Recurrent Fever Of Unknown Origin Research Articles

Recurrent (or episodic) fever of unknown origin (FUO) as a variant subgroup of classical FUO: A French multicentre retrospective study of 170 patients

BackgroundRecurrent FUO (fever of unknown origin) is a rare subtype of FUO for which diagnostic procedures are ill-defined and outcome data are lacking. MethodsWe performed a retrospective multicentre study of patients with recurrent FUO between 1995 and 2018. By multivariate analysis, we identified epidemiological, clinical and prognostic variables independently associated with final diagnosis and mortality. ResultsOf 170 patients, 74 (44%) had a final diagnosis. Being ≥ 65 years of age (OR = 5.2; p < 0.001), contributory history (OR = 10.4; p < 0.001), and abnormal clinical examination (OR = 4.0; p = 0.015) independently increased the likelihood of reaching a diagnosis, whereas lymph node and/or spleen enlargement decreased it (OR = 0.2; p = 0.004). The overall prognosis was good; 58% of patients recovered (70% of those with a diagnosis). Twelve (7%) patients died; patients without a diagnosis had a fatality rate of 2%. Being ≥ 65 years of age (OR = 41.3; p < 0.001) and presence of skin signs (OR = 9.5; p = 0.005) significantly increased the risk of death. ConclusionThis study extends the known yield of recurrent FUO and highlights the importance of repeated complete clinical examinations to discover potential diagnostic clues during follow-up. Moreover, their overall prognosis is excellent.

Infective endocarditis in a young woman with a bicuspid aortic valve and a history of recurrent fever of unknown origin.

Infective endocarditis in a young woman with a bicuspid aortic valve and a history of recurrent fever of unknown origin.

Congenital idiopathic generalized anhidrosis: A rare cause of recurrent fever of unknown origin in children and review of existing literature.

Congenital idiopathic generalized anhidrosis: A rare cause of recurrent fever of unknown origin in children and review of existing literature.

Recurrent fever of unknown origin: An overlooked symptom of Fabry disease

ObjectiveFabry disease (FD) is a rare X‐linked lysosomal storage disorder due to the absent or deficient activity of lysosomal hydrolase a‐galactosidase A (α‐Gal A), which leads to the accumulation of its substrates in various organs and tissues. Classic clinical manifestations include angiokeratomas, proteinuria, renal failure, neuropathic pain, and left ventricular hypertrophy. Fever is one of the rare symptoms that may occur during FD.MethodsThree Chinese Han patients with FD referred to Peking Union Medical College Hospital were reported. The complete medical records were established, and detailed data were collected. Whole‐exome sequencing by next‐generation sequencing and α‐Gal A enzyme activity assay were performed to confirm the diagnosis.ResultsThese three patients all presented with recurrent fever of unknown origin initially, accompanied with arthralgia/arthritis and other symptoms. We identified two known variants in the GLA gene, c.1176_1179delGAAG and c.782G>A (p.G261D), and a novel variant c.440G>A (p.G147E) which is likely pathogenic in our patient.ConclusionsFD should be considered as a rare cause of recurrent fever of unknown origin. The coexistence of gene variants related to systemic autoinflammatory diseases may make the clinical phenotypes of FD more complex and prone to recurrent fever.

P3.CR-14 A Case of EGFR Tyrosine Kinase Inhibitor (TKI), Osimertinib Induced Pneumonitis in a Patient with Recurrent Fevers of Unknown Origin

P3.CR-14 A Case of EGFR Tyrosine Kinase Inhibitor (TKI), Osimertinib Induced Pneumonitis in a Patient with Recurrent Fevers of Unknown Origin

Clinical characteristics of adult patients with autoinflammatory diseases presenting as recurrent fever of unknown origin

Objective To analyze the clinical characteristics of adult patients with autoinflammatory diseases (AUID) presenting as recurrent fever of unknown origin (FUO). Methods The clinical and genetic features of 51 adult patients with recurrent FUO, who were suspected of monogenic AUID admitted in adult AUID center Department of Rheumatology, Peking Union Medical College Hospital from April 2015 to March 2017, were prospectively studied. The clinical phenotypes were compared between patients with pathogenic gene mutations and diagnosed as monogenic AUID (gene-positive group), and those without pathogenic gene mutations (gene-negative group). Results Among 51 patients, there were 26 patients with positive monogenic mutations (51.0%); in addition 6 patients were diagnosed as periodic fever-aphthous stomatitis-pharyngitis-adenitis (PFAPA) syndrome. Finally 32 patients (63.0%) were diagnosed as AUID, including 11 cases of familial Mediterranean fever (34.4%), 5 cases of cryopyrin-associated periodic syndrome (15.6%), 5 cases of NLRP12-autoinflammtory disease (15.6%), 2 cases of Blau syndrome (6.3%), 2 cases of Yao syndrome (6.3%), 1 case of tumor necrosis factor-receptor associated periodic syndrome (3.1%), and 6 cases of PFAPA syndrome (18.8%). Among 25 gene-negative patients except 6 cases of PFAPA syndrome, 9 were diagnosed as other diseases, and the diagnosis of AUID was not confirmed in 10 cases (40.0%). Compared with gene-negative group, gene-positive group had more common childhood-onset (30.8% vs. 8.0%, P=0.041), longer disease duration (11.2±10.1 vs. 6.1±5.9, P=0.031), and more common abdominal pain/diarrhea (42.3% vs.12.0%, P=0.015). There were no significant differences in manifestations such as rash, arthralgia/arthritis, thoracic pain, eye inflammation and oral ulcers between two groups. One patient had family history of AUID, and finally diagnosed as Blau syndrome with NOD2 gene mutation. Conclusion AUID is one of the main causes of adult patients with recurrent FUO. Childhood-onset, long disease duration, abdominal pain/diarrhea, and family history of AUID are more common in patients with AUID pathogenic gene variations. Recognizing these symptom patterns can provide the clues, leading to the initiation of gene testing for patients with recurrent FUO. Adults patients with recurrent FUO suspected of AUID should be referred to specialist physicians in adult AUID center. Key words: Fever of unknown origin; Autoinflammatory diseases; Disease attributers

TNFRSF1A gene variant identified in a boy with recurrent episodes of fever

Introduction. Fever of unknown origin is an important diagnostic challenge. Although rare, periodic fever syndromes may often present with a chronic or recurrent febrile condition with a variable temporal pattern of occurrence. Although clinical characteristics often indicate the syndrome in question, there are many atypical forms, and the genotype?phenotype relationship is highly complex, warranting in many cases the designation of a ?syndrome spectrum? rather than a syndrome per se. The aim of this paper was to present a boy with recurrent fever of unknown origin. Case outline. We hereby present a boy with recurrent fever of unknown origin who was by clinically guided partial exome sequencing found to have a heterozygous variant 434A&gt;G in the TNFRSF1A gene, otherwise connected with tumor necrosis factor receptor-associated periodic fever syndrome. The patient responded well to short courses of glucocorticoids and is no longer subjected to unnecessary antibiotic treatment he had frequently received in the past. Conclusion. Periodic fever syndromes should be kept in mind as a differential diagnostic possibility in children with fever of unknown origin.

Recommendations for the inclusion of Fabry disease as a rare febrile condition in existing algorithms for fever of unknown origin.

Fever of unknown origin (FUO) is a rather rare clinical syndrome representing a major diagnostic challenge. The occurrence of more than three febrile attacks with fever-free intervals of variable duration during 6months of observation has recently been proposed as a subcategory of FUO, Recurrent FUO (RFUO). A substantial number of patients with RFUO have auto-inflammatory genetic fevers, but many patients remain undiagnosed. We hypothesize that this undiagnosed subgroup may be comprised of, at least in part, a number of rare genetic febrile diseases such as Fabry disease. We aimed to identify key features or potential diagnostic clues for Fabry disease as a model of rare genetic febrile diseases causing RFUO, and to develop diagnostic guidelines for RFUO, using Fabry disease as an example of inserting other rare diseases in the existing FUO algorithms. An international panel of specialists in recurrent fevers and rare diseases, including internists, infectious disease specialists, rheumatologists, gastroenterologists, nephrologists, and medical geneticists convened to review the existing diagnostic algorithms, and to suggest recommendations for arriving at accurate diagnoses on the basis of available literature and clinical experience. By combining specific features of rare diseases with other diagnostic considerations, guidelines have been designed to raise awareness and identify rare diseases among other causes of FUO. The proposed guidelines may be useful for the inclusion of rare diseases in the diagnostic algorithms for FUO. A wide spectrum of patients will be needed to validate the algorithm in different clinical settings.

English

English

Fever of unknown origin in the outpatient setting: A retrospective analysis of 30 cases of familial Mediterranean fever.

In Japan, familial Mediterranean fever (FMF) is a rare cause of fever of unknown origin (FUO). However, we experienced an extraordinary number of FMF cases over 3 years. This suggests that many patients with FMF remain misdiagnosed in Japan. This study examines the clinical picture of FMF to assist Japanese clinicians in daily practice dealing with FUO. Three years of medical records were reviewed, and 38 patients with FMF or suspected FMF were collected from our patient database. We applied the Tel-Hashomer criteria to those patients. Of the 38 patients, 30 were classified as having FMF in this investigation. The mean patient age was 27.8 years. MEFV gene mutations were detected in 14 patients. Three cases were colchicine-resistant. Clinicians should recognize the pattern of short, spontaneously resolving attacks of fever with fever-free intervals, especially when they see patients with recurrent FUO in the outpatient setting.

Démarche diagnostique des fièvres récurrentes prolongées chez l’adulte

Recurrent fever of unknown origin is probably the most difficult to diagnose subtype of fever of unknown origin. It represents between 18 and 42% of the cases in large series of patients with fever of unknown origin. The limited literature data do not allow one to construct a diagnostic algorithm. However, the diagnostic strategy is different from classic fever of unknown origin. The spectrum of causative disorders is different from continuous fever with less infections and tumors. Among systemic inflammatory diseases, adult-onset Still's disease is the most common cause. More than 50% of the cases remain unexplained. Hereditary recurrent fevers, the prototype of autoinflammatory diseases, are now more easily discuss in a young adult.

Consensus guidelines for the use of empiric and diagnostic-driven antifungal treatment strategies in haematological malignancy, 2014.

Invasive fungal disease (IFD) causes significant morbidity and mortality in patients undergoing allogeneic haemopoietic stem cell transplantation or chemotherapy for haematological malignancy. Much of these adverse outcomes are due to the limited ability of traditional diagnostic tests (i.e. culture and histology) to make an early and accurate diagnosis. As persistent or recurrent fevers of unknown origin (PFUO) in neutropenic patients despite broad-spectrum antibiotics have been associated with the development of IFD, most centres have traditionally administered empiric antifungal therapy (EAFT) to patients with PFUO. However, use of an EAFT strategy has not been shown to have an overall survival benefit and is associated with excessive antifungal therapy use. As a result, the focus has shifted to developing more sensitive and specific diagnostic tests for early and more targeted antifungal treatment. These tests, including the galactomannan enzyme-linked immunosorbent assay and Aspergillus polymerase chain reaction (PCR), have enabled the development of diagnostic-driven antifungal treatment (DDAT) strategies, which have been shown to be safe and feasible, reducing antifungal usage. In addition, the development of effective antifungal prophylactic strategies has changed the landscape in terms of the incidence and types of IFD that clinicians have encountered. In this review, we examine the current role of EAFT and provide up-to-date data on the newer diagnostic tests and algorithms available for use in EAFT and DDAT strategies, within the context of patient risk and type of antifungal prophylaxis used.

Erdheim–Chester disease: A rare cause of recurrent fever of unknown origin mimicking lymphoma

We report the case of a patient with recurrent fever of unknown origin (FUO) with prominent back pain, hepatosplenomegaly, and abdominal/pelvic adenopathy suggesting lymphoma. A bone biopsy showed histiocytic infiltration. Studies for lymphoma were negative, but immunohistochemical stains were diagnostic of Erdheim-Chester disease (ECD). ECD should be included as a rare cause of recurrent FUO with bone involvement.

Recurrent Fever of Unknown Origin (FUO) Due to Periodic Fever, Aphthous Stomatititis, Pharyngitis and Adenitis (FAPA) Syndrome in an Adult.

FAPA syndrome (periodic fever, aphthous stomatititis, pharyngitis and adenitis) is a relatively new entity described in pediatric patients. In adults, reports of FAPA are limited to rare case reports. The differential diagnosis of FAPA in adults includes Behcet’s syndrome, familial Mediterranean fever (FMF), Hyper IgD syndrome and juvenile rheumatoid arthritis (JRA), i.e., adult Still’s disease. With FAPA syndrome, between episodes patients are completely asymptomatic and serologic inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and white blood cell (WBC) count are normal. The etiology of FAFA is unknown, but lack of secondary cases or clustering in close contacts, lack of seasonality, and the lack of progression for years argue against an infectious etiology. We describe an extremely rare case of an adult with a recurrent FUO with profuse night sweats and prominent chills due to FAPA syndrome.

Recurrent Cholangitis with Congenital Hepatic Fibrosis and Pancreaticobiliary Maljunction after Roux-en-Y Reconstruction

A 1-year-old girl had pancreaticobiliary maljunction, a choledochal cyst, and polycystic kidney. At the age of 4 years, she was treated by resection of the choledochal cyst and Roux-en-Y reconstruction because of the cyst's risk of cancer. She was diagnosed as having congenital hepatic fibrosis based on the histological findings. Postoperatively, she suffered recurrent fever of unknown origin, refractory to several antibiotics. At the age of 6 years, she underwent living donor liver transplantation from her father. Multi-drug-resistant Pseudomonas aeruginosa was cultured in the recipient's liver. After liver transplantation, she had no episodes of recurrent fever. Roux-en-Y reconstruction should be avoided for ductal plate malformations such as congenital hepatic fibrosis.

Mevalonate kinase genotype in children with recurrent fevers and high serum IgD level

In selected cases, childhood's recurrent fevers of unknown origin can be referred to systemic autoinflammatory diseases as mevalonate kinase deficiency (MKD), caused by mutations in the mevalonate kinase gene (MVK), previously named "hyper-IgD syndrome" due to its characteristic increase in serum IgD level. There is no clear evidence for studying MVK genotype in these patients. From a cohort of 305 children evaluated for recurrent fevers in our outpatient clinic during the decade 2001-2011, we have retrospectively selected 10 unrelated Italian children displaying febrile episodes, associated with recurrent inflammatory signs (variably involving gastrointestinal tube, joints, lymph nodes, and skin) and persistently increased serum IgD levels. All these patients were examined for MVK genotype: only 2 presented bonafide MVK mutations, 5 showed the same S52N MVK polymorphism, while the remaining 3 had a wild-type MVK sequence. Clinical details of these patients have been reviewed through the critical analysis of their medical charts. Our report underscores the pitfalls of MKD diagnosis based on clinical grounds and IgD levels, emphasizing the uncertain contribution of MVK polymorphisms in the diagnostic assessment of the syndrome.

Hodgkin's lymphoma in a patient with cystic fibrosis: a clinical challenge

Dear Editor, Cystic fibrosis (CF) is the most common life-limiting autosomal recessive hereditary disorder in Europe; the mean expected lifetime is approximately 35 years and has significantly increased over the last decades because of major advances in supportive treatment, especially treatment of infectious complications [1, 2]. In patients with CF, digestive tract cancers remain the majority of malignancies, whereas the risk for hematological neoplasias is low [5]. We hereby present a case of a patient with CF and newly diagnosed Hodgkin's Lymphoma (HL). Due to infectious issues and pulmonary comorbidity, the curative treatment of HL in this particular clinical setting is a challenge. A 21-year-old male patient with a history of CF was newly diagnosed with HL, Ann Arbor stage IIIb. Sputum samples repeatedly showed colonization with Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, and Mycobacterium abscessus that had already been present prior to the diagnosis of HL. The previous prophylactic antibiotic regimen at that time consisted of inhaled colistin (polymyxin E). To prevent infectious complications caused by A. fumigatus, Mycobacterium abscessus, gram-negative bacteria, or Pneumocystis jirovecii during chemotherapy-induced immunosuppression, the anti-infective prophylaxis was expanded to include voriconazole, clarithromycin, levofloxacinand trimethoprim/sulfamethoxazole, as well as regular prophylactic applications of G-CSF after chemotherapy to prevent neutropenia. Chemotherapy was based on a modified BEACOPPbasis regime without bleomycine due to the patient's impaired lung function. To maximize curative potential, eight cycles of “EACOPPbasis” were initially planned. However, due to recurring infectious complications of increasing length and severity (fever of unknown origin after the first course of chemotherapy preceding primarily lower respiratory tract infections with distinctly increasing pulmonary infiltrates), the cytotoxic treatment had to be delayed for a total of 42 days after only six cycles. Recurrent fever of unknown origin and documented infections (increased lung infiltrates) were treated with adequate antibiotic agents (e.g., imipenem, ceftazidime, cefepime, and aztreonam, intermittently supplemented with clindamycin or vancomycin). Microbiological sampling (blood culture and respiratory specimens) did not yield any additional pathogens. Despite intensive antimycobacterial treatment with clarithromycin, amikacin, imipenem, cefoxitin, moxifloxacin, linezolid, or tigecyclin [4], M. abscessus was repeatedly cultured from respiratory samples [3]. Chest CT scans revealed a moderate increase of preexisting lung infiltrates (Fig. 1). Restaging procedures including positron emission tomography CT showed a persisting complete remission after 17 months of follow-up care. Infectious complications, Stefan Baumann and Friederike Kuchler contributed equally to this work. S. Baumann : F. Kuchler :M. Reinwald :N. Hartel : W.-K. Hofmann :D. Buchheidt (*) Department of Haematology and Oncology, Hospital Mannheim University, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany e-mail: dieter.buchheidt@umm.de

Fièvre révélatrice d’un cancer colique : 11 observations

IntroductionFever happens frequently in colon cancer but it is rarely the presenting manifestation. Patients and methodsWe report a case series of patients with colon cancer revealed by fever in the three military hospitals in Paris. ResultsOf the 11 patients studied, seven were men and four were women, and their mean age was 70 years. Cancer was localized in the sigmoid colon (n=6), left colon (n=3) and right colon (n=2). Cancer staging (UICC TNM classification 2002) was respectively pTis (n=1), I (n=4), II (n=3) and III (n=3). Fever was the only reason for admission and two patients had a recurrent fever of unknown origin. All patients but one had bacterial infection. Blood cultures grew up in six cases, Escherichia coli (n=3), Streptococcus gallolyticus (ex bovis) (n=2) and anaerobic bacteria (n=1). There was one case of infective endocarditis caused by S. gallolyticus. Imaging showed a liver abscess (n=3) and a colon cancer complicated by an abscess (n=3). In seven patients, a familial history of colon cancer and symptoms of underlying colic disease were present (neglected rectal bleeding, iron deficiency anaemia, clinical evidence of an abdominal mass). ConclusionsFever may reveal colon cancer at an early stage. Its main cause is a bacterial infection, such as bacteremia or abscess. Fever of unknown origin is a rare presentation. Detailed history, careful clinical examination and analysis of imaging contribute to recommend the prescription of colonoscopy.

Disseminated intracardiac thrombosis: a rare manifestation of antiphospholipid syndrome

A 39-year-old severely obese male (body mass index 39 kg/m²) patient was referred to our department with suspected endocarditis. He presented with dyspnoea and recurrent fever of unknown origin. Infection parameters were found to be positive (C-reactive protein 24 mg/dL, reference <0.5 mg/dL; white blood cells 12 900/nL) and platelet count was low (16 000/µL). Other blood tests including troponin and blood cultures were normal. Transthoracic echocardiography showed a complex and irregular mass adherent to the endocardial surface of the right outflow tract and smaller floating structures of the right atrium (RA) and right ventricle (RV). Transoesophageal …

Successful surgical treatment of pulmonary artery aneurysm in Behcet's syndrome

We report herein an uncommon clinical case of pulmonary artery aneurysm in Behçet's syndrome, for which only a few reports have been published in the literature to date. A 68-year-old Japanese male, who was referred for recurrent fever of unknown origin, anemia and pulmonary nodular opacities, was treated by right lower lobectomy followed by postoperative oral administration of colchicine and corticosteroid. Postoperative pathological examination confirmed a diagnosis of pulmonary artery aneurysm accompanied by vasculitis and thrombi. Clinical and radiographic feature are presented herein.