computed tomography in patients with fever of unknown origin

European Journal of Internal Medicine 22 (2011) 112–116

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European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m

Original article

Diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in patients with fever of unknown origin☆ Ji-Fang Sheng a,⁎, Zi-Ke Sheng a, Xiao-Min Shen a, Sheng Bi a, Jun-Jie Li a, Guo-Ping Sheng a, Hai-Ying Yu a, Hai-Jun Huang a, Jun Liu a, Dai-Rong Xiang a, Meng-Jie Dong b, Kui Zhao b,⁎, Lan-Juan Li a a Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China b PET Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China

a r t i c l e

i n f o

Article history: Received 23 June 2010 Received in revised form 20 September 2010 Accepted 24 September 2010 Available online 27 October 2010 Keywords: Fever of unknown origin PET/CT Fluorodeoxyglucose Infection Malignancy

a b s t r a c t Background: While fever of unknown origin (FUO) remains a challenging problem in clinical practice, fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) has been considered helpful in diagnosing its cause. The present study is set to evaluate the diagnostic value of PET/CT for patients with FUO. Methods: We analyzed the records of 48 patients with FUO (34 men and 14 women; mean age of 57-year-old with a range between 24- and 82-year-old). The patients were examined by 18F-FDG PET/CT and the results were compared to a final diagnosis that was established by additional procedures. Results: A final diagnosis was established for 36 patients (75%). Among them, 15 patients had infectious diseases, 12 patients had malignancies, and 9 patients had non-infectious inflammatory diseases. Thirty-two abnormal PET/CT results correctly revealed the source of fever (true-positives). Abnormal PET/CT results were considered false-positives for 8 patients without diagnoses. Normal PET/CT results in 4 patients with no diagnoses were classified as true-negatives. Four patients with normal PET/CT results with diagnosed cause for FUO were considered false-negatives. Therefore, PET/CT had a positive predictive value of 80%, a negative predictive value of 50%, a sensitivity of 89%, and a specificity of 33% in patients with FUO. Conclusions: Our study demonstrated that FDG-PET/CT is a valuable imaging tool for the identification of the etiology in patients with FUO. The results suggest that this procedure may be considered as a second-line test, especially when conventional structural imaging was normal or unable to distinguish lesions from benign and malignant. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction Fever of unknown origin (FUO) was originally defined in 1961 by Petersdorf and Beeson as an illness with recurrent fever of N38.3 °C lasting 3 weeks or more, and without a diagnosis after 1 week of detailed clinical investigation [1]. In 1991, Durack and Street suggested classifying FUO as classic, nosocomial, neutropenic, and FUO in immunocompromised patients [2]. Currently, based on possible causes, FUO is mainly classified under four categories including infection, malignance, non-infectious inflammatory disease, and unknown cause [2–4]. Early identification and precise localization

☆ The authors declare that they have no potential conflicts of interest. ⁎ Corresponding authors. Sheng is to be contacted at Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China. Tel.: +86 571 87236759; fax: +86 571 87236755. Zhao, Tel.: +86 571 87236432, fax: +86 571 87236755. E-mail addresses: [email protected] (J.-F. Sheng), [email protected] (K. Zhao).

of the cause for FUO are critical in promoting initiation of appropriate treatment of patients, and has a significant impact on patient care. Despite advances in diagnostic techniques, defining the etiology of FUO remains a continuous clinical challenge. PET using 18F-FDG is a well-established imaging tool for assessment of malignancy [5–9]. Due to an increased rate of glycolysis, malignant tissues typically demonstrate higher 18F-FDG uptake than benign lesions and normal tissues [10]. Since inflammatory cells share the similar molecular basis of 18F-FDG uptakes as tumor cells [2,11], e.g., overexpression of glucose transporter (GLUT-1 and -3) and glycolytic enzymes, studies have indicated 18F-FDG PET is a valuable imaging technique for diagnosis of infection and inflammation and to be a promising tool in the diagnosis of FUO [2,12–14]. The development of a hybrid of PET with CT (PET/CT) is one of the most significant milestones in medical imaging. Whole-body screening PET provides the detailed metabolic and functional information of the foci while the addition of CT offers precise anatomic and morphologic data. In the cases of infection and inflammation, the use of structural imaging alone, such as MRI, X-ray, or CT, might be

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J.-F. Sheng et al. / European Journal of Internal Medicine 22 (2011) 112–116

limited when there are no evident anatomic changes, or the images are indistinguishable from non-infectious lesions. Meanwhile, due to the limited spatial resolution of PET, annotation of small hypermetabolic lesions without an anatomic reference annotation could be problematic. However, through whole-body screening, PET/CT can provide comprehensive metabolic and anatomic information of the whole-body in one study. Therefore, imaging of 18F-FDG uptakes with a hybrid PET/CT scanner should have advantages over either PET or CT alone in the diagnosis of FUO. However, since the first clinical PET/CT system became operational in 2001[15], there are only limited studies that have used PET/CT in patients with FUO [16–19]. Much of this is due to the uncertainty that remains about which stage of diagnosis a PET/CT should be ordered [16–19]. We reported here that 18F-FDG PET/CT is a useful second-line test in the diagnosis of FUO. 2. Material and methods 2.1. Patients From July 2007 to February 2009, all consecutive patients with FUO who received PET/CT examinations at the First Affiliated Hospital (a 2500-bed hospital), School of Medicine of Zhejiang University, China, were enrolled in this study. All patients had the classic-type of FUO. None of the patients had an immunocompromised condition, a different spectrum of diseases causing fever [20,21], or had nosocomial fever. The patients were ordered for PET/CT scanning by attending physicians when the first-line diagnostic tests did not find abnormalities, or when the cause of the abnormalities was unclear. 2.2. Diagnostic work-up All the enrolled patients underwent detailed physical examination and medical history assessment. Subsequent diagnostic procedures were followed as the first-, second-, and third-line investigations. First-line investigations including routine laboratory tests (Table 1) were performed in all FUO patients. If the etiology of FUO was not found or no diagnosis was reached by the first-line investigation, the second-line investigation was performed in most patients. Typically, the 18F-FDG PET/CT was performed when conventional structural imaging was normal or unable to distinguish the lesions from benign Table 1 Major clinical approaches to diagnose FUO. Categories

Methods

First-line

Complete blood count with leucocyte differentiation stool and urine routine examination ESR*, CRP*, TP*, ALT*, AST*, ALP*, LDH*, CK*, GGT*, albumin–globulin ratio, level of blood glucose and fat, electrolytes, renal function tests cultivation for blood, urine, throat and sputum,(when needed) rheumatoid factor, antistreptolysin O titer, PPD* chest radiography, ECG*, abdominal ultrasonography Serologic antibodies tests for cytomegalovirus, Epstein–Barr virus, rubeola, toxoplasma, hepatitis viruses, and HIV serology C3, C4, protein electrophoresis ANA*, AMA*, ANCA*, hydrothorax and seroperitoneum test for tumor cell, the thyreoid function test, Widal and Wright agglutination tests biopsy for bone marrow, lymph node, and skin, (when diagnostic clues recommend), bone marrow culture CT and/or MRI of abdomen, chest or cerebrum, echocardiography, colonoscopy, ECT* scanning (e.g., bone, parotid, thyroidea), PET/CT scanning Liver biopsy, surgery (e.g., splenectomy and pancreectomy)

Second-line

Third-line

ESR*, erythrocyte sedimentation rate; CRP*, C-reactive protein; TP*, total protein; ALT*, alanine aminotransferase; AST*, aspartate aminotransferase; ALP*, alkaline phosphatase; LDH*, lactate dehydrogenase; CK*, creatine kinase; GGT*, γ-glutamyl transpeptidase; PPD*, purified protein derivatives tuberculin test; ECG*, electrocardiogram; ANA*, antinuclear antibodies; AMA*, anti-mitochondrion antibodies; ANCA*, anti-neutrophil cytoplasmic antibodies; ECT*, emission computed tomography.

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to malignant. Liver biopsy and surgery were prescribed as third-line investigations for these patients when it was necessary. Table 1 illustrates the major procedures practiced on the patients in our study. 2.3.

18

F-FDG PET/CT imaging

After at least 6 h of fasting, patients received an intravenous injection of FDG at 5.5–7.4 MBq/kg of body weight. Patients were hydrated with 1000 ml of water 1 h prior to image acquisition. Blood glucose levels were checked in all patients before FDG injection and no patients were found to have blood glucose levels greater than 160 mg/dl. Whole-body PET/CT scans were acquired using a combined PET/CT scanner (Siemens Biograph Sensation 16, Germany). Wholebody CT and PET covered a region ranging from the meatus of the ear to the mid thigh. Approximately 1 h after FDG injection, the PET/CT session was conducted. The procedure for data acquisition was as follows: 16 section multidetection row CT scanning was performed first, from the head to the mid thigh with 120 Kv, 100 mA s. A tube rotation time of 0.5 s and a 5 min section thickness, which was matched to the PET section thickness. Immediately after CT scan, a whole-body emission PET scan was obtained with 3-minute acquisition per bed position using a 3-dimensional acquisition mode. Attenuation-corrected PET images were reconstructed with an ordered-subset expectation maximization iterative reconstruction algorithm (8 subsets, 3 iterations). PET, CT, and fused PET/CT images were generated and reviewed on a computer workstation (Virtual Place version 3.0035, AZE). The PET/CT scans were independently interpreted by two staff members of the PET center. The increased uptake of 18F-FDG with intensity higher than that of surrounding tissues in at least one area was considered as positive, while no sites of increased 18 F-FDG uptake was defined as negative. Disagreements between respective independent interpretations were resolved by consensus. 2.4. Clinical evaluation of PET/CT findings The diagnostic contributions of abnormal PET/CT results were retrospectively evaluated after incorporation into the final diagnoses, which were established by summarizing all test results obtained during hospitalization or outpatient care (Table 2). Abnormal results were classified as either “helpful in diagnosis” or “noncontributory to diagnosis”. The elevated uptake of FDG was regarded as helpful in diagnosis when it pointed to the organ or tissue where the cause of the fever was finally established. Abnormal PET/CT findings were considered as noncontributory to diagnosis when no final diagnosis were reached or a location of pathology identified is different from the site demonstrated on PET/CT scans. An abnormal PET/CT result was considered a true positive when it revealed an infection, a malignancy or a non-infectious inflammatory disease as the cause of the fever that was subsequently confirmed by additional investigations. An abnormal PET/CT result was considered a false-positive when it failed to reveal the underlying cause of an infection, a malignancy or a noninfectious inflammatory disease or when no final diagnosis could be Table 2 Establishment of the causes in the 36 patients with FUO. Confirmation of FUO cause

No. of cases

PET/CT results Normal

Abnormal

Biopsy Surgery Serology Immunology Cultivation Clinical course Follow-up Total

12 3 1 1 1 16 2 36

1 0 0 0 0 3 0 4

11 3 1 1 1 13 2 32

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made during a follow-up period of at least 6-month. A normal PET/CT scan was called true negative when no cause related to the fever was identified despite extensive diagnostic procedures and clinic followup for at least 6 months. A normal PET/CT result was considered false negative when an infectious, malignant or non-infectious inflammatory process was verified as the cause of the fever. Final diagnosis was determined by the treating physician based on positive serologic assays, biopsy, surgery or autopsy. 2.5. Statistical analysis Data were analyzed with SPSS software version 11.5. The 95% confidence intervals were calculated for sensitivity, specificity, positive predictive value, and negative predictive value. 3. Results Forty-eight patients were included in our study. They all met the criterion for classic FUO mentioned above. Thirty-six patients (75%, 36/48) had a final diagnosis, as determined by additional examinations (Table 2). The final diagnosis was established through clinical course in 15 cases (42%, 15/36) and biopsy in 13 cases (36%, 13/36). Among the FUO patients, an infectious disease was established in 15 patients (31%, 15/48), a malignancy in 12 (25%, 12/48), a noninfectious inflammatory disease in 9 (19%, 9/48), and 12 (25%, 12/48) with no diagnosis (Table 3). All 12 patients without a diagnosed cause of fever were followedup for at least 4 months. In 6 patients, the fever disappeared spontaneously within the first month of follow-up. In 4 other patients, the fever had recurred for several years. The fever lasted for 1 week each time and then subsided spontaneously. In the remaining 2 patients, the fever subsided when treated with corticosteroids during 6 weeks of hospitalization and remained fever free in our 7-month and 10-month follow-up, respectively. PET/CT scan was ordered in 3 patients with a malignancy relapse suspicion as a first-line investigation. In the remaining 45 patients, this procedure was prescribed as a second-line test. Table 2 shows the establishments of the causes of fever in 36 patients with a final diagnosis.

Forty (83%, 40/48) of the total PET/CT findings were considered abnormal, while eight (17%, 8/48) were considered normal (Table 3). Thirty-two of abnormal PET/CT results revealed the source of fever and therefore they were considered true positive (80%, 32/40). The abnormal uptake of 18F-FDG in the bone marrow or lymph nodes was considered true positive in 2 patients with an infectious disease and in 4 patients with non-infectious inflammatory disease, based on the final diagnosis determined by the imaging-oriented additional procedures. In another 4 patients, the increased uptake of 18F-FDG representing as a manifestation of malignancy was also considered true positive, as a final diagnosis was established through the imaging-guided biopsy or surgery. The abnormal PET/CT results were considered false-positive in 8 patients without diagnosis. Normal PET/CT results were classified as true negative in 4 patients with no diagnosis, while the remaining 4 normal PET/CT results were considered false negative in patients with diagnoses of adult-onset Still's disease, viral hepatitis, upper respiratory tract infection, and pulmonary infection, respectively, through clinical courses (n = 3) and biopsy (n = 1). Therefore, the 18F-FDG PET/CT results had a positive predictive value of 80% (32/40), and a negative predictive value of 50% (4/8), respectively, in patients with FUO. The sensitivity and the specificity of the 18F-FDG PET/CT results were 89% (32/36) and 33% (4/12), respectively. 4. Discussion An increased uptake of FDG has been found in tumor cells as well as in a variety of inflammatory cells [2]. Because the main causes of FUO are inflammatory and malignant processes, 18F-FDG PET has been demonstrated to be useful in providing diagnoses for patients with FUO [12–14]. However, the limited anatomic information acquired by 18 F-FDG PET may restrict its use in some situations. The combination of PET with CT (PET/CT) could overcome this disadvantage. In the present study, PET/CT contributed to final diagnoses in 67% of the enrolled patients, while the probability of an eventual diagnosis was 75%. In a retrospective study by Jasper et al., 53% of the 30 PET/CT scans were considered helpful [18]. Similarly, 46% of the PET/CT scans were considered to contribute to the diagnosis of the underlying cause of the fever in another prospective study by Keidar et al. [19]. Ferda et

Table 3 Final diagnosis of patients with FUO and contribution of PET/CT to FUO. Categories

Infection Pulmonary infection Upper respiratory tract infection Tuberculosis Subacute thyroiditis Abdominal infection Viral hepatitis Biliary tract infection Chronic pancreatitis Neoplasm Malignant lymphoma Lung cancer Relapse of gastric cancer Myelodysplastic syndrome Non-infectious inflammatory disease Adult-onset Still's disease Sjogren syndrome Systemic lupus erythematosus Vasculitis Sarcoidosis No diagnosis Total (%)

Final diagnosis, No.(%) of cases

PET/CT results

15(31%) 6 1 2 1 2 1 1 1 12(25%) 8 2 1 1 9(19%) 5 1 1 1 1 12(25%) 48(100%)

3 1 1 0 0 0 1 0 0 0 0 0 0 0 1 1 0 0 0 0 4 8

Normal

Abnormal Helpful

Noncontributory

12 5 0 2 1 2 0 1 1 12 8 2 1 1 8 4 1 1 1 1 0 32

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 8

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al. demonstrated that the cause of the FUO was explained by PET/CT findings and the subsequent imaging-guided tests for 92% of the cases in their retrospective study [17]. In our study, of the 36 final diagnoses received by patients with FUO, 32 (89%, 32/36) were established by imaging-oriented additional procedures (Table 2), which encourages the future use of this test in diagnosis of FUO. Moreover, neoplasms were identified in 12 patients; among which eleven were detected for the first time (lymphoma, n = 8; lung cancer, n = 2; myelodysplastic syndrome, n = 1), and one was diagnosed as a relapse of gastric cancer. In addition, among the afore-mentioned eleven patients, 8 (73%, 8/11) received their diagnoses through additional tests guided by the PET/CT findings. Therefore, PET/CT showed good performance in diagnosing FUO among patients with a hematologic malignancy. The proportion of 18F-FDG PET scans that were reported in the literature to be helpful for diagnosis among patients with FUO ranged from 25% to 69% [12,14,20,22–25], while the percentage of patients with FUO who had final diagnoses varied from 54% to 66% [12– 14,22,23]. Notably, these studies are not comparable because several objective variables, such as, the different conditions of the patients and the performance of PET/CT at different stages of FUO, were not well controlled. Therefore, further studies were needed in order to evaluate the potential clinical value of PET/CT in the diagnosis of FUO. In the present study, the sensitivity of 18F-FDG PET/CT for detecting the cause of FUO was 89% and the specificity was 33%. The number of false-positive PET/CT results is responsible for the poor specificity. We don't have sufficient PET/CT data to review in the patients with no diagnosis because the follow-up PET/CT scanning was not performed in these patients. This has contributed to the number of false-positive PET/CT results. As reported in previous publications, the sensitivity and the specificity for 18F-FDG PET and PET/CT in patients with FUO ranged from 50% to 93% and from 46% to 90%, respectively [12,23,25]. It remains challenging to obtain the precise sensitivity and specificity for PET/CT scan in patients with FUO for various reasons [2,13,18]: (a) a high rate of false-positives is inevitable because the causes of FUO are obscure in a number of patients [2–4]; (b) without sufficient follow-up, the abnormal PET/CT results in patients with FUO but without final diagnoses are usually classified as false-positive findings; (c) when the additional procedures fail to reveal an infection, a malignancy, or a non-infectious inflammatory disease, it is probably legitimate to consider the abnormity as a false-positive [13]; and (d) it is also difficult to separate physiologic from pathologic accumulation of 18F-FDG, which causes variation in the number of positive results. In our study, PET/CT imaging contributed to the final diagnosis of 89% patients with FUO (32/36) (Table 2), which encouraged the future use of this test in the diagnosis of FUO. Moreover, the FDG-PET/CT findings have guided the final diagnosis of neoplasm in patients with FUO. This led to the early identification of 12 patients with neoplasm, among which 11 patients were detected for the first time with malignancy. The results revealed a significant impact of the FDG-PET/ CT study on the final diagnosis for the cause of FUO. It is more so on the patients with FUO who have a hematological malignancy. However, for the final validation of the positive PET/CT studies in the patients with FUO, a careful evaluation of the clinical assessments, conventional first-line tests and other investigations should be included. Controversy remains about when PET/CT scanning should be performed during the course of FUO. In this study PET/CT was performed as a second-line test in most FUO patients when conventional structural imaging was normal or unable to distinguish lesions from benign and malignant. The obvious advantage of PET/CT is that it is an accurate, noninvasive test for diagnosing FUO, with providing comprehensive information through whole-body scanning. For timely identification and precise localization of the cause for FUO, the PET/CT scanning may be considered as a second-line test for the patients of FUO, although the high cost and limited availability may limit the use of this technique.

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5. Conclusion 18 F-FDG PET/CT imaging plays an increasingly important role in identifying the underlying causes of FUO. The data in the present study demonstrated that 18F-FDG PET/CT helped to establish the final diagnosis among 67% of the 48 patients with FUO. Our results demonstrate the diagnostic value of 18F-FDG PET/CT for patients with FUO and encourage the future use of this protocol as a second-line test among patients with FUO, especially when conventional structural imaging is normal or inadequate to distinguish lesions from benign and malignant. Furthermore, FDG-PET/CT could be a useful test for the earlier identification of hematological malignancy in patients with FUO.

6. Learning points •

18

F-FDG PET/CT is a valuable second-line test in the diagnosis of patients with FUO. • 18F-FDG PET/CT is also an essential examination to localize the origin of FUO. Acknowledgments The authors thank Jun Li for constructive suggestions, Zheng-Zheng Shi for comments on the manuscript and Suzhen Chen for critical reading of the manuscript. This study was supported by the National Basic Research Programs (973) of China (No. 2007CB513004) and the Major National S&T Projects for Infectious Diseases (2008ZX10002007). References

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