Kveim Test Research Articles

Diagnostic yield of the Kveim test in sarcoidosis patients.

Sarcoidosis is a granulomatous disorder of unknown etiology characterized by the existence of non-caseating granulomatous inflammation. Diagnosis can be challenging due to the presence of comprehensive clinical, laboratory, and radiologic manifestations. We have evaluated the diagnostic yield of the Kveim test and compared this test with the other conventional laboratory modalities. Our aim was to reach the highest level of diagnostic confidence acknowledging the absolute uncertainty in diagnosis with the current diagnostic enterprises. Medical records of 300 sarcoidosis patients were reviewed. Patients were classified into two categories as the conventional laboratory and the Kveim test group to compare the diagnostic yield. Sensitivity of the Kveim test was 76.4% while the conventional laboratory tests provided a 64% diagnostic yield. The conventional tests had a low diagnostic rate in the early disease stages. Kveim test revealed a high yield diagnosis for all stages of sarcoidosis. Integrated assessment of the two modalities reached a 96.8% sensitivity and a 94,6% specificity. Conventional laboratory modalities were useful for the assessment of disease activity and identification of organ involvement. Kveim test revealed a significant diagnostic yield for all stages of sarcoidosis. The lowest output was achieved in stage IV patients due to the waning of active granulomatous inflammation. The highest diagnostic sensitivity was obtained by an integrated analysis of the conventional laboratory and the Kveim test results for all aspects of sarcoidosis.

308. Revisiting Association Between Systemic Sclerosis and Sarcoidosis: Prevalence and Clinical Features

We identified a sub-cohort of 827 patients. From these, 11 patients (1.33%) were found to have both SSc and sarcoidosis. The median age was 63.0 11.2 (years SD). The majority of patients (63.7%) were Caucasians. The diagnosis of sarcoidosis preceded SSc in 7 patients and was contemporaneous in one patient. The median interval for diagnosis between the two diseases was 14.0 11.4 years. All patients, but one, were anti-nuclear antibodies (ANA) positive with homogenous pattern identified in 5 patients (45.5%) and centromere pattern in 4 (36.4%). Extra-nuclear antibodies (ENA) were positive in 5 patients, mainly anti-Scl70 (36.4%). Sarcoidosis was biopsy proven in 6 patients, one had a positive Kveim test and 4 were considered to have sarcoidosis based on clinical features and supportive investigations. Five patients had single-organ involvement related to sarcoidosis (lung, lacrimal gland, lymph nodes). Interstitial lung disease (ILD) was present in 5 patients (45.5%), a majority of these harboured anti-Scl70 antibodies. 40% of these had radiological changes attributable to both diseases and the remaining 3 patients had changes related to SSc or sarcoidosis alone. Three of the patients with ILD required immunosuppression. Apart from two patients who developed pulmonary arterial hypertension and one with suspected cardiac sarcoidosis, no other major organ involvement was documented.

Seasonality of the onset of symptoms, Tuberculin test anergy and Kveim positive reaction in a large cohort of patients with sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown aetiology and pathogenesis. This study evaluated the seasonal variation in the onset of symptoms, Tuberculin anergy and Kveim positive reaction in a cohort of 492 patients with sarcoidosis and in a subgroup of 248 patients with known Kveim test responses. The medical records of 492 patients with sarcoidosis were retrospectively reviewed. Roger's test for cyclic variation was used to assess the statistical significance of the observed seasonal variation. For all sarcoidosis patients (n = 492) the onset of symptoms was most frequent in spring (61.8%) and least frequent in summer (31.7%) (P < 0.001). For patients with Tuberculin anergy (n = 364) the onset of symptoms was most frequent in spring and least frequent in autumn (P < 0.001); there was no seasonal variation among Tuberculin positive patients (n = 128). Of those patients with a Kveim test result (n = 248), the onset of symptoms was most frequent in spring and least frequent in summer (P < 0.001); there was no seasonal variation for patients with a negative Kveim results (n = 50 patients). The onset of the symptoms was most frequent in spring and least frequent in the second half of the year (summer or autumn) in patients with sarcoidosis, Tuberculin anergy and a positive Kveim reaction. The significance of this finding in relation to aetiology and clinical utility needs to be further assessed.

Isolated neurosarcoidosis presenting as headache and multiple brain and spinal cord lesions mimicking central nervous system metastases

Sarcoidosis is uncommon in children. Although isolated neurosarcoidosis has been seen in 15% adults with sarcoidosis, pediatric neurosarcoidosis is rarely reported. Neurosarcoidosis may present with cranial neuropathy, including facial palsy, optic nerve or other cranial nerve involvement, peripheral neuropathy, or manifestations of the central nervous system affecting the hypothalamus, pituitary gland, cerebral cortex, cerebellum, meninges, and spinal cord. The useful diagnostic investigations include magnetic resonance imaging of the brain and spinal cord, cerebrospinal fluid studies, brain and meningeal biopsy if feasible, chest radiography to reveal sarcoidosis, angiotensin-converting enzyme level in the serum or cerebrospinal fluid, and Kveim test when available. We herein report a case of isolated brain biopsy-confirmed neurosarcoidosis in a 17-year-old boy presenting with severe unilateral headache and multiple brain and spinal cord MRI lesions mimicking central nervous system metastases.

Merkel cell carcinoma in a patient with chronic sarcoidosis

In 1983 a 75‐year‐old woman presented with epistaxis and nasal crusting. She had nasal bridge depression, nasal septal erosion and a 3‐cm indurated, violaceous plaque on her neck. Haemoglobin was 10.6 g/dL; normal indices. Erythrocyte sedimentation rate was 47 mm/h. Calcium and autoimmune screen, including ANCA were normal. CT scan of sinuses demonstrated mucosal thickening in the right antrum and medial wall thinning. Chest X‐ray was clear. Antral and bronchial mucosa biopsies showed noncaseating granulomata. The neck lesion biopsy showed dermal caseating granulomata. Fungal and Ziel‐‐Nielson stains were negative as were cultures for acid fast bacilli from skin, sputum and bronchial aspirate. Mantoux test (1 : 1000) was positive. Kveim test was negative. An initial diagnosis of tuberculosis was treated unsuccessfully with triple therapy. Six months later, repeat chest X‐ray and CT scan revealed extensive interstitial shadowing of lung fields. A gallium 67 isotope lung scan showed uptake of gallium throughout the lung fields and the lacrimal gland. Pulmonary function tests showed a restrictive pattern. Bronchial biopsy showed noncaseating granulomata. Repeat Mantoux tests were negative. Angiotensin converting enzyme was 109 µ/L (normal range, 27–100 µ/L). Sarcoidosis was diagnosed and prednisolone 60 mg commenced. Over the next year there was marked clinical and radiological improvement. Prednisolone was stopped 2 years later. Nasal and pulmonary disease remained quiescent. Cutaneous lesions persisted.

Experimental Skin Sarcoidosis In A Doctor Volunteer

Scientists couldn't discover the causative agent of sarcoidosis for more than a hundred years. A biopsy of lung taken from a patient with sarcoidosis [Lofgren syndrome] was used to isolate the erythrocyte-like microorganisms [ELM] on human blood agar. It took 5 months of incubation at 37°C and a doctor volunteer producing an experimental sarcoidosis in his skin. The autoinfection resulted in typical sarcoid granulomas and a positive Kveim test 2 years later. It took two auto-infections in 7 days intervals with a suspension of the new microorganism containing 1 million CFU. The sarcoidosis granulomas in the skin biopsy specimens were confirmed by four professors in medicine and the biopsies as well as the ELM cultures were at disposal of every specialist interested in PCR in sarcoidosis and in Crohn's diseases.

Peripheral anergy and local immune hyperactivation in sarcoidosis: a paradox or birds of a feather

Sarcoidosis is a multisystem non-caseating granulomatous disorder, which is frequently self-limiting. Not only does its aetiology remain an enigma, but equally curious is its immunological background, which appears to be pathognomonic for this disease. Studies have shown aberrant cell-mediated active, if not overactive, immune responses at sites of inflammation [1] in the presence of hypergammaglobulinaemia [2] and cutaneous anergy to particular antigens, including tuberculoprotein but not Kveim antigen [3]. This apparent paradox in peripheral and local cellular immune responses, with preferential activation at the organ level, has provoked a great deal of interest over the years, and begged the question of whether the proposed depression in peripheral cellmediated immunity in sarcoidosis is in fact real or apparent. The accumulation of activated oligoclonal CD4 T lymphocytes [4] and specific subpopulations of macrophages [5,6], together with a release of various proinflammatory cytokines [7], determine the immune phenomena as well as the development and fate of granulomata at the sites of sarcoid inflammation. The recruitment of CD4 T lymphocytes around granulomata is more prominent within fresh active lesions, and tends to diminish as the granulomata mature [8]. Indeed, as lesions become less active, these cell types decrease, and T cells expressing CD8 surface antigens predominate [8]. A similar switch in immunoregulatory T cells has also been observed in animal models of granulomatous lung disease [9,10]. In patients with active sarcoidosis, the increase in activated T cell numbers at sites of granulomatous inflammation is simultaneously accompanied by an absolute decrease in the number of circulating T cells in autologous peripheral blood. One of the earliest immunological abnormalities to be observed in active sarcoidosis is a partial to complete anergy to tuberculin purified protein derivative (PPD). Such skin anergy also extends to certain antigens, e.g. Trichophyton, mumps virus, streptokinase/ streptodornase, Candida, as well as dinitrochlorobenzene. The incidence of anergy to tuberculoprotein and other antigens in sarcoid patients varies from 30% to 70%, depending on the number of antigens used [3,11,12]. This anergy appears to parallel disease severity, being especially marked when the sarcoidosis is clinically active, and disappearing months to years after resolution of the disease. Usually such cutaneous anergy is associated with depressed cellular immunity. The partial cutaneous anergy observed in sarcoidosis is frequently attributed to a reduction in the number and function of circulating T lymphocytes [13]. It has been suggested that the reduction of delayed-type skin test reactivity could reflect a depletion of the population of immunoreactive cells being sampled from the skin. It is recognized that in granulomatous disease there is an altered circulating pattern for T lymphocytes with the onset of inflammation. In particular, CD4 T cells become sequestrated in central lymphoid organs and sites of inflammation, leaving proportionately increased numbers of CD8 T cells in the peripheral blood [14]. In sarcoid patients, the ratio of CD4 to CD8 T cells in the blood may be normal or slightly decreased, with corresponding T cell ratio in the lung being 4–10 times greater than normal [15]. At the height of inflammation, the compartmentalized CD4 T cells have been shown to express IL-2R, very late activation Ag1, and DR class II MHC molecules: the hallmarks of antigenstimulated T cells [16,17]. In addition, it appears that these CD4 T lymphocytes are oligoclonal, consistent with a conventional antigen-driven process [18,19] (albeit the nature of the antigenic stimulus in sarcoidosis remains unclear). However, whilst T cells obtained from inflamed sites appear to be activated both morphologically and functionally, with augmented responses to external stimuli such as lectins and antigens, the functional response of autologous peripheral blood lymphocytes to mitogen and recall antigen is impaired, with consequent depression of B cell function in vitro. In addition, inhibitory factors, partly derived from monocytes, have been isolated from the blood of active sarcoid patients, and shown to inhibit the in vitro response of normal lymphocytes to mitogens and antigens [13,20,21]. Such findings in the peripheral blood have been related to the observed depression in certain cutaneous delayed hypersensitivity responses [13,22]. Despite this apparent cutaneous anergy, patients with sarcoidosis are uniquely capable of mounting a positive cutaneous reaction to a Kveim antigen. The mechanisms of this Kveim response are not entirely clear. Although Kveim test lesions exhibit histopathologic similarities to sarcoid granulomata, there are marked differences between the Kveim reaction and the classic DTH skin response. The most obvious difference is in the kinetics of the two reactions. DTH reaction begins at 8 h, peaks at 24–48 h, and resolves by 96–120 h. By contrast, the Kveim reaction takes 4–6 weeks to develop. Furthermore, no specific antigen in the Kveim preparation has been identified as the inducing agent in this response, and no convincing data have been generated to show reproducibly that sarcoid lymphocytes are actively sensitized to the Clin Exp Immunol 1997; 110:1–3

Etiology of Sarcoidosis: the Role of Propionibacterium acnes

Sarcoidosis, of unknown etiology, may result from exposure of a genetically susceptible subject to a specific environmental agent(s), possibly an infectious one, although none has been identified. Propionibacterium acnes is so far the only bacterium to be isolated from sarcoid lesions. Genomes of P. acnes have been detected in large numbers in sarcoid lymph nodes by the quantitative polymerase chain reaction. By in situ hybridization, P. acnes genomes were found in sarcoid lymph nodes in and around sarcoid granulomas. These results point to an etiological link between P. acnes and some cases of sarcoidosis. Host factors may be more critical than agent factors in the etiology of sarcoidosis, as already suggested from the phenomenon of the Kveim test, in which a suspension of sarcoid tissues injected intracutaneously causes sarcoid granulomas in patients with sarcoidosis but not in healthy people or patients with other diseases. A recombinant trigger-factor protein, RP35, from P. acnes causes a cellular immune response in some patients with sarcoidosis, but not in subjects without sarcoidosis. RP35 caused pulmonary granulomas in mice sensitized with the protein and adjuvant. Sarcoid granulomas may form during hypersensitivity to antigens of P. acnes indigenous to or proliferating in the affected organ.

The relationship between the tuberculin test and the Kveim test in sarcoidosis in Ireland

The aim of this study was to correlate tuberculin reactivity with the Kveim test in sarcoidosis. Case records 1983-91 inclusive, of those patients with positive Kveim tests and recorded tuberculin tests in an acute regional general hospital serving south-west Ireland (counties Cork and Kerry) were reviewed. Of 39 patients with positive Kveim tests 28 (72%) were tuberculin negative to a test dose of 10 tuberculin units or more. The group was slightly though significantly younger (p < 0.05) in age than the corresponding group (n = 11; 28%) with positive tuberculin tests. The incidence of tuberculin reactivity in the presence of Kveim reaction is higher than that expected for sarcoidosis. Corresponding studies in Britain and Scandinavia show a considerably lower tuberculin positive rate, which may be due to a lower prevalence of tuberculosis in these countries. However the younger age of the tuberculin negative group in our study may reflect a continuing decline in tuberculosis prevalence in south-west Ireland.

Asystolic arrest as a presentation of sarcoidosis

A 41-year-old man who presented with a history of sudden loss of consciousness suffered two further episodes during which asystole was documented. Subsequent investigations included exercise stress testing, thallium scintigraphy, electrophysiological studies, CT-scan of chest, Kveim test and a gallium-67 scan, which led to a presumptive diagnosis of averted sudden death as a first presentation of sarcoidosis with primary cardiac involvement.

Positive Kveim Test in Patients with Coexisting Sarcoidosis and Human Immunodeficiency Virus Infection

We present two cases of sarcoidosis complicated by HIV infection. Each case had a different level of sarcoidosis activity and coexisted with either an AIDS-related infection or a HIV-positive state. Manifestations of sarcoidosis were not apparent in the patient with the AIDS-defining opportunistic infection, but were active in the patient with asymptomatic HIV infection. Both patients had granulomatous reactions to Kveim antigen, and one had such a reaction following an AIDS-defining infection. These findings suggest that non-T-cell mechanisms may be involved in granuloma formation in sarcoidosis.

Seminoma or sarcoid?

A 33-year-old man subsequently diagnosed as having sarcoidosis presented with the clinical features of a testicular tumour with metastatic spread to para-aortic lymph nodes. Histological examination of the testis and para-aortic lymph node biopsy showed florid granulomatous change and a Kveim test was positive. This is a previously unreported presentation of sarcoidosis and emphasizes that histological confirmation of malignancy is essential prior to institution of cytotoxic therapy.

Gamma/Delta T-Lymphocytes Are Not Increased in Number in Granulomatous Lesions of Patients with Tuberculosis or Sarcoidosis

gamma delta T-lymphocytes have been suggested to play a role in granuloma formation and to participate in the immune responses observed in tuberculosis and sarcoidosis. To further evaluate the role of gamma delta T-lymphocytes in these disorders, we used immunohistochemical techniques and specific monoclonal antibodies to characterize the number of distribution of T-lymphocytes expressing alpha beta and gamma delta T-cell receptors in granulomatous lesions from patients with sarcoidosis (n = 8) or tuberculosis (n = 4). The vast majority of T-lymphocytes present in lymph nodes from patients with tuberculosis or sarcoidosis expressed alpha beta TCR, whereas only rare gamma delta T-lymphocytes were observed inside or at the periphery of the granulomas. Recently formed granulomas induced by positive Kveim test reactions in patients with sarcoidosis also contained only small numbers of gamma delta T-lymphocytes, including those present in biopsies from two patients with increased numbers of circulating gamma delta T-lymphocytes. These observations demonstrate that T-cells involved in immune granulomatous reactions in sarcoidosis and tuberculosis express predominantly alpha beta TCR, and they do not support the conclusion that gamma delta T-lymphocytes necessarily play an important role in granuloma formation.

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.

Observations on the Kveim reaction using an animal model of granulomatous bowel disease.

Striking differences were observed between the visceral and cutaneous responses after tests with validated Kveim and normal spleen suspensions in a guinea pig model of granulomatous bowel disease. Five of six animals sensitised with BCG showed positive responses at the ileal Kveim test site whereas all six had negative cutaneous Kveim tests. Conversely, two of six animals sensitised with irradiated Mycobacterium leprae showed positive cutaneous Kveim tests and only one a positive response in the ascending colon. All six showed negative responses at the ileal Kveim test site. No positive visceral or cutaneous responses were observed in either group of animals after tests with normal spleen suspension. These findings are discussed in relation to the positive Kveim responses previously reported among patients with Crohn's disease, tuberculoid and lepromatous leprosy, and among seemingly healthy BCG vaccinated subjects. The findings provide further evidence in support of a possible mycobacterial aetiology for sarcoidosis and Crohn's disease.

Spinal cord sarcoidosis with intramedullary cyst formation

We report a case of spinal cord sarcoidosis with surgically confirmed localized cyst formation and probably syringomyelia involving almost the entire spinal cord, an association which has not been documented previously. The magnetic resonance (MR) findings before and after gadolinium diethylenetriamine-pentaacetic acid (Gd-DTPA) are described. There has been only one previous report of the MR findings in histologically confirmed spinal cord sarcoidosis, and in this case Gd-DTPA was not given. A 49-year-old man presented with a 3-week history of progressive urinary hesitancy and weakness of both legs. Three years previously he was diagnosed as having sarcoidosis on the basis of bilateral hilar adenopathy on plain chest radiography, and a positive Kveim test. Ten months before this admission he had developed granulomatous uveitis. On initial examination there was moderate reduction of muscle power in all four limbs, whilst tone and co-ordination were normal. Reflexes were generally brisk, abdominal reflexes were absent, and there were bilateral extensor plantar responses. Vibration and joint position sensation were absent bilaterally in his feet, and there was a spinothalamic sensory level at C8 on the right and D6 on the left.

Positive kveim reaction in eosinophilic pneumonia

The Kveim test is generally regarded as highly specific for sarcoidosis. We report two patients with pulmonary eosinophilia who had positive Kveim reactions. This association has not been previously reported.

Upper respiratory tract involvement in sarcoidosis and its management

Of some 750 sarcoidosis patients, 27 were found to have involvement of their nasal mucosa. Most had multisystem disease, which was usually chronic. Nasal stuffiness or blockage and crusting were the major symptoms, and were usually present at the first presentation with sarcoidosis. The larynx was involved in five cases. The Kveim test was positive in twelve of the fourteen patients in whom it was performed, serum angiotensin converting enzyme was frequently elevated and sinus radiographs were often abnormal. Topical medication improved symptoms in some patients, but the majority required systemic corticosteroids. It was possible to withdraw medication completely after seven years in only one patient. Relapse was encountered during reduction of dosage in other patients. Random biopsy of macroscopically normal nasal mucosa did not yield histological support for a diagnosis of sarcoidosis in twelve out of thirteen patients, but upper respiratory tract lymphoid tissue may contain granulomas in patients with sarcoidosis.

Rentabilité des prélèvements histologiques au cours de la sarcoïdose: Analyse rétrospective multicentrique de 618 biopsies pratiquées chez 416 malades

The diagnosis of sarcoidosis is based on the finding of an epithelioid granuloma at histological examination. A retrospective study of 618 biopsies obtained from 416 patients with sarcoid disease showed an average sensitivity of 69 p. 100. The sensitivity of guided biopsies, especially skin and lymph node biopsies, was almost 90 p. 100, whereas that of blind biopsies tended to increase with the degree of hazard involved, ranging from 49 p. 100 in proximal bronchial biopsy to 70 p. 100 in liver needle biopsy. When treatment is not urgently required, the Kveim test is safe, cheap and fairly sensitive (65 p. 100 positive results).

Cutaneous sarcoidosis in Caucasians

One hundred eighty-eight Caucasian patients with cutaneous sarcoid lesions were studied prospectively. Twenty-five had erythema nodosum, while 163 had infiltrative cutaneous lesions. One hundred thirty-eight patients had systemic as well as cutaneous lesions, and fifty had cutaneous lesions only. All types of clinical lesions were seen among patients with cutaneous lesions only. The extent of cutaneous lesions did not correlate with the extent of systemic disease. Papular lesions were relatively uncommon and occurred as the only manifestation of the disease or were associated with hilar adenopathy and acute disease. Lupus pernio, scar infiltrates, and plaque lesions were the most common clinical lesions and were typically chronic and commonly associated with pulmonary mottling and/or fibrosis. Forty-eight of 127 had a histologically positive Kveim test. Among patients followed for more than 2 years, dinitrochlorobenzene (DNCB) sensitivity was higher among those with acute disease than among those with chronic disease. Seventy-nine patients with infiltrative cutaneous lesions were followed until the cutaneous lesions had healed. Those with lupus pernio were often left with unsightly telangiectatic scars, while the other types of lesions left either pale, slightly depressed scars or no scars at all.