Factors associated with false negative interferon-γ release assay results in patients with tuberculosis: A systematic review with meta-analysis

Abstract

Which factors are related to false negative results of the interferon-γ release assay (IGRA) is unclear. This systematic review described the risk factors associated with false negative IGRA results. Two authors independently identified studies designed to evaluate risk factors for false negative IGRA results from PubMed, the Cochrane Register of Control Trial database, and EMBASE, accessed on October 22, 2018. Meta-analyses were conducted with random-effect models, and heterogeneity was calculated with the I² method. Of 1,377 titles and abstracts screened, 47 full texts were selected for review, and we finally included 17 studies in this systematic review. The most commonly studied risk factor (14 studies) was advanced age, followed by low peripheral lymphocyte counts (7 studies), and these factors were associated with false negative results even with different tuberculosis incidences (pooled odds ratio 2.06; 95% CI, 1.68-2.52 in advanced age and 2.68; 95% CI, 2.00-3.61 in low peripheral lymphocyte counts). Advanced age and low peripheral lymphocyte counts may be common risk factors for false negative IGRA results, suggesting that people with these factors need to be carefully followed, even if they have negative IGRA results.

Figure 1

Flow diagram of the study selection. *Eighteen studies are not shown because the results from Denmark (low-incidence country) and Tanzania (high-incidence country) were reported collectively in a single study, so the total number of studies was 17. **Smoking, hospitalization, immunosuppressive conditions, immunosuppressive therapy, malignancy, CRP, low albumin, and HLA type (DRB1*0701 alleles): n = 1.

Figure 2

Forest plot for estimating the possibility of advanced age as a risk factor for false negative IGRA results.

Figure 3

Forest plot for estimating the possibility of low peripheral lymphocyte counts as a risk factor for false negative IGRA results.

Figure 4

Forest plot for estimating the possibility of HIV positivity as a risk factor for false negative IGRA results.

Figure 5

Forest plot for estimating the possibility of extrapulmonary TB as a whole (a) and CNS TB specifically (b) as risk factors for false negative IGRA results.

Figure 6

Forest plot for estimating the possibility of the BMI as a risk factor for false negative IGRA results.