Seminar

Fever of unknown origin

¹⁸F-FDG PET/CT, ⁶⁷Ga-citrate and white blood cell (WBC) scintigraphy are molecular imaging techniques currently used in the diagnostic workup of fever of unknown origin. However, it is unknown which technique fits which patient group best. A systematic literature search has been performed for original articles regarding the use of molecular imaging in fever of unknown origin. A total of 820 eligible studies were screened of which 63 articles evaluating 5094 patients met the inclusion criteria. ¹⁸F-FDG PET/CT provided good diagnostic accuracy (with a weighted mean sensitivity, specificity, positive predicting value, negative predictive value, accuracy and helpfulness of 84.4%, 61.8%, 80.7%, 67.8%, 76.3%, and 61.1%, respectively). Even within specific patient groups such as children, elderly, patients with connective tissue diseases, patients on renal replacement therapy, and HIV-infected patients, ¹⁸F-FDG PET/CT provided good diagnostic values. For ⁶⁷Ga-citrate scintigraphy, the weighted mean sensitivity, specificity, positive predictive value, negative predictive value, and helpfulness were 42.2%, 80.3%, 82.4%, 41.9%, and 42.2%, respectively. WBC scintigraphy shows a weighted mean sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 73.5%, 86.3%, 79.1%, 82.4%, and 79.5%, respectively. However, compared to ⁶⁷Ga-citrate and WBC scintigraphy, significantly more research has been performed using ¹⁸F-FDG PET/CT and ¹⁸F-FDG PET/CT has the advantage of relatively short procedural duration; it is therefore the preferred molecular diagnostic imaging technique. ⁶⁷Ga-citrate and WBC scintigraphy can only be considered if ¹⁸F-FDG PET/CT is not available.

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  Fever may be associated with infectious, inflammatory, immune-mediated, and neoplastic disease.

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  True fever is associated with a rise in the hypothalamic set point, and body temperature is increased by enhanced heat production and conservation.

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  Fever of unknown origin (FUO) is defined as persistent or recurrent fever which is not responsive to treatment and for which a cause is not easily determined.

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  Major endogenous pyrogens are cytokines such as IL-1β, IL-6, and TNF-α. These act to increase synthesis of prostaglandin E2 which acts on thermoregulatory neurons to raise the hypothalamic set point.

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  The diagnostic approach to FUO requires consideration of a large number of differential diagnoses and a staged diagnostic investigation with thorough and repeated physical examinations.

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  Therapeutic trials should be a last resort as they have the potential to mask underlying disease, contribute to adverse outcomes, and result in unnecessary expense.

To improve the diagnostic efficacy of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) for Chinese patients with fever of unknown origin (FUO) and inflammation of unknown origin (IUO), with combined clinical parameters.

FUO/IUO patients who underwent a standard diagnostic work-up and ¹⁸F-FDG PET/CT scanning were enrolled and divided into a local uptake lesion subgroup and a non-specific abnormal uptake subgroup. Beneficial clinical parameters for improving the diagnostic efficacy of PET/CT were identified.

From January 2014 to January 2019, 253 FUO/IUO patients were studied. In total, 147 patients had local uptake lesions and 106 patients had non-specific abnormal uptake. In the local uptake lesion group, the positioning accuracy of PET/CT was 37.2% in grades 1 and 2, and 66.3% in grades 3 and 4. With the following combination of clinical parameters, the positioning accuracy increased to 75.0% and 90.0%, respectively: time from admission to performing PET/CT scanning <6.5 days and C-reactive protein level >95 mg/l. In the non-specific abnormal uptake group, the combination of sex (male), bicytopenia, and lactic dehydrogenase improved the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignancy from 64.3%, 69%, 60%, and 72.7%, respectively, to 83.3%, 81%, 81.4%, and 82.9%, respectively. With the combination of sex (male), white blood count, serum ferritin level, and hepatosplenomegaly, the infection prediction model had a sensitivity, specificity, PPV, and NPV of 78%, 76.2%, 76.6%, and 77.6%, respectively.

Combined clinical parameters improved the localization diagnostic value of ¹⁸F-FDG PET/CT in the local uptake lesion subgroup and the etiological diagnostic value in the non-specific abnormal uptake subgroup.

Reliable non-invasive methods for measuring body temperature are essential for the diagnosis and monitoring of infectious disease.

This study used Intraclass Correlation Coefficients (ICC) and the Bland- Altman plot to analyse the agreement between temperature measurements using an ingestible capsule sensor, a skin sensor and two non-invasive peripheral temperature measurements (axillary and infrared non-contact), collected from a population of febrile patient admitted for infectious disease.

Of the 77 febrile patients screened, 26 patients were enrolled. The ICC between axillary temperature measurements (Taxi) vs. non-contact measurements (Tno-c) were 0.34 [−0.18; 0.63], 0.87 [0.55; 0.94] between Taxi vs. ingestible capsule measurements (Tcap) and 0.12 [−0.09; 0.37] between Taxi vs. Tetac. The mean difference between Taxi vs Tno-c was −1.18 °C with limits of agreement (LoA) from −2.96 to 0.58 °C. The mean difference between Taxi vs Tcap was 0.48 °C, with LoA from −0.60 to 1.56 °C. The mean difference between Taxi vs Tetac was −4.23 °C with LoA from −7.22 to −1.23°C.

Ingestible capsule measurements are reliable enough to adequately estimate the core body temperature in clinical practice. Its non-invasiveness, and the real-time remote control offer new opportunities for future research into fever during infectious diseases.

Fever of unknown origin is defined as a clinically documented temperature of 101°F or higher on several occasions, coupled with an unrevealing diagnostic workup. The differential diagnosis is broad but is typically categorized as infection, malignancy, noninfectious inflammatory disease, or miscellaneous. Most cases in adults occur because of uncommon presentations of common diseases, and up to 75% of cases will resolve spontaneously without reaching a definitive diagnosis. In the absence of localizing signs and symptoms, the workup should begin with a comprehensive history and physical examination to help narrow potential etiologies. Initial testing should include an evaluation for infectious etiologies, malignancies, inflammatory diseases, and miscellaneous causes such as venous thromboembolism and thyroiditis. If erythrocyte sedimentation rate or C-reactive protein levels are elevated and a diagnosis has not been made after initial evaluation, ¹⁸F fluorodeoxyglucose positron emission tomography scan, with computed tomography, may be useful in reaching a diagnosis. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. Depending on clinical indications, this may include liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow biopsy. Empiric antimicrobial therapy has not been shown to be effective in the treatment of fever of unknown origin and therefore should be avoided except in patients who are neutropenic, immunocompromised, or critically ill.