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

BACKGROUND: Recurrent FUO (fever of unknown origin) is a rare subtype of FUO for which diagnostic procedures are ill-defined and outcome data are lacking. METHODS: We 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. RESULTS: Of 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. CONCLUSION: This 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.

Fever As the Exclusive Presenting Symptom in a Case of Colon Cancer.

The definition of fever of unknown origin (FUO) has evolved overtime. Most recently, FUO is recognized as fever with uncertain diagnosis despite three days of hospital admission or three or more outpatient visits. Despite diagnostic medical advancements, FUO remains quite a challenge. In the past, infections, such as abscesses, endocarditis, tuberculosis, and complicated urinary tract infections, were common etiologies of FUO; however, at present, such conditions are readily diagnosed. FUO secondary to malignancy has also been decreasing as a result of radiological advancements. Patients with colon cancer usually present with symptoms secondary to the local anatomy of the tumor. Conversely, fever is an uncommon presentation, especially if it is the sole symptom. Here, we report a unique presentation of colon cancer. Our patient only had intermittent fever for one year before being diagnosed with colon cancer. The fever subsided after resection of the tumor. Despite breakthroughs in diagnostic medicine, FUO remains a challenging diagnosis. Practicing clinicians should have a high level of suspicion to rule out underlying malignancy in the setting of recurrent fevers or FUO.

What General Neurologists Should Know about Autoinflammatory Syndromes?

Autoinflammatory disorders encompass a wide range of conditions with systemic and neurological symptoms, which can be acquired or inherited. These diseases are characterized by an abnormal response of the innate immune system, leading to an excessive inflammatory reaction. On the other hand, autoimmune diseases result from dysregulation of the adaptive immune response. Disease flares are characterized by systemic inflammation affecting the skin, muscles, joints, serosa, and eyes, accompanied by unexplained fever and elevated acute phase reactants. Autoinflammatory syndromes can present with various neurological manifestations, such as aseptic meningitis, meningoencephalitis, sensorineural hearing loss, and others. Early recognition of these manifestations by general neurologists can have a significant impact on the prognosis of patients. Timely and targeted therapy can prevent long-term disability by reducing chronic inflammation. This review provides an overview of recently reported neuroinflammatory phenotypes, with a specific focus on genetic factors, clinical manifestations, and treatment options. General neurologists should have a good understanding of these important diseases.

[B symptoms in unexplained mediastinal lymphadenopathy : Case report of a 72-year-old male patient with VEXAS syndrome]. / B-Symptomatik bei unklarer mediastinaler Lymphadenopathie : Fallbericht eines 72-jährigen Patienten mit VEXAS-Syndrom.

The case of a 72-year-old male patient who presented to our centre for rare diseases with recurrent fever, night sweats and weight loss with initially confirmed mediastinal lymphadenopathy is reported. Investigation of lymph node material was unrevealing. As an additional finding, the patient had a myelodysplastic syndrome. VEXAS syndrome (vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) could be confirmed on the basis of a bone marrow biopsy and genetic testing.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome and Syndrome of Unexplained Recurrent Fevers in Children and Adults.

Children and adults with autoinflammatory disorders, who often experience recurrent fevers, rashes, cold-induced symptoms, conjunctivitis, lymphadenopathy, recurrent infections, aphthous stomatitis, and abnormal blood cell counts, may present to the allergist/immunologist because the symptoms mimic allergies and disorders of immunity. In recent years, there has been increased recognition of non-monogenic autoinflammatory disorders, including periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome and syndrome of undifferentiated recurrent fevers. For many clinical practitioners, the natural history, diagnostic criteria, differential diagnoses, and preferred therapies remain challenging because of the presumed rarity of patients and the evolving field of autoinflammation. Here, we aim to provide a practical framework for the clinical allergist/immunologist to evaluate and treat this patient population.

Clinical and Therapeutic Aspects of Sideroblastic Anaemia with B-Cell Immunodeficiency, Periodic Fever and Developmental Delay (SIFD) Syndrome: a Systematic Review.

BACKGROUND AND PURPOSE: Sideroblastic anaemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD) syndrome is a novel rare autoinflammatory multisystem disorder. We performed a systematic review of the available clinical and therapeutics aspects of the SIFD syndrome. METHODS: A systematic review according to PRISMA approach, including all articles published before the 30th of July 2021 in Pubmed and EMBASE database, was performed. RESULTS: The search identified 29 publications describing 58 unique patients. To date, 41 unique mutations have been reported. Onset of disease is very early with a median age of 4 months (range 0-252 months). The most frequent manifestations are haematologic such as microcytic anaemia or sideroblastic anaemia (55/58), recurrent fever (52/58), neurologic abnormalities (48/58), immunologic abnormalities in particular a humoral immunodeficiency (48/58), gastrointestinal signs and symptoms (38/58), eye diseases as cataract and retinitis pigmentosa (27/58), failure to thrive (26/58), mucocutaneous involvement (29/58), sensorineural deafness (19/58) and others. To date, 19 patients (35.85%) died because of disease course (16) and complications of hematopoietic cell stems transplantation (3). The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) is dramatically changing the natural history of this disease. CONCLUSIONS: SIFD syndrome is a novel entity to consider in a child presenting with recurrent fever, anaemia, B-cell immunodeficiency and neurodevelopmental delay. To date, therapeutic guidelines are lacking but anti-TNFα treatment and/or HCST are attractive and might modify the clinical course of this syndrome.

Diagnostic and therapeutic algorithms for monogenic autoinflammatory diseases presenting with recurrent fevers among adults.

Autoinflammatory diseases (AIDs) are defined as disorders of innate immunity. They were initially defined in contrast to autoimmune diseases because of the lack of involvement of the adaptive immune system and circulating autoantibodies. The four monogenic AIDs first described are called the 'historical' AIDs and include FMF (associated with MEFV mutations), cryopyrinopathies (associated with NLRP3 mutations), TNF receptor-associated periodic syndrome (associated with TNFRSF1A mutations) and mevalonate kinase deficiency (MKD; associated with MVK mutations). In the last 10 years, >50 new monogenic AIDs have been discovered due to genetic advances. The most important discovery for adult patients is VEXAS syndrome associated with somatic UBA1 mutations leading to an AID affecting mostly elderly men. Diagnosis of monogenic AIDs is based on personal and family history and detailed analysis of symptoms associated with febrile attacks in the context of elevated peripheral inflammatory markers. This review proposes a practical approach for the diagnosis of the main monogenic AIDs among adult patients.

Hemodialysis catheter-related infection caused by Pannonibacter phragmitetus: a rare case report in China.

Pannonibacter phragmitetus (P. phragmitetus) is rarely related with human disease. We reported a case of catheter-related infection caused by P. phragmitetus in a 68-year-old woman on hemodialysis. The patient developed recurrent fever during hemodialysis and blood cultures were positive for P. phragmitetus. The patient's body temperature returned to normal after intravenous cefoperazone/sulbactam treatment, and the hemodialysis catheter was locked with gentamicin and urokinase. The potential anti-infective treatment against P. phragmitetus was discussed.

Childhood-onset Caroli's disease as a cause of recurrent fever: A case report.

Caroli's disease is a rare congenital bile duct malformation characterized by intrahepatic bile duct dilatation. This kind of situation is seldom encountered in clinical work. We report such a case who presented to our emergency department with recurrent fever as initial symptom. According to the clinical manifestation and imaging examination, a 13-year-old boy was diagnosed with suppurative cholangitis and sepsis caused by Caroli's disease. The symptoms were got relieved after antibiotic therapy upgraded from cephalosporins to carbapenems. After 5 months of follow-up, he did not have fever, abdominal pain or any other discomfort. We believe the present report is of medical significance since it serves as a reminder that Caroli's disease may have atypical presentations and be masked by non-specific clinical findings. The report hopes to enlighten our pediatric colleagues by providing more knowledge on such rare congenital disease.

Use of the Auto-inflammatory Disease Activity Index to monitor disease activity in patients with colchicine-resistant Familial Mediterranean Fever, Mevalonate Kinase Deficiency, and TRAPS treated with canakinumab.

OBJECTIVES: To evaluate the feasibility of the autoinflammatory disease activity index (AIDAI) as a tool to assess disease activity in patients with hereditary recurrent fever syndromes (HRFs) treated with canakinumab. METHODS: Patients with active colchicine-resistant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), or tumor necrosis factor receptor-associated periodic syndrome (TRAPS) were enrolled in the phase III CLUSTER study and asked to complete the AIDAI questionnaire daily. All patients included in the analysis were treated with canakinumab, but regimens and periods of treatment varied per study protocol. The AIDAI for each patient was calculated weekly over the first 40 weeks of study, based on the diaries completed over 30 days. Disease-specific cut-off AIDAI values for inactive disease were calculated in a ROC analysis by comparing AIDAI scores with the occurrence of clinically inactive disease, based on the physician global assessments of disease activity and the occurrence of flares. RESULTS: Sixty patients with crFMF, 70 with MKD, and 43 with TRAPS were included in the analysis. Median AIDAI scores were high during the first 4 weeks for the three disease cohorts, and decreased afterwards, with some differences between disease cohorts. AIDAI values of 12.0, 9.6 and 15.5 were obtained as the most optimal thresholds to discriminate patients with inactive disease, with sensitivity and specificity values mostly over 75%. CONCLUSIONS: The AIDAI allows to discriminate between patients with active and inactive HRFs, and can be used in clinical practice to monitor the disease course of patients and the effect of medications.

NLRP12-associated systemic autoinflammatory diseases in children.

Systemic autoinflammatory diseases (SAIDs) are a group of monogenic diseases characterized by disordered innate immunity, which causes excessive activation of inflammatory pathways. Nucleotide-binding leucine-rich repeat-containing receptor 12-related autoinflammatory disease (NLRP12-AID) is a newly identified SAID and a rare autosomal dominant disorder caused by mutations in the NLRP12 gene, which is also known as familial cold autoinflammatory syndrome 2 (FCAS2) and mostly occurs in childhood. A total of 33 cases of NLRP12-AID in children and 21 different mutation types have been reported to date. The disease is mainly characterized by periodic fever, accompanied by multisystem inflammatory damage. NLRP12-AID is diagnosed through early clinical identification and genetic detection. Emerging drugs targeting interleukin-1-related inflammatory pathways are expected to change the treatment options and improve the quality of life of pediatric patients. This article aims to summarize the characteristics and pathogenesis of reported NLRP12-AID cases in children and provide ideas for clinical diagnosis and treatment.

The Persistent Approach to Diagnose Infectious Hepatic Cysts in a Patient With Recurrent Fever: A Case Report.

Diagnosing infectious hepatic cysts (IHCs) can be challenging. Moreover, patients with IHCs may present with various symptoms. Diagnosis of IHCs can be even more difficult in patients with multiple liver cysts. For appropriate diagnosis, the detection of infectious sections in the liver is essential. However, diagnosing and determining definite treatments for patients with IHCs can be particularly challenging when they have polycystic liver disease. We present a case of a 70-year-old man who visited a rural community hospital with a primary complaint of recurrent fever and pain in the right upper quadrant. Based on his clinical history, physical examination findings, and imaging findings after three admissions, he was diagnosed with IHCs. This case demonstrates the challenges in diagnosing IHCs in patients with multiple hepatic cysts and highlights the necessity of a careful follow-up of clinical histories and findings of definitive imaging tests in the diagnosis of IHCs in patients with recurrent fever. To diagnose IHCs effectively, a comprehensive approach including history taking, physical examination, and diagnostic testing, is essential. IHCs should be considered by physicians when patients present with recurrent fever. To avoid missing IHCs, physicians in outpatient departments should continuously follow up on patients' IHC-related symptoms such as fever and right upper quadrant pain.

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: A review.

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is the most common periodic fever condition in children, with most cases appearing by the age of 5. Although PFAPA is generally a self-limited condition, it can have a major impact on a child's quality of life, as well as that of their family. Recent research has continued to shed light on the genetic and immunologic factors that play a role in the pathogenesis of PFAPA. There also exists significant heterogeneity in treatment strategies, and progress has been made to develop evidence-based management strategies and establish a standard of care. This review will outline current knowledge regarding the pathogenesis of PFAPA, as well as treatment strategies and our clinical experience.

A case report of a boy suffering from type 1 diabetes mellitus and familial Mediterranean fever.

BACKGROUND: Type 1 diabetes mellitus could be associated with other autoimmune diseases, such as autoimmune thyroid disease, celiac disease, but the association with Familial Mediterranean Fever is rare, we describe a case of a boy with type 1 Diabetes Mellitus associated with Familial Mediterranean Fever (FMF). CASE PRESENTATION: A 13 year old boy already suffering from Diabetes Mellitus type 1 since the age of 4 years, came to our attention because of periodic fever associated with abdominal pain, chest pain and arthralgia. The fever appeared every 15-30 days with peaks that reached 40 °C and lasted 24-48 h. Laboratory investigation, were normal between febrile episodes, but during the attacks revealed an increase in inflammatory markers. Suspecting Familial Mediterranean Fever molecular analysis of MEFV gene, was performed. The genetic analysis showed homozygous E148Q mutation. So Familial Mediterranean Fever was diagnosed and colchicine treatment was started with good response. CONCLUSION: Familial Mediterranean Fever could be associated with other autoimmune diseases such as Ankylosing Spondylitis, Rheumatoid Arthritis, Polyarteritis Nodosa, Behcet disease, Systemic Lupus, Henoch-Schönlein Purpura, and Hashimoto's Thyroiditis. Association of type 1 Diabetes Mellitus and Familial Mediterranean Fever has been newly reported in the medical literature, this is the third association of these two diseases described in the medical literature so far.

Síndrome de fiebre periódica, estomatitis aftosa, faringitis y adenitis / Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome

Introducción: El síndrome de fiebre periódica, estomatitis aftosa, faringitis y adenitis es un cuadro relativamente frecuente de curso autolimitado y buen pronóstico. Es la más común de las enfermedades autoinflamatorias que presentan fiebre recurrente y su etiología y fisiopatogenia permanecen inciertas. Objetivo: Describir el caso clínico de un niño que consultó por fiebre recurrente y faringitis y se arribó al diagnóstico de síndrome de fiebre periódica, estomatitis aftosa, faringitis y adenitis. Presentación del caso: Se trata de un paciente de 5 años que consultó por un episodio febril acompañado de faringitis y adenitis, con antecedente de múltiples episodios previos. Conclusiones: El síndrome fiebre periódica, estomatitis aftosa, faringitis y adenitis, es una entidad de curso benigno y autolimitado que constituye la causa más común de fiebre recurrente con un gran impacto en la vida de los pacientes. La fisiopatogenia permanece incierta. Es destacable la sospecha clínica para arribar al diagnóstico ya que no existen en la actualidad exámenes complementarios específicos(AU)

Introduction: Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome is a relatively common picture of self-limiting course and good prognosis. It is the most common of self-inflammatory diseases with recurrent fever and its etiology and physiopathology remain uncertain. Objective: Describe the clinical case of a boy who was checked due recurrent fever and pharyngitis and being diagnosed with Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. Case presentation: This is a 5-year-old patient who was consulted due to a febrile episode accompanied by pharyngitis and adenitis, with a history of multiple previous episodes. Conclusions: Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome is a benign, self-limiting course entity that is the most common cause of recurrent fever with a large impact on patients' lives. Its physiopathology remains uncertain. Clinical suspicion for diagnosis is noteworthy as there are currently no specific complementary test for it(AU)

Case Report: Expanding Clinical, Immunological and Genetic Findings in Sideroblastic Anemia With Immunodeficiency, Fevers and Development Delay (SIFD) Syndrome.

Since the first description of the syndrome of sideroblastic anemia with immunodeficiency, fevers and development delay (SIFD), clinical pictures lacking both neurological and hematological manifestations have been reported. Moreover, prominent skin involvement, such as with relapsing erythema nodosum, is not a common finding. Up to this moment, no genotype and phenotype correlation could be done, but mild phenotypes seem to be located in the N or C part. B-cell deficiency is a hallmark of SIFD syndrome, and multiple others immunological defects have been reported, but not high levels of double negative T cells. Here we report a Brazilian patient with a novel phenotype of SFID syndrome, carrying multiple immune defects and harboring a novel mutation on TRNT1 gene.

The everchanging framework of autoinflammation.

The innate immunity works as a defence bullwark that safeguards healthy tissues with the power of detecting infectious agents in the human body: errors in the context of innate immunity identify autoinflammatory disorders (AIDs), which arise as bouts of aberrant inflammation with little or no involvement of T and B cells and neither recognized infections, nor associated autoimmune phenomena. Hereditary AIDs tend to have a pediatric-onset heralded by stereotyped inflammatory symptoms and fever, while AIDs without an ascertained cause, such as systemic juvenile idiopathic arthritis, derive from the interaction of genetic factors with environmental noxae and are unevenly defined. A dysregulated inflammasome activation promotes the best-known family of AIDs, as well as several degenerative and metabolic disorders, but also nuclear factor κB- and interferon-mediated conditions have been framed as AIDs: the zenith of inflammatory flares marks different phenotypes, but diagnosis may go unnoticed until adulthood due to downplayed symptoms and complex kaleidoscopic presentations. This review summarizes the main AIDs encountered in childhood with special emphasis on the clinical stigmata that may help establish a correct framework and blueprints to empower young scientists in the recognition of AIDs. The description focuses inflammasomopathies as paradigms of interleukinopathies, nuclear factor-κB -related disorders and interferonopathies. The challenges in the management of AIDs during childhood have been recently boosted by numerous therapeutic options derived from genomically-based approaches, which have led to identify targeted biologic agents as rationalized treatments and achieve more tangible perspectives of disease control.

Recurrent Fevers in a Triathlete.

Human granulocytic anaplasmosis (HGA) is a tick-borne illness that typically causes a self-limited febrile illness. We describe herein a healthy triathlete who had recurrent fevers for six weeks as a result of HGA and discuss the impact of this patient's HGA on his metabolic fitness during training over a three month time period. We also review the literature for other cases of Ehrlichia and Anaplasma with prolonged courses.

Undifferentiated recurrent fevers in pediatrics are clinically distinct from PFAPA syndrome but retain an IL-1 signature.

Autoinflammatory disorders of the innate immune system present with recurrent episodes of inflammation often beginning in early childhood. While there are now more than 30 genetically-defined hereditary fever disorders, many patients lack a clear diagnosis. Many pediatric patients are often grouped with patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome despite failing to meet diagnostic criteria. Here, we categorize these patients as syndrome of undifferentiated recurrent fever (SURF), and identify the unique features which distinguish them from the PFAPA syndrome. SURF patients were more likely to report gastrointestinal symptoms of nausea, vomiting and abdominal pain, and experienced inconsistent responses to on-demand steroid therapy compared to PFAPA patients. For this previously undefined cohort, an optimal course of therapy remains uncertain, with medical and surgical therapies largely driven by parental preference. A subset of patients with SURF underwent tonsillectomy with complete resolution. Flow cytometric evaluation demonstrates leukocytic populations distinct from PFAPA patients, with reduced CD3+ T cell numbers. SURF patient tonsils were predominantly characterized by an IL-1 signature compared to PFAPA, even during the afebrile period. Peripheral blood signatures were similar between groups suggesting that PFAPA and SURF patient tonsils have localized, persistent inflammation, without clinical symptoms. These data suggest that SURF is a heterogenous syndrome on the autoinflammatory disease spectrum.