Nuclear Medicine Imaging Tools in Fever of Unknown Origin: Time for a Revisit and Appropriate Use Criteria.

Fever of unknown origin (FUO) is a clinical conundrum for patients and clinicians alike, and imaging studies are often performed as part of the diagnostic workup of these patients. Recently, the Society of Nuclear Medicine and Molecular Imaging convened and approved a guideline on the use of nuclear medicine tools for FUO. The guidelines support the use of 2-18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in adults and children with FUO. 18F-FDG PET/CT allows detection and localization of foci of hypermetabolic lesions with high sensitivity because of the 18F-FDG uptake in glycolytically active cells that may represent inflammation, infection, or neoplasia. Clinicians should consider and insurers should cover 18F-FDG PET/CT when evaluating patients with FUO, particularly when other clinical clues and preliminary studies are unrevealing.

FDG-PET/CT for investigation of pyrexia of unknown origin: a cost of illness analysis.

BACKGROUND: Our study aims to explore the current utilisation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the diagnostic pathway of pyrexia of unknown origin (PUO) and associated cost of illness in a large tertiary teaching hospital in Australia. METHOD: 1257 febrile patients between June 2016 and September 2022 were retrospectively reviewed. There were 57 patients who met the inclusion criteria of "classical PUO", of which FDG-PET/CT was performed in 31 inpatients, 15 outpatients and 11 inpatients did not have an FDG-PET/CT scan. The patient demographics, clinical characteristics and inpatient cost were analysed, together with the diagnostic performance of FDG-PET/CT and impact on clinical management. RESULT: The mean age, length of stay and total cost of admission were higher for inpatients who received FDG-PET/CT versus those who did not. The median cost per patient-bed-day did not differ between the two groups. Inpatients who received earlier FDG-PET/CTs (≤ 7 days from admission) had shorter length of stays and lower total cost compared to those who received a later scan. A negative FDG-PET/CT scan, demonstrating no serious or life-threatening abnormalities resulted in subsequent discharge from hospital or outpatient clinic in 7/10 (70%) patients. There were 11/40 (28%) scans where ancillary abnormalities were identified, requiring further evaluation. CONCLUSION: FDG-PET/CT showed high diagnostic accuracy and significant impact on patient management in patients with PUO. FDG-PET/CT performed earlier in admission for PUO was associated with shorter length of stay and lower total cost.

Pyrexia of unknown origin (PUO) and the cost of care in a tertiary care institute in Sri Lanka.

BACKGROUND: Despite advancements in diagnostic technology, pyrexia of unknown origin (PUO) remains a clinical concern. Insufficient information is available regarding the cost of care for the management of PUO in the South Asian Region. METHODS: We retrospectively analyzed data of patients with PUO from a tertiary care hospital in Sri Lanka to determine the clinical course of PUO and the burden of the cost incurred in the treatment of PUO patients. Non-parametric tests were used for statistical calculations. RESULTS: A total of 100 patients with PUO were selected for the present study. The majority were males (n = 55; 55.0%). The mean ages of male and female patients were 49.65 (SD: 15.55) and 46.87 (SD: 16.19) years, respectively. In the majority, a final diagnosis had been made (n = 65; 65%). The mean number of days of hospital stay was 15.16 (SD; 7.81). The mean of the total number of fever days among PUO patients was 44.47 (SD: 37.66). Out of 65 patients whose aetiology was determined, the majority were diagnosed with an infection (n = 47; 72.31%) followed by non-infectious inflammatory disease (n = 13; 20.0%) and malignancies (n = 5; 7.7%). Extrapulmonary tuberculosis was the most common infection detected (n = 15; 31.9%). Antibiotics had been prescribed for the majority of the PUO patients (n = 90; 90%). The mean direct cost of care per PUO patient was USD 467.79 (SD: 202.81). The mean costs of medications & equipment and, investigations per PUO patient were USD 45.33 (SD: 40.13) and USD 230.26 (SD: 114.68) respectively. The cost of investigations made up 49.31% of the direct cost of care per patient. CONCLUSION: Infections, mainly extrapulmonary tuberculosis was the most common cause of PUO while a third of patients remained undiagnosed despite a lengthy hospital stay. PUO leads to high antibiotic usage, indicating the need for proper guidelines for the management of PUO patients in Sri Lanka. The mean direct cost of care per PUO patient was USD 467.79. The cost of investigations contributed mostly to the direct cost of care for the management of PUO patients.

Improving protocols for whole-body magnetic resonance imaging: oncological and inflammatory applications.

Whole-body MRI is increasingly used in the evaluation of a range of oncological and non-oncological diseases in infants, children and adolescents. Technical innovation in MRI scanners, coils and sequences have enabled whole-body MRI to be performed more rapidly, offering large field-of-view imaging suitable for multifocal and multisystem disease processes in a clinically useful timeframe. Together with a lack of ionizing radiation, this makes whole-body MRI especially attractive in the pediatric population. Indications include lesion detection in cancer predisposition syndrome surveillance and in the workup of children with known malignancies, and diagnosis and monitoring of a host of infectious and non-infectious inflammatory conditions. Choosing which patients are most likely to benefit from this technology is crucial, but so is adjusting protocols to the patient and disease to optimize lesion detection. The focus of this review is on protocols and the elements impacting image acquisition in pediatric whole-body MRI. We consider the practical aspects, from scanner and coil selection to patient positioning, single-center generic and indication-specific protocols with technical parameters, motion reduction strategies and post-processing. When optimized, collectively these lead to better standardization of whole-body MRI, and when married to systematic analysis and interpretation, they can improve diagnostic accuracy.

Progress Report: Next-Generation Sequencing, Multiplex Polymerase Chain Reaction, and Broad-Range Molecular Assays as Diagnostic Tools for Fever of Unknown Origin Investigations in Adults.

Even well into the 21st century, infectious diseases still account for most causes of fever of unknown origin (FUO). Advances in molecular technologies, including broad-range polymerase chain reaction (PCR) of the 16S ribosomal RNA gene followed by Sanger sequencing, multiplex PCR assays, and more recently, next-generation sequencing applications, have transitioned from research methods to more commonplace in some clinical microbiology laboratories. They have the potential to supplant traditional microbial identification methods and antimicrobial susceptibility testing. Despite the remaining challenges with these technologies, publications in the past decade justify excitement about the potential to transform FUO investigations. We discuss available evidence using these molecular methods for FUO evaluations, including potential cost-benefits and future directions.

Sub-Acute Thyroiditis presenting as pyrexia of unknown origin: A rare case with literature review.

Pyrexia of unknown origin (PUO) is a challenging entity in medical practice from a diagnostic point of view. Sub-Acute Thyroiditis (SAT), that is an inflammatory condition of thyroid, self-limiting and easily treatable, is a very rare cause for PUO with a few published cases and unfortunately not considered in routine for the differential diagnosis (DD) of PUO. Usually, it presents with mild thyrotoxicosis signs and symptoms, painful goiter, and rarely with cervical Lymph adenopathy. Thyroid antibodies might be negative, but inflammatory markers are usually raised. Anti-inflammatory drugs (NSAID) and steroids are a simple but very effective treatment. We present our experience for diagnosing and treating a female patient presenting with PUO. She was diagnosed as a case of sub-acute Thyroiditis on nuclear thyroid scan, High resolution ultrasound (HR-USG) of Thyroid and radioimmunoassay (RIA) for thyroid hormones and thyroid antibodies. The Patient was successfully treated with NSAIDs and steroids. The consent of the patient was taken to publish her case.

Systemic Lupus Erythematosus and Third Nerve Palsy: Unusual Presentation and Review of the Literature.

We report the case of a young female with pyrexia of unknown origin, cutaneous macules and an incomplete third cranial nerve palsy, that led to the diagnosis of systemic lupus erythematosus (SLE) with neurological manifestations. Her visual acuity was normal. Fundus examination showed cotton wool spots in both eyes. Neuroimaging was also normal. Systemic work up revealed pancytopaenia, hypocomplementaemia, and the presence of multiple autoantibodies including anti-double stranded deoxyribonucleic acid and lupus anticoagulant. She was effectively treated with intravenous pulsed corticosteroid therapy, cyclophosphamide, and oral hydroxychloroquine. This case highlights the uncommon involvement of cranial nerve mononeuropathy in SLE, the importance of systemic examination and autoimmune workup in young patients with such a presentation.

First Report of Candidatus Mycoplasma haemohominis Infection in Australia Causing Persistent Fever in an Animal Carer.

BACKGROUND: Hemotropic mycoplasmas (hemoplasmas) infect animals and humans and can lead to clinical syndromes mainly characterized by hemolytic anemia. A novel pathogen, Candidatus Mycoplasma haemohominis, was recently associated with a case of human hemoplasmosis in Europe. Here we report the first detection of this pathogen in an Australian patient exhibiting persistent fever, hemolytic anemia, and pancytopenia over a 10-month period. METHODS: After exhaustive negative testing for human infectious diseases, whole genome sequencing (WGS) was performed on the patient's bone marrow aspirate, using an Illumina NextSeq500 platform. Conventional polymerase chain reaction (PCR), followed by Sanger sequencing, was then performed on blood samples using novel Mycoplasma-specific primers targeting the 16S ribosomal RNA gene. In addition, a Mycoplasma-specific fluorescence in situ hybridization (FISH) assay was developed to differentiate Mycoplasma cells from other erythrocyte inclusions (eg, Pappenheimer and Howell-Jolly bodies) which are morphologically similar to bacterial cocci by light microscopy. RESULTS: WGS analysis revealed that approximately 0.04% of the total number of unmapped reads to human genome corresponded to Mycoplasma species. A 1-kb Mycoplasma 16S fragment was successfully amplified by conventional PCR, and sequence analyses revealed 100% identity with Candidatus Mycoplasma haemohominis. FISH confirmed that several (approximately 2%) epierythrocytic inclusions initially observed by light microscopy corresponded to Mycoplasma cells. CONCLUSIONS: This represents the second report of hemolytic anemia associated with hemoplasma infection in a human, and the first report of human hemoplasmosis in Australia. This study highlights the importance of new and emerging diagnostic approaches and need for further investigations on the epidemiology of Candidatus Mycoplasma haemohominis in Australia.

Imaging a Fever-Redefining the Role of 2-deoxy-2-[18F]Fluoro-D-Glucose-Positron Emission Tomography/Computed Tomography in Fever of Unknown Origin Investigations.

Growing evidence suggests that 2-deoxy-2-[18F]fluoro-D-glucose (18FDG)-positron emission tomography/computed tomography (PET/CT) is a useful imaging technique for the evaluation of fever of unknown origin (FUO). This imaging technique allows for accurate localization of foci of hypermetabolism based on 18FDG uptake in glycolytically active cells that may represent inflammation, infection, or neoplasia. The presence of abnormal uptake can help direct further investigation that may yield a final diagnosis. A lack of abnormal uptake can be reasonably reassuring that these conditions are not present, thereby avoiding unnecessary additional testing. Insurers have not routinely covered outpatient 18FDG-PET/CT for the indication of FUO in the United States. However, data published since 2007 suggest early use in FUO diagnostic evaluations improves diagnostic efficiency and reduces costs. Clinicians and insurers should consider 18FDG-PET/CT as a useful tool when preliminary studies are unrevealing.

Post kidney transplant histoplasmosis: An under-recognized diagnosis in India.

Histoplasmosis is an invasive mycosis caused by fungus Histoplasma capsulatum. Clinical features of histoplasmosis are often nonspecific, but patients with disseminated infection may present with severe manifestations posing an increasing threat to patients with various immunocompromised conditions. It is often misdiagnosed as tuberculosis in endemic regions leading to high mortality. There is under-reporting of histoplasmosis in solid organ transplant from India undermining its actual incidence and impact. As a result of the potentially fatal nature of the disease, careful evaluation with tissue diagnosis is recommended. We present a series of five cases of disseminated histoplasmosis in renal transplant recipients from our centre, highlighting its significance as differential diagnosis in this population. To our knowledge, this is the largest case series reported from India in renal transplant patients.

Pyrexia of unknown origin as clinical presentation of Renal Cell Carcinoma: Role of F18-FDG PET/CT.

The synergy of the anatomic-metabolic details provided by PET-CT plays a substantial role in the diagnostic workup of Pyrexia of Unknown Origin (PUO). Although several imaging modalities have been used in the detection of cause of PUO, PET-CT is the most sensitive and specific modality for detection of cause. RCC is a rare cause of PUO.

Primary Adrenal Angiomatoid Fibrous Histiocytoma With Novel EWSR1-ATF1 Gene Fusion Exon-Exon Breakpoint.

We describe the clinical, pathological, and molecular features of a primary adrenal angiomatoid fibrous histiocytoma (AFH) in an 11-year-old girl presenting with pyrexia of unknown origin. We performed next-generation sequencing-based anchored multiplex polymerase chain reaction (Archer® FusionPlex® sarcoma assay), which revealed an EWSR1-ATF1 gene fusion with novel breakpoints in exon 11 of EWSR1 and exon 3 of ATF1. The pyrexia resolved fully after surgical resection, and the patient was disease-free on follow-up at 1 year and 6 months. This case exemplifies the value of molecular testing of pediatric neoplasms presenting at unusual sites for diagnosis and identification of novel gene fusion breakpoints.

Bartonella henselae infection in diverse clinical conditions in a tertiary care hospital in north India.

BACKGROUND & OBJECTIVES: : Bartonella henselae causes infections which closely resemble febrile illness and chronic diseases such as tuberculosis and haematological malignancies. There are not many studies on Bartonella infections from India. The present study was undertaken to diagnose B. henselae infection in diverse clinical conditions in a tertiary care hospital in north India. METHODS: A total of 145 patients including those with fever and lymphadenopathy, infective endocarditis and neuroretinitis were enrolled in the study. Whole blood, serum and lymph node aspirate and valvular vegetations if available, were obtained. Samples were plated on chocolate agar and brain-heart infusion agar containing five per cent fresh rabbit blood and were incubated at 35°C for at least four weeks in five per cent CO2with high humidity. Immunofluorescent antibody assay (IFA) was done for the detection of IgM antibodies in the serum using a commercial kit. Whole blood was used to perform polymerase chain reaction (PCR) for the citrate synthase gene (gltA). RESULTS: IFA was positive in 11 of 140 (7.85%) patients and PCR was positive in 3 of 140 (2.14%) patients. Culture was negative in all the cases. A higher incidence of Bartonella infection was seen in patients with fever and lymphadenopathy (n=30), seven of whom were children. In ophthalmological conditions, four cases were IFA positive. INTERPRETATION & CONCLUSIONS: The present study shows that the threat of Bartonella infection is a reality in India. It is also an important treatable cause of fever and lymphadenopathy in children. Serology and PCR are useful tests for its diagnosis. Clinicians should consider. BARTONELLA: infection in the differential diagnosis of febrile illnesses and chronic diseases.

Adult-onset Still's disease with prominent polyserositis.

Adult-onset Still's disease is a systemic autoinflammatory disease the presentation of which can often mimic infection. As a consequence, there is often a delay in diagnosis. Serositis is a recognised but less common clinical feature that can result in complications including cardiac tamponade and constrictive pericarditis. We describe a case of adult-onset Still's disease without the hallmark rash or significant arthritis, presenting with polyserositis that showed a good response to initial steroid treatment and sustained remission with anakinra. An elevated procalcitonin level was due to active adult-onset Still's disease, not bacterial infection.

Fever of unknown origin, giant cell arteritis, and aortic dissection.

Giant cell arteritis is one of the most frequent causes of pyrexia of unknown origin after infectious or malignant causes have been ruled out. In this case report we describe a 66-year old female patient, who after five weeks of remitting fever developed a life-threatening, painless severe aortic dissection. The timely use of modern imaging technologies such as magnetic resonance angiography or positron emission computed tomography could in the future be of help to recognize aortic involvement early and to avoid this devastating complication in patients with fever of unknown origin.

Pyrexia of unknown origin: causes, investigation and management.

Pyrexia of unknown origin (PUO) is a syndrome that has long tested the skills of physicians to achieve a diagnosis in affected patients. By definition, patients included in this syndrome will be more difficult to diagnose as they have already resisted classification during baseline investigations. Furthermore, investigation of PUO requires knowledge of many diseases across a range of clinical specialties, as well as knowledge of less commonly used investigative tools. As both society and medicine continue to change, the aetiology and epidemiology of the diseases that cause PUO also change. For these reasons, it is important for physicians to approach PUO in a logical manner, and for the causes and approach to PUO to be continuously reviewed. In this article, we review the aetiology of PUO and the diagnostic strategies that may be used to investigate it.

Pyrexia of Unknown Origin Caused by Non-Hodgkin's Lymphoma: A Diagnostic Challenge for Clinicians.

Non-Hodgkin's lymphomas (NHLs) are a group of lymphoproliferative diseases that originate from different cell types, namely B cells, T cells, or natural killer cells. Herein, we report the case of a 69-year-old male patient who presented with a gradual-onset, intermittent, low-grade fever for four months and a right-sided neck lump for two months. On examination, a right-sided enlarged lymph node sized 1 × 1 cm2 was noted, which was mobile, hard in consistency, and non-tender. No other lymphadenopathy was noted in other parts of the body. Imaging and biochemical studies done at the initial stages did not reveal features in favor of any lymphoproliferative disorders, and the two lymph node biopsies done two weeks apart were inconclusive as well. An extended panel of investigations was done in view of excluding other infective and inflammatory pathologies, which was negative, making the patient undiagnosed of any disease state despite being symptomatic for four months. Finally, the third lymph node biopsy tested positive, which paved the way for the diagnosis of NHL. This diagnosis underlines the importance of this case. Following the diagnosis, the patient was initiated on a few chemotherapeutic agents, after which a mild symptomatic improvement was achieved.

Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel.

Background: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are syndromes commonly used as medical diagnoses. Since the existing literature has a mixture of diagnostic approaches, developing consensus-based recommendations would be helpful for clinicians, researchers, and patients. Methods: A modified Delphi process was performed from October 2022 to July 2023, involving 4 rounds of online surveys and 2 live video conferences. The panel comprised international experts recruited based on peer-reviewed published publications and studies. Results: Among 50 invited experts, 26 (52.0%) agreed to participate. Twenty-three panelists completed round 1 of the survey, 21 completed rounds 2 and 3, 20 completed round 4, and 7 participated in round 5 live video discussions. Of the participants, 18 (78.3%) were academic-based clinicians and researchers, 5 (21.7%) practiced in a community-based hospital, and 6 (26.1%) were female. Consensus was reached on 5 themes: (1) incorporating epidemiologic factors, such as geographic location and travel history; (2) updated criteria for classifying FUO or IUO; (3) initial evaluation approaches; (4) a classification system for diagnoses; and (5) recommendations for judicious limitation of empiric therapies. Experts strongly disagreed with using 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography as part of the diagnostic criteria for FUO. There were mixed opinions about the importance of the temperature measurement site, the 3-week minimum illness criterion, the need for a standard definition of relapsing fevers, and the use of similar evaluation strategies for FUO and IUO. Conclusions: These Delphi-generated consensus-based recommendations offer potential improvements compared with earlier definitions and a guide for clinical practice and future research.

Prospective randomized trial comparing relapse rates in dogs with steroid-responsive meningitis-arteritis treated with a 6-week or 6-month prednisolone protocol.

BACKGROUND: Traditionally, 6-month courses of prednisolone are used to treat steroid-responsive meningitis-arteritis (SRMA), but this medication is associated with adverse effects that can lead to poor quality of life. HYPOTHESIS/OBJECTIVES: Resolution of clinical signs and rate of relapse of SRMA would not be significantly different between a 6-month prednisolone protocol and a 6-week protocol. ANIMALS: Forty-four hospital cases from multiple referral centers in the United Kingdom (2015-2019). Twenty of 44 were treated with the 6-month protocol and 24/44 with the 6-week protocol. METHODS: Prospective, randomized trial with 12-month follow-up. The same prednisolone protocol reinitiated in the event of relapse. Analysis of relapses with binary logistic and Poisson regression modeling. RESULTS: All cases responded to their treatment protocol. Relapses occurred in 6/20 (30%) of the 6-month protocol and 9/24 (38%) of the 6-week protocol. There was no statistical difference in the incidence risk of at least 1 relapse between the 2 groups (odds ratio = 1.40; 95% confidence interval [CI], 0.40-4.96, P = 0.60). Among the 15 dogs that relapsed, 10/15 (67%) relapsed once, 3/15 (20%) relapsed twice, and 2/15 (13%) relapsed 3 times. No statistical difference was detected in the incidence rate ratio (IRR) of total relapse events between the 2 groups (IRR = 1.46; 95% CI, 0.61-3.48; P = 0.40). CONCLUSIONS AND CLINICAL IMPORTANCE: "Short" 6-week prednisolone protocols could be used to treat SRMA, thereby presumably reducing the duration and severity of prednisolone's adverse effects.