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Original Research: TUBERCULOSIS |

Drug Lymphocyte Stimulation Test in the Diagnosis of Adverse Reactions to Antituberculosis Drugs FREE TO VIEW

Yuzo Suzuki, MD; Seiichi Miwa, MD, PhD; Masahiro Shirai, MD, PhD; Hisano Ohba, MD; Miho Murakami, MD; Kaoru Fujita, MD; Takafumi Suda, MD, PhD; Hirotoshi Nakamura, MD, PhD; Hiroshi Hayakawa, MD, PhD; Kingo Chida, MD, PhD
Author and Funding Information

*From the Second Division (Drs. Suzuki, Suda, Nakamura, and Chida), Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; and Department of Respiratory Medicine (Drs. Miwa, Shirai, Ohba, Murakami, Fujita, and Hayakawa), Tenryu Hospital, National Hospital Organization, Hamamatsu, Japan.

Correspondence to: Seiichi Miwa, MD, PhD, 4201-21 Oro, Hamamatsu, 434-8511, Japan; e-mail: hirosei@za.tnc.ne.jp

†These authors contributed equally to this work.


The authors have no conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2008;134(5):1027-1032. doi:10.1378/chest.07-3088
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Background:  Tuberculosis (TB) is a worldwide infectious disease. Recently, standard therapy has become very effective for treating patients with TB; however, as a result of this powerful regimen, serious side effects have become an important problem. The aim of this prospective study was to evaluate the usefulness of the drug lymphocyte stimulation test (DLST) to determine anti-TB drugs causing side effects.

Method:  Four hundred thirty-six patients with TB were admitted to our hospital for treatment between January 2002 and August 2007. DLST was performed in patients who had certain adverse drug reactions during TB treatment. The causative drug was identified by the drug provocation test (DPT). The tested drugs were mainly isoniazid (INH), rifampin (RIF), ethambutol (EMB) and pyrazinamide (PZA).

Results:  Of 436 patients, 69 patients (15.8%) had certain adverse drug reactions to anti-TB drugs. Of the 261 agents that underwent the DLST and DPT, 28 agents (10.7%) in 20 patients (28.9%) were positive by DLST, and 67 agents (25.7%) in 46 patients (66.6%) were identified as causative drugs by DPT. The sensitivity of DLST was only 14.9% for all drugs (INH, 14.3%; RIF, 13.6%; EMB, 14.3%; PZA, 0%).

Conclusions:  DLST offers little contribution to the detection of causative agents in patients with adverse anti-TB drug reactions.

Figures in this Article

Tuberculosis (TB) is a worldwide infectious disease and is occasionally life threatening. Current standard therapy consists of isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA), which is very effective for treating patients with TB14; however, as a result of these powerful regimens, serious side effects may occur.1,58 The most effective management of drug adverse reactions is discontinuation of the medication, and alternative medications with different chemical structures should be substituted.9 However, in TB treatment, first-line drugs, in particular INH and RIF, are the most important agents and their continued use should be attempted.

Approximately 10% of drug side effects are immunologically mediated,10 in which the diagnosis of adverse drug reaction is usually based on clinical judgment and not only in vitro methods such as the drug lymphocyte stimulation test (DLST), but also in vivo methods such as a challenge test or skin tests.

DLST is an in vitro method for diagnosing drug hypersensitivity.11,12 The scientific basis for DLST has been well established, and its usefulness has been demonstrated in various diseases with different drugs1317; however, for anti-TB drugs, only small studies have been reported,18,19 and there is little information on DLST for anti-TB drugs. In this study, we focused on the usefulness of DLST for determining drug-induced immune adverse reactions in patients with TB by comparing the results of the drug provocation test (DPT) and DLST.

This study was prospective and was approved by the ethics committee of our hospital, and informed consent was obtained according to hospital guidelines.

Subjects

Between January 2002 and August 2007, 455 TB patients without HIV infection who were admitted to Tenryu Hospital, National Hospital Organization for TB treatment were included in this study. TB was confirmed by the isolation of Mycobacterium tuberculosis from culture. Nineteen patients given parenteral treatment were excluded.

The 436 patients (mean age, 70.0 years; range, 26 to 95 years; 280 men and 156 women) had initially received first-line standard anti-TB therapy, including INH (5 mg/kg/d), RIF (10 mg/kg/d), and EMB (15 mg/kg/d), with or without PZA (25 mg/kg/d). During the clinical course, patients with first-line drug-induced adverse reactions were treated with paraminosalicylic acid (PAS) [200 mg/kg/d], streptomycin (SM) [15 mg/kg three times a week], levofloxacin (LVFX) [8 mg/kg/d], ethionamide (TH) [10 mg/kg/d], and/or cycloserine (10 mg/kg/d), alternatively.

Classification of Adverse Events

Adverse events were categorized as those related to eruption, hepatitis, or drug fever. Eruption was diagnosed based on the clinical manifestations, showing generalized morbilliform eruption.18 Hepatitis was defined as a liver transaminase value more than three times the upper limit of normal.1 The clinical hallmark of drug fever was defined as recurrence of fever despite microbiological and radiographic improvement by therapy for several weeks. Fever due to infection, including TB, was excluded.1 Drug-related fever spontaneously resolved when drugs were stopped. GI events and hematologic toxicity were excluded because they are normally not considered to be immune-mediated side effects.

DLST

Heparinized, 12.0-mL blood from patients with a possible drug adverse reaction was sedimented at 2,000 revolutions per minute for 5 min, and then 3,000 revolutions per minute for 5 min to obtain autologous plasma. The remaining pellets were centrifuged at 1,800 revolutions per minute for 20 min, and lymphocytes were isolated via density gradient centrifugation. After washing with phosphate-buffered saline solution at 2,000 revolutions per minute for 5 min twice, the cells were set to a cell density of 106 cells/mL and were floated in RPMI 1640 medium (SIGMA; St. Louis, MO) with 20% autologous plasma and a penicillin-streptomycin mixture but not with serum from type AB blood. The floated cells (200 μL per well) were seeded in 96-well dishes and cultured with the added drug in a 5% CO2 incubator for 5 days. We normally used drug doses of 1, 10, and 100 μg, but occasionally a lower or higher concentration (0.01 μg or 200 μg, 500 μg, and 1 mg) was used. The appropriate drug concentration was evaluated as the inhibitory capacity of the drug on phytohemagglutinin stimulation of the cells; thereafter, [3H] thymidine was added and the cells were incubated in 5% CO2. After 16 to 18 h, the cells were harvested and mitogenic activity was quantified by [3H] thymidine incorporation (count per minute) using a scintillation counter (PerkinElmer; Tokyo, Japan). The positive control was phytohemagglutinin, and the negative control was the same condition without the drug. Experiments were performed in triplicate. The stimulation index (SI) is defined as count per minute of the stimulation/count per minute of the negative control. DLST findings were considered positive if the SI was > 180%. All patients were assessed within 1 week after the initiation of adverse drug reactions. None of the patients were treated with glucocorticoids before the DLST was completed.

Identification of Drug Causing an Adverse Reaction

When drug adverse reactions were observed, all drugs were temporarily stopped. Resolved symptoms and laboratory data after withdrawal were confirmed, and then DPT was performed with careful observation and under informed consent. The usual dosage of each agent was administrated at intervals of 3 to 4 days according to American Thoracic Society guidelines.1 If the same adverse reaction occurred, the drug was stopped and considered DPT positive, and the next drug was started. We identified the causative drugs in accordance with the results of DPT.

Statistical Analysis

Statistical analysis was performed using the Mann-Whitney U test; p values < 0.05 were considered significant.

Clinical Characteristics

Of 436 patients, 69 patients (15.8%) [mean age, 70.0 years; range, 26 to 95 years; 33 men, 11.7%; 36 women, 23.0%] had certain adverse drug reactions to anti-TB drugs. As shown in Table 1, of the 69 patients, 52 had pulmonary TB alone, 12 had pulmonary TB and tuberculous pleurisy, and 5 had miliary TB. None of the patients had multidrug-resistant (MDR)-TB. Regarding underlying disease, 13 patients had chronic respiratory disease, 7 patients had sequelae of TB, and 6 patients had viral hepatitis (hepatitis B virus, n = 2; hepatitis C virus, n = 4). Three patients had an allergic history (foods, n = 2; unknown drug, n = 1). Initial treatment of TB was with INH, RIF, EMB, and PZA in 61 patients, and INH, RIF, and EMB in 8 patients. The five deaths during TB treatment were three cases of aspiration pneumonia and one each of advanced cancer and malnutrition. No deaths resulted from side effects of anti-TB drugs.

Table Graphic Jump Location
Table 1 Characteristics of Patients With Anti-TB Drug-Induced Adverse Reaction*

*Data are presented as No. unless otherwise indicated.

Adverse Events

There were 84 events of adverse drug reactions in 69 TB patients (Table 2). Eruption showed 44 events; hepatitis, 29 events; fever, 9 events; and eosinophilic pneumonia, 2 events. Time of onset was 45.3 ± 7.6 days for eruption, 28.8 ± 5.2 days for hepatitis, 35.6 ± 11.7 days for fever, and 18.5 ± 6.5 days for eosinophilic pneumonia, respectively. Several adverse reactions occurred in 16 patients; reactions occurred at the same time in 9 patients and separately in 7 patients.

Table Graphic Jump Location
Table 2 Adverse Reactions

*Mean ± SE.

Laboratory Findings

As shown in Table 3, when laboratory data were compared, the percentage of lymphocytes in DLST-positive patients was statistically higher than in DLST-negative patients (p = 0.048); however, there was no significant difference regarding DLST control (counts per minute).

Table Graphic Jump Location
Table 3 Laboratory Findings*

*Data are presented as mean ± SE unless otherwise indicated. GOT = glutamic oxaloacetic transaminase; GPT = glutamic pyruvic transaminase; NS = not significant; cpm = counts per minute.

†On admission.

‡At the time of DLST.

Comparison of DLST With DPT

As shown in Table 4, of 261 agents assessed by DLST, 28 agents (10.7%) in 20 patients (28.9%) were positive (INH, n = 15; RIF, n = 5; EMB, n = 4; PZA, n = 0; SM, n = 2; LVFX, n = 1; PAS, n = 1), whereas 67 agents (25.7%) [INH, n = 21; RIF, n = 22; EMB, n = 14; PZA, n = 6; SM, n = 1; TH, n = 1; PAS, n = 2] were identified as causative drugs in 46 patients (66.6%) by DPT. DPT did not cause adverse reactions in 23 patients (23.4%). There was no significant difference in SI between DPT-positive and DPT-negative drugs in DLST (Fig 1). As shown in Table 5, while the sensitivity of DLST was only 14.9% for all drugs (INH, 14.3%; RIF, 13.6%; EMB, 14.3%; PZA, 0%), the specificity was 90.7% for all drugs (INH, 74.5%; RIF, 95.7%; EMB, 96.2%; PZA, 100%). The false-positive rate was 9.3% for all drugs (INH, 25.5%; RIF, 4.3%; EMB, 3.8; PZA, 0%). According to each adverse reaction, there was also little difference in the sensitivity and specificity of eruption (16.7%, 88.3%), hepatitis (13.0%, 94.1%), and fever (20.0%, 90.0%), respectively. Overall, the false-positive rate for INH was higher than that for other drugs.

Table Graphic Jump Location
Table 4 Results of DLST and DPT
Figure Jump LinkFigure 1 Analysis of differences in SI between DPT-positive and DPT-negative casesGrahic Jump Location
Table Graphic Jump Location
Table 5 Sensitivity of DLST*

*Data are presented as %.

In this study, we prospectively analyzed TB patients who had certain adverse drug reactions to evaluate the sensitivity of DLST. Notably, DLST contributed little to identifying the causative anti-TB drugs.

DPT is generally accepted as the “gold standard” for allergy tests11,20; however, because intentional reproduction of drug adverse reactions is thought to be unethical, DPT should only be considered after balancing the risk-benefit ratio in individual patients.11,20 In this study, careful observation and frequent laboratory testing did not induce life-threatening complications, such as hepatic insufficiency or Stevens-Johnson syndrome/toxic epidermal necrosis. Interestingly, in this study, 23 patients (23.4%) were not reexposed to adverse reactions by DPT. Although the mechanism remains to be understood, it is possible that, initially, the combination of several anti-TB drugs yielded a complicated drug interaction, eliciting adverse drug reactions. After the drug adverse reactions resolved, drugs were administered separately for DPT, so spontaneous desensitization may have been induced.

DLST, which measures the incorporation of [3H] thymidine during DNA synthesis for the proliferation of T cells in reaction to a drug, is a unique in vitro method to identify the causative drug of adverse reactions.11,12 If performed correctly, it is not only safe for patients but also a generally accepted in vitro test, at least in our institutions; however, DLST is controversial for several reasons, one of which is that its sensitivity differs greatly among published reports. Several studies have examined the usefulness of DLST with many different drugs in different diseases. For example, Everness et al13 reported a sensitivity of 92% in 66 patients with nickel allergy, Luque et al14 showed a sensitivity of 62% with β-lactams, and Warrington et al15 revealed a sensitivity of 50% with INH-induced hepatitis. Moreover, Nyfeler and Pichler16 and Kano et al17 concluded that DLST was a reliable method to support the diagnosis of a drug allergy. In contrast, consistent with the present study, a lower sensitivity of 33% was observed by Barna et al21 and 38% by Berg et al.22 Matsuno et al23 showed that DLST was not useful to diagnose drug-induced pneumonia. In particular, our study showed that the sensitivity of DLST for PZA was 0%. Thus, we consider that the sensitivity of DLST depends on the tested drug or examined disease. Second, because the pathogenesis of drug adverse reactions is complicated, the immune response of T cells themselves does not explain the various clinical adverse reactions, and we should interpret DLST results as an indication of T-cell sensitization.

Contrary to the low sensitivity, the relatively higher specificity was due to the fact that the false-positive rate was low, except for INH. Consistent with our result, Nyfeler and Pichler16 reported that nonsteroidal antiinflammatory drugs comprised the majority of false-positive cases, although it was unclear why T cells of only some but not all patients proliferated better than after the addition of INH or nonsteroidal antiinflammatory drugs. Therefore, for diagnosis, other approaches, such as a detailed history, skin tests, determination of specific IgE, or DPT, should be used.

Recently, PZA has become an important first-line drug as the most effective TB chemotherapy, along with INH, RIF, and EMB.1 The incidence of PZA-induced side effects is substantially higher than INH or RIF, and it was reported that elderly patients were at increased risk of adverse reactions2426; however, in the present study, the DPT-positive result for PZA was 12.8%. Furthermore, in our TB patients, older patients did not have a greater risk with PZA treatment (data not shown), and we consider that PZA is comparatively easy to use.

There are several limitations of the present study. First, all patients were investigated 1 week after initiation of adverse drug reactions. Usually, a disease-free interval of 4 to 24 weeks is proposed for the performance of diagnostic tests because the response of T memory lymphocytes develops later; however, since therapy needs to be initiated, we consider that later DLST is of no clinical use. Second, this study had no healthy control group. We actually tried to perform the DLST on healthy people, but we could not obtain informed consent. Further study is needed to clarify these problems in the future.

In summary, in patients with anti-TB drug-induced reactions, the diagnostic value of DLST is considered to be minimal. Clinically, we recommend DPT for anti-TB drug-induced reactions.

DLST

drug lymphocyte stimulation test

DPT

drug provocation test

EMB

ethambutol

INH

isoniazid

LVFX

levofloxacin

MDR

multidrug resistant

PAS

paraminosalicylic acid

PZA

pyrazinamide

RIF

rifampin

SI

stimulation index

SM

streptomycin

TB

tuberculosis

TH

ethionamide

Treatment of tuberculosis.Joint Statement of the American Thoracic Society (ATS), Center for Disease Control and Prevention, and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2003;167:603-662. [PubMed] [CrossRef]
 
East African/BMJ Research Council Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet. 1973;1:1331-1339. [PubMed]
 
British Thoracic Association A controlled trial of six months of chemotherapy in pulmonary tuberculosis: second report; results during the 24 months after the end of chemotherapy. Am Rev Respir Dis. 1982;126:460-462. [PubMed]
 
Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis. 1986;133:423-430. [PubMed]
 
An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174:935-952. [PubMed]
 
Combs DL, O'Brien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability. Ann Intern Med. 1990;112:397-406. [PubMed]
 
Westphal JF, Vetter D, Brogard JM. Hepatic side-effects of antibiotics. J Antimicrob Chemother. 1994;33:387-401. [PubMed]
 
Dutt AK, Moers D, Stead WW. Undesirable side-effects of isoniazid and rifampin on largely twice weekly short-course chemotherapy for tuberculosis. Am Rev Respir Dis. 1994;128:419-424
 
Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003;68:1781-1790. [PubMed]
 
Gruchalla RS. Drug allergy. J Allergy Clin Immunol. 2003;111:548-559
 
Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy. 2004;59:809-820. [PubMed]
 
Beeler A, Pichler WJ.Pichler WJ. In vitrotests of T-cell-mediated drug hypersensitivity. Drug hypersensitivity. 2007;:380-390
 
Everness KM, Gawkrodger DJ, Botham PA, et al. The discrimination between nickel-sensitive and non-nickel-sensitive subjects by anin vitrolymphocyte transformation test. Br J Dermatol. 1990;122:293-298. [PubMed]
 
Luque I, Leyva L, Jose Torres M, et al. In vitroT-cell responses to β-lactam drugs in immediate and nonimmediate allergic reactions. Allergy. 2001;56:611-618. [PubMed]
 
Warrington RJ, McPhilips-Feener S, Rutherford WJ. The predictive value of the lymphocyte transformation test in isoniazid-associated hepatitis. Clin Allergy. 1982;12:217-222. [PubMed]
 
Nyfeler B, Pichler WJ. The lymphocyte transformation test for the diagnosis of drug allergy: sensitivity and specificity. Clin Exp Allergy. 1997;27:175-181. [PubMed]
 
Kano Y, Hirahara K, Mitsuyama Y, et al. Utility of lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy. 2007;62:1439-1444. [PubMed]
 
Schreiber J, Zissel G, Greinert U, et al. Lymphocyte transformation test for the evaluation of adverse effects of antituberculous drugs. Eur J Med Res. 1999;25:67-71
 
Miyazawa T, Doi M, Mineshita M, et al. Comparison of lymphocyte stimulation test results and challenge test results in 19 cases of antituberculous drug-induced allergy. Nihon Kyobu Shikkan Gakkai Zasshi. 1993;31:920-923. [PubMed]
 
Aberer W, Bircher A, Romano A, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy. 2003;58:854-863. [PubMed]
 
Barna BP, Gogate P, Deodhar SD, et al. Lymphocyte transformation and radioallergosorbent tests in drug hypersensitivity. Am Soc Clin Pathol. 1980;73:172-176
 
Berg PA, Brattig N, Diao GJ, et al. Diagnose arzneimittel-bedingter Nebenwirkungen mit Hilfe des Lymphozytentransformationstests. Allergologie. 1983;6:77-81
 
Matsuno O, Okubo T, Hiroshige S, et al. Drug-induced lymphocyte stimulation test is not useful for the diagnosis of drug-induced pneumonia. Tohoku J Exp Med. 2007;212:49-53. [PubMed]
 
Schaberg T, Rebhan K, Lode H. Risk factor for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J. 1996;9:2026-2030. [PubMed]
 
Yee D, Valiqutte C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003;167:1472-1477. [PubMed]
 
Marra F, Marra CA, Bruchet N, et al. Adverse drug reactions associated with first-line antituberculosis drug regimen. Int J Tuberc Lung Dis. 2007;11:868-875. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Analysis of differences in SI between DPT-positive and DPT-negative casesGrahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Characteristics of Patients With Anti-TB Drug-Induced Adverse Reaction*

*Data are presented as No. unless otherwise indicated.

Table Graphic Jump Location
Table 2 Adverse Reactions

*Mean ± SE.

Table Graphic Jump Location
Table 3 Laboratory Findings*

*Data are presented as mean ± SE unless otherwise indicated. GOT = glutamic oxaloacetic transaminase; GPT = glutamic pyruvic transaminase; NS = not significant; cpm = counts per minute.

†On admission.

‡At the time of DLST.

Table Graphic Jump Location
Table 4 Results of DLST and DPT
Table Graphic Jump Location
Table 5 Sensitivity of DLST*

*Data are presented as %.

References

Treatment of tuberculosis.Joint Statement of the American Thoracic Society (ATS), Center for Disease Control and Prevention, and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2003;167:603-662. [PubMed] [CrossRef]
 
East African/BMJ Research Council Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet. 1973;1:1331-1339. [PubMed]
 
British Thoracic Association A controlled trial of six months of chemotherapy in pulmonary tuberculosis: second report; results during the 24 months after the end of chemotherapy. Am Rev Respir Dis. 1982;126:460-462. [PubMed]
 
Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis. 1986;133:423-430. [PubMed]
 
An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174:935-952. [PubMed]
 
Combs DL, O'Brien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability. Ann Intern Med. 1990;112:397-406. [PubMed]
 
Westphal JF, Vetter D, Brogard JM. Hepatic side-effects of antibiotics. J Antimicrob Chemother. 1994;33:387-401. [PubMed]
 
Dutt AK, Moers D, Stead WW. Undesirable side-effects of isoniazid and rifampin on largely twice weekly short-course chemotherapy for tuberculosis. Am Rev Respir Dis. 1994;128:419-424
 
Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003;68:1781-1790. [PubMed]
 
Gruchalla RS. Drug allergy. J Allergy Clin Immunol. 2003;111:548-559
 
Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy. 2004;59:809-820. [PubMed]
 
Beeler A, Pichler WJ.Pichler WJ. In vitrotests of T-cell-mediated drug hypersensitivity. Drug hypersensitivity. 2007;:380-390
 
Everness KM, Gawkrodger DJ, Botham PA, et al. The discrimination between nickel-sensitive and non-nickel-sensitive subjects by anin vitrolymphocyte transformation test. Br J Dermatol. 1990;122:293-298. [PubMed]
 
Luque I, Leyva L, Jose Torres M, et al. In vitroT-cell responses to β-lactam drugs in immediate and nonimmediate allergic reactions. Allergy. 2001;56:611-618. [PubMed]
 
Warrington RJ, McPhilips-Feener S, Rutherford WJ. The predictive value of the lymphocyte transformation test in isoniazid-associated hepatitis. Clin Allergy. 1982;12:217-222. [PubMed]
 
Nyfeler B, Pichler WJ. The lymphocyte transformation test for the diagnosis of drug allergy: sensitivity and specificity. Clin Exp Allergy. 1997;27:175-181. [PubMed]
 
Kano Y, Hirahara K, Mitsuyama Y, et al. Utility of lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy. 2007;62:1439-1444. [PubMed]
 
Schreiber J, Zissel G, Greinert U, et al. Lymphocyte transformation test for the evaluation of adverse effects of antituberculous drugs. Eur J Med Res. 1999;25:67-71
 
Miyazawa T, Doi M, Mineshita M, et al. Comparison of lymphocyte stimulation test results and challenge test results in 19 cases of antituberculous drug-induced allergy. Nihon Kyobu Shikkan Gakkai Zasshi. 1993;31:920-923. [PubMed]
 
Aberer W, Bircher A, Romano A, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy. 2003;58:854-863. [PubMed]
 
Barna BP, Gogate P, Deodhar SD, et al. Lymphocyte transformation and radioallergosorbent tests in drug hypersensitivity. Am Soc Clin Pathol. 1980;73:172-176
 
Berg PA, Brattig N, Diao GJ, et al. Diagnose arzneimittel-bedingter Nebenwirkungen mit Hilfe des Lymphozytentransformationstests. Allergologie. 1983;6:77-81
 
Matsuno O, Okubo T, Hiroshige S, et al. Drug-induced lymphocyte stimulation test is not useful for the diagnosis of drug-induced pneumonia. Tohoku J Exp Med. 2007;212:49-53. [PubMed]
 
Schaberg T, Rebhan K, Lode H. Risk factor for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis. Eur Respir J. 1996;9:2026-2030. [PubMed]
 
Yee D, Valiqutte C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003;167:1472-1477. [PubMed]
 
Marra F, Marra CA, Bruchet N, et al. Adverse drug reactions associated with first-line antituberculosis drug regimen. Int J Tuberc Lung Dis. 2007;11:868-875. [PubMed]
 
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