Abstract Objectives Little is known about the prevalence of febrile illness in the Arabian region as clinical, laboratory and immunological profiling remains largely uncharacterised. Methods A total of 2018 febrile patients from Jazan, Saudi Arabia, were recruited between 2014 and 2017. Patients were screened for dengue and chikungunya virus, Plasmodium, Brucella, Neisseria meningitidis, group A streptococcus and Leptospira. Clinical history and biochemical parameters from blood tests were collected. Patient sera of selected disease‐confirmed infections were quantified for immune mediators by multiplex microbead‐based immunoassays. Results Approximately 20% of febrile patients were tested positive for one of the pathogens, and they presented overlapping clinical and laboratory parameters. Nonetheless, eight disease‐specific immune mediators were identified as potential biomarkers for dengue (MIP‐1α, MCP‐1), malaria (TNF‐α), streptococcal and meningococcal (eotaxin, GRO‐α, RANTES, SDF‐1α and PIGF‐1) infections, with high specificity and sensitivity profiles. Notably, based on the conditional inference model, six of these mediators (MIP‐1α, TNF‐α, GRO‐α, RANTES, SDF‐1α and PIGF‐1) were revealed to be 68.4% accurate in diagnosing different febrile infections, including those of unknown diseases. Conclusions This study is the first extensive characterisation of the clinical analysis and immune biomarkers of several clinically important febrile infections in Saudi Arabia. Importantly, an immune signature with robust accuracy, specificity and sensitivity in differentiating several febrile infections was identified, providing useful insights into patient disease management in the Arabian Peninsula.
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