Pyrexia of Unknown Origin (PUO) in South Asia: A Systematic Review of Diagnostic Gaps and Management Strategies.

Background: Pyrexia of Unknown Origin (PUO) represents a persistent diagnostic challenge in clinical practice. In South Asian regions, this challenge is compounded by a high burden of endemic infections, resource constraints, and varied clinical practices. This systematic review aimed to synthesize the available evidence on the etiology, diagnostic approaches, management, and systemic barriers related to PUO in the region to inform improved clinical guidelines and health policies. Methods: A systematic literature search was conducted in major electronic databases following PRISMA 2020 guidelines and registered prospectively in PROSPERO (CRD420251170142). Observational studies and case series reporting PUO among all populations in South Asian countries were included. Dual independent screening, data extraction, and quality assessment were performed. Risk of bias was evaluated using the Joanna Briggs Institute (JBI) tools for observational studies and QUADAS-2 for diagnostic accuracy studies. Findings were synthesized narratively due to substantial clinical and methodological heterogeneity. Results: Thirty-seven studies were included, with infectious diseases predominating, most commonly tuberculosis, enteric fever, and scrub typhus. Non-infectious inflammatory diseases and malignancies accounted for significant minorities. Diagnostic yield varied substantially across studies, with higher yields reported in settings with greater access to advanced diagnostic modalities. Key systemic barriers included limited laboratory and imaging capacity, high rates of empirical antimicrobial use, absence of standardized diagnostic protocols, and patient-related factors like late presentation and cost. Management was largely empirical, with third-generation cephalosporins and doxycycline commonly used. A striking geographical imbalance in evidence was noted, with most studies originating from India. Conclusions: PUO in South Asia is characterized by a heterogeneous etiological spectrum, persistent diagnostic uncertainty, and widespread reliance on empirical management. The findings indicate that it is necessary to develop standardized, context-appropriate PUO definitions and diagnostic algorithms, improve access to targeted investigations, and strengthen antimicrobial stewardship to enhance patient care in resource-limited settings. Future research must address the significant geographical gaps in evidence and focus on implementing standardized approaches across the region.