The Comparison of Diagnostic Criteria in Children with Familial Mediterranean Fever

Abstract Familial Mediterranean Fever (FMF) is an autoinflammatory disease characterized with recurrent attacks of fever and serositis. The diagnosis is made according to clinical findings and supported by genetic analysis. The most used adult diagnostic criteria are the Tel-Hashomer criteria. The pediatric criteria for the FMF diagnosis of children were described in 2009, but their efficacy should be supported with further reports. In this study, we planned to compare the pediatric criteria and the Tel-Hashomer criteria in our FMF patients. We also aimed to evaluate the importance of the 2019 Eurofever/PRINTO classification criteria in this patient group. A total of 113 patients diagnosed with FMF were included in our study. Demographic features and laboratory findings were retrospectively recorded from the patients’ files. The patients were evaluated with the Tel-Hashomer, pediatric and Eurofever/PRINTO classification criteria. At least two of five new pediatric criteria were as sensitive (88.6%) and specific (84.62%) as the Tel-Hashomer criteria (sensitivity 69.9%, specificity 95.7%). We also evaluated the Eurofever/PRINTO classification criteria in our patients and found its sensitivity 93.8% and specificity 90.6%. Conclusion: Using pediatric criteria in the diagnosis of FMF in children is a feasible and simple method that can diagnose the disease based on at least two criteria. Therefore, our study supports the use of pediatric criteria in the diagnosis of FMF in children. Our results also confirm that the Eurofever/PRINTO classification criteria can be successfully used in the diagnosis of FMF due to their high sensitivity (93.8%) and specificity (90.6%).

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Abdominal syndrome in monogenic autoinflammatory disease – is it just a familial Mediterranean fever?

Modern Rheumatology Journal ◽

10.14412/1996-7012-2020-4-144-149 ◽

2020 ◽

Vol 14 (4) ◽

pp. 144-149

Author(s):

S. O. Salugina ◽

E. S. Fedorov ◽

N. G. Volf

Keyword(s):

Familial Mediterranean Fever ◽

Autoinflammatory Disease ◽

Bowel Perforation ◽

Interleukin 1 ◽

Diagnostic Features ◽

Peritoneal Adhesions ◽

Strict Adherence ◽

Surgical Interventions ◽

Abdominal Symptoms ◽

Mediterranean Fever

Gastrointestinal (GI) manifestations, such as abdominal pain, nausea, vomiting, and diarrhea, are common autoinflammatory disease (AID) symptoms. The abdominal symptomatology reflecting serositis is one of the most important classification and diagnostic criteria for the classic monogenic AID (MAID) – familial Mediterranean fever (FMF). Failure to timely diagnose FMF frequently leads to unjustified surgical interventions. Other periodic fevers may also present as abdominal symptoms; however, the latter are outside their diagnostic features. These diseases include, first of all, tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Interleukin 1 (IL1) inhibitors serve as the major targeted drugs for the treatment of TRAPS. Russia has registered the IL1 inhibitor canakinumab that prevents the development of organ damages, including those in the GI tract. The paper describes a clinical case of the classic manifestations of TRAPS (fever, rash, periorbital edema, arthritis, and elevated levels of acutephase inflammatory markers) concurrent with severe abdominalgia during attacks and with the development of severe peritoneal adhesions, which led to bowel perforation and emergency surgical intervention. The prolonged persistence of inflammatory attacks before the initiation of therapy, as well as violation of the IL1 inhibitor administration regimen facilitated the development of an urgent exacerbation. Thus, TRAPS should be included in the differential diagnostic circle for patients with severe gastrointestinal manifestations characterized by an attack-like course. These patients need timely prescription of targeted therapy, strict adherence to the dosing and intervals between drug administrations, and careful monitoring to prevent serious complications with the visceral organs, including the gastrointestinal tract, and their immediate correction.

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THE EFFECT OF TRACHOMA VIRUS VACCINE ON THE COURSE OF EXPERIMENTAL TRACHOMA INFECTION IN BLIND HUMAN VOLUNTEERS

Journal of Experimental Medicine ◽

10.1084/jem.115.5.1009 ◽

1962 ◽

Vol 115 (5) ◽

pp. 1009-1022 ◽

Cited By ~ 26

Author(s):

J. Thomas Grayston ◽

San-Pin Wang ◽

Yen-Fei Yang ◽

Robert L. Woolridge

Keyword(s):

Clinical Picture ◽

Egg Yolk ◽

Adenovirus Type ◽

Clinical Findings ◽

Elementary Body ◽

Laboratory Findings ◽

Simple Method ◽

Sulfa Drug ◽

Course Of Illness ◽

Human Volunteers

The TRIC-Taiwan-1-1958 strain of elementary body virus isolated from a trachoma patient on Taiwan has been proven capable of reproducing trachoma by experimental inoculation of six human volunteers. Virus material derived from the seventh passage in embryonated hen eggs caused the clinical picture of trachoma in every inoculation, even at the dilution of 10–4 of infected yolk sacs (approximately 1 EID50). There was a similar clinical picture with each inoculation beginning with an acute follicular conjunctivitis which progressed for 4 months and then persisted with chronic changes until 9 months when treatment was begun. The illness was generally more acute than would be expected in natural trachoma. That trachoma was reproduced was shown by the involvement of the cornea with epithelial keratitis and pannus, and by the occurrence of gelatinous follicles and eventual cicatrization of the conjunctiva. These clinical findings were supported by repeated demonstrations of typical inclusion bodies of Halberstaedter-Prowazek from conjunctival and even corneal cells, by repeated reisolation of elementary body virus in egg yolk sacs, and by the development of complement-fixing antibody with a "specific" trachoma antigen in each volunteer. Control inoculations with adenovirus type 4 and normal yolk sac showed different clinical and laboratory findings. Experimental trachoma vaccine was given to three of the volunteers to study its effect on the course of illness. An antibody response to the vaccine was demonstrated and there was a modification of disease in the volunteers receiving vaccine. While the three volunteers who received placebo each developed cross-infection of their uninoculated eye and had an acute reactivation of the bilateral disease after 1 to 2 months of antibiotic eye ointment therapy, the vaccinated volunteers remained free of infection in uninoculated eyes and showed no relapse after ointment therapy. Treatment with sulfamethoxypyridazine, a sulfa drug with prolonged action, proved to be an effective and relatively simple method of therapy for experimental trachoma.

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Choroidal Thickness Changes in the Acute Attack Period in Patients with Familial Mediterranean Fever

Ophthalmologica ◽

10.1159/000442216 ◽

2015 ◽

Vol 235 (2) ◽

pp. 72-77 ◽

Cited By ~ 12

Author(s):

Fatih C. Gundogan ◽

Fahrettin Akay ◽

Salih Uzun ◽

Gokhan Ozge ◽

Sami Toyran ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Choroidal Thickness ◽

Serum Levels ◽

Acute Attack ◽

Clinical Findings ◽

Healthy Controls ◽

Reactive Protein ◽

Mediterranean Fever ◽

Acute Attacks ◽

Positive Correlations

Purpose: The aim of this study was to evaluate choroidal thickness changes during acute attacks of familial Mediterranean fever (FMF). Methods: Fifty patients with FMF and 50 healthy controls were included. Choroidal thickness of each participant was measured at the foveola and horizontal nasal and temporal quadrants at 500-µm intervals to 1,500 µm from the foveola using spectral-domain optical coherence tomography. White blood cell count, erythrocyte sedimentation rate (ESR) and serum levels of fibrinogen and C-reactive protein (CRP) were evaluated. The clinical findings (peritonitis, arthritis and pleuritis) were noted. Results: Choroidal thickness was significantly thicker at all measurement points in FMF patients compared to healthy controls during an acute attack (p < 0.05). There were positive correlations between the choroidal thickness and ESR, fibrinogen and, particularly, CRP levels. Clinical findings did not change the choroidal thickness significantly (p > 0.05). Conclusions: Increased choroidal thickness in the acute phase of FMF is possibly related to the inflammatory edematous changes in the choroid.

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Performance of Different Diagnostic Criteria for Familial Mediterranean Fever in Children with Periodic Fevers: Results from a Multicenter International Registry

The Journal of Rheumatology ◽

10.3899/jrheum.141249 ◽

2015 ◽

Vol 43 (1) ◽

pp. 154-160 ◽

Cited By ~ 26

Author(s):

Erkan Demirkaya ◽

Celal Saglam ◽

Turker Turker ◽

Isabelle Koné-Paut ◽

Pat Woo ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Diagnostic Criteria ◽

Pediatric Patients ◽

Eastern Mediterranean Region ◽

The Other ◽

Control Group ◽

Mevalonate Kinase Deficiency ◽

Periodic Syndrome ◽

International Registry ◽

Mediterranean Fever

Objective.Our aims were to validate the pediatric diagnostic criteria in a large international registry and to compare them with the performance of previous criteria for the diagnosis of familial Mediterranean fever (FMF).Methods.Pediatric patients with FMF from the Eurofever registry were used for the validation of the existing criteria. The other periodic fevers served as controls: mevalonate kinase deficiency (MKD), tumor necrosis factor receptor–associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), and undefined periodic fever from the same registry. The performances of Tel Hashomer, Livneh, and the Yalcinkaya-Ozen criteria were assessed.Results.The FMF group included 339 patients. The control group consisted of 377 patients (53 TRAPS, 45 MKD, 32 CAPS, 160 PFAPA, 87 undefined periodic fevers). Patients with FMF were correctly diagnosed using the Yalcinkaya-Ozen criteria with a sensitivity rate of 87.4% and a specificity rate of 40.7%. On the other hand, Tel Hashomer and Livneh criteria displayed a sensitivity of 45.0 and 77.3%, respectively. Both of the latter criteria displayed a better specificity than the Yalcinkaya-Ozen criteria: 97.2 and 41.1% for the Tel Hashomer and Livneh criteria, respectively. The overall accuracy for the Yalcinkaya-Ozen criteria was 65 and 69.6% (using 2 and 3 criteria), respectively. Ethnicity and residence had no effect on the performance of the Yalcinkaya-Ozen criteria.Conclusion.The Yalcinkaya-Ozen criteria yielded a better sensitivity than the other criteria in this international cohort of patients and thus can be used as a tool for FMF diagnosis in pediatric patients from either the European or eastern Mediterranean region. However, the specificity was lower than the previously suggested adult criteria.

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Differentiating children with familial Mediterranean fever from other recurrent fever syndromes: The utility of new Eurofever/PRINTO classification criteria

Archives of Rheumatology ◽

10.46497/archrheumatol.2021.8616 ◽

2021 ◽

Vol 36 (4) ◽

pp. 493-498

Author(s):

Rabia Miray Kışla Ekinci ◽

Sibel Balcı ◽

Ahmet Hakan Erol ◽

Dilek Karagöz ◽

Derya Ufuk Altıntaş ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Sensitivity And Specificity ◽

Mefv Gene ◽

Classification Criteria ◽

Recurrent Fever ◽

Control Group ◽

Mevalonate Kinase Deficiency ◽

Cross Sectional ◽

M694v Mutation ◽

Mediterranean Fever

Objectives: In this study, we aimed to investigate the performance of Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria in pediatric patients with familial Mediterranean fever (FMF). Patients and methods:This retrospective, cross-sectional study included a total of 130 pediatric FMF patients (67 males, 63 females; mean age: 12.4±3.6 years; range, 2.5 to 17.7 years) with at least one M694V mutation in MEFV gene between July 2010 and July 2019. Demographic features and disease characteristics were recorded. The control group was consisted of 41 patients (19 males, 22 females; mean age: 7.8±4.0 years; range, 2.1 to 17.8 years) with other hereditary autoinflammatory diseases (AIDs), including periodic fevers with aphthous stomatitis, pharyngitis, and adenitis syndrome (n=30), mevalonate kinase deficiency (n=9), and tumor necrosis factor receptor-associated periodic syndrome (n=2). Sensitivity and specificity of the Eurofever/PRINTO classification criteria were calculated. Results: The sensitivity and specificity were 97.7% and 56.1% for Yalcinkaya-Ozen criteria, respectively and 93.1% and 90.2% for Tel Hashomer criteria, respectively. The Eurofever/PRINTO classification criteria reached a sensitivity and specificity of 94.6% and 82.9% and 93.1% and 80.5%, respectively, when genetic plus clinical criteria and clinical-only criteria were applied. Conclusion: The Eurofever/PRINTO classification criteria have a comparable sensitivity for avoidance of FMF underdiagnosis in childhood. The Yalcinkaya-Ozen criteria have the highest sensitivity without a significant specificity. The Tel Hashomer criteria and Eurofever/PRINTO classification criteria were superior to Yalcinkaya-Ozen criteria to differentiate FMF from other AIDs, thus leading to less complications relevant to underdiagnosis of other AIDs.

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Kawasaki disease triggered by EBV virus in a child with Familial Mediterranean Fever

Italian Journal of Pediatrics ◽

10.1186/s13052-019-0717-8 ◽

2019 ◽

Vol 45 (1) ◽

Cited By ~ 2

Author(s):

Maria Cristina Maggio ◽

Carmelo Fabiano ◽

Giovanni Corsello

Keyword(s):

Kawasaki Disease ◽

Familial Mediterranean Fever ◽

Epstein Barr Virus ◽

Autoinflammatory Disease ◽

Mefv Gene ◽

Clinical Manifestations ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Mediterranean Fever ◽

Epstein Barr

Abstract Background Familial Mediterranean Fever is a monogenic autoinflammatory disease, secondary to mutation of MEFV gene, and typically expressed with recurrent attacks of fever, serositis, rash, aphthous changes in lips and/or oral mucosa. Kawasaki Disease, an acute systemic vasculitis with persistent fever (5 or more days), rash, stomatitis, conjunctivitis, lymphadenopathy, changes in extremities, is currently considered a multifactorial autoinflammatory disease. An infection, as Epstein Barr virus, can be the trigger of Kawasaki Disease. Case presentation We describe the clinical case of a 3-year-old boy with Kawasaki disease. Successfully treated with intravenous immune globulin, acetyl salicylate acid, he late developed anaemia and thrombocytopenia. The Epstein-Barr virus infection has been demonstrated and he showed a resolution of the clinical manifestations of Kawasaki disease with the persistence of coronaritis, without aneurisms. However, for the personal and familial history of monthly recurrent attacks of fever, pharyngitis, abdominal pain, the genetic study of MEFV was performed and demonstrated 3 heterozygous mutations of MEFV (E148Q, P369S, R408Q). Conclusions Mutations of MEFV can contribute to increase inflammatory expression in other diseases, as Kawasaki disease.

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RECURRENT POLYSEROSITIS ("PERIODIC DISEASE," "FAMILIAL MEDITERRANEAN FEVER") IN CHILDREN

PEDIATRICS ◽

10.1542/peds.30.3.443 ◽

1962 ◽

Vol 30 (3) ◽

pp. 443-449

Author(s):

Tehila R. Shapiro ◽

Ernest N. Ehrenfeld

Keyword(s):

Familial Mediterranean Fever ◽

Acute Rheumatic Fever ◽

Age Of Onset ◽

Clinical Manifestations ◽

C Reactive Protein ◽

Laboratory Findings ◽

Reactive Protein ◽

Periodic Disease ◽

Mediterranean Fever ◽

The Difference

A series of 19 cases of recurrent polyserositis is presented. All but one child were of Oriental Jewish parentage, and the disease sometimes showed a familial occurrence. The average age of onset was 4 years. The symptoms consisted of fever; abdominal, chest, and joint pains; and skin eruptions. The clinical manifestations often simulated those of acute rheumatic fever, particularly since cardiac murmurs occurred in more than half of the patients. The laboratory findings were those accompanying nonspecific inflammations such as leukocytosis, accelerated enythrocyte sedimentation rate, elevated antistreptolysin titer, and positive C-reactive protein. Though some patients showed transitional albuminunia, no cases of amyloidosis were found. The difference in the clinical manifestations in children as compared with adults, and possible etiological factors are discussed.

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Unresponsiveness to Colchicine Therapy in Patients with Familial Mediterranean Fever Homozygous for the M694V Mutation

The Journal of Rheumatology ◽

10.3899/jrheum.090273 ◽

2009 ◽

Vol 37 (1) ◽

pp. 182-189 ◽

Cited By ~ 26

Author(s):

OGUZ SOYLEMEZOGLU ◽

MUSTAFA ARGA ◽

KIBRIYA FIDAN ◽

SEVIM GONEN ◽

HAMDI CIHAN EMEKSIZ ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Colchicine Treatment ◽

Response To Treatment ◽

Therapeutic Implications ◽

Mefv Mutations ◽

Increased Risk ◽

M694v Mutation ◽

Group A ◽

Mediterranean Fever ◽

Group B

Objective.More than 50 disease-associated mutations of the Mediterranean fever gene (MEFV) have been identified in familial Mediterranean fever (FMF), some of which were shown to have different clinical, diagnostic, prognostic, and therapeutic implications. The aim of our study was to define the frequency of mutation type, genotype-phenotype correlation, and response to colchicine treatment in patients with FMF.Methods.This study included 222 pediatric FMF patients. All patients were investigated for 6 MEFV mutations. Then patients were divided into 3 groups according to the presence of M694V mutation on both of the alleles (homozygotes), on only 1 allele (heterozygotes), and on none of the alleles, and compared according to their phenotypic characteristics and response to treatment. M694V/M694V was denoted Group A, M694V/Other Group B, and Other/Other, Group C.Results.Complete colchicine response was significantly lower while the rate of unresponsiveness was significantly higher in Group A compared to Groups B and C (p = 0.031, p < 0.001 and p = 0.005, p = 0.029, respectively). No differences except proteinuria were found between the phenotypic features of 3 groups. Group C had the lowest rate of proteinuria development (p = 0.024). All the amyloidosis patients were in Group A.Conclusion.Our results indicate that the M694V/M694V mutation is associated with lower response to colchicine treatment. Therefore, patients homozygous for M694V/M694V may be carrying an increased risk for development of amyloidosis.

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