Tuberculosis remains a major global public health challenge. According to the World Health Organization (WHO) in 2024, approximately 10.7 million people contracted the disease, resulting in 1.23 million deaths [1].

Despite ongoing eradication efforts, incidence remains high, although mortality has declined due to the demonstrated effectiveness of current first-line therapies [2].

The principal challenges today lie in expanding therapeutic coverage in developing countries and in detecting and managing resistant forms of tuberculosis [3].

Paradoxical Reaction (PR) is defined as the worsening of clinical signs or the appearance of new lesions despite Appropriate Antituberculosis Treatment (ATT), in the absence of other explanations such as resistance, intercurrent infection, or drug toxicity. It is therefore considered a diagnosis of exclusion [4][5]. It is more frequently observed and better understood in patients co-infected with Human Immunodeficiency Virus (HIV), particularly following the initiation of Antiretroviral Therapy (ART) [6][7]. Its incidence in HIV-positive patients with tuberculosis ranges from 3% to 25%, typically occurring 2 - 8 weeks after ART initiation. These reactions are most often seen in extrapulmonary and miliary forms of the disease [4]. Risk factors include high mycobacterial load, extrapulmonary involvement, and immunosuppression such as malnutrition [9]. Although less common, PR has also been reported in HIV-negative patients. The pathophysiological mechanism appears similar, attributed to the release of bacterial antigens following treatment-induced macrophage lysis [10][11].

Such cases can create diagnostic uncertainty and complicate management, particularly when the patient is initially immunocompetent.

Here, we report a case of miliary tuberculosis presenting as a paradoxical reaction in a severely malnourished patient initially treated for pulmonary tuberculosis.

The patient was a 31-year-old Congolese housewife, mother of six, with no prior history of tuberculosis exposure but severely malnourished (BMI 14 kg/m²). She was transferred to the Bukavu Provincial General Referential Hospital (HPGRB) for suspected pulmonary tuberculosis. On admission, her complaints included chronic cough, evening and nighttime fever, and progressive deterioration of health.

The illness had begun approximately four months earlier, characterized by a productive cough with yellowish sputum (without hemoptysis), chest pain without dyspnea, evening and nighttime fever, night sweats without chills, anorexia, and unintentional weight loss.

She had previously undergone several consultations where nonspecific antibiotic therapy was prescribed, but without improvement.

On admission, clinical examination revealed fever (38.9˚C), severe asthenia, pallor of the skin and mucous membranes, polypnea, and diminished breath sounds throughout the left lung field and the lower third of the right lung.

Laboratory investigations showed leukocytosis (12,310 cells/μL) with neutrophilia (11,079 cells/μL) and lymphopenia (923 cells/μL). C-reactive protein was markedly elevated (>300 mg/L). Additional findings included compensated normocytic hypochromic anemia (hemoglobin 9.7 g/dL; MCV 85 fL; MCHC 34 g/dL), electrolyte disturbances (hyponatremia 132 mmol/L, hypocalcemia 1.09 mmol/L, hypomagnesemia 1.09 mmol/L), mild hypoalbuminemia (3.3 g/dL), and total protein of 6.3 g/dL. Liver function tests (AST, ALT) were within normal limits. Ziehl-Neelsen staining of sputum was negative, as was the polymerase chain reaction for Mycobacterium tuberculosis testing (GeneXpert^®). The limited technical facilities did not allow for the mycobacterial culture to be carried out. The diagnosis was therefore strictly clinical and radiological.

Chest X-ray (Figure 1) showed bilateral diffuse interstitial pneumonia, presumed bacterial.

Figure 1. Initial chest X-ray showing bilateral infiltrative reticular opacities.

Given the chronic nature of her condition and lack of improvement after several courses of nonspecific antibiotics (Amikacin, Augmentin®), a standard weight-based antituberculosis regimen was initiated: isoniazid 300 mg daily, rifampicin 600 mg, ethambutol 800 mg, and pyrazinamide 1000 mg. Electrolyte correction and nutritional support were also provided. The clinical picture was consistent with smear-negative pulmonary tuberculosis.

Initial evolution was favorable, with resolution of fever, regression of pulmonary symptoms, and weight gain of 3 kg.

On day 13, however, the patient became febrile again. CRP rose above 300 mg/L, whereas it had decreased to 24 mg/L at day 6 follow-up. The clinical context initially suggested nosocomial infection.

Examination revealed no signs of secondary infection; blood cultures were negative, and empiric antimalarial therapy provided no improvement. Persistent fevers (38.5˚C - 40˚C) were unresponsive to antipyretics and broad-spectrum antibiotics (Levofloxacin, Ceftriaxone).

After ruling out drug resistance and concurrent illness, the most likely diagnosis was a paradoxical reaction to antituberculosis treatment.

Comparison of chest X-rays showed new diffuse micronodular opacities with cavitation (Figure 2), consistent with miliary tuberculosis as part of a paradoxical reaction.

Figure 2. X-ray results showing a worsening of initial infiltrative pulmonary lesions.

Corticosteroid therapy with prednisolone 40 mg (1 mg/kg/day) was initiated, resulting in marked improvement: resolution of fever, weight gain, and radiological improvement (Figure 3).

Figure 3. X-ray of the same patient showing a marked improvement in the initial lesions.

Throughout treatment, nutritional support was maintained with a high-protein diet.

This case illustrates the occurrence of a PR in the form of worsening radiological lesions during antituberculosis treatment in an HIV-negative patient with pulmonary tuberculosis. In our patient, onset occurred at 13 days, which aligns with reports in the literature indicating a range of 2 - 8 weeks [4][12]. The initial improvement followed by recurrence of fever and radiological deterioration (appearance of diffuse miliary opacities in a patient with initially limited pulmonary disease), together with the absence of evidence of drug resistance or intercurrent infection, supports this diagnosis [13][14].

Several studies have identified immunological abnormalities such as anemia, lymphopenia, and hypoalbuminemia as well as malnutrition, as predictive or aggravating factors [15][16]. This is consistent with the biological profile observed in our patient.

It should be noted that paradoxical manifestations are heterogeneous and not yet fully defined. Pulmonary aggravation, characterized by new micronodular opacities or cavitary lesions, is described in 15% - 25% of paradoxical pulmonary reactions, as seen in our case [16][17].

Management relies on continued Antituberculosis Therapy (ATT) and, in severe cases, the use of corticosteroids to modulate the excessive inflammatory response [18]. Corticosteroids have demonstrated clinical benefit, particularly in life-threatening or functionally disabling disease [19]. Withdrawal should be gradual to prevent relapse. Nutritional support is also essential for a favorable outcome.

The favorable evolution of our patient following corticosteroid therapy strongly supports the diagnosis of PR. Our observation underscores the importance of recognizing this phenomenon promptly to avoid unjustified discontinuation of treatment or premature modification of the therapeutic regimen.

Paradoxical reaction is a possible immunological complication of antituberculosis treatment, even in HIVnegative patients. It should be considered in any case of clinical and radiological worsening after initial improvement under ATT, but only after other causes have been excluded. This case highlights the importance of screening for risk factors such as malnutrition, hypoalbuminemia, or other causes of immunosuppression at the start of treatment and addressing them during management. Identifying these factors enables continued vigilance regarding the possibility of PR during therapy.

Written informed consent was obtained from the patient for publication of this case and associated radiological images. This report respects patient anonymity and adheres to the ethical principles of the Declaration of Helsinki.