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BACKGROUND: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. METHODS: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. RESULTS: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher. CONCLUSION: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.
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Abscesso , Agamaglobulinemia , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Masculino , Abscesso/diagnóstico , Abscesso/complicações , Doenças Musculares/diagnóstico , Doenças Musculares/complicações , Imageamento por Ressonância MagnéticaRESUMO
Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by molecular defects in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. p67phox-CGD is an autosomal recessive CGD, which is caused by a defect in the cytosolic components of NADPH oxidase, p67phox, encoded by NCF2. We previously established a flow cytometric analysis for p67phox expression, which allows accurate assessment of residual protein expression in p67phox-CGD. We evaluated the correlation between oxidase function and p67phox expression, and assessed the relevancy to genotypes and clinical phenotypes in 11 patients with p67phox-CGD. Reactive oxygen species (ROS) production by granulocytes was evaluated using dihydrorhodamine-1,2,3 (DHR) assays. p67phox expression was evaluated in the monocyte population. DHR activity and p67phox expression were significantly correlated (r = 0.718, p < 0.0162). Additionally, DHR activity and p67phox expression were significantly higher in patients carrying one missense variant in combination with one nonsense or frameshift variant in the NCF2 gene than in patients with only null variants. The available clinical parameters of our patients (i.e., age at disease onset, number of infectious episodes, and each infection complication) were not linked with DHR activity or p67phox expression levels. In summary, our flow cytometric analysis revealed a significant correlation between residual ROS production and p67phox expression. More deleterious NCF2 genotypes were associated with lower levels of DHR activity and p67phox expression. DHR assays and protein expression analysis by using flow cytometry may be relevant strategies for predicting the genotypes of p67phox-CGD.
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Citometria de Fluxo , Doença Granulomatosa Crônica , NADPH Oxidases , Fosfoproteínas , Espécies Reativas de Oxigênio , Humanos , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Citometria de Fluxo/métodos , Masculino , Feminino , Criança , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Pré-Escolar , Lactente , Adolescente , Genótipo , Granulócitos/metabolismo , Adulto , Monócitos/metabolismoRESUMO
OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.
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Anticorpos Monoclonais Humanizados , Síndromes Periódicas Associadas à Criopirina , Humanos , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Japão , Feminino , Masculino , Estudos Retrospectivos , Criança , Pré-Escolar , Adulto , Adolescente , Adulto Jovem , Resultado do Tratamento , Pessoa de Meia-Idade , Lactente , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Mutação , Indução de RemissãoRESUMO
DNA polymerase epsilon (Pol ε), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ε have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE, encoding Pol ε catalytic subunit A (POLE1), in siblings with a syndromic form of severe congenital transfusion-dependent anaemia. In contrast to Diamond-Blackfan anaemia, marked reticulocytopenia or marked erythroid hypoplasia was not found. Their bone marrow aspirates during infancy revealed erythroid dysplasia with strongly positive TP53 in immunostaining. Repetitive examinations demonstrated trilineage myelodysplasia within 2 years from birth. They had short stature and facial dysmorphism. HEK293 cell-based expression experiments and analyses of patient-derived induced pluripotent stem cells (iPSCs) disclosed a reduced mRNA level of Asp1131fs-POLE1 and defective nuclear translocation of Thr1891del-POLE1. Analysis of iPSCs showed compensatory mRNA upregulation of the other replisome components and increase of the TP53 protein, both suggesting dysfunction of the replisome. We created Pole-knockout medaka fish and found that heterozygous fishes were viable, but with decreased RBCs. Our observations expand the phenotypic spectrum of the Pol ε defect in humans, additionally providing unique evidence linking Pol ε to haematopoiesis.
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DNA Polimerase II , Replicação do DNA , Animais , Humanos , DNA Polimerase II/genética , DNA Polimerase II/metabolismo , Células HEK293 , Replicação do DNA/genética , Proteína Supressora de Tumor p53/genética , RNA MensageiroRESUMO
INTRODUCTION: The melting temperature (Tm) mapping method (TM) identifies bacterial species by intrinsic patterns of Tm values in the 16S ribosomal RNA gene (16S rDNA) extracted directly from whole blood. We examined potential clinical application of TM in children with bloodstream infection (BSI). METHODS: This was a prospective observational study at a children's hospital in Japan from 2018 to 2021. In patients with diagnosed or suspected BSI, we investigated the match rates of pathogenic bacteria identified by TM and blood culture (BC), the inspection time to identification of TM, and the amount of bacterial DNA in blood samples. RESULTS: The median age of 81 patients (93 samples) was 3.6 years. Of 23 samples identified by TM, 11 samples matched the bacterial species with BC (positive-match rate, 48 %). Of 64 TM-negative samples, 62 samples were negative for BC (negative-match rate, 97 %). Six samples, including one containing two pathogenic bacterial species, were not suitable for TM identification. In total, the matched samples were 73 of 93 samples (match rate, 78 %). There were seven samples identified by TM in BC-negative samples from blood collected after antibiotic therapy. Interestingly, the bacteria were matched with BC before antibiotic administration. These TM samples contained as many 16S rDNA copies as the BC-positive samples. The median inspection time to identification using TM was 4.7 h. CONCLUSIONS: In children with BSI, TM had high negative-match rates with BC, the potential to identify the pathogenic bacteria even in patients on antibiotic therapy, and more rapid identification compared to BC. REGISTERING CLINICAL TRIALS: UMIN000041359https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000047220.
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Introduction: Primary immunodeficiency diseases (PIDs) are rare inherited diseases resulting in impaired immunity. People with PID experience lower health-related quality of life (HR-QOL) and disease-related burdens in daily activities. This ongoing, prospective observational study aims to evaluate disease activity, treatment status, treatment-related burden, daily activities, and HR-QOL in patients with PID in Japan over a 1-year period. In this interim report (database lock: July 29, 2022), we present baseline results. Methods: Participants were enrolled between November 2021 and May 2022; data were collected four times/year per participant until May 2023 using an online electronic patient-reported outcomes system. Patients with PID and healthy volunteers aged ≥12 years, residing in Japan, and with access to a smartphone were eligible. HR-QOL (primary endpoint) was assessed by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Work productivity was assessed by the Work Productivity and Activity Impairment (WPAI) Questionnaire. Other aspects of PID and burden were assessed with a new questionnaire developed in-house. The study is registered at the University hospital Medical Information Network clinical trials registry (UMIN000045622). Results: The full interim analysis set comprised 71 patients with PID and 47 healthy volunteers. The most common International Union of Immunological Societies PID category was primary antibody deficiency (56.3% of patients). Complications were common, especially recurrent respiratory tract infections (63.4%). Most patients with PID were treated with immunoglobulin replacement therapy (73.2%); 22.4% of these patients had serum immunoglobulin levels <700 mg/dL. Among patients who did not undergo hematopoietic cell transplantation, EQ-5D-5L (n=67) and SF-36 (n=59) Physical and Mental Component Summary scores were significantly lower than in healthy volunteers (p < 0.001). WPAI absenteeism, work productivity loss, and activity impairment scores were significantly lower in 42 working patients with PID than in 37 working healthy volunteers (p < 0.05). Other results indicated that patients with PID experience substantial burdens related to medical visits, expenses, work, and daily activities. Discussion: This interim analysis confirms that patients with PID in Japan have lower HR-QOL and work productivity compared with healthy individuals and experience substantial limitations and burdens in their daily lives.
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Doenças da Imunodeficiência Primária , Qualidade de Vida , Humanos , Imunoglobulinas , Japão/epidemiologia , Medidas de Resultados Relatados pelo Paciente , Doenças da Imunodeficiência Primária/terapia , Estudos ProspectivosRESUMO
Stem cell gene therapy using the MFGS-gp91phox retroviral vector was performed on a 27-year-old patient with X-linked chronic granulomatous disease (X-CGD) in 2014. The patient's refractory infections were resolved, whereas the oxidase-positive neutrophils disappeared within 6 months. Thirty-two months after gene therapy, the patient developed myelodysplastic syndrome (MDS), and vector integration into the MECOM locus was identified in blast cells. The vector integration into MECOM was detectable in most myeloid cells at 12 months after gene therapy. However, the patient exhibited normal hematopoiesis until the onset of MDS, suggesting that MECOM transactivation contributed to clonal hematopoiesis, and the blast transformation likely arose after the acquisition of additional genetic lesions. In whole-genome sequencing, the biallelic loss of the WT1 tumor suppressor gene, which occurred immediately before tumorigenesis, was identified as a potential candidate genetic alteration. The provirus CYBB cDNA in the blasts contained 108 G-to-A mutations exclusively in the coding strand, suggesting the occurrence of APOBEC3-mediated hypermutations during the transduction of CD34-positive cells. A hypermutation-mediated loss of oxidase activity may have facilitated the survival and proliferation of the clone with MECOM transactivation. Our data provide valuable insights into the complex mechanisms underlying the development of leukemia in X-CGD gene therapy.
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Doença Granulomatosa Crônica , Síndromes Mielodisplásicas , Humanos , Adulto , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/terapia , NADPH Oxidases/genética , Hematopoiese Clonal , Terapia Genética , Retroviridae/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , NADPH Oxidase 2/genéticaRESUMO
BACKGROUND: Allergic diseases were long considered to be complex multifactorial disorders. However, recent findings indicate that severe allergic inflammation can be caused by monogenic immune defects. OBJECTIVES: We sought to clarify the molecular pathogenesis of a patient with early-onset multiple allergic diseases, a high serum IgE level, hypereosinophilia, treatment-resistant severe atopic dermatitis with increased dermal collagen fiber deposition, and eosinophilic gastrointestinal disorder with numerous polypoid nodules. METHODS: A missense variant in STAT6 was identified, and its function was examined using peripheral blood, transfected HEK293 cells, lymphoblastoid cell lines, and knock-in mice with the corresponding mutation. RESULTS: Whole-exome sequencing identified a de novo heterozygous missense variant in signal transducer and activator of transcription 6 (STAT6) (p.Asp419Asn). Luciferase reporter assay revealed that the transcriptional activity of this STAT6 mutant was upregulated even without IL-4 stimulation. Phosphorylation of STAT6 was not observed in either the patient's TH2 cells or lymphoblastoid cell lines without stimulation, whereas it was induced more strongly in both by IL-4 stimulation compared with healthy controls. STAT6 protein was present in the nuclear fraction of the lymphoblastoid cell lines of the patient even in the absence of IL-4 stimulation. The patient's gastric mucosa showed upregulation of STAT6-, fibrosis-, and germinal center formation-related molecules. Some of the knock-in mice with the corresponding mutation spontaneously developed dermatitis with skin thickening and eosinophil infiltration. Moreover, serum IgE levels and mRNA expression of type 2 cytokines were increased in the knock-in mice-with or without development of spontaneous dermatitis-compared with the wild-type mice. CONCLUSIONS: A novel STAT6 gain-of-function variant is a potential cause of primary atopic disorders.
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Dermatite Atópica , Hipersensibilidade , Camundongos , Humanos , Animais , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Interleucina-4/genética , Células HEK293 , Mutação com Ganho de Função , Transdução de Sinais , Dermatite Atópica/genética , Hipersensibilidade/genética , Imunoglobulina E , Células Th2RESUMO
BACKGROUND: Pure red cell aplasia (PRCA) is a hematological disorder characterized by anemia with severe reticulocytopenia caused by a marked reduction in erythroid precursors in the bone marrow. PRCA is known to be associated with pregnancy, but thymoma-associated PRCA during pregnancy is very rare, and its successful management has not been reported. CASE PRESENTATION: A 37-year-old primiparous woman with severe anemia was referred to our center at 27 weeks' gestation. She was diagnosed with PRCA based on bone aspiration findings at 33 weeks' gestation. Magnetic resonance imaging (MRI) revealed an anterior mediastinal mass 4 cm in size suspected of being thymoma. She was therefore diagnosed with thymoma-associated PRCA during pregnancy. Surgery for thymoma was planned after delivery, since the imaging findings were suggestive of early-stage thymoma (Masaoka stage I or II). With transfusion of a total 3,360 ml of red blood cells (RBCs) during pregnancy, the patient gave birth to a baby girl weighing 2,548 g at 40 weeks' gestation. The baby showed transient congenital cutaneous candidiasis. The placental pathology revealed subamniotic inflammation with a fungal structure. Treatment with topical anti-fungal cream immediately ameliorated the baby's skin lesion. Maternal anemia did not improve after delivery; however, the thymoma did not increase in size. At five months after delivery, the mother underwent thymectomy with oral cyclosporine A. A pathological examination revealed Masaoka stage II-a thymoma. She completely had recovered from anemia at six months after surgery. Cyclosporine A treatment was discontinued three years after surgery. Remission has been sustained for four years since surgery. CONCLUSIONS: A very rare case of thymoma-associated PRCA during pregnancy was diagnosed without any subjective symptoms and was expectantly managed, resulting in a good prognosis. Although bone marrow aspiration during pregnancy is an invasive test, it is important to confirm the diagnosis. Conservative management with blood transfusion was possible for early-stage thymoma-associated PRCA during pregnancy. Active surveys, including MRI, for PRCA during pregnancy led to the detection of thymoma at an early stage and the achievement of a preferable pregnancy outcome.
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Aplasia Pura de Série Vermelha , Timoma , Neoplasias do Timo , Feminino , Humanos , Gravidez , Recém-Nascido , Adulto , Timoma/complicações , Timoma/diagnóstico por imagem , Timoma/cirurgia , Ciclosporina , Gestantes , Placenta/patologia , Neoplasias do Timo/complicações , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/cirurgia , Aplasia Pura de Série Vermelha/complicações , Aplasia Pura de Série Vermelha/patologiaRESUMO
Purpose: Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature. Methods: The type I IFN signature was measured in patients' whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature. Results: A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling. Conclusions: Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.
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Interferon Tipo I , Inibidores de Janus Quinases , Biomarcadores , Humanos , Interferon Tipo I/genética , Japão , Complexo de Endopeptidases do Proteassoma/genética , Estudos RetrospectivosRESUMO
BACKGROUND/AIMS: Very early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed in patients younger than 6 years, is a challenge for pediatric gastroenterologists. Although there have been reports regarding VEO-IBD in Western countries, those in Asia are still lacking. This study aimed to investigate the clinical features of Japanese VEO-IBD patients. METHODS: Patients with VEO-IBD diagnosed between 2006 and 2019 were evaluated retrospectively. The disease phenotypes were classified into ulcerative colitis type (UC-type) and Crohn's disease type (CD-type), and the clinical features and courses were compared between the phenotypes. RESULTS: Overall, 54 VEO-IBD patients (19 patients with UC-type and 35 patients with CD-type) were evaluated. The median age at onset was 18 months. One patient had severe combined immunodeficiency (SCID), and 9 patients had monogenic IBD. Monogenic IBD was more prevalent in the CD-type patients with perianal disease (CD-type (PD)). The age at onset was significantly lower in the CD-type group (P<0.05). The most common initial symptom was bloody stools (70%), followed by diarrhea (63%), weight loss (24%), fever (20%), and perianal disease (20%). Excluding patients with SCID and monogenic IBD, 23 out of 44 patients (52%) required biologics. The biologics were switched in 11 out of 44 patients (25%), and the majority of these patients (82%) were in the CD-type group. Overall, 9 patients (20%) required intestinal resection or ostomy placement. CONCLUSIONS: CD-type tends to occur at an earlier age, and monogenic IBD occurs significantly more frequently in CD-type (PD). Disease severity and treatment should be individualized, owing to the disease heterogeneity.
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Vedolizumab, an immunosuppressive drug that acts locally on the gastrointestinal tract, is mainly used for the treatment of inflammatory bowel disease, and has been reported to be effective against gastrointestinal acute graft-versus-host disease (GI-aGVHD) in adults. However, there is insufficient evidence for pediatric GI-aGVHD. We used vedolizumab to treat three cases of GI-aGVHD in patients aged 1.5-4.4 years. It was significantly effective in two patients and did not cause serious side effects in any patient. Vedolizumab might be effective and safe for pediatric GI-aGVHD refractory to other treatments, but this must be confirmed in future studies.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Aguda , Anticorpos Monoclonais Humanizados , Pré-Escolar , Trato Gastrointestinal , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Esteroides/uso terapêuticoRESUMO
Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22phox, NCF1, encoding p47phox, NCF2, encoding p67phox and NCF4, encoding p40phox. This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b558 chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91phox (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article.
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Doença Granulomatosa Crônica/genética , Mutação , Humanos , NADPH Oxidases/genéticaRESUMO
Hepcidin is an iron metabolism inhibitor that increases with chronic inflammation. However, it is unclear whether hepcidin indicates acute inflammatory response in Kawasaki disease (KD), which is an acute systemic vasculitis. In this study, we examined the serum hepcidin levels before and after intravenous immunoglobulin (IVIG) therapy in responders and non-responders to IVIG. This was a pilot prospective observational study at a university hospital. All KD patients were initially administered 2 g/kg of IVIG as the first IVIG therapy (IVIG1) on day 4 to day 7 after onset. Non-responders to IVIG1 were additionally treated with the second IVIG therapy (IVIG2) using 1 g/kg of IVIG. All KD patients were also treated with aspirin. We measured serum hepcidin levels before IVIG1, after IVIG1, and during the recovery period. Among the 31 KD patients, 21 patients and 5 patients improved after IVIG1 (responders-1) and IVIG2 (responders-2), respectively, but 5 patients did not improve after IVIG2 (non-responders). Serum hepcidin levels before IVIG1 were significantly higher in responders-2 (159.0 ng/mL) and non-responders (240.0 ng/mL), compared to responders-1 (103.0 ng/mL). Serum hepcidin levels after IVIG1 were significantly higher in non-responders (163.0 ng/mL), compared to responders-1 (43.4 ng/mL) and responders-2 (54.6 ng/mL). Serum hepcidin levels of non-responders to IVIG were higher before IVIG and remained high after IVIG. Erythrocyte-related indexes, including hemoglobin, reticulocytes, iron, and ferritin before IVIG1, were not significantly different among the three groups. Serum hepcidin might be excessively upregulated by acute inflammation in KD patients having resistance to IVIG. Key Points ⢠Hepcidin, an iron metabolism inhibitor in chronic inflammation, increases during the acute phase of Kawasaki disease. ⢠Hepcidin levels before IVIG of non-responders were higher than those of responders in Kawasaki disease. ⢠Hepcidin might be excessively upregulated by acute inflammation in KD patients having resistance to IVIG.
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Imunoglobulinas Intravenosas , Síndrome de Linfonodos Mucocutâneos , Hepcidinas , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Inflamação , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Regulação para CimaRESUMO
Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe bacterial and fungal infections. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide and subsequently formed other reactive oxygen species (ROS) are instrumental in killing phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients in Europe and in about 20% in countries with a high ratio of parental consanguinity. This article lists all mutations identified in CYBB and should therefore help in genetic counseling of X-CGD patients' families. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of disease-causing mutations. In addition, we also include some mutations in G6PD, the gene on the X chromosome that encodes glucose-6-phosphate dehydrogenase, because inactivity of this enzyme may lead to shortage of NADPH and thus to insufficient activity of NADPH oxidase. Severe G6PD deficiency can induce CGD-like symptoms.