Reply to Which Role for [18F]FDG PET/CT in the “Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel” by Wright et al.?

To the  Editor—We appreciate Albano and Treglia's interest in our study [1] and their questions that allow us to clarify some key points as well as bring to our attention the articles by Hess et al [2] and Ly et al [3]. These references are represented as evidence-based data that would contradict our consensus recommendation for early use of 2-deoxy-2-[¹⁸F] fluoro-D-glucose positron emission tomography/computed tomography (¹⁸FDG-PET/CT) only after a patient fulfills classic fever (fever of unknown origin [FUO]) or inflammation of unknown origin (IUO) criteria. We concur that the recommended diagnostic flowchart by Hess et al [2] is important and may represent a cost-effective strategy for ¹⁸FDG PET-CT in both defining and evaluating these patients. However, we would consider this as hypothesis-generating. Although both publications report significant diagnostic contributions of ¹⁸FDG PET-CT, particularly compared to chest-abdomen-pelvis CT, we question their conclusions that ¹⁸FDG-PET/CT should replace the minimal imaging criteria to define FUO patients [2, 3].

We are unaware of any study directly comparing ¹⁸FDG PET-CT to the current minimal imaging investigations defining a patient as classic FUO or IUO. Therefore, our Delphi consensus did not advocate using ¹⁸FDG PET-CT as part of the inclusionary criteria. The question of which imaging studies should be used in this role remains unanswered. Furthermore, we did not pursue consensus recommendations for pediatric or immunocompromised patients as the diseases, diagnostic, and empiric antimicrobial principles are substantially different compared to classic FUO patients, which was the focus of this Delphi panel. We support further research into the optimal imaging methods that could define these patients but maintain that there remains little compelling evidence that ¹⁸FDG-PET/CT should play a role in the defining criteria. The lack of multicenter, high-quality studies, and the extensive differential diagnosis of FUO or IUO mean that clinical judgment remains an essential component of care. Referring these patients to expert physicians to evaluate for potential diagnostic clues (PDCs) from the history and physical examination before the use of ¹⁸F-FDG PET/CT or rendering a FUO or IUO diagnosis is consistent with the goals of diagnostic stewardship, ultimately reducing unnecessary radiation exposure and expensive diagnostic investigations. Therefore, we retain our conclusion that ¹⁸FDG-PET/CT currently does not have a role in the FUO definition but should be considered early in the evaluation process, after a patient fulfills classic FUO or IUO diagnostic defining criteria, particularly in the absence of PDCs (Figure 1) [1, 4].

Figure 1.

General diagnostic evaluation of patients with fever and inflammation of unknown origin. Abbreviations: ¹⁸FDG-PET, ¹⁸fluorodeoxyglucose–positron emission tomography; ANA, antinuclear antibodies; CBC, complete blood count; CMP, comprehensive metabolic panel; CRP, C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging; RF, rheumatoid factor; TEE, transesophageal echocardiogram; TSH, thyroid-stimulating hormone; TTE, transthoracic echocardiogram.

Regarding the authors' suggested discordant findings and challenges involved in summarizing the main findings of complex Delphi method studies, we assure readers that our study approach and reporting complied with the Conducting and Reporting of Delphi Studies standards [1]. By using this approach, we sought to develop consensus among a group of experts on current research and practice trends, with the first 3 rounds devoted to reaching a consensus on the diagnostic defining criteria for these conditions and later rounds focused on the clinical evaluation of patients [1]. In round 2, question 3 of this survey, we asked experts to agree or disagree if “the combination of a chest x-ray and abdominal ultrasound (without CT-scan) are sufficient imaging components for the minimal diagnostic criteria for FUO/IUO.” Among 21 experts, 3 (14.3%) strongly agreed, 10 (47.6%) agreed, 2 (9.5%) were neutral, and 6 (28.6%) disagreed. In round 2, question 10, we also asked experts for their agreement or disagreement if “an ¹⁸FDG PET-CT scan result is an important component of the diagnostic defining criteria for FUO/IUO.” Among these same 21 experts, 2 (9.5%) agreed, 6 (28.6%) were neutral, 10 (47.6%) disagreed, and 3 (14.3%) strongly disagreed.

We also valued the input concerning results from round 4 of our study on the best solution to incorporating ¹⁸FDG PET-CT in evaluating FUO and IUO patients. Recognizing the importance of accurate comparisons among open-ended survey responses to this issue, the consensus among experts was that limited access in some geographical locations and costs of performing scans presented significant barriers to using ¹⁸FDG PET-CT compared to plain film, ultrasound, or conventional CT. Although a greater representation of knowledgeable experts from public and private sector entities across geographically broader healthcare systems and specialties in this study, particularly regarding the role of ¹⁸FDG PET-CT in the defining criteria, would enhance the robustness of our findings, we surmise the overall outcome in round 4 would not be significantly different given the current evidence-based data. Our study emphasizes the need for further investigations into diagnostic testing strategies to meet geographical variations in diseases across heterogeneous populations and the ecology of medical care.

Notes

Author contributions. All authors participated and approved the development of this letter and met the ICMJE authorship requirements. We verify that all information and materials in the manuscript are original.

Financial support. This work and publication were made possible through support from the Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases. Its contents are solely the authors' responsibility and do not necessarily represent the official view of the Johns Hopkins University School of Medicine.