Further observations on tuberculin reactions in active tuberculosis

doi:10.1016/0002-9343(76)90718-X

The American Journal of Medicine

Volume 60, Issue 4, April 1976, Pages 517-522

https://doi.org/10.1016/0002-9343(76)90718-X Get rights and content

Abstract

One hundred patients with active tuberculosis were tested for tuberculin reactivity within 24 hours of their admission to the hospital. Commercial intermediate tuberculin, Tween stabilized intermediate tuberculin and the Tine test as well as a mumps antigen were applied simultaneously. False negative reactions were obtained in 28 per cent with Tine testing and in 21 per cent with Tween stabilized as well as plain tuberculin. These nonreactors were clinically identifiable as seriously ill with manifestations primarily attributable to protein depletion as a result of their illness. This is not specifically related to the effects of tuberculosis itself, but can be demonstrated in patients suffering the same sequelae of other debilitating illness. After two weeks of protein supplementation via a high calorie, high protein, hospital diet, skin reactivity was restored in the vast majority of these nonreactors. It is concluded that the lack of tuberculin reactivity on hospital admission probably results from impaired lymphocyte function in patients suffering serious protein depletion as a result of their illness; it is not attributable to deficiencies in the tuberculin test itself.

References (21)

BDW Harrison et al.
Tuberculin reaction in adult Nigerians with sputum positive pulmonary tuberculosis
Lancet
(1975)
ML Furcolow et al.
Quantitative studies of the tuberculin reaction. Tuberculin sensitivity in relation to active tuberculosis
Am Rev Tuberc
(1942)
DB Capabres et al.
Experience with the Tuberculosis Tine Test
JAMA
(1962)
PQ Edwards et al.
Story of the tuberculin test
Am Rev Respir Dis
(1960)
CF Lester et al.
Tuberculin skin test reaction in active pulmonary tuberculosis
Am Rev Tuberc
(1958)
B Hewell et al.
Tuberculin reactions of tuberculous patients on INH therapy
Am Rev Tuberc
(1954)
M Holden et al.
Frequency of intermediate strength tuberculin sensitivity in patients with active tuberculosis
N Engl J Med
(1971)
A Browder et al.
Tuberculin Tine test on medical wards
Am Rev Respir Dis
(1972)
L Hyde
Clinical significance of tuberculin skin test
Am Rev Respir Dis
(1972)
JW Ledwith et al.
The tuberculin reaction in patients admitted to a military tuberculosis service, 1958–1960
Am Rev Respir Dis
(1961)

There are more references available in the full text version of this article.

Cited by (83)

Tests for latent tuberculosis in people with ESRD: A systematic review
2013, American Journal of Kidney Diseases
Citation Excerpt :
This method is dubious because active and latent TB are distinct disease states that elicit different responses from the host immune system and therefore it may be inappropriate to use active TB as an immunologic model for latent TB.1,62 Several studies have shown that responses to the TST and IGRAs diminish during untreated active TB infection, but rapidly increase after treatment, suggesting that active TB may suppress the host immune response to these tests.63-66 Another limitation of this review is that the implications of our results rely on the assumption that a high proportion of people with clinical risk factors for latent TB actually have latent TB.
The relative diagnostic accuracy of interferon γ release assays (IGRAs; based on ELISA [enzyme-linked immunosorbent assay] or ELISPOT [enzyme-linked immunosorbent spot], ie, the QuantiFERON and T-SPOT.TB tests, respectively) and the tuberculin skin test (TST) for latent tuberculosis (TB) infection in people with end-stage kidney disease is uncertain and national guidelines for their use are inconsistent.
Systematic review.
Evaluated performance of tests for latent TB with clinical risk-factor assessment.
People with end-stage kidney disease (chronic kidney disease stage 5 [eGFR <15] or kidney transplant recipients). No limits on setting.
ELISA- or ELISPOT-based IGRAs, TST, assays to detect antimycobacterial antibodies, and flow cytometry–based tests.
Odds of test positivity with clinical risk factor for latent TB, expressed as ORs and relative ORs (RORs).
47 studies (6,828 participants) were included, but only 30 studies (4,546 participants) contained sufficient data to contribute to meta-analysis. Studies were predominately in the dialysis population (23/30; 3,700 participants) in countries with low to moderate TB prevalence (0.0-50.0 cases/10⁵ persons). BCG vaccination rate was variable (2.7%-100.0%). 9 studies compared IGRAs with the TST directly, 17 studies evaluated the TST only, and the other 4 studies evaluated other tests. Compared to a positive TST result, a positive ELISA-based IGRA result was associated more strongly with radiologic evidence of past TB (ROR, 4.29; 95% CI, 1.83-10.3; P = 0.001) and contact with active TB (ROR, 3.36; 95% CI, 1.61-7.01; P = 0.001). Compared to a negative TST result, a negative ELISA-based IGRA result was associated more strongly with BCG vaccination (ROR, 0.30; 95% CI, 0.14-0.63; P = 0.002). There were insufficient data to compare performance of the ELISPOT-based IGRA with the TST or ELISA-based IGRA.
17 of 47 included studies (36.2%) did not contain sufficient data to contribute to meta-analysis.
Compared to the TST, the ELISA-based IGRA was associated more strongly with risk factors for latent TB in end-stage kidney disease.
Tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS)
2012, Journal des Anti-Infectieux
Le syndrome inflammatoire de reconstitution immune (IRIS) au cours du traitement de la tuberculose se traduit par l’apparition ou l’aggravation de symptômes cliniques, liées à la tuberculose (fièvre, adénopathie, pleurésie, infiltrat pulmonaire…) après une amélioration initiale. La physiopathologie associe une reconstitution excessive des réponses immunitaires T spécifiques, dirigée contre des antigènes tuberculeux, probablement médiée par l’immunité innée sous le contrôle du polymorphisme génétique de l’hôte. Le traitement antituberculeux seul peut être à l’origine d’un IRIS, appelé aussi aggravation paradoxale, mais les IRIS sont plus fréquents après l’introduction du traitement antirétroviral chez les patients infectés par le VIH et la tuberculose. Malgré l’existence de critères cliniques, le diagnostic reste complexe et nécessite d’éliminer un échec (résistance, inobservance) ou un effet secondaire du traitement antituberculeux. Les principaux facteurs de risques de la survenue d’un IRIS sont représentés par la dissémination de la tuberculose, l’immunodépression, l’introduction rapide du traitement antirétroviral. Le pronostic est habituellement favorable sauf en cas d’atteintes neurologiques. La prise en charge thérapeutique des IRIS reste controversée. L’évolution, souvent spontanément favorable sans traitement spécifique, plaide en faveur d’une abstention thérapeutique pour les IRIS non grave. Les corticoïdes permettent de raccourcir la durée des symptômes mais leur utilisation est associée à la survenue de rechutes, ce qui pourrait faire réserver leur usage aux formes graves où ils sont recommandés. Le développement de stratégies thérapeutiques et préventives sont nécessaires compte-tenu de la grande fréquence de l’IRIS en particulier dans les pays où la tuberculose et le VIH sont endémiques.
The main clinical manifestations of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) are the appearance or the worsening of tuberculosis lesions (fever, adenopathies, pleural effusion, pleural infiltrate…) after an initial improvement. Physiopathology includes a reconstitution of an exaggerated specific T cell response against tuberculosis antigens probably mediated by innate immunity under the control of the host genetic polymorphism. Tuberculosis therapy alone could be responsible of IRIS also called paradoxical worsening, however IRIS is more frequent after antiretroviral therapy initiation in HIV tuberculosis co-infected patient. Despite the definition of clinical criteria, the diagnosis remains difficult and need to eliminate a failure (resistance, non adherence) or an adverse effect of tuberculosis treatment. Main IRIS risk factors are tuberculosis dissemination, immunodepression and early antiretroviral therapy initiation. Prognosis is usually favourable except in case of neurological involvement. Therapeutic strategies of IRIS remain controversial. The outcome, usually favourable without specific treatment, is an argument for therapeutic abstention in non-severe IRIS. Steroids allow a shortening of IRIS symptoms, however their use is associated with relapses which suggested that they could be reserved for severe IRIS where they are recommended. The development of therapeutic and preventive strategies is needed considering the high frequency of IRIS especially in high endemic countries of HIV and tuberculosis.
Evaluation of a new interferon-gamma release assay and comparison to tuberculin skin test during a tuberculosis outbreak
2012, International Journal of Infectious Diseases
Citation Excerpt :
These could be interpreted as false-negative TST results. As reported elsewhere, 5–25% of patients with active TB show a negative skin test (≥10 mm cutoff).12,13 However, since the index case was reported on March 6 and these two cases were identified on April 14 and 21, the negative TST could have been due to a delayed response.
The tuberculin skin test (TST) is commonly used for the diagnosis of latent tuberculosis infection (LTBI) in non-bacille Calmette–Guérin (BCG) vaccination settings. In recent years, attention has been drawn to interferon-gamma release assays (IGRAs), especially in BCG-vaccinated populations. In this study, we evaluated the TST and a new whole blood IGRA in BCG-vaccinated individuals during a tuberculosis (TB) outbreak in China.
A TB outbreak occurred at a university in Dalian, China from March to November 2010. The TST and a whole blood IGRA were used to screen for TB infection. The correlation between exposure levels, TST, and the IGRA were evaluated.
We found that agreement between the IGRA and TST was poor (kappa 0.182–0.290). IGRA positivity was associated with the level of exposure, and IGRA positivity and the level of exposure were risk factors for TB incidence. Neither the IGRA nor the TST alone picked up all TB incidences. However, if a 10 mm cutoff for the TST was used in the highest risk exposure group and IGRA positivity was used in the other risk groups, 19 of the 20 (95%) TB cases were identified.
A recommended preventive treatment regimen for China should be based on the level of exposure in conjunction with IGRA and TST test results.
Osteoarticular tuberculosis in a developed country
2007, Journal of Infection
Citation Excerpt :
However, 50% of patients with extrapulmonary tuberculosis confirmed by histological testing or microbiology had false negative results of Mantoux test in one previous study from Naples area.11 Our result could be explained by coexisting debilitating illnesses affecting our patients on admission that provoked lack of reactivity on skin tests carried out within 48 h.26 The selected 10 mm cut-off also may have contributed to lessen the sensitivity of skin tests.27 In patients with negative skin tests the diagnosis of OT was always confirmed by histological testing, microbiological testing, or ELISA-TB test before the treatment was started.
To evaluate the clinical and diagnostic features of osteoarticular tuberculosis (OT) from a series of cases seen over 30 years in a large university hospital in Naples, Italy.
We reviewed the files of all patients admitted to our department from 1975 to 2004 with a diagnosis of osteoarticular tuberculosis.
We identified 136 patients with 140 osteoarticular tuberculosis lesions. Fifty-three cases were diagnosed from 1975 to 1984, 36 cases from 1985 to 1994, and 47 cases from 1995 to 2004. Eleven patients (8%) were from high-incidence areas outside of Italy. The mean delay until diagnosis was 216.6 days. Pain, low-grade fever, and loss of weight were the most common presenting symptoms. Neurological involvement was present in 11 cases out of 79 spinal lesions (13.9%). Serological methods were used to study antimycobacterial antibodies using enzyme-linked immunosorbent assays (ELISA-TB test) in 59 patients (42.1%). Positive results on this test were obtained in 43 patients (72.9%). ELISA-TB test was the only diagnostic test associated with a shorter diagnostic delay in a model of multivariate regression analysis (p = 0.001). Tc-99m MDP bone scans were obtained from 83 patients with 84 lesions and increased uptake in the affected area was noted in 72 lesions (85.7%). Histological and microbiological examinations were positive in 97 (69.3%) and 57 (40.7%) lesions, respectively. In 43 (30.7%) lesions, we could not definitively confirm the diagnosis. In these cases chemotherapy was nevertheless initiated.
Thorough and even invasive diagnostic work-up is mandatory for the proper and timely management of patients with OT. Tc-99m MDP bone scanning and ELISA-TB test are useful diagnostic tools. We always used microbiological testing and histological examination to confirm the diagnosis of OT, but empirical antituberculosis treatment was nevertheless initiated in the patients with high clinical suspicion in order to limit the potentially permanent destruction of affected skeletal segments.
Immune reconstitution syndrome in systemic mycoses in HIV infected patients
2005, Journal de Mycologie Medicale
Le traitement par antirétroviraux de l'infection par le virus de l'immunodéficience humaine (VIH) entraîne une reconstitution des réponses immunitaires et a permis une diminution de la mortalité et de la fréquence des infections opportunistes. Cependant, cette reconstitution peut parfois être pathologique et être à l'origine de la survenue de syndrome de reconstitution immunologique (SRI). Ce syndrome regroupe l'ensemble des manifestations pathologiques lié à la présence d'une réponse immunitaire excessive dirigée contre des antigènes d'un agent infectieux ou non infectieux. Les manifestations du SRI sont polymorphes, le diagnostic est complexe puisqu'il n'existe aucun critère de certitude et que ce diagnostic doit faire éliminer d'autres étiologies, comme par exemple, une intolérance à un traitement, une autre infection, une inobservance aux traitements. La physiopathologie est partiellement élucidée et associe une reconstitution des réponses immunitaires acquises, mais aussi innées, et des phénomènes inflammatoires sous le contrôle du polymorphisme génétique de l'hôte. Deux formes distinctes de SRI peuvent s'observer, elles ont en commun la présentation inflammatoire des manifestations cliniques. La première est caractérisée par une aggravation paradoxale des manifestations liées à un agent infectieux malgré un traitement spécifique efficace. Elle témoigne de la reconstitution de la réponse immunitaire excessive vis-à-vis d'un agent pathogène inactif microbiologiquement. La seconde est caractérisée par l'apparition de manifestations inhabituelles démasquant une infection latente. Elle témoigne d'une réponse immunitaire excessive vis-à-vis d'un agent infectieux quiescent. La survenue d'un SRI est un événement relativement fréquent après l'introduction du traitement antirétroviral. Même si les principales étiologies sont représentées par la tuberculose, les mycobactéries atypiques et le cytomégalovirus, la place des infections fungiques et en particulier celles liées à Cryptococcus neoformans est importante. La survenue d'un SRI au cours d'infections à Histoplasma capsulatum est plus rare. Au cours des infections fongiques, la forme clinique de SRI la plus fréquente est l'aggravation paradoxale des lésions, après l'introduction des antirétroviraux, malgré un traitement antifongique efficace. La fréquence de la survenue d'un SRI au cours des cryptococcoses a été évaluée à 28 % dans une étude. Les principales manifestations du SRI au cours des cryptococcoses sont dominées par la survenue de méningites aseptiques ou d'adénopathies inflammatoires ou nécrotiques souvent médiastinales, dans un contexte fébrile dans la moitié des cas. Plus rarement, des lésions abcédées pulmonaires, intracérébrales, intramédullaires, sous cutanées et rétropharyngées ont été identifiées. Ces manifestations surviennent en médiane trois mois après le début du traitement antirétroviral. Les principales manifestations observées au cours des histoplasmoses sont dominées par la survenue d'adénopathies inflammatoires, mais d'autres manifestations ont été observées : abcès hépatiques, uvéite, arthrite. Le diagnostic de SRI est confirmé par la négativité des prélèvements mycologiques, l'augmentation importante des lymphocytes CD4 (proches de 200/mm³), la charge virale VIH souvent indétectable et l'absence d'autre étiologie. L'aspect histologique est très évocateur, montrant des granulomes épithélioïdes et gigantocellulaires bien formés contenant de rares éléments fongiques. Ces aspects, habituellement observés chez les patients non immunodéprimés, confirment la reconstitution fonctionnelle de la réponse immunitaire. La prise en charge thérapeutique des SRI n'est pas codifiée. La reconstitution immunitaire étant l'objectif du traitement antirétroviral, ce traitement ne doit pas, dans la mesure du possible, être arrêté. L'évolution est spontanément favorable dans environ la moitié des cas. Il est parfois nécessaire d'utiliser des anti-inflammatoires, en particulier stéroïdiens, qui entraînent une amélioration rapide des symptômes. Le rapport bénéfice/risque d'une corticothérapie doit être réfléchi compte tenu des risques d'infections opportunistes et en particulier à cytomégalovirus chez ces patients immunodéprimés. La survenue de lésions abcédées rend parfois nécessaire le recours à un traitement chirurgical. Les principaux facteurs de risques de la survenue d'un SRI au cours des cryptococcoses sont représentés par la dissémination de l'infection initiale et le délai d'introduction du traitement antirétroviral par rapport au traitement antifongique inférieur à un mois. Retarder l'introduction du traitement antirétroviral pourrait faire diminuer l'incidence du SRI mais cette stratégie risque d'occasionner la survenue d'infections opportunistes et elle paraît dangereuse pour les patients les plus immunodéprimés. La survenue de SRI complique la prise en charge des patients infectés par le VIH. Une meilleure connaissance du SRI est nécessaire afin d'améliorer le diagnostic et de développer des stratégies préventives.
Antiretroviral treatment of immunodeficiency virus (HIV) infection induces the restoration of immune responses and has led to a decrease in mortality and in the frequency of opportunistic infections. However, restoration is sometimes deleterious and the cause of the immune reconstitution syndrome (IRS). This syndrome includes all unusual manifestations related to excessive immune response against antigens of an infectious or non infectious agent. Signs and symptoms of IRS are polymorphous. Their diagnosis is difficult as there is no absolute criterion and all other possible etiologies have to be ruled out, such as a relapse of infection, intolerance to drugs, other infections and poor compliance to treatment. Pathogenesis was partially elucidated; it combines a reconstitution of both acquired and innate immune responses and inflammatory phenomena which are under the control the of host's genetic polymorphism. Two different forms of IRS can be seen, they share the clinical manifestations of inflammation. One is the excessive immune response against a micro-organism diagnosed and controlled by an anti-infectious treatment, with a paradoxical recurrence or aggravation of signs and symptoms of the disease being treated. The other form is an excessive immune response against an infectious agent, which is viable but quiescent, revealing a latent infection, which was not previously diagnosed. The occurrence of an IRS after introduction of antiretroviral treatment is well known particularly with tuberculosis, atypical mycobacterial infections and cytomegalovirus infections. It is not uncommon in fungal infections particularly in cryptococcosis; its occurrence in histoplasmosis is less frequent. In fungal infections the most common presentation of IRS is the paradoxical aggravation of lesions after introduction of antiretroviral treatment despite an efficacious antifungal treatment. In one study the incidence of IRS in cryptococcosis was 28%. Among the main manifestations of IRS in cryptococcosis the most frequent are aseptic meningitis, inflammatory or necrotic adenopathies, often mediastinal — with fever in half the cases—; pulmonary, cerebral intramedullary and subcutaneous abscesses have been reported. Manifestations of IRS occur with a median time of 3 months after starting antiretroviral treatment. In histoplasmosis the main manifestations are inflammatory adenopathies, occasionally liver abscesses; uveitis and arthritis have been reported. The diagnosis of IRS relies on negative culture of clinical samples for fungi, a marked increase in the CD4 lymphocyte cell count (close to 200/mm³), a HIV viral load which is often undetectable and lack of other etiology. Pathologic aspects in favor of IRS are epithelioid granulomas with giant cells and rare intracellular fungal elements. These features are usually observed in immunocompetent hosts and thus confirm the functional reconstitution of immune response. There is no consensus regarding the management of IRS. Immune reconstitution being the goal of therapy, if possible antiretroviral treatment should not be stopped. Spontaneous outcome is favorable in about half the cases. The use of anti-inflammatory drugs may be necessary, particularly corticosteroids, which allow rapid clearance of symptoms. The benefit of corticosteroids must be weighted against the risk of opportunistic infections in immuno-suppressed patients. Surgical treatment of abscesses may be needed. The main risk factors for IRS in cryptococcosis are dissemination of the infection at diagnosis and the introduction of antiretroviral treatment less than one month after initiation of antifungal treatment. A delay in initiation of antiretroviral treatment may decrease the incidence of IRS; however this strategy may facilitate the emergence of opportunistic infections and be hazardous, particularly for the most severely immuno-suppressed patients. IRS makes the management of HIV infection more difficult. A better knowledge of this syndrome should improve the prognosis and allow a strategy for its prevention.
Sensitivity of human gamma interferon assay and tuberculin skin testing for detecting infection with Mycobacterium tuberculosis in patients with culture positive tuberculosis
2005, Tuberculosis
Setting: Nine university-affiliated chest clinics in Australia.
Objective: To evaluate the sensitivity of a whole blood human gamma-interferon assay (HGIA, QuantiFERON^®-TB) for specific T lymphocyte responses and Tuberculin skin testing (TST) for the detection of Mycobacterium tuberculosis infection in subjects with culture-proven M. tuberculosis disease (TBCP).
Design: Prospective testing of 129 patients with recent TBCP and 100 patients with non-tuberculosis lung disease (NTBLD).
Results: Using a defined level of specific IFN-γ production and TST ⩾10 mm as positive cut-offs, the sensitivity of HGIA was 81% compared to 89% for TST ( $p = 0.06$ ). When positive responses in both TST and HGIA were combined, 96% of TB patients were detected. For the NTBLD group, 43% of whom were born overseas, 73% were negative for both the HGIA and TST. Prior immunization with M. bovis (bacille Calmette–Guerin) (BCG) or the type of TB had no effect on the sensitivities of the assays. For those treated for <2 months, the sensitivities for both assays were 84%, but for those treated for >2 months the sensitivity of TST (90%) tended to be higher than for HGIA (81%) ( $p = 0.07$ ). The distribution of TST results in TB patients showed a broad peak between 10 and 25 mm, while the results in the HGIA were bimodal in both TB and NTBLD patients.
Conclusion: HGIA may prove an alternative to skin testing for detecting M. tuberculosis infection in certain settings.

View all citing articles on Scopus

¹: From the Division of Pulmonary Diseases of the Department of Medicine, Kings County Hospital Center and State University of New York-Down-state Medical Center, Brooklyn, New York 11203.

^∗: Present Address: Department of Medicine, St. Vincent's Hospital and Medical Center, 153 West 11th Street, New York, New York 10011.

View full text

Clinical studyFurther observations on tuberculin reactions in active tuberculosis

Abstract

Lancet

Quantitative studies of the tuberculin reaction. Tuberculin sensitivity in relation to active tuberculosis

Am Rev Tuberc

Experience with the Tuberculosis Tine Test

JAMA

Story of the tuberculin test

Am Rev Respir Dis

Tuberculin skin test reaction in active pulmonary tuberculosis

Am Rev Tuberc

Tuberculin reactions of tuberculous patients on INH therapy

Am Rev Tuberc

Frequency of intermediate strength tuberculin sensitivity in patients with active tuberculosis

N Engl J Med

Tuberculin Tine test on medical wards

Am Rev Respir Dis

Clinical significance of tuberculin skin test

Am Rev Respir Dis

The tuberculin reaction in patients admitted to a military tuberculosis service, 1958–1960

Am Rev Respir Dis

Clinical study
Further observations on tuberculin reactions in active tuberculosis