The febrile dilemma: Clinical differential diagnosis of dengue, chikungunya and Zika in the acute phase

Abstract

Objective: To systematically analyze the available scientific evidence on the clinical and epidemiological characteristics that enable the differential diagnosis of dengue, chikungunya and Zika in the acute phase. The aim is to identify the signs and symptoms with the greatest predictive value to guide early diagnosis.

Methods: A systematic literature review was conducted based on the PRISMA 2020 guidelines to analyze evidence on the differential diagnosis of dengue, chikungunya and Zika. The search was performed in PubMed and SciELO using a structured strategy with MeSH terms and Boolean operators. Studies in adult humans (older than 18 years) comparing clinical symptoms in the acute phase were included. Risk of bias was assessed by two independent reviewers using the QUADAS-2 tool, and data were synthesized qualitatively and descriptively to compare the frequency and predictive value of distinctive signs and symptoms.

Results: The aim of this study was to clinically differentiate acute dengue (DENV), chikungunya (CHIKV) and Zika (ZIKV) infections in adult patients, based on a qualitative synthesis of 5 studies. Most included studies were cross-sectional (n=4), and research concentrated in coendemic regions of Brazil, although one Caribbean study corroborated the consistency of findings. Results confirmed substantial symptomatic overlap in the initial phase, with fever as the universal and cardinal symptom, which hinders early diagnosis. Nevertheless, distinctive clinical markers were identified: chikungunya (CHIKV) was predominantly associated with intense, polyarticular and disabling arthralgia, with potential for chronification; Zika (ZIKV) was characterized by a pruritic maculopapular rash and nonpurulent conjunctivitis; dengue (DENV) was characterized by intense retro-orbital pain, as well as a greater propensity for laboratory abnormalities such as leukopenia and thrombocytopenia in the acute phase. It is concluded that, despite the difficulty of achieving early diagnosis, the combination of clinical criteria, a detailed medical history and a high index of clinical suspicion is crucial for differential diagnosis and appropriate patient management in coendemic settings.

Conclusions: The literature analysis confirms that, although dengue, chikungunya and Zika share an initial common clinical presentation (“febrile dilemma”), certain symptom patterns emerge that facilitate differential diagnosis in the acute stage. Intense and often disabling arthralgia is the most notable clinical indicator of chikungunya; pruritic maculopapular rash together with nonpurulent conjunctivitis stands out as the most significant sign of Zika; whereas dengue tends to be associated with retro-ocular pain, nausea, vomiting and hematological abnormalities such as leukopenia and thrombocytopenia. Early recognition of the causative agent is crucial to improve individual clinical care and strengthen surveillance strategies. Nonetheless, variation in research methods still limits the external applicability of results, and multicenter studies with uniform criteria are essential to develop more robust clinical prediction algorithms. In summary, although early clinical diagnosis of these arboviruses remains an ongoing challenge, incorporating the clinical patterns identified in this analysis constitutes an important step toward more accurate and timely care.