Fever of Unknown Origin (FUO) in Elderly Patients (FUO)

April 28, 2026 updated by: Nathalie compté, Universitair Ziekenhuis Brussel

Objective: Fever of unknown (FUO) origin remains challenging in geriatric patients. Geriatric patients have a blunted immune response responsible for altered fever mechanisms and immune cells responses. Consequently, FUO could be inappropriately named and could be changed in Inflammation of unknown origin (IUO) in this specific population. Furthermore, the studies of FUO in this group are (out)dated and the diagnostic methods have evolved achieving a better sensitivity and specificity. The aim of our study is to assess the spectrum of diseases responsible of FUO or IUO in elderly patients compared to younger patients and to define the diagnostic approach using new diagnostic investigations. The second aim of our study is to assess the usefulness of inflammatory markers, demographic data and comorbidity to differentiate the cause of FUO/IUO.

Design: Patients with FUO or IUO will prospectively be recruited at the geriatric unit and the internal medicine unit of the UZ hospital during four years. The demographic, social and medical data will be screened. All diagnostic methods will be described.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Until today, diagnose of fever of unknown origin remains challenging in elderly patients. The presentation of the disease is often atypical and this can delay diagnose and treatment. Geriatric patients have a blunted immune response responsible for altered fever mechanisms. For example, thirty-two percent of geriatric patients presented an infection at the emergency service having no pyrexia or increased white blood cell count in the presence of an infection.

Consequently, the definition of FUO in older patients is different from younger patients. FUO in older patients is defined as tympanic or axillar fever > 37.2.0C, a rectal fever more than 37.50C or a change of > 1.3 centigrade from basal temperature during more than 3 weeks. Furthermore, the name FUO is probably not appropriate in this population and should be replaced with inflammation of unknown origin. However, Unger et al also proposed inflammation of unknown origin in a younger population.

Knockaert et al have shown that the causes of FUO are different in older patients compared to young patients. The causes of FUO are more frequently found in older patients (> 65 years old) compared to younger patients (87-95% and 79% respectively). One explanation is the atypical presentation of classic diseases in geriatric patients. Infection, multi-system diseases and neoplasms were the most prevalent causes. These studies are old and the sensitivity and specificity of the diagnostic methods used presently, such as FDG-Pet-CT, have changed. The spectrum of diseases responsible of FUO or IUO in older patients could therefore have changed since the Knockaert studies. These new diagnostic methods allow better diagnose but also faster diagnose. Consequently the definition of FUO can become obsolete in the field of the duration of the fever.

Materials and Methods

The design of the study is an observational prospective study which will start in juli 2021 until open date in function of the number of included patient (at least 50 patients in both groups).

Patients will be recruited at the geriatric unit and internal medicine unit or geriatric outpatient clinic or internal medicine outpatient clinic of UZ Brussel and will be followed during one year.

The outpatient clinic patients will be recruited during the consultation; the patients who are hospitalized will be recruited during the first week of hospitalization.

The exclusion criteria are the impossibility to have an informed consent from the patient of a representative of the patient. Neutropenia, HIV or nosocomial fever of unknown origins are excluded. Immunodepressed patients are also excluded.

Patients:

All subjects will be screened for underlying illnesses by direct questioning, medical archives and blood sampling. Social evaluation will include determination of age, gender, home (private versus institution), and marital status. Clinical data will comprise: smoking and alcohol habits, old work, hobbies, travel, animal's owner, pneumococcal and influenza vaccine status, allergy, Body mass index (BMI), medical history, current treatment and reasons for hospitalization, recent antibiotic or corticoid treatment. For the older patients (> 70 years old) we will perform a CGA to identify comorbidity and common geriatric conditions. The polypathology and the severity of the medical problems will be scored using the "Charlson comorbidity Index"15 and "Cumulative Illness Rating Scale-Geriatric" (CIRS-G). It is an instrument to quantify disease burden. It comprises a comprehensive review of medical problems of 14 organ systems. It is based on a 0 to 4 rating of each organ system. The "Geriatric Depression Scale" will be used to assess the probability of depressed mood (GDS-15) in 15 questions. The assessment of "Activities of Daily Living" (ADL) will be made by using Katz's scale. It includes the following items: bathing, dressing, transfer, toilet, continence and eating. Each task is graded on a 3-level scale (1 to 3 for Katz's scale), where lower levels represent the absence of dependence and upper level the maximal dependence for the task. Cognitive functions will be assessed using the "Mini Mental State Examination" (MMSE). Possible scores range from 0 to 30 points, with lower scores indicating impaired cognitive function. Nutritional status was assessed using the "Mini Nutritional Assessment" (MNA). A score ≥ 24 identifies patients with a good nutritional status. Scores between 17 and 23.5 identify patients at risk of malnutrition. These latter patients have not yet started to lose weight and do not show low plasma albumin levels but have lower protein-caloric intakes than recommended. A score < 17 indicates protein-caloric malnutrition. Pain will be assess using a visual analogical scale from 0 to 10 points.

Methods

All diagnostic method means from the standard care of the patients during the hospital stay performed for the assessment of the fever or inflammatory syndrome will be collected:

  • biological analyses, (such as CRP, renal function, lever function, electrolytes, sedimentation rates, uric acid, TSH, vitamin B12, folic acid, 25(OH) vitamin D, hemoglobin, hematocrit, proteins, albumin, white blood cells and formula, creatinine clearance (Cockcroft and de Gault formula), autoimmune assessment, viral or bacterial serology,…
  • urine analyses
  • Bacterial culture or PCR, viral PCR test in body fluids.
  • Pleural puncture
  • Lumbar puncture
  • body sonography
  • body X-rays and tomography
  • Pet Ct
  • Temporal artery biopsy
  • Tissue biopsy
  • Bronchoscopy
  • Laparoscopy
  • Bone marrow aspirate
  • ….

Statistics:

Description statistics will be used such as means, medians, standard deviation and interquartile ranges.

Confidentiality All data will be collected by the investigators. The data will be collected in a way that patient names will not appear in the database (Redcap) and that individual patients will not be recognized by the examination of the collected data. Each patients will receive a code to preserve the anonymization. This code is a nummer that will be record on a listing of patients participating to the study in KWS. The listing in KWS is recorded in the worklisting CGER and is named FUO. Each investigator will be responsible of the anonymization of his/her recruiting. The database will only be accessible by the investigators and protected in Redcap by a password. The database (Excel) will be saved on UZBrussel server (CGER) in a folder named FUO.

Study Type

Observational

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
    • Jette
      • Brussels, Jette, Belgium, 1090
        • UZ Brussel

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients will be recruited at the geriatric unit and internal medicine unit or geriatric outpatient clinic of UZ Brussel and will be followed during one year.

Cfr inclusion and exclusion criteria

Description

Inclusion criteria

  • fever during more than one week out of hospital or more than 3 weeks with an intelligent appropriate workup
  • an inflammatory syndrome during more than one week out of hospital or more than 3 weeks out of hospital
  • The exclusion criteria :
  • no inform consent
  • Age < 18 years old
  • Neutropenia, HIV or nosocomial fever of unknown origins are excluded. Immunodepressed patients are also excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Younger 1
young patients ( 18-69 years old) with oral or rectal fever > 37°8 or tympanic fever > 37°2 or CRP > 30 mg/dl during more than one week but less than three weeks of hospital with appropriate intelligent standard inpatient or outpatient workup to rule out usual causes of fever
Other: observational study
There is no intervention. It is an observational study
Older 1
old patients ( > 70 years old) with oral or rectal fever > 37°8 or tympanic fever > 37°2 or CRP > 30 mg/dl during more than one week but less than three weeks out of hospital with appropriate intelligent standard inpatient or outpatient workup to rule out usual causes of fever
Other: observational study
There is no intervention. It is an observational study
Young 2
young patients (18-69 years old) with oral or rectal fever > 37°8 or tympanic fever > 37°2 or CRP > 30 mg/dl during more than 3 weeks with appropriate intelligent standard inpatient or outpatient workup to rule out usual causes of fever.
Other: observational study
There is no intervention. It is an observational study
Older 2
old patients ( > 70 years old) with oral or rectal fever fever > 37°8 or tympanic fever > 37°2 or CRP > 30 mg/dl during 3 weeks with appropriate intelligent standard inpatient or outpatient workup to rule out usual causes of fever13 .
Other: observational study
There is no intervention. It is an observational study

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
the spectrum of diseases responsible of FUO or IUO
Time Frame: through study completion, an average of 1 year
The proportion of infectious diseases, of neoplasm, of multi system disease of pulmonary embolism or deep vein thrombosis, of intoxication door medication will be measured in both groups
through study completion, an average of 1 year
definition of FUO
Time Frame: through study completion, an average of 1 year
we would like to compare fever of unknown origin since three weeks with fever of unknown origin since one week
through study completion, an average of 1 year
Diagnostic approach of FUO
Time Frame: through study completion, an average of 1 year
To describe the diagnostic approach and compare these diagnostic test in young and old population.
through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Factors which influence FUO
Time Frame: At baseline
Univariate and multivariate analyses will be used to measure the influence of age (years), gender, marital status, current treatment, comorbidities, recent use of antibiotics or corticoïd, Comprehensive geriatric assesment (MMSE, MNA, Katz, Lawton, CIRS-G, Charlson Index, GDS) on the cause of fever of unknown origin in both groups.
At baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Universitair Ziekenhuis Brussel

Investigators

  • Principal Investigator: Nathalie Compte, MD, PhD, Universitair Ziekenhuis Brussel

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2021

Primary Completion (Actual)

December 31, 2023

Study Completion (Actual)

December 31, 2023

Study Registration Dates

First Submitted

March 11, 2021

First Submitted That Met QC Criteria

March 19, 2021

First Posted (Actual)

March 22, 2021

Study Record Updates

Last Update Posted (Actual)

May 4, 2026

Last Update Submitted That Met QC Criteria

April 28, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UZCompte2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

No plan

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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