Summary: Appropriate Use Criteria for the Use of Nuclear Medicine in Fever of Unknown Origin

Christopher J. Palestro; Gad Abikhzer; Zvi Bar-Sever; Twyla Bartel; Rebecca Brady; Erin E. Grady; Ora Israel; Sanjay K. Jain; Sheetal Kandiah; Machaba M. Sathekge; Barry L. Shulkin

doi:10.2967/jnumed.124.268797

Abstract

The diagnostic work-up of patients with fever of unknown origin (FUO) begins with a thorough history and physical examination, complete blood count with differential, chest x-ray, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, and C-reactive protein level. Additional imaging procedures, including nuclear medicine tests, are generally used as second-line procedures, with ¹⁸F-FDG PET and PET/CT assuming increasingly important roles in the diagnostic work-up. The Society of Nuclear Medicine and Molecular Imaging, the Infectious Diseases Society of America, and the American College of Nuclear Medicine convened an autonomous expert work group to comprehensively review the published literature for nuclear imaging in adults and children with FUO and establish appropriate use criteria (AUC). This process was performed in accordance with the Protecting Access to Medicare Act of 2014, which requires that all referring physicians consult AUC by using a clinical decision support mechanism before ordering advanced diagnostic imaging services. The complete findings and discussions of the work group were published on January 8, 2023, and are available at https://www.snmmi.org/ClinicalPractice/content.aspx?ItemNumber=15666. The AUC in the final document are intended to assist referring health care providers in appropriate use of nuclear medicine imaging procedures in patients with FUO. The work group noted limitations in the current literature on nuclear medicine imaging for FUO, with the need for well-designed prospective multicenter investigations. Consensus findings from published data and expert opinions were used to create recommendations in common clinical scenarios for adults and children. Included in the complete document is a discussion of inflammation of unknown origin (IUO), a recently described entity. In view of the fact that the criteria for FUO and IUO are similar (except for fever > 38.3°C [100.9°F]) and that the most common etiologies of these 2 entities are similar, it is the expert opinion of the work group that the recommendations for nuclear medicine imaging of FUO are also applicable to IUO. These recommendations are included in the full guidance document. This summary reviews rationale, methodology, and main findings and refers the reader to the complete AUC document.

Fever of unknown origin (FUO) in children and adults is among the more challenging clinical conditions for both patients and treating physicians. In up to 50% of cases, no definite diagnosis is established. Important subsets of the classic FUO include nosocomial, neutropenic, HIV-associated, and organ transplant–associated FUOs. Nuclear medicine imaging studies are often performed as part of the diagnostic work-up of patients with FUO. In vitro–labeled leukocytes and ⁶⁷Ga were, for many years, the mainstay of nuclear medicine imaging in this population. ¹⁸F-FDG PET and PET/CT, however, have rapidly assumed an increasingly important role in the diagnostic work-up of these patients.

The Society of Nuclear Medicine and Molecular Imaging (SNMMI), the Infectious Diseases Society of America, and the American College of Nuclear Medicine convened an autonomous expert work group to comprehensively review the published literature for nuclear imaging in adults and children with FUO and establish appropriate use criteria (AUC). This process was performed in accordance with the Protecting Access to Medicare Act of 2014, which requires that all referring physicians consult AUC by using a clinical decision support mechanism before ordering advanced diagnostic imaging services. The complete findings and discussions of the work group were published on January 8, 2023, and are available at https://www.snmmi.org/ClinicalPractice/content.aspx?ItemNumber=15666.

METHODOLOGY

Expert Work Group

The experts of this AUC work group were convened by the SNMMI to represent a multidisciplinary panel of health care providers with substantive knowledge in the use of nuclear medicine procedures in FUO. A complete list of work group participants and external reviewers can be found in Appendix A in the online version of the AUC, where additional appendices and tabular material provide term definitions and acronyms, author disclosures, and the process used to engage public commentary. Also included are extensive supporting references, qualifying statements, evidence limitations, and radiation considerations appropriate to the relevant modalities and radiopharmaceuticals.

AUC Development

The process for AUC development was modeled after the RAND/UCLA Appropriateness Method. It included identifying a list of relevant clinical scenarios in which nuclear medicine imaging can be used in the patient with FUO, a systematic review of evidence related to these clinical scenarios, and a systematic synthesis of available evidence. This was followed by development of AUC for each of the clinical scenarios. The final document was drafted on the basis of group ratings and discussions. The scope and development of clinical scenarios (3 for adults, 3 for children) are described in detail in the full published AUC.

Systematic Review

A systematic review of the relevant literature was conducted by the Pacific Northwest Evidence-Based Practice Center at the Oregon Health and Science University to synthesize information on the accuracy of nuclear medicine imaging techniques for diagnosis of FUO and the effects of nuclear medicine imaging on clinical outcomes and clinical decision making. The following key questions guided the review: (1) What is the accuracy of ⁶⁷Ga scintigraphy with or without SPECT or SPECT/CT for diagnosis of FUO in adults and children? (2) What is the accuracy of in vitro–labeled leukocyte scintigraphy with or without SPECT or SPECT/CT for diagnosis of FUO in adults and children? (3) What is the accuracy of PET, PET/CT, or PET/MRI with ¹⁸F-FDG for diagnosis of FUO in adults and children? (4) What are the effects of nuclear medicine imaging for FUO on clinical outcomes or clinical decision making (e.g., use of treatments, subsequent tests)? The reviewer assessment processes, inclusion and exclusion criteria for articles/data, rating and scoring methodologies, and quality standards for inclusion for consideration are reported in detail in the complete AUC. Database searches, reviews of reference lists, and suggestions from experts resulted in 6,537 potentially relevant articles, of which 1,334 were selected for full-text dual review. Of these, 51 were determined to meet the inclusion criteria for AUC considerations, with 24 systematic reviews on diagnostic accuracy also included. After the rating process was completed, the final appropriate use ratings were summarized in a format similar to that outlined by the RAND/UCLA Appropriateness Method (Table 1).

View this table:

TABLE 1.

Clinical Scenarios for Diagnosis of FUO (Tables 3 and 5 in Final Published AUC)

FUO IN ADULTS

Persistent undiagnosed fever, now referred to as FUO, was first recognized in the early 20th century, and many investigations of FUO have been conducted over the years. It is important to be cognizant of the fact that FUO is not a biologically uniform phenomenon but a common manifestation of many different disease processes, with clinically defining features that have evolved over time. The core features of FUO are failure to identify a cause of the fever after reasonable inpatient or outpatient investigations and persistence of fever for a sufficient length of time to exclude self-limiting fevers. FUOs are generally categorized as classic, nosocomial, neutropenic, or HIV-related. Etiologies fall mainly into 5 groups: infection, neoplasm, inflammatory (e.g., connective tissue diseases), miscellaneous causes, and undiagnosed illness. Distributions of these etiologies vary over time and in relation to age, income level, and geographic area. Many patients with FUO have complex medical histories and comorbidities and may be taking various medications, all of which can complicate interpretation of diagnostic tests.

FUO represents an estimated 1.5%–2% of hospital admissions, with estimated mortality rates ranging from less than 10% to greater than 30%. Several factors contribute to morbidity associated with FUO, including prolonged hospital stay, repeated invasive and noninvasive investigations, and presumptive treatment and cost implications. The cornerstones of diagnostic work-up remain a thorough history, physical examination, and routine initial testing. Signs, symptoms, and abnormalities pointing toward a possible diagnosis are referred to as potentially diagnostic clues (PDCs). In general, first-line evaluation includes basic laboratory and imaging tests, followed by more advanced imaging if first-line evaluation is not conclusive. In virtually all cases, PDCs will be present. Invasive procedures have now largely been replaced by advanced diagnostic imaging, although laparoscopy and laparotomy are still useful for FUO in the setting of solid tumors, peritoneal carcinomatosis, lymphoma, and disseminated tuberculosis.

When a diagnosis is not evident from basic PDCs, radiologic imaging is most often used as part of the work-up. Conventional radiologic techniques such as CT, MRI, and ultrasound are most often used and are generally readily available. A limitation of these modalities is difficulty in detecting early inflammatory or infectious lesions because significant anatomic changes may be absent early on. When PDCs are absent or misleading and first-line investigations are inconclusive, second-line investigations, including nuclear medicine imaging, may be used. Determination of the most appropriate investigation should be directed toward a diagnostic algorithm aimed at a cost-effective, noninvasive approach that ultimately expedites a diagnosis and minimizes prolonged hospitalization and unnecessary investigations.

Summary Recommendations

¹⁸F-FDG PET and PET/CT are the nuclear medicine tests of choice in adults with FUO and should be included in the diagnostic algorithm for this indication. ⁶⁷Ga scintigraphy should be reserved for those situations in which ¹⁸F-FDG PET and PET/CT are not available. Labeled leukocyte scintigraphy should be reserved for those situations in which ¹⁸F-FDG PET and PET/CT are not available and there is a high index of suspicion for infection as the cause of the fever.

FUO IN CHILDREN

The definition of FUO in children has continued to evolve over time, with a general consensus today of persistent fever for longer than 1 wk with negative initial work-up. This definition takes into consideration that most common viral infections (e.g., upper respiratory infections, acute gastroenteritis) and uncomplicated bacterial infections (e.g., otitis media, pharyngitis) have fevers of less than 7-d duration. Early investigations of pediatric FUO established 4 major causes: infectious diseases, inflammatory conditions, neoplasms, and miscellaneous/undiagnosed causes. Infectious diseases, especially bacterial infections, and osteomyelitis made up 29%–52% of cases; inflammatory disorders (e.g., juvenile idiopathic arthritis and systemic lupus erythematosus) accounted for 10%–20% of cases; and malignancies (e.g., leukemia, lymphoma, and neuroblastoma) accounted for 4%–13%. In about 12%–20% of children, fevers resolved without a specific diagnosis being established.

The first step in evaluation of FUO in children is to confirm the fevers by repeated measurements of temperature, both in the health care setting and at home. The patient and the patient’s parents/caregivers are often asked to keep a fever diary. Next, a thorough history and a comprehensive physical examination are performed to assess for signs and symptoms that may be indicative of specific clinical syndromes. Initial laboratory work-up often includes a complete blood cell count with differential, inflammatory markers, liver and renal function tests, urinalysis, and urine and blood cultures. Initial imaging studies are frequently guided by signs and symptoms (e.g., chest radiograph for tachypnea and cough). If a specific anatomic region is identified, more detailed imaging, such as ultrasound, CT, and MRI, may be performed. When fever persists and its etiology cannot be identified by these evaluations, nuclear medicine imaging is often performed. The work group noted a paucity of qualifying data for definitive nuclear medicine AUC in FUO in children and cited the need for well-designed prospective multicenter investigations.

Summary of Recommendations

¹⁸F-FDG PET and PET/CT are the nuclear medicine tests of choice in children with FUO. From the results that have been reported for both ⁶⁷Ga and labeled leukocyte scintigraphy, neither test is recommended for children with FUO.

ADDITIONAL CONSIDERATIONS

The work group noted that these AUC are not intended as definitive guidance but, instead, may provide support for considered clinical judgment on the basis of available or prevailing evidence related to the use of nuclear medicine techniques in the evaluation of FUO. Because FUO may be addressed with a variety of nuclear medicine techniques and radiopharmaceuticals, the AUC are not confined to a single target or technique, with the intention of providing clinicians with scientifically based flexibility in their approach to clinical questions. At the same time, the work group noted that the integration and complementary use of nuclear and morphologic techniques may indeed provide the most appropriate strategy for what are often complex questions of extent and severity of disease.

SUMMARY

This report is a summary of the complete Appropriate Use Criteria for the Use of Nuclear Medicine in Fever of Unknown Origin, available at https://www.snmmi.org/ClinicalPractice/content.aspx?ItemNumber=15666.