Diagnosis of tuberculosis by an enzyme-linked immunospot assay for interferon-[gamma].
We evaluated an enzyme-linked immunospot assay for interferon-[gamma] (T SPOT-TB) for rapid diagnosis of active tuberculosis (TB) in a disease-endemic area. From January to June 2005, patients whose clinical symptoms and radiographic radiographic (rā´dēōgraf´ik),
adj relating to the process of radiography, the finished product, or its use. findings were compatible with TB were recruited, and a blood sample was obtained for T SPOT-TB assay within 7 days of microbiologic studies. Sixty-five patients were studied, including 39 (60%) with active TB. Thirty-five (53.8%) patients had underlying medical conditions. Thirty-seven patients had positive cultures for Mycobacterium tuberculosis, and 11 patients had positive cultures for nontuberculous mycobacteria. The sensitivity, specificity, positive predictive value Positive predictive value (PPV)
The probability that a person with a positive test result has, or will get, the disease.
Mentioned in: Genetic Testing
positive predictive value , and negative predictive value The negative predictive value is the proportion of patients with negative test results who are correctly diagnosed. Worked example
(as determined by "Gold standard")
True False of the T SPOT-TB assay were 87.2%, 88.5%, 91.9%, and 82.1%, respectively. The accuracy of this test in diagnosing active TB is >80%, even in an area with a high incidence of nontuberculous mycobacterial mycobacterial
emanating from or pertaining to mycobacterium.
may be caused by Mycobacterium tuberculosis (see cutaneous tuberculosis), M. disease.
Tuberculosis (TB) is one of the most important infectious disease in the world. In 2003, the incidence and death rates for TB in Taiwan were 62.38 and 5.80 per 100,000, respectively (1). Successful control of TB depends on prompt detection of patients with Mycobacterium tuberculosis infection. The conventional methods for laboratory diagnosis of TB, including acid-fast staining and culture, are either insensitive (2,3) or time-consuming (4). Although new diagnostic methods that use nucleic acid amplification and detection may provide quick and specific results for identifying the M. tuberculosis complex (5,6), their sensitivities are considerably less than those of culture (6).
Recent studies demonstrated that an enzyme-linked immunospot (ELISPOT ELISPOT Enzyme-Linked Immunospot Assay
ELISPOT Interferon-Gamma Enzyme-Linked Immunospot ) assay for interferon-[gamma] (IFN-[gamma]) produced by activated T cells after exposure to antigens of M. tuberculosis, early secretory antigenic target 6 (ESAT-6), and culture filtrate filtrate /fil·trate/ (fil´trat) a liquid or gas that has passed through a filter.
To put or go through a filter.
n. protein 10 (CFP-10) is a specific method for identifying M. tuberculosis infection (7-9). However, its performance in rapid diagnosis of active TB in disease-endemic areas is still unknown. We evaluated the ELISPOT (T SPOT-TB) assay in clinically suspected cases of TB.
This study was conducted from January to June 2005 in northern Taiwan at a tertiary care referral center with 2,000 beds; the study was approved by the ethics committee of the hospital. Patients with fever or respiratory symptoms (cough, dyspnea dyspnea /dysp·nea/ (disp-ne´ah) labored or difficult breathing.dyspne´ic
paroxysmal nocturnal dyspnea , or hemoptysis Hemoptysis Definition
Hemoptysis is the coughing up of blood or bloody sputum from the lungs or airway. It may be either self-limiting or recurrent. Massive hemoptysis is defined as 200-600 mL of blood coughed up within a period of 24 hours or less. ) for [greater than or equal to] 2 weeks and compatible radiographic findings were considered to have clinically suspected cases of TB. The compatible findings included fibroexudative or fibrotic lesions over upper lung, pulmonary nodules Nodules
A small mass of tissue in the form of a protuberance or a knot that is solid and can be detected by touch.
Mentioned in: Leprosy with or without cavitation cavitation
Formation of vapour bubbles within a liquid at low-pressure regions that occur in places where the liquid has been accelerated to high velocities, as in the operation of centrifugal pumps, water turbines, and marine propellers. , multiple patches of alveolar alveolar /al·ve·o·lar/ (al-ve´o-lar) [L. alveolaris ] pertaining to an alveolus.
Relating to an alveolus. infiltrates, miliary miliary /mil·i·ary/ (mil´e-ar?e)
1. like millet seeds.
2. characterized by lesions resembling millet seeds.
1. shadowing, and pleural effusion with lymphocytotic and exudative exudative
of or pertaining to a process of exudation.
a disease of young pigs and chickens caused by a nutritional deficiency of vitamin E. Characterized by severe edema of the subcutaneous tissues. characteristics. Patients were invited to provide informed consent and were interviewed and examined. A blood sample was obtained for ELISPOT within 7 days of microbiologic studies (including acid-fast smears [AFS A distributed file system for large, widely dispersed Unix and Windows networks from Transarc Corporation, now part of IBM. It is noted for its ease of administration and expandability and stems from Carnegie-Mellon's Andrew File System.
AFS - Andrew File System ] and mycobacterial culture). Twelve healthcare workers (HCWs) in the hospital were included as a healthy control group.
AFS for respiratory samples and mycobacterial culture were performed as previously described (5). If the primary care physician deemed it necessary, samples were screened for infection with HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. type 1 or type 2 viruses by using competitive ELISAs (Wellcome Laboratories, Beckenham, UK), and infection was confirmed by Western blotting (Diagnostics Pasteur, Marnes-la-Coquette, France).
Five milliliters of blood was obtained from each patient and processed within 2 hours. ELISPOT was performed by using a commercial kit (T SPOT-TB; Oxford Immunotec Ltd, Oxford, UK) as previously described (10). Briefly, peripheral blood mononuclear mononuclear /mono·nu·cle·ar/ (-noo´kle-er)
1. having but one nucleus.
2. a cell having a single nucleus, especially a monocyte of the blood or tissues.
adj. cells were separated by using Ficoll-Paque centrifugation Centrifugation
A mechanical method of separating immiscible liquids or solids from liquids by the application of centrifugal force. This force can be very great, and separations which proceed slowly by gravity can be speeded up enormously in centrifugal . Cells were washed, resuspended, and counted. Ninety-six well polyvinylidene fluoride backed plates (MAIPS4510; Millipore, Billerica, MA, USA) were coated with 15 [micro]g/mL of monoclonal antibody 1-D1K against IFN-[gamma] (Mabtech, Nacka Strand, Sweden). Cells (250,000/well) were added to duplicate wells containing antigen (ESAT-6 or CFP-10) or mitogen mitogen /mi·to·gen/ (mit?o-jen) a substance that induces mitosis and cell tranformation, especially lymphocyte transformation.mitogen´ic
n. . No antigen was added to the background control wells. After incubation for 18 h, plates were washed, 100 [micro]L (1 [micro]g/mL) of biotinylated monoclonal antibody 7-B6-1-biotin against IFN-[gamma] (Mabtech) was added, and plates were incubated for 2 h. Plates were then washed, streptavidin-alkaline phosphatase toxoid toxoid, protein toxin treated by heat or chemicals so that its poisonous property is destroyed but its capacity to stimulate the formation of toxin antibodies, or antitoxins, remains. (Mabtech) was added and incubated for 1.5 h; plates were washed again and 100 [micro]L of chromogenic chro·mo·gen·ic
Of or relating to a chromogen or to chromogenesis.
adj pertaining to color production. alkaline phosphatase substrate (Bio-Rad Laboratories, Hercules, CA, USA) was added. After 10-15 min, the plates were washed and spots were enumerated This term is often used in law as equivalent to mentioned specifically, designated, or expressly named or granted; as in speaking of enumerated governmental powers, items of property, or articles in a tariff schedule. with a stereomicroscope ster·e·o·mi·cro·scope
A microscope equipped for stereoscopic viewing.
stere·o·mi independently by 2 observers. Mean values determined by the 2 observers and both duplicate wells were used in all calculations. The number of spots in the background control wells was subtracted from the number in the test wells, and a response was considered positive if the number of spots per test well was [greater than or equal to] 10 and at least twice the value found in the background control wells.
Clinical Evaluation of Patients
All medical records including history, symptoms, signs, radiologic, pathologic, and microbiologic results, and follow-up observations were carefully reviewed to obtain data for generating a clinical diagnosis. On the basis of clinical findings, 2 categories of patients were considered to have active TB: those whose clinical specimens were culture-positive for M. tuberculosis and those whose biopsy specimens had caseating granulomas that showed marked improvement after treatment.
Patient characteristics are summarized in Table 1. All patients were previously vaccinated with bacillus Calmette-Guerin (BCG BCG bacille Calmette-Guérin.
1. bacillus Calmette-Guérin
n.pr See bacille Calmette-Guórin. ). Laboratory tests for HIV infection were performed for 42 patients and results were positive for 3 patients. Of 23 patients with an unknown HIV status, all had an initial lymphocyte count >1 x [10.sup.9]/L and did not have AIDS-defined illness (11). Thirty-nine (60%) had active TB; 37 had culture-confirmed TB and 2 had histopathology-proved TB with marked improvement of their clinical conditions after treatment. Thirty-one patients had pulmonary TB, 3 had TB pleurisy pleurisy (plr`ĭsē), inflammation of the pleura (the membrane that covers the lungs and lines the chest cavity). It is sometimes accompanied by pain and coughing. (M. tuberculosis was isolated from pleural effusion), and 2 had concomitant pulmonary TB and TB pleurisy. The remaining 3 patients had pulmonary and extrapulmonary TB. Of the 26 non-TB patients, all were culture negative for M. tuberculosis' for multiple specimens (mean 8.3, range 3-20).
Eight (12.3%) fulfilled the diagnostic criteria for nontuberculosis mycobacterial (NTM NTM New Tribes Mission
NTM Notice to Members (NASD)
NTM Notice To Mariners
NTM Nontuberculous Mycobacteria
NTM Non-Tariff Measures
NTM National Technical Means (formerly National Assets) ) disease (12). Of these 8 patients, 2 infected with M. avium-intracellulare complex responded to treatment with clarithromycin, ethambutol ethambutol /etham·bu·tol/ (e-tham´bu-tol) an antibacterial, specifically effective against Mycobacterium; used with one or more other antituberculous drugs in the treatment of pulmonary tuberculosis, administered as the , and rifampin rifampin (rĭfăm`pĭn), antibiotic used in the treatment of tuberculosis. It is also used to eliminate the meningococcus microorganism from carriers and to treat leprosy, or Hansen's disease. ; 1 infected with M. kansasii responded to treatment with isoniazid isoniazid (ī'sōnī`əzĭd), drug used to treat tuberculosis. Also known as isonicotinic acid hydrazide, isoniazid is the most effective antituberculosis drug currently available. , rifampin, and ethambutol; and 3 infected with M. abscessus responded to treatment with clarithromycin. Clinical conditions and radiographic abnormalities improved in 9 patients after treatment with antimicrobial drugs and in 2 patients after treatment with antifungal drugs. Three other patients provided biopsy specimens, which showed malignancy in 2 patients and a benign tumor in 1 patient. Another patient died of Staphylococcus aureus pneumonia and bacteremia bacteremia: see septicemia.
Presence of bacteria in the blood. Short-term bacteremia follows dental or surgical procedures, especially if local infection or very high-risk surgery releases bacteria from isolated sites. . Three other patients showed no clinical and radiographic improvement after empiric treatment for 2 weeks. Specimens from 2 these patients were tested by a nucleic acid amplification assay (BD ProbeTec ET DTB See Deutsche Terminbörse. system; Becton Dickinson Instrument Systems, Sparks, MD, USA) and showed negative results. Nine of 12 patients with diabetes and the 3 patients infected with HIV had active TB. In the 48 patients with mycobacteria mycobacteria
members of the genus Mycobacterium.
see opportunist (atypical) mycobacteria (below).
see opportunist (atypical) mycobacteria (below). isolated from respiratory specimens, the average interval between the date when microbiologic studies were performed and the date when the result of mycobacterial culture was available was 49.9 days (range 14-77 days). However, the average interval for the ELISPOT assay for these patients was 4.5 days (range 1-8 days) after microbiologic studies were performed.
Table 2 shows the correlation between ELISPOT results and the final diagnosis for the 65 patients. Of the 22 patients with AFS-positive TB, 19 (86.4%) were ELISPOT positive. Three showed false-negative results in the ELISPOT, including a 41-year-old HIV-positive man, a 47-year-old HIV-negative man with diabetes mellitus, and a 78-year-old woman with diabetes mellitus and Sjogren syndrome. Of the 11 non-TB patients with positive AFS, mycobacterial culture showed NTM disease in 8 patients. Three showed false-positive results in the ELISPOT, including a 74-year-old man with diabetes who was culture positive for M. chelonae, a 50-year-old previously healthy man who was culture positive for M. marinum, and a 21-year-old previously healthy woman who was culture positive for M. avium-intracellulare complex. The positive predictive value (PPV Positive predictive value (PPV)
The probability that a person with a positive test result has, or will get, the disease.
Mentioned in: Genetic Testing
PPV Positive-pressure ventilation ) of ELISPOT for AFS-positive patients was 86.4% (Table 2).
Of the 17 patients with AFS-negative TB, 2 (11.8%) showed negative results in the ELISPOT (Table 2). Both were previously healthy and had culture-positive TB pleurisy with pleural effusions with lymphocytotic and exudative characteristics. Chest radiographs for these 2 patients showed pleural effusion without parenchymal pa·ren·chy·ma
1. Anatomy The tissue characteristic of an organ, as distinguished from associated connective or supporting tissues.
2. lesions. Their sputum cultures were negative for M. tuberculosis. HIV status was tested in only 1 patient. For the 15 non-TB patients with negative AFS, all showed negative results in the ELISPOT, i.e., the specificity and PPV of the ELISPOT were 100% (Table 2).
Among the 28 ELISPOT-negative patients, 3, including 1 with culture-confirmed TB, were retested 2, 4, and 5 weeks later, respectively. All were again ELISPOT negative. Among the 12 HCWs, all were ELISPOT negative except 1 who previously had culture-confirmed TB and had been treated for 10 months.
Delayed diagnosis and treatment can increase the risk for dissemination of M. tuberculosis and decrease survival for some subgroups of TB patients (13-15). Thus, new technologic developments, which facilitate rapid diagnosis, are needed for successful control of this disease. Besides the development of nucleic acid amplification assays for rapid detection of M. tuberculosis complex, attempts have been made to exploit the T-cell response for rapid diagnosis of M. tuberculosis infection (16,17). The major problem with tuberculin skin testing (TST TST 1 Toxic shock toxin 2 Treadmill stress test, see there ) is cross-reactivity with antigens in other mycobacteria, such as the M. bovis BCG vaccine strain and environmental mycobacterial species. This cross-reactivity leads to false-positive results and decreased PPV, especially in BCG-vaccinated persons and in areas of high incidence of NTM disease, such as Taiwan. In Taiwan in 2001, 2.74% of preschool children were TST positive, whereas active TB developed in only 2.29/100,000 children 5-9 years of age (1). Use of ESAT-6 and CFP-10, two antigens encoded in the region of difference 1, which distinguishes M. tuberculosis from other mycobacteria, has increased the specificity and PPV of IFN-[gamma] ELISPOT assays (10,18-22). Our study showed that the sensitivity, specificity, PPV, and negative predictive values (NPV NPV
See: Net present value ) of the ELISPOT assay were >80% in the diagnosis of active TB in clinically suspected patients. Results were also available [approximately equal to] 45 days earlier than those obtained with mycobacterial culture.
The genes coding for ESAT-6 and CFP-10 are absent from most environmental mycobacteria, except for M. kansasii, M. marinum, M. szulgai, M. flavescens, and M. gastrii (23-25). Whether ESAT-6 or CFP-10 is present in M. chelonae and the M. avium-intracellulare complex has not yet been determined. Although PPV is associated with pretest probability of active TB in a cohort, our results showed that the ELISPOT can accurately discriminate TB from NTM disease and other respiratory diseases. All 3 patients with false-positive ELISPOT results had NTM disease. The 3 AFS-positive TB patients with false-negative ELISPOT results had other diseases (2 had diabetes mellitus and 1 had AIDS), which could weaken the T-cell response (26,27). However, neither of the 2 AFS-negative ELISPOT false-negative TB patients had another disease. Because HIV status was not routinely tested, the possibility of asymptomatic HIV infection asymptomatic HIV infection AIDS A state in which HIV is present in a person without signs of clinical disease; AIDS may follow infection by HIV by up to 10 yrs. See AIDS, HIV. that potentially influenced the ELISPOT results cannot be excluded.
Consistent with previous reports (sensitivity 80.7% 94.4%) (20,28-30), assays detecting secretion of IFN-y caused by stimulation with ESAT-6 or CFP-10 for diagnosis of TB have a sensitivity >80%. However, specificity (45.5%-69.2%), PPV (65.4%-85.4%), and NPV (53.6%-90.0%) were highly variable, which was probably due to different criteria for patient selection and diagnosis of active TB. In a study conducted in Japan (20), only patients with culture-confirmed infection were considered to have active TB. Thus, culture-negative TB patients would be classified into a non-TB group, but some showed positive test results, which resulted in decreased specificity and PPV. In the study conducted in Denmark (28), several risk factors predisposing persons to recent M. tuberculosis infection were observed in the 10 patients with false-positive results, including a history of recent exposure, immigration immigration, entrance of a person (an alien) into a new country for the purpose of establishing permanent residence. Motives for immigration, like those for migration generally, are often economic, although religious or political factors may be very important. from a highly disease-endemic area, intravenous drug use intravenous drug use Intravenous drug abuse The habitual IV injection of drugs of abuse Epidemiology In the US ± 2.5 million–population ± 235 million have used IVDs Infections Pyogenic–eg, endocarditis, pneumonia, sepsis Common agents , and HIV positivity. In the study conducted in Brazil (30), controls were medical students, who were at high risk for nosocomial nosocomial /noso·co·mi·al/ (nos?o-ko´me-il) pertaining to or originating in a hospital.
1. Of or relating to a hospital.
2. exposure; 50% of them were ELISPOT positive, which resulted in low specificity and PPV.
Many of our patients without active TB were ELISPOT negative. In a study in Taiwan in 2001, 2.74% of preschool children were TST positive, and the annual estimated infection rate was 0.43% (1). Therefore, it is unlikely that all of our ELISPOT-negative patients had never been infected with M. tuberculosis. Furthermore, the results with samples from HCWs decrease the possibility that acute illness caused a false-negative result. Previous studies with sequential testing showed that responses of ESAT-6- or CFP-10-specific T cells decay progressively with treatment for TB (9,22,31-34). Our ELISPOT-negative patients may not have been recently infected with M. tuberculosis; thus, levels of their circulating ESAT-6- or CFP-10-specific effector effector /ef·fec·tor/ (e-fek´ter)
1. an agent that mediates a specific effect.
2. an organ that produces an effect in response to nerve stimulation. T cells, rather than memory T cells, decreased and failed to yield a positive ELISPOT result (35,36). Further long-term follow-up study of ELISPOT-positive TB patients is needed to better understand the dynamic changes in ESAT-6- or CFP-10-specific effector T cells.
Patients with AFS-negative TB should be further investigated because this type of TB is usually diagnosed late and has been reported to be responsible for [approximately equal to] 17% of TB transmission (37,38). Our study showed that all AFS-negative ELISPOT-positive patients had true cases of TB, i.e., PPV = 100%. Only 2 patients with TB pleurisy and negative sputum culture for M. tuberculosis showed false-negative ELISPOT results. The cause of this finding is not known because the current hypothesis for the pathogenesis of TB pleurisy is that the caseous caseous /ca·se·ous/ (ka´se-us) resembling cheese or curd; cheesy.
Of, relating to, or having the gross and microscopic features of tissue affected by caseation. material from a subpleural focus ruptures into the pleural space 6-12 weeks after a primary infection. This material then interacts with previously sensitized sensitized /sen·si·tized/ (sen´si-tizd) rendered sensitive.
see sensitization (2). T cells, which results in a delayed hypersensitivity reaction and accumulation of fluid (39, 40). The 2 patients with false-negative ELISPOT results might have been at a early stage of primary TB, and their sensitized T cells had not yet returned to the systemic circulation before sampling was conducted. Further investigation is needed to assess the performance of the ELISPOT assay in patients suspected of having TB with negative AFS results.
The resurgence of TB has prompted the need for sensitive, accurate, and fast methods for laboratory detection of M. tuberculosis infection. Although previous studies demonstrated that the ELISPOT assay for 1NF-[gamma] is a powerful tool for detecting latent M. tuberculosis infection, our results showed that in patients who were previously vaccinated with BCG, the diagnostic value of this test in detecting active TB approached 90% in sensitivity, specificity, PPV, and NPV, even in an area with a high incidence of NTM disease.
Dr Wang is an attending physician at the National Taiwan University Hospital National Taiwan University Hospital (NTUH, 國立台灣大學醫學院附設醫院) started operations under Japanese rule in Dadaocheng on June 18, 1895, and moved to its present location in 1898. and a student at the Graduate Institute of Clinical Medicine, National Taiwan University National Taiwan University (Traditional Chinese: 國立臺灣大學; Simplified Chinese: 国立台湾大学 . His primary research interest is pulmonary infectious disease, especially TB.
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Address for correspondence: Po-Ren Hsueh, Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Rd, Taipei, 100, Taiwan, Republic of China; email: firstname.lastname@example.org
Jann-Yuan Wang, * Chien-Hong Chou, * Li-Na Lee, * Hsiao-Leng Hsu, * I-Shiow Jan, * Po-Ren Hsueh, * Pan-Chyr Yang, * and Kwen-Tay Luh *
* National Taiwan University Hospital, Taipei, Taiwan, Republic of China
Table 1. Clinical characteristics of 65 patients suspected of having tuberculosis, Taiwan, 2005 * Characteristic Value Mean age, y (range) 52.2 (2-84) Male-female (% male) 37:28 (56.9) Underlying medical condition 35 (53.8) Malignancy 17 (26.2) Diabetes mellitus 12 (18.5) Other ([dagger]) 11 (16.9) Symptoms ([double dagger]) Cough or dyspnea [no. with hemoptysis] 44 (67.7)  Fever 35 (53.8) Mean duration of symptoms (range) 23.4 wk (2 wk- 5 y) Radiographic finding Upper lobe fibroexudative lesions 25 (38.5)  [no. with cavitation] Multiple patches of alveolar infiltrates 20 (30.8)  [no. with cavitation] Multiple nodules or mass 10 (15.4)  [no. with cavitation] Upper lobe fibrotic change 5 (7.7) Pleural effusion [no. with upper lobe 3 (4.6)  fibrotic change] Miliary lesion 2 (3.1) Acid-fast smear positive 33 (50.8) Mycobacterial culture 48 (73.8) Mycobacterium tuberculosis 37 (56.9) M. avium-intracellulare complex 2 (3.1) M. chelonae 2 (3.1) M. abscessus and M. chelonae 2 (3.1) M. abscessus 1 (1.5) M. marinum 1 (1.5) M. kansasii 1 (1.5) Unidentified species 2 (3.1) * Values are no. (%) unless otherwise indicated. ([dagger]) Underlying disease was alcoholism in 4 patients, AIDS in 3 patients, end-stage renal disease in 2 patients, Sjogren syndrome in 1 patient, and hepatitis B--related liver cirrhosis in 1 patient. ([double dagger]) Two patients were asymptomatic and had abnormal chest radiographs noted incidentally. Table 2. Correlation between results of enzyme-linked immunospot (ELISPOT) assay and diagnosis of 65 patients suspected of having tuberculosis (TB), Taiwan, 2005 No. samples TB (n = 39) No TB (n = 26) Results of acid- fast smears (no. ELISPOT ELISPOT samples) (+) (-) ELISPOT (+) ELISPOT (-) Positive (33) 19 3 3 8 Negative (32) 15 2 0 15 Total (65) 34 5 3 23 Results of acid- Predictive value, % fast smears (no. Sensi- Sensi- samples) tivity, % tivity, % Positive Negative Positive (33) 86.4 72.7 86.4 72.7 Negative (32) 88.2 100 100 88.2 Total (65) 87.2 88.5 91.9 82.1