LONDON – The use of combined modality imaging with 18F-fluorodeoxyglucose-PET/CT may provide enough information to make a definitive diagnosis in patients who present with fever or inflammation of unknown origin, particularly in those who are aged 50 years or older, have elevated C-reactive protein, and have no fever, according to findings from a single-center study of 240 cases.
The retrospective study of patients seen at the University Clinic of Erlangen (Germany) during 2007-2015 found that 18F-FDG-PET/CT was helpful in finding a diagnosis for a majority of patients with fever of unknown origin (FUO) and inflammation of unknown origin (IUO).
In an interview prior to his presentation at the European Congress of Rheumatology, the study’s senior investigator Dr. Georg Schett said that “By implementing a single 18F-FDG-PET/CT scan in a structured diagnostic approach for patients with FUO or IUO we were able to catch the underlying disease in the majority (79%) of the 240 patients studied. In the FUO group the leading diagnosis was adult-onset Still’s disease, [and] in the IUO group it was large-vessel vasculitis and polymyalgia rheumatica.”
FUO was defined about 50 years ago as several episodes of temperature exceeding 38.3° C that accompany an illness lasting more than 3 weeks, with no diagnosis after a week of testing following hospital admittance. If inflammation but no fever is involved, the condition is termed IUO.
FUO and IUO are severe, sometimes even life-threatening conditions, in which the cause of fever and inflammation, respectively, has not been defined using standard diagnostic approaches. This makes diagnosis challenging and requires a costly and complicated work-up. A delayed diagnosis can be serious, resulting in severe organ damage in patients with FUO and IUO due to the underlying, and uncontrolled, inflammatory disease.
The current diagnostic approaches for FUO and IUO include a thorough medical history, physical examination, laboratory testing, and imaging. 18F-FDG-PET/CT imaging could be potentially useful for the diagnosis of FUO/IUO because of its high-resolution detection of inflammation and malignancy. Dr. Schett and his colleagues explored this potential and examined clinical markers that would increase the likelihood of accurate 18F-FDG-PET/CT-based diagnosis in patients presenting with FUO or IUO.
The 240 patients in the study included 72 with FUO and 142 with IUO; the remaining 26 no longer fulfilled the criteria for either condition when they presented to the clinic (“ex-FUO/IUO” patients). The diagnostic work-up included 18F-FDG-PET/CT scans. Scans were considered to be positive when uptake of the tracer occurred at foci in addition to the other expected locations. The investigators explored whether the scans aided the final diagnosis, with multivariable regression analysis clarifying clinical parameters that aided the success of the scans in patients with and without FUO or IUO.
The mean age was 52 for FUO patients, 61 for IUO, and 51 for patients who no longer had IUO or FUO symptoms at presentation. These patients had mean C-reactive protein (CRP) levels of 95, 48, and 2 mg/L, respectively. Males comprised 64% of FUO, 40% of IUO, and 58% of ex-FUO/IUO patients.
18F-FDG-PET/CT was helpful in finding the diagnosis in 57% of all patients and 72% of the patients with a later diagnosis. A definitive diagnosis was not reached in 29% of patients with FUO and 17% of patients with IUO. Predictive markers for a diagnostic 18F-FDG-PET/CT for FUO and IUO were age over 50 years (P = .002 and P = .005, respectively), CRP level over 30 mg/L (P = .003 and P = .005, respectively), and the absence of fever (both P = .003). If all three parameters were fulfilled, 18F-FDG-PET/CT was diagnostic in nearly 80% of the cases, while it was successful in only 8% of cases where none of the three parameters was met.
The latter finding is particularly important, according to Dr. Schett, as it “indicates which patient subgroup is profiting the most from 18F-FDG-PET/CT.”
“FUO and IUO patients should be referred to specialized centers where 18F-FDG-PET/CT scanning is available to improve diagnosis. Simple clinical parameters such as age, CRP-level, and presence/absence of fever can guide targeted use of 18F-FDG-PET/CT,” said Dr. Schett, director of the department of internal medicine III and the Institute for Clinical Immunology at the University of Erlangen-Nuremberg (Germany).
False-positive results with 18F-FDG-PET/CT – when patients had tracer uptake that did not lead to diagnosis of the underlying diseases – are a challenge. “False-positives happen quite often due to activation of bone marrow and lymph node metabolism during inflammation, which does not support diagnosis,” Dr. Schett said. He added that, when tracer uptake associated with systemic inflammation was not considered, false positives were much less common. False-negative results – when 18F-FDG-PET/CT was negative but a diagnosis was made using other approaches – were rare, occurring in only 12 out of the 240 patients.