Inflammation Precedes Paradoxical Reactions in HIV-Negative Patients With Pulmonary Tuberculosis

"Paradoxical reactions" are a poorly understood phenomenon of clinical worsening during adequate antibiotic tuberculosis treatment. We aimed to characterize and predict paradoxical reactions using clinical, microbiological, and inflammatory factors in human immunodeficiency virus (HIV)-negative patients with pulmonary tuberculosis.

We closely monitored HIV-negative patients aged ≥16 years who were admitted to a Dutch referral center. Paradoxical reactions were defined as new or increased tachypnea with hypoxemia or new or increased need for supplemental oxygen, after exclusion of alternative causes. Blood inflammatory parameters at onset of paradoxical reaction, and 1 and 2 weeks prior were matched for treatment duration to those of patients without paradoxical reactions and compared using Stouffer z scores. Baseline and longitudinal mycobacterial load, clinical parameters, chest radiographic involvement, and antibiotic plasma concentrations were assessed for association with paradoxical reactions.

Among 81 HIV-negative patients with pulmonary tuberculosis, 19 (24%) experienced a paradoxical reaction, after a median of 13 days of antituberculosis treatment (interquartile range, 8-18 days). Paradoxical reactions were characterized by higher C-reactive protein level (Stouffer z = 4.22), neutrophil count (z = 3.65), neutrophil-to-lymphocyte ratio (z = 4.94), and ferritin level (z = 4.12) and lower lymphocyte count (z = -3.26), monocyte count (z = -4.72), albumin level (z = -6.33), and hemoglobin level (z = -2.32). More extensive lung involvement and higher mycobacterial loads at initiation of antituberculosis treatment were associated with paradoxical reactions. Antituberculosis drug levels were adequate, and mycobacterial loads declined in both groups. High C-reactive protein and neutrophil-to-lymphocyte ratio and lymphopenia at initiation of antituberculosis treatment predicted paradoxical reactions.

Paradoxical reactions in HIV-negative individuals with pulmonary tuberculosis concur with, and are preceded by, outspoken systemic inflammation. Baseline inflammatory parameters may guide future stratified preemptive immunomodulation.