Paradoxical reaction manifesting as new pulmonary nodules emerging synchronously and sequentially in the lung ipsilateral to pleural effusion in an HIV-negative patient with tuberculous pleuritis: A case report

Abstract

Paradoxical reaction (PR) refers to an abnormal and exaggerated immune response triggered by viable or nonviable Mycobacterium tuberculosis. This reaction can develop during or after standard antituberculous therapy (ATT), more frequently in HIV-positive individuals and occasionally in HIV-negative ones. Pulmonary nodules are a rare presentation of PR, which is easily misdiagnosed as pulmonary malignancy, fungal infection and other thoracic diseases. Herein we present a 19-year-old HIV-negative young male with right tuberculous pleuritis who underwent standardized ATT. Three months into treatment, routine chest computed tomography (CT) detected multiple new pulmonary nodules on the affected side. CT-guided percutaneous lung biopsy confirmed caseating granulomatous inflammation. After ruling out other potential etiologies, the patient was diagnosed with a tuberculous paradoxical reaction. The original ATT regimen was maintained. During follow-up, three pre-existing nodules in the right lung gradually regressed, while one enlarged and an additional nodule developed. The patient was asymptomatic and declined further examinations, and the initial ATT regimen continued. He eventually finished the full 12-month ATT course. Nine months after treatment completion, the majority of lesions resolved nearly completely. Clinicians should be highly alert to paradoxical reaction when new pulmonary nodules emerge synchronously or asynchronously in the ipsilateral lung with pleural effusion among tuberculous pleurisy patients on ATT. The diagnosis depends on the exclusion of alternative causes. For asymptomatic patients, the original ATT regimen should be continued. Long-term regular follow-up is essential.

1. Introduction

Tuberculosis (TB) remains a major global public health threat with high morbidity and mortality [1]. Fortunately, diverse effective anti-tuberculosis treatment regimens have been widely applied to control TB. Paradoxical reaction (PR) refers to transient clinical and radiological worsening of pre-existing TB lesions or the appearance of new lesions in patients on standard ATT, which generally occurs after an initial clinical improvement [2], [3]. This phenomenon often leads to diagnostic dilemmas. PR is much more prevalent in HIV-coinfected patients following the start of antiretroviral therapy (ART), but rarely seen in HIV-negative individuals [4]. In addition, PR mostly involves extrapulmonary sites, and cases manifesting as new pulmonary nodules are uncommon [5]. Here, we report an unusual case of tuberculous pleurisy in an HIV-negative young male patient who developed PR during the course of illness, characterized by the synchronous and sequential emergence of new pulmonary nodules in different segments of the right lung with tuberculous pleurisy. This article aims to improve clinicians’ recognition of this disorder.

2. Case presentation

A 19-year-old male was admitted to our hospital with recurrent fever, right chest pain and shortness of breath for ten days. The patient denied any past medical history. Physical examination: T 36.8°C, P 72 beats/min, R 21 breaths/min, BP 103/57 mmHg. The right hemithorax was full with reduced respiratory excursion, slight leftward tracheal deviation and diminished right-sided tactile vocal fremitus. Percussion dullness was detected over the right lower lung, where breath sounds were absent, while bronchial breath sounds were audible over the right upper lung. The remainder of the examination was unremarkable. HIV infection test was negative. The lymphocyte count was 0.99 × 10⁹/L (reference lower limit: 1.1 × 10⁹/L). Interferon-gamma release assays (IGRAs) and tuberculin skin tests were positive. Procalcitonin, haemoglobin, platelet count, and liver and renal function were all within normal limits.

Chest CT scans showed moderate right pleural effusion, thickened right pleura, and the partial compressive atelectasis of the right lower lobe (Fig. 1A1, B1 and C1). Closed thoracic drainage was subsequently performed using a pigtail catheter. Pleural fluid obtained from drainage was sent for laboratory analysis. The pleural fluid demonstrated the following results: pleural protein 54 g/L, pleural lactate dehydrogenase (LDH) 674 U/L. The corresponding serum protein was 69.8 g/L. These values were consistent with an exudative effusion according to Light's criteria. The pleural adenosine deaminase (ADA) level was 52 U/L. Pleural fluid acid-fast bacilli (AFB) smear and pleural fluid Mycobacterium tuberculosis deoxyribonucleic acid (DNA) were negative. Pleural fluid Mycobacterium tuberculosis culture was pending at this time. A percutaneous closed pleural biopsy revealed granulomatous inflammation (Fig. 2A). The patient was diagnosed with tuberculous pleuritis and immediately started on the intensive anti-tuberculosis regimen consisting of isoniazid, rifampicin, ethambutol and pyrazinamide. Meanwhile, pleural effusion was drained daily via closed thoracic drainage using a pigtail catheter until no further fluid could be aspirated. The patient's symptoms gradually improved, and he was discharged home to continue oral anti-tuberculosis therapy.

Fig. 1.

Serial chest CT examinations of the right lung were performed throughout treatment. Baseline imaging showed moderate right pleural effusion (A1, B1, C1), focal atelectasis of the right lower lobe anterior basal segment (A1, short arrow), inflammatory linear opacities within the right middle lobe (B1, short arrow), and pleural thickening at its medial segment (C1). Six days following anti-tuberculosis therapy and pleural drainage, a new lesion was identified in the re-expanded anterior basal segment of the right lower lobe (A2, short arrow). In addition, inflammatory streaks were widened in the lateral segment (B2, short arrow), and a pleural nodule was observed in the medial segment of the right middle lobe (C2, short arrow). At the 3-month follow-up after chemotherapy, pulmonary nodules were observed in the anterior basal segment and posterior basal segment of the right lower lobe, as well as the lateral and medial segments of the right middle lobe (A3, B3 and C3). Five months after treatment initiation, nodules in the anterior basal and posterior segments of the right lower lobe improved, whereas previously documented nodules in the remaining lung segments all regressed (A4, B4 and C4). Nine months after treatment completion, the nodule in the posterior basal segment further decreased (A5), and lesions in all other pulmonary segments achieved near-complete resolution (A5, B5 and C5).

Fig. 2.

Pathological results. Percutaneous pleural biopsy showed granulomas composed of Langerhans cells and mononuclear cells in the background of fibrinoid necrosis. Hematoxylin and eosin, × 400 (A). CT-guided percutaneous lung biopsy revealed caseous necrosis accompanied by infiltration of epithelioid cells, multinucleated giant cells and lymphocytes. Hematoxylin and eosin, × 100 (B).

Unfortunately, routine outpatient imaging three months after discharge identified a new 4.8 cm × 3.1 cm pleural-based nodule in the posterior basal segment of the right lower lobe (Fig. 1A3, long arrow) and a concomitant 1.9 cm × 2.8 cm nodule in the lateral segment of the right middle lobe (Fig. 1B3, short arrow). The lesion in the anterior basal segment of the right lower lobe showed mild enlargement (Fig. 1A3, short arrow). The pre-existing pleural nodule in the medial segment enlarged to 1.9 cm × 3.4 cm (Fig. 1C3, short arrow), and an additional small pleural nodule emerged in the posterior segment of the right lower lobe (Fig. 1C3, long arrow). Given these new abnormal findings, the patient was readmitted for further evaluation. To clarify the timeline, imaging acquired six days after initiation of anti-tuberculosis therapy and pleural drainage revealed early radiological changes: a new lesion was first detected within the re-expanded anterior basal segment of the right lower lobe (Fig. 1A2, short arrow). In parallel, inflammatory streaks in the lateral segment of the right middle lobe became more extensive (Fig. 1B2, short arrow), and a pleural nodule appeared in its medial segment (Fig. 1C2, short arrow). Notably, the inflammatory streaks marked by the short arrow in Fig. 1B2 progressed into a distinct pulmonary nodule on the 3-month follow-up scan (Fig. 1B3, short arrow).

At readmission, the patient had no symptoms. IGRAs and tuberculin skin tests remained positive. Other laboratory results, including erythrocyte sedimentation rate, C-reactive protein, complete blood count, liver and renal function tests, galactomannan (GM) test, (1, 3)-β-D glucan (G) test, tumor markers, autoantibodies, and Mycobacterium tuberculosis culture of pleural fluid obtained during the initial admission, were normal or negative. Flexible bronchoscopy was performed to collect bronchoalveolar lavage (BAL) fluid from the right lower lobe. AFB smear and Mycobacterium tuberculosis DNA testing of BAL fluid were negative. Thereafter, CT-guided percutaneous lung biopsy demonstrated epithelioid granulomas with caseous necrosis (Fig. 2B). A diagnosis of paradoxical reaction was made. As the patient had finished the 2-month intensive phase and switched to the continuation phase, isoniazid and rifampicin were continued. The patient was discharged again for ongoing outpatient follow-up. Following this second discharge, the patient remained under clinical surveillance.

At follow-up two months post-readmission, the nodule in the right lower lobe was reduced to 3.7 cm × 2.0 cm (Fig. 1A4, long arrow). Nodules in the lateral segment of the right middle lobe (Fig. 1B4, short arrow) and the medial segment of the right middle lobe (Fig. 1C4, short arrow) regressed substantially. However, the lesion at the anterior basal segment of the right lower lobe progressed into a 3.7 cm × 2.0 cm interlobar pleural-based nodule (Fig. 1A4, short arrow), while a new 2.3 cm × 1.5 cm pleural-based nodule arose in the posterior segment of the right lower lobe (Fig. 1C4, long arrow). The patient declined further investigations due to the absence of symptoms, and continued the original treatment for a total duration of 1 year. During subsequent surveillance, the patient recovered well. The nodule in the posterior basal segment of the right lower lobe further regressed to 2.0 cm × 2.3 cm (Fig. 1A5, long arrow). Nodules in the remaining lobes nearly completely resolved nine months after treatment completion (Fig. 1A5, B5 and C5).

3. Discussion

Paradoxical reaction is a well‐recognized phenomenon following the initiation of antituberculous therapy. As a form of tuberculosis-associated immune reconstitution inflammatory syndrome, it manifests as an aberrant, exaggerated immune response to viable or non-viable Mycobacterium tuberculosis [4]. This inflammatory reaction can develop in both HIV-positive patients and, less commonly, HIV-negative individuals, emerging during antituberculous treatment or even after treatment completion [4], [6].

The prevalence of paradoxical reaction following the initiation of anti-tuberculosis therapy varies by tuberculosis infection site. A large-scale study encompassing mixed tuberculosis phenotypes reported a PR incidence of 2.4% [4]. Overall, PR is more frequently observed in patients with extrapulmonary tuberculosis, irrespective of HIV status [7], [8]. In 1954, PR was first described in HIV-negative patients after the initiation of antituberculosis drugs [9]. Subsequently, PR has been increasingly documented in HIV-negative patients, particularly in those with extrapulmonary tuberculosis, notably pleuritis and scrofula [10]. In the case we reported, the primary site of tuberculosis was the pleura, and PR occurred indeed in the right lung.

Risk factors for paradoxical reaction include younger age and low lymphocyte count before anti-tuberculosis treatment, which is consistent with the findings in our case [4]. At present, the pathogenesis of PR is believed to be associated with the reversal of immunosuppression after rapid clearance of Mycobacterium tuberculosis. This process elicits an exaggerated inflammatory response and even a cytokine storm mediated by tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), which may lead to clinical deterioration accompanied by high fever, severe cough and other manifestations [11], [12]. Notably, the patient in our study only developed newly emerging radiological abnormalities, without deterioration of clinical symptoms or physical signs.

PR generally develops within one week to several months after the commencement of anti-tuberculosis treatment (ATT) [13]. In our case, the interval was approximately 3 months, which is in line with previous reports. PR may affect multiple organs, but isolated pulmonary nodule involvement is uncommon [5], [13], [14]. A retrospective study demonstrated that 17 out of 18 episodes of new pulmonary lesions arose ipsilateral to the prior pleural effusion, a finding consistent with our patient, who presented with new right pulmonary nodules on the same side as the initial effusion [15]. Further research is required to determine whether this observation is purely coincidental or whether the anatomical features of the right lung contribute to the pathogenesis of PR. Notably, three newly formed right pulmonary nodules gradually regressed and resolved, while one concurrent lesion within the ipsilateral lung progressively enlarged, alongside the development of an additional new nodule in the right lung. This suggests that PR may not be adequately suppressed by anti-tuberculosis treatment and can present as a single episode or repeated recurrent episodes.

Nowadays, no specific laboratory tests are available to confirm or exclude the diagnosis of PR [16]. Pulmonary nodule manifestation of PR is relatively rare, and it is challenging to differentiate it from lung malignancy, secondary infection, recurrent tuberculosis, treatment failure, rheumatic diseases, poor medication adherence, and malabsorption of anti-tuberculosis treatment [17]. In our case, all the above differential possibilities were excluded after comprehensive and repeated examinations.

Currently, no consensus has been reached on the standard treatment regimen for PR. To our knowledge, corticosteroids are the only anti-inflammatory agents currently used for PR management, while anti-tuberculosis treatment should be continued. Additional adjunctive therapies may be administered according to the location and severity of PR. For patients with abscesses, drainage and surgical debridement are recommended therapeutic options [18]. Although the optimal duration of treatment for PR remains controversial, it should be individualized based on the patient's clinical condition. Given the recurrent and multiple pulmonary lesions in this case, we extended the continuation anti-tuberculosis therapy by 3 months.

4. Conclusion

In conclusion, paradoxical reaction should be suspected when new pulmonary nodules arise synchronously or sequentially in different segments of the ipsilateral lung with pleural effusion in patients with tuberculous pleurisy receiving antituberculous treatment. Its diagnosis depends on excluding other pulmonary disorders. The initial antituberculous regimen should be maintained upon the development of a paradoxical reaction. Close longitudinal follow-up is essential due to the recurrent tendency of paradoxical reaction. Further studies are warranted to clarify its underlying immunological mechanisms and identify valid prognostic indicators and feasible therapeutic targets.

CRediT authorship contribution statement

Yujiao Xiong: Writing – original draft, Data curation. Yongqiang Bao: Writing – review & editing. Bei Jia: Writing – review & editing, Supervision.

Ethics declaration

Written informed consent to take part in the study and to publish the article has been obtained from all participants or their legal representatives. The privacy rights of participants have been observed.

This study was performed in compliance with relevant laws, regulatory frameworks and guidelines where the research took place. This study was approved by the Ethics Committee of Leshan People's Hospital. (Approval No. LYLL [2026]KY171)

This research follows the CARE guidelines and the CARE checklist.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

PR

paradoxical reaction

ATT

antitubercular therapy

HIV

human immunodeficiency virus

CT

computed tomography

HAART

highly active antiretroviral therapy

IGRAs

interferon-gamma release assays