Clinical Utility of FDG PET-CT in Acute Febrile Illness and Fever of Unknown Origin

INTRODUCTION

The definition of fever of unknown origin (FUO) by Petersdorf and Beeson was a temperature of more than 38.3°C for at least 3 weeks with no detectable etiology after a week of hospitalization and evaluation.^[1] The necessity for inpatient evaluation was modified by Durack and Street in 1991.^[2] Acute febrile illness (AFI) or acute undifferentiated febrile illness is defined as a fever of duration <2 weeks without evidence of localization.^[1,2] About 1.5%–3% of hospitalized patients are managed for FUO.^[3] The magnitude of the challenge could be understood from the fact that about 7% to 53% of patients remain undiagnosed.^[4] There are more than 200 causes of fever described in the medical literature, broadly classified such as infection, malignancy, autoimmune disorders, and noninfective inflammation.^[5] The hundreds of etiological causes and varied geographical influences in the disease presentation are the prime factors that hinder the development of a uniform diagnostic algorithm. Fever evaluation starts with patient history, clinical examination, laboratory tests, and noninvasive medical imaging. Nevertheless, arriving at the etiological diagnosis of fever of unknown origin is a significant challenge in modern clinical practice. The challenge starts with laboratory investigations being nonspecific to direct an etiological diagnosis. The invasive modalities, such as endoscopy and biopsy, are inconvenient and time-consuming.^[6] Noninvasive conventional imaging, such as ultrasonography, computed tomography (CT), and magnetic resonance imaging, detects the pathology by means of structural changes, and they are more apt for evolved disease. Whereas the evaluation of febrile illness requires a highly sensitive modality that can detect the disease early.

The radiologic imaging do not have the high sensitivity to detect the cause of febrile illness early.^[6] Positron emission tomography (PET) can detect the changes at the molecular level and in any pathology, the functional changes precede the structural changes, thereby helping in the early diagnosis of pathology. F-18 fluorodeoxy glucose (FDG) PET-CT utilizes the principle of increased glucose consumption by the infective/inflammatory cells and tumor cells that comprise the etiological spectrum of FUO. FDG PET-CT is a hybrid whole-body imaging that gives instantaneous information about the focus and extent of disease, thereby guiding the diagnosis and treatment.^[7,8] Nevertheless, there is no uniform approach or guidelines regarding the timing of PET-CT, and sequencing it among the array of investigations is still a practical challenge for the physicians. So far, PET-CT has been used in patients with inconclusive or equivocal results from the initial laboratory investigations and anatomical imaging assessment.^[9-13] The established role of FDG PET in the FUO warrants its exploration in the evaluation of undifferentiated fever, thereby helping to reach the diagnosis earlier. The growing availability of PET-CT in India allows its utilization in a variety of clinical scenarios, acute fever being a practically more useful one. This study aimed to assess the diagnostic utility of FDG PET-CT in the broad patient population of AFI and fever of unknown origin.

MATERIAL AND METHODS

The study period was from January 2022 to December 2024. Patients who presented with fever and underwent glucose metabolism PET-CT were included in the study. The decision to perform PET-CT was made by the treating team after clinical examination and laboratory investigations, such as complete hemogram, erythrocyte sedimentation rate, and C-reactive protein (with or without anatomical imaging), and bringing PET-CT earlier in the diagnostic workup in view of guiding further management. About 41 patients in the AFI group and 15 patients in the FUO group had undergone ultrasonography of the abdomen as part of the workup. Adult patients presenting with fever and managed as outpatients or inpatients were included in the study. Pregnant women, patients with retrovirus serology positive (human immunodeficiency virus), proven prior malignancy, nosocomial infections, and immunosuppressive therapy were excluded, but for a post renal transplant patient. In total, 160 patients were studied, with 104 in the AFI group and 56 in the FUO group. In the AFI group, 84 were inpatients (81%) and 20 were outpatients (19%). In the FUO group, 43 were inpatients (77%) and 13 were outpatients (23%).

RESULTS

In the abovementioned study period from January 2022 to December 2024, 186 patients underwent FDG PET-CT as part of evaluation for febrile illness. Most of the patients were from the department of general medicine, and the others were from pulmonology, gastroenterology, and cardiology. Twenty-six patients were excluded from the study as four of them expired, and the rest could not be followed up. Therefore, 160 patients were included for the final analysis; 104 patients in the AFI group and 56 patients in the FUO group. The patient demographics of the respective groups are as depicted in Table 1.

Owing to the different specialties involved in the management of the patients, the partly retrospective nature, patients were evaluated an outpatient basis and hospitalized; a common diagnostic algorithm could not be followed. The discretion of performing PET-CT was made by the treating physician after a minimum laboratory workup in all the patients and conventional imaging in some of the patients.

A final diagnosis was arrived in 144 patients (90%) and etiological classification into three groups as infection, inflammation, and malignancy. The diagnostic yield of FDG PET-CT in our study was found to be 76.9%. The diagnostic yield in the AFI category was 78.8% (95% CI = 0.7–0.856) and the FUO category was 73.2% (95% CI = 0.604–0.83), respectively. The number of patients in either group with respect to etiological classification as infection, inflammation, and neoplasm, and their FDG PET-CT findings are represented in Table 2.

In the AFI group, out of the 84 FDG PET-CT positive patients, 82 were considered TP and two were considered FP. In the FUO group, out of the 44 FDG PET-CT positive patients, 41 were considered TP and three were considered FP. The TP PET-CT included 42 out of 55 infectious diseases in the AFI group and 19 out of 24 infectious diseases in the FUO group. Thirteen patients in the AFI group had FN PET-CT findings (three each with UTI and enteric fever, two each with dengue and infective endocarditis, one each with CMV (cytomegalovirus), BK virus (Human polyoma virus 1) and lower respiratory tract infection, respectively) and five patients in the FUO group had FN PET-CT findings (two each with infective endocarditis and urosepsis and one with dengue).

In the patients diagnosed with inflammation as the cause of fever, PET-CT was TP in all the ten patients in the AFI group but FN in 3 out of 15 patients in the FUO group (colitis, rheumatoid arthritis, and systemic lupus erythematosus). FDG PET was TP in all the patients diagnosed to have neoplastic etiology in both the groups, 10 in the AFI and 7 in the FUO, respectively. The number of patients in each etiological category and final diagnosis is presented in Table 3.

DISCUSSION

Fever of unknown origin and AFI are among the most challenging clinical scenarios in modern medicine for physicians.^[3,18,19,20] The multitude of investigations, time and effort required to arrive at the final diagnosis, as well as the costs involved, are of discomfiture to the patients. FDG PET-CT, a hybrid imaging modality incorporating structural and functional information, helps in the evaluation of FUO and AFI to reach the diagnosis early, avoiding an array of investigations, and is cost-effective and time-saving.^[6,21-24] The role of FDG PET in FUO was studied by many and found useful as a second-line investigation, and a few had emphasized its use early in the diagnostic workup.^[23-26] Our study is the first of its kind to assess the utility of FDG PET in the broad clinical spectrum of fever, including FUO and AFI.

In our group of 160 patients, the final diagnosis was reached in 144 patients (90%). The diagnostic yield of FDG PET in the combined FUO and AFI spectrum in our study is 76.9%.

The yield is in concordance with the latest meta-analysis of 36 studies including 3516 patients by Buchrits et al., in which they found the contributory effect of FDG PET-CT to be 81.3%.^[27] FDG PET has helped in avoiding many other laboratory investigations and in reaching the diagnosis earlier. The initiation of timely, appropriate treatment minimizes the hospital stay for inpatients and faster recovery for both the inpatients and outpatients. Moreover, the financial costs incurred are reduced significantly, and cost-effectiveness has been reported by a few authors.^[25,27,28]

The etiological classification in our study was in the descending order as infection (49.4%), followed by inflammation (30%), and neoplasm (10.6%). The proportion of etiological classification is similar to the studies by the authors.^{[9,12,24,26,28,29]} Out of the 144 patients with the final diagnosis, FDG PET-CT was FN in 18 patients (11.3%). The distribution of etiological classification and the number of patients in each class is displayed in Table 3.

The most common cause of fever of unknown origin and AFI in our study was infection, about 79 patients (49.4%). This is similar to the results of previous studies done in India and Asia.^{[8,12,24,25,28-30]} The reason could be due to the tropical geographic location and prevalence of the infectious disease among the population. Tuberculosis was the most common infective etiology in our study [Fig. 1 and 2], concurring with the previous Indian and Asian studies.^[8,24,29,30]

Close

Fig. 1:

A 23-year-old gentleman presented with a fever of duration of 3 months, with associated cough and weight loss of about 8 kg in the same period. Fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) (a) maximum intensity projection and fused cross-sectional images in (b) axial and (c) coronal views, with respective CT show cavitating lesion in the right lung upper lobe with centrilobular tree in bud nodules in both lung upper lobes. Bronchoalveolar lavage cytology and culture revealed Mycobacterium tuberculosis.

Export to PPT

Close

Fig. 2:

A 40-year-old female, a known case of Systemic Lupus Erythematosus (SLE), presented with fever of duration 6 weeks. Fluorodeoxy glucose positron emission tomography-computed tomography (CT) (a) maximum intensity projection and fused cross-sectional images in (b) coronal and (c) axial views, with respective CT show hypermetabolic thickening in the ileocecal junction, including terminal ileum, multiple mediastinal lymph nodes, splenomegaly with multiple hypermetabolic hypodense lesions and foci of marrow hypermetabolism. Histopathological examination from the terminal ileum was consistent with Mycobacterium tuberculosis.

Export to PPT

The inflammatory diseases as the cause of fever were found in about 48 patients (30%) in our study. Vasculitis is the most common inflammatory cause of [Fig. 3] in most of the previous studies.^[24,31,32] However, in our study, the most common inflammatory cause for fever was Kikuchi disease (histiocytic necrotizing lymphadenitis), a representative case depicted in [Fig. 4], followed by arthritis, predominantly adult-onset still disease (AOSD). In a Chinese study, more than half of the inflammatory etiology was due to AOSD.^[32]

Close

Fig. 3:

A 36-year-old male presented with a history of fever for 4 weeks, Fluorodeoxy glucose positron emission tomography-computed tomography (PET-CT) (a) maximum intensity projection and fused cross-sectional images in (b) axial and (c) coronal views with respective CT show hypermetabolic enlarged right axillary lymph nodes. Histopathological examination revealed necrotizing histiocytic lymphadenitis.

Export to PPT

Close

Fig. 4:

A 54-year-old female, with a history of fever for 10 days and associated weight loss of 6 kg. Fluorodeoxy glucose positron emission tomography-computed tomography (PET-CT) (a) maximum intensity projection and fused cross-sectional images in (b) coronal view with respective CT show mural metabolic activity in the ascending, arch, and descending thoracic aorta and abdominal aorta consistent with vasculitis. Note the diffuse hypermetabolism in the spleen, representing reticuloendothelial activity.

Export to PPT

About 17 patients (10.6%) were found to have malignancy as the etiology of fever, lymphoma [Fig. 5] being the most common (11 patients).^[15,24] The sequence differs from a large study by Chen et al.^[32] where malignancy contributed 23% of fever cases and preceding inflammatory etiology; however, lymphoma was the most common malignancy. We had a patient with myeloma and solid tumors one each from the lung [Fig. 6], liver, kidney, and thyroid gland. A patient had gallbladder carcinoma diagnosed to be the cause of fever and succumbed to the disease within 4 months.

Close

Fig. 5:

A 74-year-old gentleman, with a history of fever for a duration of 15 days. Fluorodeoxy glucose positron emission tomography-computed tomography (PET-CT) (a) maximum intensity projection and fused cross-sectional images in (b) coronal view with respective CT show multiple groups of metabolically active lymph nodes above and below the diaphragm, splenomegaly with intense hypermetabolism consistent with lymphoma. Biopsy from the left supraclavicular lymph node showed classic Hodgkin’s lymphoma.

Export to PPT

Close

Fig. 6:

A 60-year-old gentleman, presented with a history of fever for days. Fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) (a) maximum intensity projection and fused cross-sectional images in (b) axial and (c) coronal view with respective CT show soft tissue lesion in the right lung upper lobe with few small mediastinal lymph nodes and metastatic marrow lesion in the sternum suggestive of stage IV malignancy and same is confirmed by histopathological examination from lung primary.

Export to PPT

In our study, the final diagnosis could not be reached in about 16 patients (10%), in which 10 patients were lost to follow-up and six patients had resolution of fever with antipyretics. Among the six patients, three had hypermetabolic lymph nodes on FDG PET-CT, and biopsy revealed paracortical hyperplasia. This is relatively better and toward the lower side of the literature so far. In the latest meta-analysis by Buchrits et al.,^[27] the etiology could not be reached in 24% of the patients, but with resolution of fever on symptomatic management.

About five patients had FP PET-CT findings in the form of hypermetabolic lymphadenopathy, two in the AFI group and three in the FUO group. The final diagnosis could not be reached in all the five patients, but symptomatically improved. In the FUO group, all the three patients had lymphadenopathy on PET-CT, and biopsy of the same turned out to be reactive hyperplasia. The lymph node biopsy was not performed in the AFI group but had resolution of fever on follow-up.

Multivariate binomial regression analysis revealed that PET-CT was the most influential factor in establishing afinal diagnosis, increasing the odds by nearly 40-fold [Table 4]. In contrast, demographic and laboratory parameters did not demonstrate significant associations, likely reflecting the constraints of the relatively small sample size.

We also faced the unique challenge of lacking a reliable reference standard in this peculiar clinical scenario. However, clinical follow-up of 6 months is practically acceptable for the diagnosis. If the final diagnosis could not be reached even after the 6-month follow-up period, and the patient is clinically improving, we labeled them as undiagnosed. More importantly, patients with an undiagnosed cause of feverperformed better with no life-threatening complications as reported in the literature.^[32,33] In a recent meta-analysis by Takeuchi et al.,^[34] it is revealed that patients with an undiagnosed focus of fever on FDG PET-CT tend to have more chances of spontaneous remission.

LIMITATIONS

The limitations are partly the retrospective nature of the study, lack of uniform lab investigations, possible referral bias, particularly withthe inpatients, and the sequencing of investigations. We suggest performing large multi-centric studies, preferably prospective, to have a uniform evaluation before requesting a PET-CT so that we could find the exact fit of PET-CT in the diagnostic algorithm of fever, be it AFI or FUO.

CONCLUSION

The diagnostic utility of PET-CT in AFI is the first of its kind, and we found its usefulness similar to the established role in FUO. In addition, there is no significant difference in the etiological distribution between the two groups in our study. Nevertheless, we recommend assessing the usefulness according to the characteristics of the population in different parts of the world, and the health conditions (infectious, malignant, etc) prevalent within those population.