kveim tests and four known foreign-body reactions. Counts in histologically positive Kveim biopsies (mean 11.3 per 200 basal cells) were significantly higher than in either negative biopsies (5.1; P less than 0.001) or foreign-body reactions (4.7; P less than 0.05). A similar difference was found, irrespective of the histological appearances, between biopsies from patients diagnosed clinically as having sarcoidosis (10.5) and those in which another diagnosis had been made (4.1; P less than 0.001). In biopsies from patients with sarcoidosis 70% had a positive Kveim test, 70% had a raised epidermal dendritic cell count and one or the other was positive in 90%. All cases in which both the Kveim test was positive and the dendritic cell count was raised had a final clinical diagnosis of sarcoidosis. Counts of S-100 positive epidermal dendritic cells are useful in differentiating positive reactions to Kveim suspension from non-specific reactions to foreign material and increase the diagnostic confidence of the Kveim test.

Cell Count

Validation and standardization of Kveim test suspensions prepared from two human sarcoid spleens.

Single lots of a Chase-Siltzbach type I Kveim test material from each of two sarcoid spleens and designated lot 5 of spleen K12 and lot 1 of spleen K13 have been validated alongside a single lot (lot 10) of a 'standard' suspension provided by Dr L. E. Siltzbach and prepared identically from the spleen of patient J (SPLEEN J) in New York. Additionally, a half-dilution of lot 5, K12, was included in this comparison. The reactivity of each suspension was assessed among patients with active and inactive sarcoidosis. The selectivity of each suspension for sarcoidosis was assessed similarly by comparison with results in patients with active and quiescent pulmonary parenchymal tuberculosis and in healthy subjects. All patients were closely matched and two Kveim tests were made in each subject according to a prearranged statistical design. The reactivity of the K12, K12 1/2 dilution, and K13 suspensions among patients with active and inactive sarcoidosis was closely similar to that with the 'standard' S10 suspension and in accordance with the expected proportions of reactions in patients at different stages of sarcoidosis. The K12, K13, and 'standard' S10 suspensions yielded a negligible proportion of positive reactions among patients with active and quiescent pulmonary tuberculosis and among healthy subjects: thus, as judged by these tests each suspension showed a high degree of selectivity for sarcoidosis. The results of this validation study are discussed in relation to the results of other studies in which lots 5 and 14 of K12 and early and late batches of a suspension prepared from another sarcoid spleen at the Commonwealth Serum Laboratories designated CSL and provided by Dr T.H. Hurley in Melbourne were employed. Using lot 5 of K12 positive reactions were found in an appreciable proportion of patients with Crohn's disease, ulcerative colitis, and tuberculous lymphadenitis. A closely similar rate of positive reactions was encountered among patients with Crohn's disease following tests with batch 0025 of CSL suspension and with another lot (lot 14) derived from spleen K12. A close concordance of results was obtained with lot 5(K12) and with batch 0042 CSL among patients with ulcerative colitis, but at a lower rate of reactivity. We conclude that positive reactions also occur in some diseases other than sarcoidosis and consider that the difficulties in determining the criteria for an acceptable test suspension become increasingly apparent as additional Kveim tests are made with one particular lot and with seqential lots of material from a 'validated' tissue source.

Adult

The Kveim test in leprosy.

The response to lepromin and Kveim antigens was compared and studied in 15 leprosy patients who were tuberculin negative. Of the 11 lepromin positive tuberculoid patients, 4 were Kveim positive, 1 was equivocal, and the rest were negative. Of the four lepromin negative lepromatous patients, one gave a positive Kveim test while the other three were negative. It has been shown that false-positive Kveim reactions are found in a higher percentage of South Indian leprosy patients than in those of other backgrounds, such as Japanese and Malaysian Chinese patients. It is also suggested that no definite relationship exists between the reaction of leprosy patients to lepromin and Kveim antigens. We further suggest that the anergy exhibited by lepromatous patients to the antigen of M. leprae is specific, as evidenced by the positive Kveim response in one lepromatous patient.

China

Reaction to Kveim test material in sarcoidosis and other diseases.

81 patients, 24 with sarcoidosis and the remainder with various other diseases, were tested with three batches of Kveim material prepared from the same spleen. Positive Kveim tests were observed in sarcoidosis, tuberculosis, Hodgkin's disease, ulcerative colitis, rheumatoid arthritis, and Weber-Christian disease. These results show that a positive Kveim reaction to the material under test was not specific to sarcoidosis.

Arthritis, Rheumatoid

[The evaluation of the Kveim test in sarcoidosis diagnostics for out-patients (author's transl)].

In a total number of 113 cases the Kveim test was performed. The antigen used was produced in the institute for pulmonary diseases and tuberculosis, Novi Sad, Yugoslavia. Patients with sarcoidosis had positive results in 65.8%, including 19.5% doubtful positive cases. In a special group of patients with sarcoidosis, who received corticosteroids at the same time, only 25.7% showed positive results. In a control group of 24 cases no positive result was observed. The Kveim test is an useful method for diagnostic purpose in out-patients. Further investigations for improvement of this method will be necessary.

Adrenal Cortex Hormones

Kveim test reactivity in Melkersson-Rosenthal syndrome (cheilitis granulomatosa).

The relation between the Melkersson-Rosenthal syndrome (MRS) and sarcoidosis is unclear. The Kveim test, a test for sarcoidosis, was performed in seven patients, two with complete and five with abortive forms of Melkersson-Rosenthal syndrome. All were found to be negative. Serum levels of angiotensin converting enzyme and calcium were normal. These facts make it unlikely that MRS is a type of sarcoidosis.

Adult

The distribution of T cell subsets of Kveim and sarcoid granulomata. An immunohistological investigation of blood, Kveim test sites and sarcoid tissue lesions from 16 patients.

T lymphocyte subsets in a positive Kveim reaction and sarcoid tissue lesions as well as peripheral blood from 16 patients with sarcoidosis were evaluated with monoclonal antibodies. The data demonstrate a redistribution of T cells from the blood to the specifically involved tissues with granulomas, i.e., sarcoid tissue lesions and positive Kveim reaction. These cells express CD2+, CD4+ phenotype as demonstrated by high CD4/CD8 ratios at the sites of positive Kveim reaction and sarcoid tissue lesions with respect to blood.

Adult