PhD defence Ilse Kouijzer

FDG-PET/CT in severe infectious diseases and fever of unknown origin 

In this thesis, the diagnostic value of 18F-FDG-PET/CT in severe infectious diseases is explored. 18F-FDG-PET/CT is increasingly utilized in diagnosing infectious diseases and therefore it is important to investigate the added value of 18F-FDG-PET/CT for the diagnosis and management of specific infectious diseases, especially severe infectious diseases that are difficult to diagnose. Besides determining in which types of infection and for which specific clinical questions in infectious diseases 18F-FDG-PET/CT can provide valuable clinical information, it is also important to know the pitfalls and the types of infection for which 18F-FDG-PET/CT is not a sufficiently adequate diagnostic test.

In chapter 2, the value of 18F-FDG-PET and 18F-FDG-PET/CT in patients with fever of unknown origin (FUO) was reviewed. In diagnosing causes of FUO, it is necessary to use a structured protocol including a thorough history, physical examination, and essential investigations such as laboratory investigations and imaging. Although several studies have investigated the value of stand-alone 18F-FDG-PET (i.e. without combined CT) in evaluation of FUO, nowadays integrated 18F-FDG-PET/CT is the imaging modality of choice and 18F-FDG-PET can be considered obsolete. 18F-FDG-PET/CT has shown to be useful in 54% of patients with FUO. 18F-FDG-PET/CT often does not directly provide a definite diagnosis, but it depicts the anatomical localization where a metabolic process is ongoing and, with help of biopsy and culture, facilitates timely definite diagnosis and therapy. Such an early and adequate diagnosis limits the number of other noncontributing and sometimes invasive tests and thus minimizes the duration of hospitalization for diagnostic purposes. Therefore, 18F-FDG-PET/CT should become a routine procedure in the work-up of FUO and should be implemented in structured diagnostic protocols.

In chapter 3, the influence of elevated CRP and the presence of fever on the diagnostic value of 18F-FDG-PET/CT in patients with FUO was investigated. Charts of 151 consecutive patients with FUO were reviewed. In a total of 223 18F-FDG-PET/CT scans, 18F-FDG-PET/CT was contributory to the final diagnosis in 24.1% of randomly performed scans. The presence of fever on the day of 18F-FDG-PET/CT significantly increased the diagnostic value to 70.0%, while the presence of elevated CRP within one week before 18F-FDG-PET/CT increased the diagnostic value to 46.6%. We concluded that whenever possible 18F-FDG-PET/CT should be scheduled within 24 hours when fever is present. Elevated CRP within one week can be used as an alternative parameter if the former is impossible.

In chapter 4, the value of 18F-FDG-PET/CT in patients with metastatic infection was reviewed. Timely detection of metastatic infectious foci is important, as these foci require prolonged antibiotic treatment and possibly surgical intervention and can result in relapse of infection if not treated adequately. However, metastatic infection is often asymptomatic. 18F-FDG-PET/CT has important advantages over anatomical imaging modalities such as CT and MRI. 18F-FDG-PET/CT has favorable characteristics for screening patients suspected of metastatic infection as it provides whole-body imaging in a relatively short, single session with limited radiation exposure. Also, 18F-FDG-PET/CT detects early metabolic activity rather than the relatively late anatomical changes that are visualized by CT or MRI. There are also less artifacts due to metallic implants and there are no contrast-related side effects. Compared to conventional nuclear imaging techniques, 18F-FDG-PET/CT is a high resolution technique that enables precise localization of sites of infections, the procedure is completed within 1-2h, and has relatively low radiation burden. In diagnosing metastatic infection, 18F-FDG-PET/CT is a valuable technique for detection of many infectious foci, including endovascular infection, spondylodiscitis, and cardiac implantable electronic device (CIED) infection. For native valve endocarditis strong evidence is lacking and further studies are needed. 

As almost all studies on the value of 18F-FDG-PET/CT in metastatic infection are performed in adult patients, in chapter 5 the value of 18F-FDG-PET/CT in children with suspected metastatic infection was investigated. 18F-FDG-PET/CT was helpful in 38% of 13 cases. Reasons for the lower rate of helpful 18F-FDG-PET/CT compared to studies in adults could be the fact that children with both Gram-positive and Gram-negative bacteremia were included and most children had hospital-acquired bacteremia that is less frequently complicated by metastatic infection. In addition, the diagnosis of endocarditis was not evaluated in this study. We concluded 18F-FDG-PET/CT to be a valuable imaging technique in children with suspected metastatic infection, but prospective studies with 18F-FDG-PET/CT as part of a structured protocol are needed.

In chapter 6, the role of 18F-FDG-PET/CT in patients with Staphylococcus aureus bacteremia was assessed for detection of metastatic infection and its consequences for treatment and outcome. A total of 184 patients were included and 99 patients with high-risk bacteremia underwent 18F-FDG-PET/CT. 18F-FDG-PET/CT detected metastatic infection in 73.7% of these high-risk patients and 71.2% of patients with metastatic infection were asymptomatic. 18F-FDG-PET/CT findings resulted in treatment modification in 70.4% of patients. When 18F-FDG-PET/CT was performed, the three-month mortality rate was significantly lower compared to when no 18F-FDG-PET/CT was performed (12.4% vs. 32.7%, p = 0.003). It was concluded that 18F-FDG-PET/CT is a valuable imaging technique in patients with S. aureus bacteremia for early detection of metastatic infection, which often leads to treatment modifications. Also, 18F-FDG-PET/CT is associated with a reduced three-month mortality.

In chapter 7, the value of 18F-FDG-PET/CT in patients with suspected infective endocarditis was studied. A total of 72 patients were included and 18F-FDG-PET/CT was compared to the modified Duke criteria for diagnosing endocarditis. Of these patients, 18 patients were diagnosed with definite endocarditis according to the modified Duke criteria, of whom 16 patients had native valve endocarditis and 2 patients had prosthetic valve endocarditis. Mortality rates were higher for patients without endocarditis according to the modified Duke criteria but with increased 18F-FDG-uptake around the heart valves compared to patients without endocarditis according to the modified Duke criteria and without increased 18F-FDG-uptake around the heart valves. However, because of its low sensitivity, it was concluded that 18F-FDG-PET/CT is currently not sufficiently adequate for the diagnosis of infective endocarditis. It was hypothesized that sensitivity of 18F-FDG-PET/CT could improve when a new generation 18F-FDG-PET/CT scanner would have been used in combination with a low carbohydrate-fat allowed diet, as in this study an older generation scanner was used and patients did not undergo a prior low carbohydrate-fat allowed diet.

In chapter 8, we investigated the value of a new generation 18F-FDG-PET/CT scanner in patients suspected of infective native valve endocarditis who underwent a successful low carbohydrate-fat allowed diet prior to the 18F-FDG-PET/CT scan. In this study, 88 patients with suspected native valve endocarditis were included. Ten patients were diagnosed with definite endocarditis according to the modified Duke criteria. In 48 patients, possible endocarditis according to the modified Duke criteria was diagnosed and in 30 patients the diagnosis of endocarditis was rejected. In this study, sensitivity of 18F-FDG-PET/CT was 30% and thereby not sufficient to be considered for diagnosing infective native valve endocarditis. It was concluded that 18F-FDG-PET/CT lacks sensitivity for diagnosing native valve endocarditis. In patients with possible infective endocarditis according to the modified Duke criteria, however, 18F-FDG-PET/CT could be used in case of sustained suspicion of infective endocarditis, because specificity is high. And, of course, 18F-FDG-PET/CT is important for detecting metastatic infection in patients with suspected endocarditis.

In chapter 9, we investigated the value of 18F-FDG-PET/CT and MRI in patients suspected of spondylodiscitis. A total of 68 patients of whom 49 had a diagnosis of spondylodiscitis were included. MRI showed an overall sensitivity of 67% and specificity of 84%. Diagnostic accuracy was 58%, when MRI was performed within 2 weeks after the start of symptoms and improved to 82%, when performed more than 2 weeks after onset of symptoms. 18F-FDG-PET/CT showed a sensitivity of 96% and a specificity of 95%, with no relation to the interval between the scan and the start of symptoms. It was concluded that 18F-FDG-PET/CT, as compared to MRI, has superior diagnostic value for detecting early spondylodiscitis. After 2 weeks both techniques perform similarly. In this study, conclusions were drawn with the original clinical reports of imaging.

In chapter 10, the value of 18F-FDG-PET/CT, MRI, and 18F-FDG-PET/MRI by soft ware fusion for diagnosing spondylodiscitis was prospectively investigated in 32 patients. For 18F-FDG-PET/CT, sensitivity and specificity in diagnosing spondylodiscitis were 100% and 83.3%. For MRI, sensitivity and specificity were 100% and 91.7%, respectively. In two patients, the original report of MRI was negative in the very early stage of spondylodiscitis and a repeated MRI 14 days later did confirm spondylodiscitis, but reevaluation of this first negative MRI by an expert team without knowledge of the original report and the clinical outcome did show spondylodiscitis in that early stage. For 18F-FDG-PET/MRI, sensitivity and specificity for diagnosing spondylodiscitis were 100% and 81.8%. However, fusion of 18F-FDG-PET and MRI images was not possible in 4 patients for technical reasons. MRI is more sensitive for diagnosing epidural and spinal abscesses than 18F-FDG-PET/CT. An important advantage of 18F-FDG-PET/CT is detection of other metastatic foci that are often present in this patient group. For 18F-FDG-PET/CT, metallic implants are no contra-indication and do not cause severe artifacts as for MRI. Degeneration may occasionally resemble infectious vertebral osteomyelitis on MRI because of the presence of bone marrow edema, which may make MRI interpretation challenging. Assessment of 18F-FDG-PET/CT is, due to the clear guidance of increased 18F-FDG uptake, more straight forward than assessment of MRI, which is an important advantage in daily clinical practice. We concluded that 18F-FDG-PET/MRI in a one-stop-shop would be the optimal imaging technique in suspected spondylodiscitis by incorporation of advantages of both 18F-FDG-PET and MRI. 

Chapter 11 describes the value of 18F-FDG-PET/CT in 273 patients with proven, probable, and possible chronic Q fever. Q fever is a zoonosis with a worldwide distribution caused by the intracellular bacterium Coxiella burnetii. In the Netherlands, a large Q fever outbreak occurred between 2007 and 2010 with over 4,000 notified cases of acute Q fever and more than 40,000 infected patients. In 1-5% of infections with C. burnetii, chronic Q fever infection develops that causes high morbidity and mortality, even if adequate treatment is started. In most patients, manifestations of chronic Q fever are endocarditis, infected aneurysms, or infected vascular prostheses. It is important to diagnose chronic Q fever in an early stage and start adequate treatment as soon as possible. However, diagnosing chronic Q fever is often difficult. In this study, at diagnosis, 18F-FDG-PET/CT contributed to the diagnosis in 13.5%, after serology and PCR testing were performed. 18F-FDG-PET/CT showed infectious foci in 63.3% of all 147 patients with definite chronic Q fever. At diagnosis, 18F-FDG-PET/CT led to treatment adjustment in 19.6% of all 18F-FDG-PET/CT scans performed and in 57.3% at follow-up 18F-FDG-PET/CT. Q-fever mortality rate was higher in patients with vascular infection based on 18F-FDG-PET/CT results compared to patients without vascular infection. In chronic Q fever endocarditis, vegetations are often not visible on echocardiography due to its small size. When adding 18F-FDG-PET/CT as a major criterion to the modified Duke criteria, we found a 1.9-fold increase of definite endocarditis. It was concluded that 18F-FDG-PET/CT is a valuable diagnostic technique in diagnosis of chronic Q fever and during follow-up often leading to a change in diagnosis and/or adjustment of treatment, also providing important prognostic information on patient survival.