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Kveim test
Kveim test
Kveim test
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Kveim test
SynonymsKveim-Siltzbach test
MeSHD007731

The Kveim test, Nickerson-Kveim or Kveim-Siltzbach test is a skin test used to detect sarcoidosis, where part of a spleen from a patient with known sarcoidosis is injected into the skin of a patient suspected to have the disease. If non caseating granulomas are found (four to six weeks later), the test is positive. If the patient has been on treatment (e.g., glucocorticoids), the test may return a false negative result. The test is not commonly performed, and in the UK no substrate has been available since 1996. There is a concern that certain infections, such as bovine spongiform encephalopathy, could be transferred through a Kveim test.[1]

It is named for the Norwegian pathologist Morten Ansgar Kveim, who first reported the test in 1941 using lymph node tissue from sarcoidosis patients.[2][3] It was popularised by the American physician Louis Siltzbach, who introduced a modified form using spleen tissue in 1954.[4] Kveim's work was a refinement of earlier studies performed by Nickerson, who in 1935 first reported on skin reactions in sarcoid.[5]

A Kveim test may be used to distinguish sarcoidosis from conditions with otherwise indistinguishable symptoms such as berylliosis.[6]

References

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Kveim test

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The Kveim test, also known as the Kveim-Siltzbach test, is a diagnostic test historically used to aid in the identification of , a multisystem granulomatous disease. It involves the of a saline suspension prepared from homogenized, autoclaved tissue (typically spleen or lymph nodes) obtained from patients with confirmed , followed by a of the injection site 4 to 6 weeks later to examine for the formation of noncaseating epithelioid granulomas, which indicate a positive reaction specific to the disease. Developed in 1941 by Norwegian pathologist Morten Ansgar Kveim, the test was first described in a study where 12 of 13 patients with biopsy-proven developed a nodule at the injection site after receiving a homogenate from an affected . It gained widespread use in the mid-20th century after refinement by Louis E. Siltzbach, who standardized the preparation and validation processes to improve reliability, making it a valuable tool for early when other methods were limited. By the and , large-scale evaluations, such as a 1961 collaborative study of 750 patients in which 84% of the 311 confirmed cases showed positive reactions, demonstrated its utility. The test's diagnostic performance has been assessed in multiple studies, with reported sensitivity ranging from 50% to 80% and specificity from 70% to 95%, depending on disease stage and quality; a 2024 analysis of 300 patients found a sensitivity of 76.4% and specificity of 72.8%, outperforming conventional lab tests alone (sensitivity 68.2%) but enhancing sensitivity to 96.8% when combined with them. False positives are rare (1-5%), while negatives may arise in anergic or treated patients. Despite its specificity, the Kveim test has largely fallen out of routine clinical use since the due to several limitations, including the risk of transmitting infectious agents (such as or ) from unsterilized human-derived , ethical concerns over sourcing tissue from patients, and the availability of safer, more accessible alternatives like transbronchial and advanced imaging. It remains available at select specialized centers, such as in New York, where it aids diagnosis in up to 80% of challenging cases, and continues to be employed in to explore pathogenesis.

Overview

Definition

The Kveim test, also known as the Nickerson-Kveim test or Kveim-Siltzbach test, is an intradermal skin test designed to detect through the elicitation of a delayed-type reaction using sarcoid tissue .90443-X/fulltext) This test exploits the immune system's response to antigens derived from sarcoidosis-affected human tissue, specifically manifesting as a localized granulomatous reaction that mirrors the pathological features of the disease itself. In essence, the test involves the of a suspension prepared from sarcoid splenic tissue (or equivalent lymphoid material), which contains putative sarcoidosis-specific antigens capable of triggering a cell-mediated in sensitized individuals. This response leads to the formation of a characteristic at the injection site, typically observable after 4 to 6 weeks, serving as an indicator of prior exposure to the disease's antigenic components. The core mechanism of the Kveim test relies on delayed-type hypersensitivity, a T-cell mediated process akin to the tuberculin skin test, where sarcoidosis-specific epitopes provoke the recruitment and activation of macrophages and lymphocytes, culminating in noncaseating granuloma development that pathologically resembles sarcoid lesions. This targeted immune mimicry distinguishes the test as a diagnostic adjunct for sarcoidosis, emphasizing the disease's hallmark granulomatous inflammation without requiring systemic invasion.

Purpose

The Kveim test serves primarily as a diagnostic aid to confirm in cases where clinical symptoms and radiological evidence are suggestive yet non-specific, particularly in early-stage or atypical presentations of the disease. By eliciting a specific granulomatous reaction through of sarcoid tissue suspension, the test provides histological evidence that supports the diagnosis when other biopsies are inaccessible or inconclusive. This role has been especially valuable in distinguishing from mimicking conditions that present with similar granulomatous inflammation. As a supportive diagnostic tool rather than a standalone method, the Kveim test integrates into a broader evaluation process, helping to differentiate from disorders such as or by leveraging its targeted immunological response. It complements clinical judgment and imaging findings, offering confirmatory value in ambiguous scenarios without replacing histopathological examination of affected tissues. Historically, the test was employed in outpatient settings due to its relative simplicity and perceived specificity, serving as a practical option before the widespread availability of advanced imaging modalities and routine techniques in the mid-20th century. Developed in the , it facilitated earlier diagnosis in resource-limited environments, though its use has since declined with the advent of safer and more precise alternatives.

History

Development

The Kveim test was developed in 1941 by Norwegian pathologist Morten Ansgar Kveim during his investigations into Boeck's , the historical term for , at the University of Oslo's department of under Nicolai Danbolt. Kveim sought a diagnostic tool to identify the disease more reliably, building on earlier observations of skin reactions to sarcoid tissue extracts. Kveim's method centered on preparing an by emulsifying and heat-sterilizing tissue obtained from a patient with , then injecting it intradermally into individuals suspected of having the condition, followed by monitoring for nodule formation at the injection site after several weeks. This approach aimed to elicit a specific granulomatous response mimicking sarcoid lesions. For early validation, Kveim applied the test to 13 patients with histologically confirmed , observing positive nodule reactions in 12 cases, while controls showed no response; these results demonstrated the test's potential specificity. He detailed these findings in a Norwegian-language publication in Nordisk Medicin titled "En ny og spesifikk kutan reaksjon ved Boecks sarcoid" (A new and specific cutaneous reaction in Boeck's sarcoid), which served as his doctoral thesis and established the foundational proof-of-concept for the test.

Adoption and standardization

Following its initial development in by Norwegian pathologist Morten Ansgar Kveim, the test gained traction in the post-World War II era, particularly through refinements introduced by American researchers in the . The test was popularized in the United States during the by Louis E. Siltzbach, who modified the original procedure to use standardized suspensions derived from sarcoid spleen tissue in 1954, leading to the variant known as the Kveim-Siltzbach test. This refinement addressed early variability in preparation and enhanced the test's reliability for clinical use. By the 1960s, the Kveim-Siltzbach test had achieved wide adoption in both and the , serving as a key diagnostic tool in research and practice across multiple institutions. A pivotal advancement came through the international collaborative trial conducted from 1960 to 1966, organized by Siltzbach and reported at the on Sarcoidosis, which tested the in over 1,000 patients and controls to establish preparation guidelines for antigen consistency and potency. This effort highlighted the need for bioassay validation in patients to confirm specificity before widespread use. Standardization efforts were further formalized by the international Kveim test group in , which defined criteria for antigen validation, including the use of heat-treated (boiled) suspensions from verified sarcoid spleens to minimize variability, ensure sterility, and promote reproducibility across laboratories. These guidelines emphasized histological confirmation of the source material and controlled processing to maintain diagnostic potency without loss of activity.

Procedure

Antigen preparation

The antigen for the Kveim test is derived from tissue harvested from deceased patients with histologically confirmed active , preferably at stages II or III to ensure high content. Preparation begins with homogenization of the fresh tissue, followed by suspension in isotonic saline to create a uniform mixture. To inactivate potential pathogens, the suspension undergoes autoclaving, ensuring safety without compromising the immunogenic properties. The material is then standardized for dosing, with each aliquot adjusted to 1-5 mg of dry weight equivalent. Quality control involves rigorous validation of each batch: potency is confirmed by intradermal testing in at least 20 patients with known , requiring a minimum 70% positive reaction rate, while sterility is verified through microbiological assays showing no viable organisms. Batches meeting these criteria are aliquoted and stored at -70°C, remaining viable for up to 5 years.

Administration and timing

The Kveim test is administered to adults with suspected through into the skin. A volume of 0.1 to 0.2 mL of the suspension is injected using a syringe equipped with a 25- or 27-gauge needle, typically into the flexor aspect of the to create a small bleb approximately 5 mm in . The injection is performed superficially into the at a 10- to 15-degree angle to ensure proper placement without deeper penetration. A control injection is simultaneously administered at a separate site on the , using an equal volume of saline solution or a suspension of heat-killed tissue from a non-sarcoid source, such as normal or , to help distinguish specific reactions from nonspecific responses. The test is contraindicated in patients with active infections at the injection site, as these could interfere with accurate interpretation, and in those with significant , which may suppress the delayed response required for a valid result. Following administration, no immediate reaction is expected, as the test relies on a type IV delayed hypersensitivity mechanism. The injection site is visually monitored for the development of a papule or nodule, with patients instructed to return for evaluation 4 to 6 weeks post-injection. If a palpable lesion forms (typically 5 mm or larger), the site is marked for excisional biopsy using a 5- to 6-mm punch tool to confirm the reaction histologically.

Interpretation

Reaction assessment

The reaction to the Kveim test is clinically evaluated 4 to 6 weeks after intradermal administration through and at the injection site, prior to any consideration of . A positive reaction manifests as a palpable, non-tender nodule typically measuring 3 to 10 mm in diameter, presenting as reddish-brown without evidence of ulceration or . The nodule is firm upon and remains stable in size during this period, distinguishing it from acute inflammatory responses. Positive clinical reactions warrant histological confirmation to verify non-caseating granulomas, as clinical assessment alone cannot exclude mimics. Assessment must account for potential factors to minimize false positives. Reactions resembling the Kveim nodule may arise from secondary at the injection site or prior local trauma, necessitating careful differentiation through history and examination. Consistency is verified by comparing the test site to a control injection site (using saline or inactivated ), where no nodule should develop in the absence of sarcoidosis-specific . therapy or advanced disease stage may attenuate the reaction, potentially leading to underestimation of positivity.

Histological confirmation

To confirm a positive Kveim test reaction, a biopsy is performed on the developing nodule at the injection site, typically 4 to 6 weeks after intradermal administration of the antigen suspension. The procedure involves a 4 mm punch biopsy under local anesthesia to excise the lesion, with the tissue sample then fixed in formalin, processed, and embedded for microscopic examination. This timing allows for the maturation of the granulomatous response while minimizing nonspecific inflammatory changes that could occur earlier or later. Under microscopy, a true positive reaction is characterized by the presence of non-caseating epithelioid granulomas that closely resemble the pathological features of in affected tissues. These granulomas consist of focal collections of epithelioid cells, often accompanied by multinucleated Langhans-type giant cells, a rim of lymphocytes, and occasional fibroblasts, but without central , caseation, or identifiable foreign material from the injected antigen. Special stains, such as acid-fast bacilli and fungal stains (e.g., Ziehl-Neelsen and periodic acid-Schiff), are routinely applied to ensure the lesions are sterile and free of infectious organisms, as positivity must exclude alternative granulomatous etiologies like or fungal infections. Diagnostic criteria for histological confirmation emphasize consistency and specificity: the granulomas must align with standardized descriptions from validated Kveim-Siltzbach reagents, showing organized epithelioid cell tubercles without atypical features. False positives are identified by deviant histology, such as caseating necrosis suggestive of tuberculosis or disorganized infiltrates lacking true granuloma formation, which occur rarely (less than 2-5% in controlled studies) but necessitate careful exclusion to maintain test reliability across antigen batches. This microscopic evaluation, ideally performed by experienced pathologists blinded to clinical details, provides the definitive criterion for a positive test beyond preliminary visual inspection.

Clinical significance

Diagnostic accuracy

The Kveim test demonstrates a sensitivity of approximately 70-80% for detecting active , with positivity rates varying based on disease activity and treatment status. In a landmark 1961 study involving 750 patients, 84% of the 311 individuals with confirmed exhibited positive reactions. Similarly, a 2024 clinical evaluation reported a sensitivity of 76.4% across 300 patients, with higher yields in active pulmonary cases (e.g., 86.6% in stage II disease) compared to inactive or advanced stages (50% in stage IV). Specificity ranges from 70-95%, reflecting low false-positive rates in non-sarcoid granulomatous conditions such as . The same 2024 study reported a specificity of 72.8%. Historical data from the 1961 cohort showed only 2 false positives among 303 non-sarcoidosis patients (specificity ≈99%), further supporting reliability in differentiating from . Diagnostic accuracy is influenced by factors such as disease stage and preparation quality, with optimal performance in untreated pulmonary . The 1967 international collaborative trial organized by Siltzbach, evaluating standardized s across multiple centers, reported an overall positivity rate of approximately 78%, highlighting variability attributable to batch differences but confirming higher reliability in active, untreated cases. In the 2024 analysis, standardization contributed to consistent results, though yields dropped in treated patients due to reduced granulomatous reactivity.

Modern applications

The Kveim test has seen limited global adoption in contemporary clinical practice, having been discontinued in most countries during the 1980s and 1990s due to the emergence of safer and more accessible diagnostic alternatives such as transbronchial biopsies and advanced imaging modalities. As of 2025, its availability remains restricted, with production and distribution of validated antigens largely ceased outside specialized settings. However, it persists at select centers equipped with historical reagent stocks, notably in New York, which is the sole facility in the United States offering the Kveim-Siltzbach test for diagnosis. In niche clinical scenarios, the test is employed when invasive biopsies are contraindicated or undesirable, such as in patients with high surgical risk or those requiring a noninvasive confirmatory approach, where it can support in up to 80% of cases by eliciting a characteristic granulomatous response. It also finds application in research contexts to differentiate subtypes or stages, as evidenced by recent retrospective analyses demonstrating its diagnostic yield across pulmonary stages, including stage 0 disease, where it aids in assessing early or atypical presentations. These studies, conducted at institutions like Cerrahpaşa Medical Faculty in , underscore its potential utility in integrating historical diagnostic tools with modern evaluations, though widespread revival efforts with safer, recombinant antigens have not yet materialized. Within multidisciplinary sarcoidosis clinics, the Kveim test is integrated adjunctively alongside serum () levels, (HRCT) or () imaging, and with to provide a comprehensive diagnostic profile, particularly in ambiguous cases where histological confirmation from is inconclusive or infeasible. This combined approach enhances overall , allowing for tailored management in specialized environments while minimizing reliance on the test as a standalone procedure.

Limitations

Safety concerns

The primary safety concern associated with the Kveim test stems from the use of human-derived tissue in antigen preparation, which carries a theoretical of transmitting bloodborne pathogens such as , , and Creutzfeldt-Jakob disease (CJD), despite sterilization efforts. This potential for pathogen transmission prompted regulatory scrutiny in the context of biological product safety, particularly during the era of heightened awareness about bloodborne infections. Adverse effects from the test are uncommon and typically limited to local reactions at the injection site, such as minor infections or scarring, based on historical usage data. Systemic reactions do not occur, owing to the test's reliance on a delayed-type mechanism that avoids immediate immune activation. Efforts to address these risks in contemporary research applications include preparing antigens through and comprehensive pathogen testing to reduce . Nonetheless, the reliance on human tissue raises ongoing ethical concerns about sourcing and consent for such materials in diagnostic procedures.

Reasons for decline

The decline of the Kveim test in clinical practice began in the late , primarily due to the emergence of more effective diagnostic alternatives for . Advances in and techniques, such as (HRCT) introduced in the 1980s and widely adopted by the 1990s, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the early 2000s, and (PET) scans, provided faster and more direct evidence of granulomatous without relying on delayed responses. These methods allowed for immediate histopathological confirmation through tissue sampling, rendering the Kveim test's 4-6 week observation period obsolete in routine diagnostics. Regulatory and ethical concerns further accelerated its obsolescence, particularly regarding the use of human-derived antigens. In the United States, the test has never received approval from the (FDA), limiting its standardization and widespread adoption due to variability in antigen preparation and potential risks. In the , a moratorium was imposed in the early 1990s amid fears of transmitting prion diseases like Creutzfeldt-Jakob disease (CJD) from unprocessed human spleen or material, effectively halting clinical use; this built on earlier ethical scrutiny in the related to inconsistent antigen sourcing and lack of commercialization. No standardized commercial Kveim antigen has ever been developed or approved, exacerbating supply inconsistencies and regulatory barriers across both regions. Practical limitations compounded these issues, making the test increasingly unfeasible in modern healthcare settings. The requirement for specialized histopathological laboratories to confirm noncaseating granulomas at the injection site, combined with the prolonged 4-6 week wait for results, contrasted sharply with the rapid turnaround of and results, reducing its utility in time-sensitive patient management. These drawbacks, alongside the shift toward evidence-based, minimally invasive diagnostics, led to the test's virtual abandonment outside research contexts by the early .

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