Acute febrile illness (AFI) remains one of the most pervasive and diagnostically complex clinical syndromes affecting populations in low- and middle-income countries, particularly within sub-Saharan Africa and South Asia. Fever is both a nonspecific symptom and a critical clinical signal, often masking a wide array of bacterial, viral, and parasitic etiologies whose epidemiology overlaps spatially, temporally, and symptomatically. This diagnostic ambiguity has profound consequences for patient outcomes, antimicrobial stewardship, and health system sustainability. The present article develops an extensive, integrative analysis of AFI grounded strictly in the existing body of literature provided, synthesizing epidemiological evidence, diagnostic practices, laboratory limitations, and clinical outcomes associated with febrile illnesses in resource-constrained settings. Drawing heavily from studies conducted in Tanzania, Nepal, and comparable endemic regions, this work examines the shifting etiological landscape of AFI in the post-malaria control era, where non-malarial febrile illnesses are increasingly recognized as dominant contributors to morbidity and mortality (Chipwaza et al., 2015; Crump et al., 2013; Hercik et al., 2017).

The article critically explores bacterial causes such as brucellosis, leptospirosis, enteric fever, and rickettsial infections, alongside viral pathogens including dengue and chikungunya, emphasizing their clinical overlap and diagnostic indistinguishability in early disease stages (Corbel, 2006; Debora et al., 2016; Karnik and Patankar, 2021). Particular attention is given to laboratory diagnostics, where reliance on serological assays such as Widal, Weil-Felix, and rapid diagnostic tests often introduces interpretive uncertainty and misclassification, especially in endemic settings with high background antibody prevalence (Mariraj et al., 2020; Udayan et al., 2014). The challenges of malaria diagnosis, including residual antimalarial drug detection and discrepancies between conventional microscopy and molecular techniques, are discussed as a paradigm of broader diagnostic limitations (Dahal et al., 2021; Gallay et al., 2018).

Beyond etiology and diagnosis, the article examines the clinical trajectory of severe AFI, focusing on complications such as acute respiratory distress syndrome, multi-organ dysfunction syndrome (MODS), and neurological impairment, with prognostic insights drawn from Glasgow Coma Scale-based mortality prediction studies (Li et al., 2007; Knox et al., 2014; Bastos et al., 1993). The role of inappropriate empiric therapy, antimicrobial resistance, and delayed diagnosis in exacerbating disease severity is analyzed through a mechanistic and evolutionary lens (Hasan et al., 2021). By synthesizing these diverse strands of evidence, this article argues for a reconceptualization of AFI as a syndromic entity requiring integrated diagnostic algorithms, strengthened laboratory capacity, and context-sensitive clinical decision-making frameworks. The findings underscore the urgent need for health system investments that align epidemiological realities with diagnostic and therapeutic practices, ultimately improving patient outcomes in regions where fever remains a leading cause of healthcare utilization and mortality.

Acute febrile illness, non-malarial fever, diagnostic challenges

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