Overview of fever of unknown origin in adult and paediatric patients L. Attard1, M. Tadolini1, D.U. De Rose2, M. Cattalini2 1Infectious Diseases Unit, Department ABSTRACT been proposed, including removing the of Medical and Surgical Sciences, Alma Fever of unknown origin (FUO) can requirement for in-hospital evaluation Mater Studiorum University of Bologna; be caused by a wide group of dis- due to an increased sophistication of 2Paediatric Clinic, University of Brescia eases, and can include both benign outpatient evaluation. Expansion of the and ASST Spedali Civili di Brescia, Italy. and serious conditions. Since the first definition has also been suggested to Luciano Attard, MD definition of FUO in the early 1960s, include sub-categories of FUO. In par- Marina Tadolini, MD Domenico Umberto De Rose, MD several updates to the definition, di- ticular, in 1991 Durak and Street re-de- Marco Cattalini, MD agnostic and therapeutic approaches fined FUO into four categories: classic Please address correspondence to: have been proposed. This review out- FUO; nosocomial FUO; neutropenic Marina Tadolini, MD, lines a case report of an elderly Ital- FUO; and human immunodeficiency Via Massarenti 11, ian male patient with high fever and virus (HIV)-associated FUO, and pro- 40138 Bologna, Italy. migrating arthralgia who underwent posed three outpatient visits and re- E-mail: [email protected] many procedures and treatments before lated investigations as an alternative to Received on November 27, 2017, accepted a final diagnosis of Adult-onset Still’s “1 week of hospitalisation” (5). on December, 7, 2017. disease was achieved. This case report In 1997, Arnow and Flaherty updated Clin Exp Rheumatol 2018; 36 (Suppl. 110): highlights the difficulties in diagnosing the FUO definition and considered the S10-S24. certain causes of FUO that requires a type of diagnostic panel to be more im- © Copyright CLINICAL AND very high index of suspicion. The main portant than the duration of investiga- EXPERIMENTAL RHEUMATOLOGY 2018. causes of FUO in paediatric and adult tions (6). They considered the follow- patients will be reviewed here, under- ing list to be the “Minimum diagnostic Key words: fever of unknown origin, lying the fact that a physician should evaluation to qualify as FUO”: com- autoinflammatory disease, infections, also consider the possibility that a pa- prehensive history; repeated physical malignancies, non-genetic periodic tient with FUO may have a monogenic examination; complete blood count, in- fevers, non-infectious inflammatory autoinflammatory disease (AID). The cluding differential and platelet (PLT) diseases, children. identification of AIDs requires a care- count; routine blood chemistry, includ- ful evaluation of both history and clini- ing lactate dehydrogenase (LDH), bili- cal details that may reveal important rubin, and liver enzymes; urinalysis, clues to identify the correct aetiology. including microscopic examination; We also provide a comprehensive ac- chest radiograph; erythrocyte sedimen- count of specific signs and symptoms tation rate (ESR); antinuclear antibod- that could suggest possible diagnoses ies; rheumatoid factor; angiotensin and guide the work-up of FUO and converting enzyme; routine blood cul- non-genetic periodic fevers in children. tures (at least three) while not receiv- ing antibiotics; cytomegalovirus IgM Introduction antibodies or virus detection in blood; Fever of unknown origin (FUO) ac- heterophile antibody test in children Funding: This paper is part of a counts for around 3% of hospital ad- and young adults; tuberculin skin test; supplemental issue supported by an missions and has a high impact on computerised tomography (CT) of ab- unrestricted grant from Novartis Farma, health care systems (1, 2). Indeed, domen or radionuclide scan; HIV an- Italy through a service agreement with more than 200 different causes of FUO tibodies or virus detection assay; and, Health Publishing & Services Srl. Health have been reported (3). further evaluation of any abnormalities Publishing & Services Srl provide The first definition of FUO dates back detected by the above tests (6). editorial assistance. Article Processing to the early 1960’s, when it was defined Following on from this, a number of di- Charges were also funded by Novartis Farma, Italy. by Petersdorf and Beeson as a “Body agnostic algorithms have been proposed. temperature of more than 38.3°C on Notably, the inclusion of 18 fluorodeox- Competing interests: M. Cattalini received speaker’s fees and consultancy honoraria several occasions, lasting for more yglucose-positron emission tomography from AbbVie, Novartis and SOBI. All the than 3 weeks and no diagnosis after 18F-FDG PET among the investigations other authors declare no competing 1 week of hospitalisation” (4). Re- has improved and shortened the diag- interests. finements to the definition have since nostic work-up of FUO (7). S-10 Clinical and Experimental Rheumatology 2018 Fever of unknown origin / L. Attard et al. Case report: an adult patient lowed by normalisation of acute phase ography, and colonoscopy were nega- An Italian male patient aged 69 years reactants. However, due to a relapse of tive. Chest high-resolution CT showed old, with a mechanical aortic valve, was these parameters (PCT 62 mg/ml, CRP bilateral peripheral micronodules and admitted to the Internal Medicine ward 27 mg/dl, lactic acid 24 mg/dl, ferritin multiple mediastinal lymphadenopa- due to high fever (up to 39°C) and mi- 6921 ng/ml, LDH 1512 U/L) the pa- thies. The patient was initially treated grating arthralgia, which had started ten tient was switched to meropenem and with piperacillin-tazobactam without days prior. Before being admitted, he linezolid with apyrexia for 7 days. Fol- effect, and then, due to an impairment had been treated with clarithromycin, lowing this, the patient experienced a of acute phase reactants (PCT 65 mg/ which was stopped due to the occur- relapse of fever. Candida spp. was iso- dl), teicoplanin and fluconazole were rence of skin rash, and later with amox- lated in blood culture, and the patient added with resolution of fever. The pa- icillin-clavulanate, without resolution was treated with caspofungin. Due to tient was discharged after 30 days and of the fever. At admission he presented a recurrence of skin rash on the arms, referred to the Fever of Unknown Ori- with papular skin rash in the pretibial legs, and trunk, the patient underwent gin outpatient clinic, Infectious Dis- region, bilaterally. Blood investiga- skin biopsy, which raised the suspicion ease Unit. At that time he was apyretic; tions showed white blood cells (WBC) of psoriasis. He was then treated with he reported asthenia and marked loss of 15,600/mmc, PLT count 405,000/mmc, topical steroids with fast improvement body weight (10 kg over the previous 2 ESR 114 mm/h, C-reactive protein of the skin rash. At the same time, fever months). WBC were 7,490/mmc (Neu- (CRP) 29 mg/dl, beta-2 microglobulin and joint pain disappeared and blood trophils: 63%, Eosinophils 9.2%), ESR 7.8 mg/L, procalcitonin (PCT) 2.2 mg/ tests were normal. He was then dis- 92 mm/h, CRP 3.38 mg/dl, beta-2 mi- dl, LDH 894 U/L; Interferon-gamma charged after 35 days in a good clinical croglobulin 8 mg/L, interleukin-6 19.8 Release Assay (IGRA) test was in- condition with a diagnosis of recurrent ng/ml, serum amyloid A 5.23 mg/dl, determinate. Widal test, serology for infections due to the onset of psoriatic fibrinogen 405 mg/dl, LDH 525 U/L, Brucella and HIV, human herpesvirus arthritis. and ferritin 2,370 ng/ml. After 10 days (HHV)-8, cytomegalovirus (CMV), Five years later, the patient reported he reported a recurrence of high fever Epstein-Barr virus (EBV), hepatitis A to the Emergency Department due to and joint pain. According to his clini- virus, hepatitis B virus (HBV), hepatitis a recurrence of fever (up to 38°C), cal history and laboratory features, a C virus (HCV), enterovirus, parvovirus night sweats, loss of body weight, and diagnosis of Adult-onset Still’s disease B19, Dengue, Chikungunya, Trepone- arthralgia over the previous month. (AOSD) was formulated based on four ma, Francisella, Bartonella, Borrelia, Before reporting to hospital, he had major and three minor Yamaguchi cri- Rickettsia, Coxiella, Leishmania, Toxo- been treated with amoxicillin-clavu- teria. Antibodies to Strongyloides ster- plasma, Chlamydia, and Mycoplasma lanate for 6 days without benefit. He coralis were positive and he was treat- did not show any active infections. complained of a transient rash on the ed with oral ivermectin for 2 days be- Polymerase chain reaction (PCR) for back. WBC were 16,670/mmc (Neu- fore starting steroids. After the start of HCV, HBV, CMV, EBV, and HHV- trophils: 93%), CRP 5.93 mg/dl, LDH steroid treatment, the patient achieved 6 were negative. More than 10 blood 600 U/L; chest x-ray was negative. He complete recovery after a period of one cultures for bacteria and mycobacteria was admitted for further investigations: month. He did not show any febrile were negative. Chest x-ray, chest and blood tests showed WBC 20,000/mmc episodes nor other symptoms while on abdominal CT scan, transthoracic and (Neutrophils: 92%), haemoglobin 10.9 steroid treatment. transoesophageal echocardiography, g/dl, beta-2 microglobulin 6.8 mg/L, The diagnostic and therapeutic ap- and colonoscopy were all negative. PCT 1.9 mg/dl, ferritin 7,500 ng/ proaches carried out in this patient 18F-FDG PET showed multiple me- ml, and thyroid function was normal. were particularly aggressive as a blood diastinal and abdominal lymph nodes Two sets of blood cultures were nega- stream infection was suspected in con- uptake (SUV max 15), diffuse splenic tive. IGRA test was negative. Widal sideration of his aortic mechanic valve (SUV max 6.5), and diffuse bone up- test and serology for Brucella and and high values of PCT.