The care and treatment of patients might be complicated by the intersection of two significant global health concerns, namely tuberculosis (TB) and HIV. In addition to being the most common cause of morbidity and death among those with HIV, TB was the main cause of mortality. Conversely, TB can accelerate the progression of HIV, creating a complex clinical scenario that requires nuanced management strategies [1]. One of the significant complications arising from the co-infection of HIV and TB is TB-Immune Reconstitution Inflammatory Syndrome (TB-IRIS). TB-IRIS, is a condition that can occur in people who have HIV and start antiretroviral therapy (ART) [2,3]. It happens when the immune system begins to recover from HIV infection and, as a result, mounts an inflammatory response against a previously treated or latent TB infection.

TB-IRIS is classified into several types based on when the symptoms appear and their severity; Paradoxical TB-IRIS: This type occurs when the symptoms of TB worsen after starting ART, despite proper TB treatment. The immune system's recovery can lead to an exaggerated inflammatory response to TB that was previously under control [4,5], Unmasking TB-IRIS: This type occurs when new TB symptoms or signs emerge after starting ART, which were previously asymptomatic or not detected. The immune system's recovery can reveal previously hidden or subclinical TB infection [2,6]. The management of TB-IRIS typically involves continuing both TB treatment and ART, along with symptomatic management and sometimes corticosteroids to control inflammation. Regular monitoring and clinical evaluation are crucial to ensure appropriate care.

The clinical management of TB-IRIS presents a formidable challenge due to its unpredictable nature and the overlap of symptoms with both TB and ART-related side effects. Understanding the clinical manifestations and microbiological underpinnings of TB-IRIS is crucial for developing effective treatment strategies and improving patient outcomes [7].

This study aims to characterize TB-IRIS in HIV patients by exploring both clinical and microbiological dimensions. By examining the specific clinical features associated with TB-IRIS and the interactions between Mycobacterium tuberculosis (M.tb.) and the recovering immune system, this research seeks to enhance the understanding of this complex syndrome. The findings are expected to contribute to better diagnostic criteria, treatment protocols, and ultimately, improved management of co-infected patients. Through this research, we hope to address existing knowledge gaps and provide insights that will benefit clinicians in managing TB-IRIS, offering a more refined approach to treating patients who face the dual burden of HIV and TB.

HIV Positive Patients

In a prospective study, 400 HIV positive patients were included. The study subjects were recruited from ART centre, King George Medical University (KGMU), Lucknow, India (Figure 1). The inclusion criteria used for the selection of the subjects were: Patients diagnosed having HIV infection, ART eligibility according to National AIDS Control Organization (NACO) Guidelines, ART naive, HIV positive patients already on ATT, and willingness to participate in the study. The exclusion criteria were: Patient not willing to give consent, and patients who were already on ART. The study experiment and data accumulation were carried out with the understanding and informed consent of the human subject and with approval from Institutional ethical committee, KGMU, Lucknow, India.

Clinical Data Measurements

All patients were diagnosed as HIV positive using Enzyme Linked Immunosorbent assay (ELISA) according to NACO guidelines (2011) [8]. A pre-designed structured performa was used to collect socio-demographic characteristics and relevant clinical data of the patients, and their information related to risk factors for acquiring IRIS. All patients subjected to thorough clinical history and examinations.

Diagnosis of Active TB

Patients were considered to have active TB when they had a two positive sputum smears by AFB, positive mycobacterium culture on Lowenstein Jensen (L-J) media and if they had TB symptoms (any one of cough of more than 2 weeks, fever, loss of appetite, night sweats or loss of weight). Patients were divided into two groups: 1) HIV patients with active TB who were receiving ATT, and 2) HIV patients with no evidence of active TB. Tuberculin skin test (TST) was also performed to assess in vivo immune response to TB. Culture and drug susceptibility testing (DST) for M.tb. were done in all cases where specimens were available to rule out drug-resistant TB.

CD₄ Cell Count

We collected blood for CD₄ cell count measurement at enrolment and at month six follow up visit. Lymphocyte subsets (CD₄ cell counts) were analysed by standard three-color flow cytometry (FACScan; Becton Dickinson, San Jose, CA, USA).

Statistical Analysis

Continuous variables such as age, Hb and CD₄ cell count were summarized into means and medians as appropriate with t test, paired and unpaired as appropriate. The 95% confidence intervals were constructed around the estimates and the p-values used as a measure of statistical significance. A p-value of 0.05 or less was considered significant. Data analysis was done using SPSS 15.0 version statistical software.

Clinical Presentation of TB-IRIS Cases

The majority of TB-IRIS cases were new ("unmasking") presentations, comprising 81.6% (31 patients). Worsening ("paradoxical") TB-IRIS was observed in 18.4% (7 patients). Tubercular Meningitis (TBM) was the most common presentation, affecting 47.3% (18 patients). Pulmonary TB was observed in 29.0% (11 patients). Cervical Lymphadenopathy was seen in 8.0% (3 patients). Abdominal Lymphadenopathy affected 13.0% (5 patients). Disseminated TB was the least common presentation, found in 2.7% (1 patient). Only 13% (5 patients) received steroid therapy for TB-IRIS. The majority, 87% (33 patients), did not receive steroid therapy. None of the patients (0%) discontinued ART during the study period. A positive outcome, defined as cured or improved, was achieved in 71% (27 patients) of cases. There were 9 deaths (23.6%) among the patients. A small proportion of patients, 2.63% (1 patient), were lost to follow up (LFU). Another 2.63% (1 patient) were transferred out during the study (Table 1).

Table 1: Clinical manifestations, treatment, and outcomes of TB-IRIS cases.

This study provides a comprehensive look into the characteristics, treatment, and outcomes of patients with TB-IRIS. Our analysis reveals that the majority of TB-IRIS cases were new ("unmasking") presentations, accounting for 81.6% of cases. This finding, is consistent with earlier studies that have noted a predominance of unmasking TB-IRIS in HIV-infected patients [9,10]. Unmasking TB-IRIS occurs when previously undiagnosed TB becomes clinically apparent following ART initiation. This is contrasted with paradoxical TB-IRIS, observed in 18.4% of patients, where pre-existing TB worsens after ART begins.

The high prevalence of TBM as the most common presentation (47.3%) aligns with other studies highlighting TBM as a severe manifestation of TB-IRIS [11]. Pulmonary TB, though less common in this cohort (29.0%), is still a significant concern. The relatively low incidence of disseminated TB (2.7%) in our study might reflect advances in early diagnosis and management of TB-IRIS [12].

Steroid therapy for TB-IRIS was administered to only 13% of patients, a notably low percentage compared to historical practices. Historically, corticosteroids were commonly used to manage severe cases of TB-IRIS [13]. The shift away from routine steroid use may reflect updated guidelines and a better understanding of TB-IRIS pathophysiology, which emphasize individualized treatment approaches [14]. The fact that none of the patients discontinued ART during the study underscores the importance of maintaining ART despite IRIS-related complications, as discontinuation can lead to worse outcomes [15].

Our findings suggest that initiating ART within less than one month of starting ATT is associated with a higher incidence of IRIS (15.4%) compared to those who started ART one month or more after ATT (5.5%). This aligns with previous studies indicating that early ART initiation can increase the risk of IRIS [10,16-18]. This might be attributed to a more pronounced immune reconstitution effect when ART is started too soon after ATT, leading to heightened inflammatory responses.

The association between lower baseline CD4 counts and higher incidence of IRIS (p=0.003) is consistent with existing literature, which shows that patients with advanced immunosuppression are at higher risk for IRIS [14,19,20]. The elevated risk for those with CD4 counts <100 cells/µL highlights the need for careful monitoring and potentially more aggressive management in this high-risk group.

Comparing new and worsening TB-IRIS cases, we observe that new TB-IRIS patients were younger and had higher baseline CD4 counts than those with worsening TB-IRIS. The differences in clinical manifestations and outcomes between these groups emphasize the variability in TB-IRIS presentations and underscore the need for tailored management strategies [9,11].

The drug resistance patterns observed in our study reveal a significant proportion of resistance to isoniazid and rifampicin (27.2% each), which are critical first-line drugs for TB treatment. This finding underscores the need for routine drug susceptibility testing and highlights the challenges in managing TB-IRIS in the context of drug-resistant TB strains [21,22]. A great approach to restrict the TB epidemic is to further develop more practical, rapid, and sensitive molecular diagnostic tools to identify subclinical HIV co-infection [23]. HIV co-infected patients can be treated with modern molecular diagnostic tests since they are either accurate or quick enough [24]. HIV patients at risk for TB-IRIS can be predicted using the reliable, sensitive, and easy-to-use TST [25].

The high cure or improvement rate (71%) observed in this study is encouraging and aligns with recent findings [26], who reported favourable outcomes with appropriate management of IRIS. The mortality rate of 23.6% is consistent with some recent studies but is notably high, indicating the need for more effective management strategies [27].

This comprehensive analysis of TB-IRIS in HIV patients underscores the complexity of this syndrome and highlights key factors influencing its development and management. The predominance of unmasking TB-IRIS, the impact of ART timing, baseline CD4 counts, and drug resistance patterns provide valuable insights for clinicians. Future research should continue to refine treatment protocols and explore strategies to mitigate the risk of IRIS, particularly in high-risk populations.

Acknowledgements

The patients' participation in the study is greatly appreciated by the authors. The contributing physicians and residents from KGMU, Lucknow's Department of Clinical Hematology and Medical Oncology for their kind assistance.

Funding

No funders had a role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The Indian Council of Medical Research (ICMR), New Delhi provided funding for this work (Grant no. 80/619/2009-ECD-I).

Conflicts of Interest

None declared.

Author Contributions

Conceptualization: PG and AKT; Investigation: PG, AKT and KPS; Methodology: PG and AKT; Visualization: PG, AKT and SG; Data curation: PG, AKT, SG and KPS; Formal analysis: PG, SG and AG; Writing original draft: PG; Writing, reviewing & editing: All authors. All authors provided technical inputs to the manuscript and approved the final version of the paper.

Ethics Approval and Consent to Participate

The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and adhered to all applicable guidelines and regulations. Study participants were informed of the study’s purpose, procedures, potential risks, and benefits. Confidentiality of the study participants’ data was strictly maintained, and the results were used solely for research purposes.

Consent For Publication

Study participants gave consent to the publication of the data.

Availability of Data

All data is available within the manuscript. Additional datasets not contained in the current manuscript will be supplied upon request from the corresponding author.

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