Revisiting Fever of Unknown Origin (FUO): A Single Tertiary Care Center Experience in North India Calls for Criteria Revision

Background Fever of Unknown Origin (FUO) is a challenging medical condition characterized by prolonged fever without an identifiable cause despite extensive evaluation. The existing definition, proposed in 1961, requires illness lasting over three weeks, fever of ≥38.3°C (≥101°F) on two occasions, and uncertain diagnosis after one week of inpatient evaluation, excluding immunocompromised patients and in-hospital evaluation. However, the current criteria may not fully capture the diverse spectrum of FUO cases, especially in resource-constrained settings like North India. This study aims to revisit the criteria for FUO in terms of durations of non-diagnosis, temperature ranges, and duration of hospitalization rather than considering the duration of illness and using a set of obligatory investigations. It will propose a more practical and effective approach based on local healthcare resources. Methods This study utilized a retrospective and prospective longitudinal-exploratory design and was conducted at a single tertiary care center, All India Institute of Medical Sciences (AIIMS) in Rishikesh, North India. The study population consisted of 228 patients meeting the inclusion criteria from January 2018 to December 2022. Inclusion criteria involved adult patients with documented fever of ≥99.1°F on at least two occasions and fever lasting for more than three days. Exclusion criteria included patients with a definitive diagnosis within three days of hospitalization. Data were collected from the hospital’s MRD section retrospectively and through prospective follow-up of eligible patients. Proposed new definitions for FUO were considered, encompassing different ranges of duration of non-diagnosis (3-21 days, >21 days) temperature ranges (99.1°F-100.9°F and ≥101°F), and durations of hospitalization (3-7 days and >7 days). The frequency of each definition was measured. The etiology and outcomes of patients under each definition were analyzed using appropriate statistical tests. Findings Among the proposed definitions, Definition B (fever lasting 3-7 days with temperatures between 99.1°F-100.9°F) had the highest prevalence (40.8%), followed by Definitions A, D, and C. In contrast, only 5 patients (2.2%) met the classical Definition H (in terms of temperature and duration of hospitalization). By closely observing the patients in Definition B group, around 36.5% patient remained non-diagnosed between >7 to 10 days which is highest among the group. Approximately 62% of patients remained undiagnosed before 21 days of hospitalization and initiated treatment, with temperatures ranging between 99.1°F to 100.9°F. The remaining 38% of patients, with temperatures ≥101°F, also remained undiagnosed before commencing treatment. The majority of patients (94%) underwent diagnostic workups and treatment within 21 days of hospitalization, reflecting the importance of early evaluation and intervention. Discussion The findings of this study underscore the need for revising the criteria for diagnosing FUO. The prevalence of FUO cases under the proposed definitions suggests that the classical criteria may not fully capture the diverse patient population’s needs and local healthcare resources. The study highlights the importance of a flexible diagnostic timeline, comprehensive clinical assessment, and individualized temperature thresholds to ensure timely and effective care for patients with undiagnosed fever. The lack of significant differences in etiology and outcomes among the various definitions further supports the idea that modifying the criteria can enhance the management of FUO cases without compromising patient outcomes. Conclusion The study emphasizes the need for a revised approach to defining FUO, taking into account the local healthcare resources and patient population. Adapting the criteria based on temperature ranges and durations can lead to a more practical and effective diagnosis and management of FUO. The proposed flexible diagnostic timeline and comprehensive clinical assessment can improve the timely identification of underlying causes and guide clinicians in providing appropriate treatment and support for patients with undiagnosed fever. Continued research and collaboration within the medical community are essential to develop context-specific guidelines for diagnosing and managing FUO. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of All India Institute of Medical Sciences (AIIMS), Rishikesh gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes It will be available by contacting the corresponding author.