A Radboudumc study published in Open Forum Infectious Diseases identifies an inflammatory pattern that develops before paradoxical reactions in HIV-negative patients with pulmonary tuberculosis. The findings offer clues for earlier recognition and may help guide future research into targeted anti-inflammatory treatment.
Some patients with tuberculosis temporarily become much sicker after starting antibiotics, even when the treatment itself is working. Symptoms can worsen so severely that intensive care is needed, and in rare cases the reaction can be fatal. This phenomenon is known as a paradoxical reaction.
It has long been suspected that excessive inflammation plays a role, but evidence in people with tuberculosis who do not have HIV has been limited. New research from Radboudumc now shows that these reactions coincide with a clear rise in systemic inflammation, which starts to develop one to two weeks beforehand.
Treatment is working, but symptoms worsen
PhD candidate Lisa Kurver analyzed patients participating in the Radboudumc Mycobacterial Cohort Study, or MyCoS, which she helped establish in 2022. The cohort brings together expertise from internal medicine, pulmonary diseases, medical microbiology, and pharmacy within the Research Program Mycobacterial Diseases.
The detailed clinical data collected within MyCoS allowed the researchers to investigate whether worsening symptoms could be explained by inadequate treatment. Antibiotic drug levels were sufficient, while the amount of tuberculosis bacteria in sputum declined as expected, including in patients who developed a paradoxical reaction.
“The striking thing about a paradoxical reaction is that patients can become sicker while the antibiotics are actually doing their job,” says first author Lisa Kurver. “By looking at drug levels and bacterial load, we could show that treatment failure did not explain this deterioration.”
Inflammation rises before symptoms worsen
Under the supervision of Arjan van Laarhoven, Kurver found a clear inflammatory pattern in patients who developed paradoxical reactions. They had higher levels of C-reactive protein, or CRP, a higher neutrophil-to-lymphocyte ratio, and lower albumin levels.
Importantly, these changes were already starting to develop one to two weeks before the paradoxical reaction became clinically apparent.
“The inflammatory pattern was already developing before patients clinically deteriorated,” says Van Laarhoven. “That opens the possibility of identifying patients at risk earlier and, in future studies, testing whether targeted anti-inflammatory treatment can prevent severe reactions.”
Toward earlier and more targeted treatment
The findings strengthen the idea that excessive inflammation is an important driver of paradoxical reactions in tuberculosis. Anti-inflammatory drugs are already sometimes used off-label in severe cases, but evidence to guide their use remains limited.
In the future, inflammatory markers may help identify patients who are at increased risk before symptoms worsen. This could support clinical trials of more targeted, preventive immunomodulatory treatment and ultimately help reduce severe complications.
About the publication
Kurver L, Klein Teeselink E, Koele SE, et al. (2026). Inflammation Precedes Paradoxical Reactions in HIV-Negative Patients With Pulmonary Tuberculosis. Open Forum Infectious Diseases, 13(10), ofag493. DOI: 10.1093/ofid/ofag493.
