Original article
Fever of unknown origin: Discrimination between infectious and non-infectious causes

https://doi.org/10.1016/j.ejim.2009.11.006Get rights and content

Abstract

Objective

The present study aimed to develop and evaluate a simple diagnostic model that could aid physicians to discriminate between infectious and non-infectious causes of fever of unknown origin (FUO).

Design/Setting/Subjects

Patients with classical FUO were studied in two distinct, prospective, observational phases. In the derivation phase that lasted from 1992 to 2000, 33 variables regarding demographic characteristics, history, symptoms, signs, and laboratory profile were recorded and considered in a logistic regression analysis using the diagnosis of infection as a dependent variable. In the validation phase, the discriminatory capacity of a score based on the derived predictors of infection was calculated for FUO patients assessed from 2001 to 2007.

Results

Data from 112 individuals (mean age 56.5 ± 11.2 years) were analyzed in the derivation cohort. The final diagnoses included infections, malignancies, non-infectious inflammatory diseases, and miscellaneous conditions in 30.4%, 10.7%, 33% and 5.4% of subjects, whereas 20.5% of cases remained undiagnosed. C-reactive protein > 60 mg/L (odds ratio 6.0 [95% confidence intervals 2.5, 9.8]), eosinophils < 40/mm3 (4.1 [2.0, 7.3]) and ferritin < 500 μg/L (2.5 [1.3, 5.2]) were independently associated with diagnosis of infection. Among the 100 patients of the validation cohort, the presence of ≥ 2 of the above factors predicted infection with sensitivity, specificity, and positive and negative predictive values of 91.4%, 92.3%, 86.5%, and 95.2%, respectively.

Conclusions

The combination of C-reactive protein, ferritin and eosinophil count may be useful in discriminating infectious from non-infectious causes in patients hospitalised for classical FUO.

Introduction

Fever of unknown origin (FUO) was defined by Petersdorf and Beeson in 1961 as a syndrome of fever lasting more than 3 weeks, with temperature higher than 38.3 °C on several occasions, the cause of which remains uncertain after 1 week of in-hospital diagnostic workup [1]. Thirty years later, Durack and Street proposed two major modifications to the initial definition: (i) the distinction between classical FUO and three other types, namely nosocomial, neutropenic and Human Immunodeficiency Virus (HIV)-associated FUO, and (ii) the shorter duration of the investigation before a case meets the FUO criteria, i.e. three outpatient visits or 3 days (instead of 1 week) of in-hospital evaluation [2]. The above changes, which have been widely accepted, reflect the evolution of modern medicine that is characterized by more extensive outpatient assessment as well as by an aetiological spectrum in the three new categories of FUO different from that of classical FUO [3], [4], [5].

FUO remains a great clinical challenge because its differential diagnosis includes more disorders than any other medical condition, encompassing both very rare and relatively common entities that can be classified in four major groups: infections, non-infectious inflammatory diseases (NIID), malignancies and miscellaneous conditions [3], [4], [5]. During the last two decades, the distribution of causes is consistently changing towards fewer infections and tumors, and more NIID. In addition, despite the development of rapid laboratory tests and powerful diagnostic instruments, the proportion of undiagnosed cases is higher in the most recently published series, ranging from 15% to 50% [6], [7], [8], [9], [10], [11], [12], [13], [14], [15].

In line with the growing trend towards the application of formal probabilistic reasoning or quantitative data as guidance to clinical decision-making, several research groups have proposed staged diagnostic algorithms to minimize non-focused testing [4], [13], [14], [15]. However, such strategies have not been universally adopted, and the approach to FUO is still being based on pattern recognition, risks and costs of tests, and patients' attitude [3], [4], [8], [16]. The aims of the present study were: (a) to develop a simple and reliable diagnostic model, which would combine initial clinical evaluation and first-line laboratory tests in order to aid physicians to discriminate between infectious and non-infectious causes of FUO, and (b) to test the diagnostic accuracy of the derived tool in an independent database of subjects with FUO.

Section snippets

Patients and methods

Data were collected and analyzed in two distinct, prospective, consecutive, observational phases: (a) a derivation cohort (112 patients), and (b) a validation cohort (100 subjects). Only subjects with classical FUO fulfilling the modified criteria of Durack and Street were included, whereas patients with immunosuppression, neutropenia or nosocomial FUO were excluded.

Results

The present single-center investigation comprised overall of 212 individuals with FUO referred to the Third University Department of Medicine, in ‘Sotiria’ General Hospital, Athens, Greece during a total period of 15 years.

Discussion

The proposed model yielded sensitivity and specificity that exceeded 90% by combining the diagnostic value of three variables in a context of independent application devoid of bias that could emerge during its original development. In fact, 95% CIs ruled out negative predictive value and discriminatory capacity inferior than 85%. If proven clinically valuable in future large-scale research, this complementary tool may have considerable implications for clinicians, because FUO remains a

Learning points

  • In patients with classical fever of unknown origin, C-reactive protein > 60 mg/L, eosinophils < 40/mm3, and ferritin < 500 μg/L are independently associated with diagnosis of infection.

  • The presence of ≥ 2 of the above factors can predict infection in patients with classical fever of unknown origin with sensitivity of 91.4% and specificity of 92.3%.

  • Including this classification tool into the diagnostic procedure may ameliorate the physicians' discriminatory capacity under the prerequisite that it will be

References (35)

  • S. Vanderschueren et al.

    From prolonged febrile illness to fever of unknown origin: the challenge continues

    Arch Intern Med

    (2003)
  • E.M.H. De Kleijn

    Fever of unknown origin (FUO), I: a prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria

    Medicine (Baltimore)

    (1997)
  • E.M. De Kleijn et al.

    Fever of unknown origin (FUO), II. Diagnostic procedures in a prospective multicenter study of 167 patients

    Medicine (Baltimore)

    (1997)
  • G.B. Gaeta et al.

    Fever of unknown origin: a systematic review of the literature for 1995–2004

    Nucl Med Commun

    (2006)
  • Z. Zhiyong et al.

    Fever of unknown origin: a report from China of 208 cases

    Int J Clin Pract

    (2003)
  • T. Zenone

    Fever of unknown origin in adults: evaluation of 144 cases in a non-university hospital

    Scand J Infect Dis

    (2006)
  • O.R. Sipahi et al.

    Pooled analysis of 857 published adult fever of unknown origin cases in Turkey between 1990–2006

    Med Sci Monit

    (2007)
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