Periodic fever: a review on clinical, management and guideline for Iranian patients - part I

Periodic fever syndromes are a group of diseases characterized by episodes of fever with healthy intervals between febrile episodes. The first manifestation of these disorders are present in childhood and adolescence, but infrequently it may be presented in young and middle ages. Genetic base has been known for all types of periodic fever syndromes except periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis [PFAPA]. Common periodic fever disorders are Familial Mediterranean fever [FMF] and PFAPA. In each patient with periodic fever, acquired infection with chronic and periodic nature should be ruled out. It depends on epidemiology of infectious diseases. Some of them such as Familial Mediterranean fever and PFAPA are common in Iran. In Iran and other Middle East countries, brucellosis, malaria and infectious mononucleosis should be considered in differential diagnosis of periodic fever disorders especially with fever and arthritis manifestation. In children, urinary tract infection may be presented as periodic disorder, urine analysis and culture is necessary in each child with periodic symptoms. Some malignancies such as leukemia and tumoral lesions should be excluded in patients with periodic syndrome and weight loss in any age. After excluding infection, malignancy and cyclic neutropenia, FMF and PFAPA are the most common periodic fever disorders. Similar to other countries, Hyper IgD, Chronic Infantile Neurologic Cutaneous and Articular, TRAPS and other auto-inflammatory syndromes are rare causes of periodic fever in Iranian system registry. In part 1 of this paper we reviewed the prevalence of FMF and PFAPA in Iran. In part 2, some uncommon auto-inflammatory disorders such as TRAPS, Hyper IgD sydrome and cryopyrin associated periodic syndromes will be reviewed

Evaluation of Antibody Response to Polysaccharide Vaccine and Switched Memory B Cells in Pediatric Patients with Inflammatory Bowel Disease

BACKGROUND/AIMS: Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract, whose etiologies are still unknown. This study was performed to evaluate the humoral immune response in terms of B cell functions in selected IBD patients. METHODS: Eighteen pediatric patients with IBD, including 12 cases of ulcerative colitis (UC) and six with Crohn disease (CD), were enrolled in this study. The pneumococcal vaccine was injected in all patients, and the IgG antibody level to the polysaccharide antigen was measured before and 4 weeks after injection. The B cell switch-recombination process was evaluated. RESULTS: Five patients with IBD (three CD and two UC) had defects in B cell switching, which was significantly higher than in controls (p=0.05). Ten patients had a specific antibody deficiency and exhibited a higher frequency of bacterial infection than the healthy group. The mean increased level of IgG after vaccination was lower in IBD patients (82.9+/-32.5 microg/mL vs 219.8+/-59.0 microg/mL; p=0.001). Among the patients who had an insufficient response, no significant difference in the number of switched memory B-cell was observed. CONCLUSIONS: A defect in B lymphocyte switching was observed in pediatric IBD patients, and especially in those patients with CD. Owing to an increased risk of bacterial infections in those patients with antibody production defects, pneumococcal vaccination could be recommended. However, not all patients can benefit from the vaccination, and several may require other prophylactic methods.

effect of positive family history of autoimmunity in juvenile idiopathic arthritis characteristics; a case control study

Patients with and without family history of autoimmune disease with respect to clinical features and laboratory data. Sixteen JIA patients with family history of autoimmune disease were identified during study, 32 patients were chosen for comparative group from referred patients to the rheumatology clinic according to the date of referral. Two groups were compared with respect to age of onset, sex, subtype, disease activity, duration of active disease and laboratory variables. The age of onset was significantly lower in JIA patients with family history of autoimmunity [4.7 years vs. 7.0 years; P=0.02], polyarthicular subtype was more frequent in patients with positive family history [50% vs.25%; P=0.04] most of JIA patients with positive family history were in the active phase at the time of study [64% vs 25%; P=0.02] and had a longer duration of active disease [21.0 months vs 12.3 months; P=0.04]. Patients with positive family history had more positive ANA [43.5%% vs 12.5%; P=0.01] and also more positive ADA [75% vs 20.8%; P=0.002]. Two groups were similar according to sex, and other laboratory variables. JIA patients with family history of autoimmune disease seem to have a more severe disease than patients without such family history, they are younger at the onset, and have mostly poyarthicular subtype. They also have more ANA and ADA positivity. These findings are different from familial JIA case-control studies according to active disease duration, subtype, and ANA positivity

Selective antibody deficiency and its relation to the IgG2 and IgG3 subclass titers in recurrent respiratory infections

Selective antibody deficiency with normal immunoglobulins [SADNI] may be identified as part of distinct primary or secondary immunodeficiency disorders. The clinical manifestations include recurrent, often severe or prolonged, upper or lower respiratory tract infections. To evaluate SADNI in patients with recurrent sinopulmonary infections and its relation to IgG subclass deficiencies. Methods: In a case-control study, anti-pneumococcal antibody titer and IgG2, IgG3 levels before injection of pneumococcal vaccine and anti-pneumococcal antibody titer at least 4 weeks the vaccination were measured in 46 patients and 54 controls. The results were compared using student's t-test. There was a significant correlation between age and anti-pneumococcal antibody titers before and after vaccination in patients. No significant relation was found between pre and post vaccination pneumococcal antibody titer and IgG2 and IgG3 in cases and controls [p>0.05]. The mean of anti-pneumococcal antibody before and after vaccination were significantly different in cases and controls and were higher in control group [p=0.01, p=0.001, respectively]. Anti-pneumococcal antibody titers in 97.8% of cases and 100% of controls group were normal [>3.4 micro g/ml]. 34.8% of cases and 9.1% of controls had low titers of anti-pneumococcal antibody [<20 micro g/ml] while 18.7% of cases and no controls failed to respond to vaccine. Evaluation of anti-pneumococcal antibody titer in patients with recurrent, chronic and severe respiratory infections with normal immunoglobulin levels seems to be necessary as early diagnosis. Treatment of such a cases could prevent later sequelae such as mastoiditis and bronchiecstasia

Neonatal marfan syndrome: report of two cases

Neonatal Marfan syndrome is a rare and severe phenotype of this disease. A poor prognosis is anticipated due to the high probability of congestive heart failure, and mitral and tricuspid regurgitations with suboptimal response to medical therapy and difficulties in surgical management at an early age. We present two consecutive patients with this disease who are the first reported cases from Iran to the best of our knowledge. Unfortunately both of them died shortly after diagnosis. Neonatal Marfan syndrome is reported from Iran and has a poor prognosis like the patients reported from elsewhere

Successful treatment of fungal osteomyelitis with voriconazole in a patient with chronic granulomatous disease

Chronic granulomatous disease [CGD] is an immunodeficiency affecting phagocytic leukocytes. Defective respiratory burst mechanism renders the affected patients to be susceptible to catalase positive microorganisms. With the great successes in antibacterial prophylaxis and therapy, fungal infections are a persistent problem. Invasive aspergillosis is the most important cause of mortality in CGD. We describe a nine-year-old boy with CGD who presented with aspergillus induced skull osteomyelitis. He was successfully treated with voriconazole after initial failure of amphotericin B therapy. Currently, newer triazoles are recommended as initial therapy for invasive aspergillosis in immunodeficiency states such as CGD

Fatality due to shigellosis with special reference to molecular analysis vi Shigella sonnet strains isolated from the fatal cases

Shigellosis as a global human health problem is more severe than other forms of gastroenteritis and causes over a million deaths in developing countries worldwide annually. Fatality due to shigellosis is usually due to dehydration and two-third of fatalities are seen among children. The aim of current study was to describe fatal cases of shigellosis due to infection with Shigella sonnei and S.flexneri. We investigated the fatal cases of shigellosis among all children with acute diarrhea admitted to Children's Medical Center, Tehran, Iran. Bacterial isolation and identification was achieved according to standard bacteriological methods. Antibiotic susceptibility tests, plasmid profiling and ribotyping were performed to investigate the clonal relationship among the isolates. Among 1200 children with acute diarrhea, 140 [12.7%] cases had shigellosis. Of these, three patients died. No signs of severe dehydration were observed among the fatal cases. The symptoms were not improved following antibiotic therapy and all three cases died after 24 h of hospitalization despite receiving intensive treatments. Stool cultures yielded S.flexneri and S. sonnei for one and two cases, respectively. The isolates were resistant to streptomycin, ampicillin, and sulfamethoxazole-trimethoprim. 5. sonnei strains were further studied and showed a single pattern of antibiotic susceptibility and ribotyping. Mortality due to species other than 5. dysenteriae is rare, however, in current study we found S. sonnei and S.flexneri as the cause of fatality among pediatric patients during the study

Assessment of pubertal development in Iranian girls

We estimated pubertal development of 7,493 normal Iranian girls aged 6 to 20 years in a cross-sectional study. Pubertal stages were assessed according to Tanner. The mean ages to achieve secondary sexual characteristics as well as the mean age at menarche were estimated. Weight and height were measured and body mass index [BMI] was calculated. Reference curves for different breast stages and menarche were constructed. The percentiles for attaining each stage were compared to data proposed by Tanner. The mean age at breast bud stage [B2] was 10.10, pubic hair stage [P2] was 9.83, and menarche age was 12.55 years. The anthropometric variables were interpreted in different maturity stages. The mean age at attainment of puberty was compared with those of other populations. Not only the onset of puberty in Iranian girls but also the duration of puberty is similar to data from most other countries. A lower age limit for the definition of precocious puberty than the traditional 8 years is documented for Iranian girls. However, it should be noted that considering the rate of evolution of pubertal findings is more important than the age of their appearance

Infectious and non-infectious complications among undiagnosed patients with common variable immunodeficiency

Common variable immunodeficiency [CVID] is a heterogeneous group of disorders, characterized by hypogammaglobulinemia, defective specific antibody responses to pathogens and increased susceptibility to recurrent bacterial infections. Delay in diagnosis and inadequate treatment can lead to irreversible complications and mortality. In order to determine infectious complications among undiagnosed CVID patients, 47 patients diagnosed in the Children's Medical Center Hospital during a period of 25 years [1984-2009] were enrolled in this study. Patients were divided into two groups including Group 1 [Gl] with long diagnostic delay of more than 6 years [24 patients] and Group 2 [G2] with early diagnosis [23 patients]. The clinical manifestations were recorded in a period prior to diagnosis in Gl and duration follow up in G2. The number of infections, non infectious complications, hospitalizations, and mortality rate was compared between the two groups. The patients in Gl group had 500 episodes of infections before diagnosis in 256 patient-years [0.08 per patient per year] and 203 times of hospitalization [0.03 per patient per year], which were significantly higher than in G2 patients, who had 75 episodes of infections [0.015 per patient per year] and 88 hospital admissions [0.018 per patient per year] during 207 patient follow-up years. Frequency of enteropathies and liver diseases in Gl were also significantly higher than in G2. Lack of awareness about nature of disease, especially among rural and suburban physicians, single organ involvement as a site of clinical presenting, and predomination of non infectious presentation in Gl were the major factors of delayed diagnosis. Diagnostic delay is a major concern in CVID patients, which could result in irreversible complications and mortality, while early diagnosis and proper initial treatment leads to better outcomes and quality of life

Presence of idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia in the patients with common variable immunodeficiency

Common Variable Immunodeficiency [CVID] is a heterogeneous group of disorders characterized by hypogammaglobulinemia and an increased susceptibility to recurrent infections as well as autoimmunity and malignancies. Idiopathic Thrombocytopenic Purpura [ITP] and Autoimmune Hemolytic Anemia [AIHA] are two autoimmune disorders which may be seen in association with CVID. Among 85 CVID patients, seven cases had ITP and/or AIHA [8%]. Four of these patients had one or more episodes of ITP, one patient had AIHA, and two patients had both ITP and AIHA [Evans syndrome]. Almost, all patients experienced chronic and recurrent infections mostly in respiratory and gastrointestinal systems during the course of the disease. Among the seven patients, five presented their underlying disease with recurrent respiratory and/or gastrointestinal tract infections, while in two remaining patients, CVID was presented with ITP. Three patients died until now; two because of hepatic failure and one due to pulmonary hemorrhage. As CVID is prone to autoimmune disorders, it should be considered as a differential diagnosis of adult-onset ITP and possibly in children. Chronic and recurrent ITP, especially in the presence of propensity to respiratory and gastrointestinal infections mandate the evaluation for an underlying immune dysregulation such as CVID

B-cell lineage study in patients with juvenile idiopathic arthritis

Juvenile idiopathic arthritis [JIA] is the most common rheumatic disease in children. The exact causes of disease are still poorly understood. It seems that B cells have several functions in JIA, including production of autoantibodies, antigen presentation, production of cytokines, and activation of T cells. Here, we aimed to evaluate B-cell lineage and its precursors in the bone marrow of patients with JIA Twenty consecutive patients with JIA were enrolled in this study. JIA is subdivided into three groups of Pauciarticular, Polyarticular, and Systemic JIA. Bone marrow mononuclear cells were separated. Then we analyzed the immunophenotype of the JIA patients by flow cytometry. After separation, the mononuclear cells were stained specific for B cell lineage [CD10, CD19 and CD20], T cell lineage [CD3] and non specific lineage [CD34, HLA-DR and TdT]. Flow cytometric study of bone marrow showed that JIA patients had low level of CD10, CD19, and CD20.Polyarticular patients had lower level of D10, CD19, and CD20 than pauciarticular JIA patients and systemic onset JIA patients had lower levels than both of them. Decreasing of B cell precursor in bone marrow is one of mechanisms for pathogenesis of JIA and the more decreased B cell precursors in bone marrow are, the worst severity of the disease is. Significant differences in CD10 content of bone marrow were detected between the polyarticular and pauciarticular groups. So, it seems that polyarticular JIA patients had lower percentage of pre B cell stage

Griscelli syndrome type 2; a pediatric case with immunodeficiency

A 3.5 month-old girl was admitted with silvery gray hair, light colored skin, recurrent diarrhea, chest infections, hepatosplenomegaly, episodes of pancytopenia, and hemophagocytosis in the bone marrow. Light microscopy of hair showed characteristic large and irregular clumps of melanin in the middle of hair shaft. Peripheral blood smear examination did not show giant granules in granulocytes. On the basis of these clinical and laboratory findings, Griscelli syndrome was diagnosed. The child succumbed to infection during an accelerated phase of the disease

Autoimmune lymphoproliferative syndrome: meticulous care for diagnosis

Autoimmune lymphoproliferative syndrome [ALPS] is a prototypic disorder of abnormal lymphocyte homeostasis. In the September 2005 issue of The Iranian Journal of Allergy, Asthma and Immunology, a patient with clinical features consistent with ALPS was described. Although the clinical presentation was in favor of ALPS, a precise diagnosis needed more laboratory evaluations

Screening of the Bruton tyrosine kinase [BTK] gene mutations in 13 Iranian patients with presumed x-linked agammaglobulinemia

X-linked agammaglobulinemia [XLA] is an immunodeficiency caused by mutations in the Bruton tyrosine kinase [Btk] gene. In order to identify the mutations in Btk gene in Iranian patients with antibody deficiency, 13 male patients with an XLA phenotype from 11 unrelated families were enrolled as the subjects of investigation for Btk mutation analysis using PCR-SSCP followed by sequencing. Five different mutations were identified in 5 patients from 5 unrelated families. Three mutations had been reported previously including TTTG deletion in intron 15 [4 bps upstream of exon 16 boundary], nonsense point mutation [1896G>A] that resulted in a premature stop codon [W588X] in kinase domain, and nucleotide alteration in invariant splice donor site of exon12 [IVS12+1G>A]. While 2 novel missense mutations [2084A>G, 1783T>C] were identified leading to amino acid changes [I651T, Y551H]. The results of this study further support the notion that molecular genetic testing represents an important tool for definitive and early diagnosis of XLA and may allow accurate carrier detection and prenatal diagnosis