Clinical and immunological predictors of paradoxical reactions in patients with tuberculous lymphadenitis

Abstract Background & Aim Tuberculous paradoxical reaction in HIV-negative patients is rare and not well understood. This study aimed to determine the incidence of paradoxical reaction and identify clinical and immunological predictors contributing to its development. Methods Patients with tuberculous lymphadenitis on anti-tuberculous therapy were monitored for paradoxical reaction. Clinical, histopathological, microbiological, and immunological parameters of paradoxical reaction (n=10) and no paradoxical reaction (n=66) groups were analysed at baseline, 2 months, and 6 months. Peripheral blood mononuclear cells from paradoxical reaction (n=9) and no paradoxical reaction (n=13) patients were stimulated with TB-ESAT peptide, and mRNA expressions of cytokines (IL-4, IL-10, IL-12, TNF-α, IFN-γ) and transcription factors (T-bet, GATA-3) were quantified. Results Paradoxical reaction incidence was 5.7% (4/70); six patients presented with paradoxical reaction at baseline. The mean paradoxical reaction onset was 3.25 months. Absence of necrosis at baseline was a significant predictor (OR: 0.069; p=0.039). IL-10 mRNA at 2 months and IL-12 mRNA at 6 months increased in the paradoxical reaction compared to no paradoxical reaction (p=0.05). In paradoxical reaction, baseline T-bet mRNA correlated with IFN-γ (r=0.79, p<0.01) and TNF-α (baseline: r=0.97, p<0.000; 2 months: r=0.86, p<0.002). In NPR, T-bet mRNA correlated with IFN-γ and TNF-α at all time points (p<0.05), while GATA-3 mRNA correlated with IL-4 and IL-10 at 2 and 6 months (p<0.05). Conclusion Differential Th1/Th2 regulation driven by transcriptional factors alters cytokine expression, influencing paradoxical reaction. Further transcriptomic/proteomic studies are needed to elucidate immune mechanisms for precise therapeutic intervention.