We retrospectively reviewed the data of all patients who received treatment for active TB at the Chonnam National University Hospital between January 2010 and December 2014. Patients with peripheral blood eosinophilia during anti-TB treatment were included in this study. Patients transferred to another institution before treatment completion, those with peripheral blood eosinophilia before anti-TB treatment, those lost to follow-up, and those started on anti-TB drugs in other hospitals were excluded.

TB was diagnosed based on Mycobacterium tuberculosis identification with culture or polymerase chain reaction from clinical specimens, or on clinical, radiological, or histological findings compatible with TB and responses to anti-TB treatment. In Korea, a 6-month regimen consisting of a 2-month initial phase of isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by a 4-month continuation phase of isoniazid, rifampicin, and ethambutol has been recommended by the National Tuberculosis Program [17]. Alternatively, a 9-month regimen with isoniazid, rifampin, and ethambutol can be administered. Therefore, all patients in this study received daily therapy consisting of isoniazid (300 mg), rifampin (450 to 600 mg), and ethambutol (800 to 1,200 mg), with or without pyrazinamide (1,500 mg). However, the decision to include pyrazinamide in the initial regimen was made by clinicians based on each patient’s clinical situation. All patients with TB in our hospital were registered in a TB registry and received health education as well as monitoring for drug compliance and ADRs during treatment by specially trained nurses who participate in the Public-Private Mix project for TB control in Korea [18]. Anti-TB drugs were self-administered with the support of trained nurses. At each clinic visit, treatment adherence was assessed by asking patients about drug intake and checking the tablets remaining from the previously prescribed regimen. In our hospital, all patients with TB underwent laboratory examinations, including complete blood cell count, liver function tests, renal function tests, and C-reactive protein, before treatment and at every hospital visit, which was scheduled every 1 to 2 months during treatment; if patients had symptoms related to ADRs, including fatigue, rash, and fever, additional laboratory examinations were performed.

The protocol of this retrospective observational study was approved by the Chonnam National University Hospital Institutional Review Board, and the requirement for informed consent was waived because of the retrospective nature of this study (IRB number, CNUH 2018-160).

Eosinophilia was defined as blood eosinophil count above 5% of total white blood cell count [19]. During a period of eosinophilia, initial peripheral counts and percentages, defined as eosinophil counts and percentages at first detection of eosinophilia, and peak eosinophil counts and percentages, defined as the highest eosinophil counts and percentages, were analyzed to evaluate the differences between patients with and without CADRs.

CADRs were defined as newly developed skin reactions including pruritus, skin rash, DRESS, and SJS/TEN during anti-TB treatment that were accompanied by peripheral blood eosinophilia. SJS/TEN was defined as epidermal detachment and mucous membrane erosion [20]. Patients with CADRs were divided into four groups based on the severity of CADRs. Group 1 had no CADRs, group 2 had itching without skin rash, group 3 had skin rash with or without itching, and group 4 had DRESS syndrome, SJS/TEN, and an uncontrolled skin rash and/or fever requiring discontinuation of anti-TB drugs.

Abnormal liver function was defined as elevated serum aminotransferase levels more than two times the upper normal limit that were accompanied by peripheral blood eosinophilia [21]. Abnormal renal function was defined as elevated serum creatinine levels more than 1.5 times baseline that were accompanied by peripheral blood eosinophilia [22].

An offending drug was identified when symptoms and signs resolved after drug withdrawal and recurred after rechallenge with that drug.

All data are expressed as medians and interquartile range (IQR) or as numbers (percentages) in the text and tables. Intergroup comparisons were performed using the Mann-Whitney U test for continuous variables, and Pearson’s chi-square test or Fisher’s exact test for categorical variables. We evaluated trends using the Jonckheere-Terpstra test. Bonferroni tests were used for post hoc correction to account for multiple comparisons. Variables that were statistically significant in univariate analysis were included in multivariable binary logistic regression analysis to determine predictors for CADRs. The level of significance was set at p < 0.05. Data were analyzed using SPSS for Windows version 22.0 (IBM Co., Armonk, NY, USA).

Of 2,234 patients who received standard anti-TB treatment during the study period, 397 (17.8%) had peripheral blood eosinophilia during treatment. Of 397 with peripheral blood eosinophilia, the following were excluded: those transferred to another institution before treatment completion (n = 58), those with peripheral blood eosinophilia before starting anti-TB drugs (n = 20), those lost to follow-up (n = 37), and those started on anti-TB drugs in other hospitals (n = 20). Finally, we enrolled 262 patients with peripheral blood eosinophilia and evaluated the clinical and laboratory findings (Fig. 1).

The median patient age was 60 years (IQR, 45 to 73), and 66.8% were men. CADRs were present in 161 (61.5%) of 262 patients with peripheral blood eosinophilia. The median blood eosinophil counts and percentage before start of anti-TB treatment were 110/mm³ (IQR, 70 to 200) and 1.9% (IQR, 0.9 to 3.1), respectively; there was no difference in median blood eosinophil counts between patients with and without CADRs (100 vs. 130, p = 0.177) or in the median blood eosinophil percentage (1.7 vs. 2.1, p = 0.429). Among 161 patients with CADRs, skin rash was the most common presentation, followed by pruritus. The median blood eosinophil counts and percentage at start of CADRs were 400/mm³ (IQR, 300 to 500) and 6.2% (IQR, 5.4 to 7.7), respectively. The peak blood eosinophil count and percentage were 465/mm³ (IQR, 300 to 650) and 7.7% (IQR, 6.0 to 10.7), respectively (Table 1). More than half of the patients (53.1%) developed peripheral blood eosinophilia within 4 weeks after anti-TB treatment (Fig. 2). Ninety-five patients (36.3%) had CADRs associated with eosinophilia within 4 weeks. Patients with peripheral blood eosinophilia within 4 weeks had a higher rate of CADRs than patients with eosinophilia after 4 weeks (68.3% vs. 54.5%, p = 0.022).

In multivariate analysis, older age, abnormal liver function, and higher peak blood eosinophil percentage were associated with CADRs (Table 2). The initial and peak blood eosinophil counts and eosinophil percentages tended to increase with the degree of clinical severity of CADRs caused by the anti-TB drug (Jonckheere-Terpstra test, p < 0.001) (Table 3).

Twenty-seven (10.3%) of 262 patients did not continue anti-TB drugs. The most common reasons for discontinuation were drug rash (44.4%) and drug fever (25.9%), followed by DRESS (25.9%). The most common offending drug was ethambutol, followed by pyrazinamide and rifampin (Table 4).