Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and fatal autosomal recessive immune ... more Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and fatal autosomal recessive immune disorder characterized by uncontrolled activation of T and NK cells, macrophages, and overproduction of inflammatory cytokines. Early hematopoietic cell transplantation (HCT) is required for long-term survival. Current therapy is based on the HLH-94/2004 protocol, but is insufficient to fully control disease activity. This case report describes an infant with FHL type 3 who, despite initial therapy with dexamethasone and etoposide, showed aberrant cytokine levels, including interleukin-18 (IL-18), chemokine ligand 9 (CXCL9), soluble interleukin-2 receptor (sIL-2R), and soluble tumor necrosis factor receptor type II (sTNF-RII). The Janus kinase inhibitor ruxolitinib was therefore coadministered. The patient was treated with dose-adjusted ruxolitinib guided by cytokine profiles, and was successfully prepared for HCT. The results demonstrate the effectiveness and safety of dose-adjusted rux...
Trisomy 21 is sometimes complicated by congenital heart disease; however, comorbid type I diabete... more Trisomy 21 is sometimes complicated by congenital heart disease; however, comorbid type I diabetes mellitus and diseases involving autoantibodies such as Hashimoto's disease and Graves' disease are not uncommon. In contrast, autoinflammatory diseases such as Kawasaki disease and systemic juvenile idiopathic arthritis are rarely observed. We report a rare case of trisomy 21 with systemic juvenile idiopathic arthritis that responded well to the first course of methylprednisolone pulse therapy, but flared up and was complicated by macrophage activation syndrome (MAS). Subsequent methylprednisolone pulse therapy and cyclosporine resolved this condition. Cytokine analyses at several time points during the clinical course revealed that interleukin-18, interleukin-6, and chemokine ligand 9 levels were elevated even MAS onset in the patient with trisomy 21 once the clinical symptoms seemed to have settled down. Thus, in the future, early analysis of cytokine profiles should be performed for risk assessments of MAS and for determining the treatment intensity, even T21 patients.
Idiopathic systemic capillary leak syndrome, or Clarkson disease, is a life-threatening condition... more Idiopathic systemic capillary leak syndrome, or Clarkson disease, is a life-threatening condition characterized by repeated episodes of an acute increase in vascular permeability. This results in loss of protein-rich fluid into the interstitial compartment. Although the pathophysiology remains unknown, Xie et al. identified angiopoietin-2 (Ang-2) as one of the putative permeability mediators in adult patients. They found that serum Ang-2 levels were only elevated in episodic sera and that antibody-based inhibition of Ang-2 counteracted permeability induced by episodic sera. Clarkson disease primarily affects middle-aged adults, and only 32 pediatric cases (≤18 years) have been reported, including one Japanese girl. We present an infant with Clarkson disease who had a fatal outcome along with measurement of serum angiopoietin-1 (Ang-1) and Ang-2 levels. An 11-month-old boy presented with vomiting, diarrhea, and fever, which developed 1 day before admission. His critical condition, including disturbed consciousness, tachypnea (72 breaths/min), tachycardia (212 bpm), and hypotension (systolic blood pressure 70 mmHg), resulted in admission to intensive care. He was born prematurely, with a gestational age of 35 weeks and 3 days, and his birthweight was 2,100 g. His past medical history was remarkable. He had been treated for a milk allergy with an elemental diet. In addition, mild thrombocytopenia of unknown etiology, which did not require any specific treatment had been also noted. On admission, his weight was 6,960 g (7,710 g 1 week previously) and body temperature was 37.8 °C. He appeared pale and drowsy. The capillary refilling time was delayed (3 s). A complete blood count showed leukocytosis (white blood cell count: 2.3 9 10/lL), anemia (hemoglobin: 8.6 g/ dL), and thrombocytopenia (platelets: 5.3 9 10/lL). Abnormal renal function (serum creatinine: 0.91 mg/dL) and altered serum electrolytes (Na: 175 mEq/L, Cl: 145 mEq/L) were found. A slightly elevated C-reactive protein level (0.5 mg/ dL) was also observed. Cultures of blood and stool detected no significant pathogens. Rotavirus antigen could not be detected in his feces. From these findings, the diagnosis of severe hypernatremic dehydration due to acute gastroenteritis was made and rapid intravenous administration of saline (0.5 L/3 h) was performed. However, systolic blood pressure did not rise but dropped to 50 mmHg, and oliguria (0.4 mL/kg/h) persisted. Anasarca developed along with hemoconcentration (hemoglobin level rose from 8.6 to 10.7 g/dL) and hypoproteinemia (serum protein level dropped from 7.1 to 4.3 g/ dL). The diagnosis was then changed to Clarkson disease and inotropic agents with blood products, including packed red blood cells, platelets, fresh-frozen plasma, and albumin, were repeatedly administered. Intravenous immunoglobulin, theophylline, and corticosteroid were also infused. However, the patient did not respond and died of fatal ventricular fibrillation on the eighth day of illness. His maximum pediatric sequential organ failure assessment score during admission had been as high as 20 indicating a high risk of mortality . Subsequently, Ang-1 and Ang-2 levels were determined using pooled sera by commercial enzyme-linked immunosorbent assays (R&D Systems, Inc., Minneapolis, MN, USA). Ang-1 levels were decreased, while Ang-2 levels were extremely elevated on the 5th and 7th days of illness. Consequently, the Ang-2/Ang-1 ratio was extraordinarily high (Table 1). To the best of our knowledge, this is the second and youngest Japanese pediatric case of Clarkson disease. Importantly, this is the first report of dysregulation of Ang-1 and Ang-2 levels in a pediatric case. Ang-1 and Ang-2 are members of a family of vascular growth factors that play opposing physiological roles in endothelial activation and dysfunction. Ang-1 binding promotes vascular growth and stability, suppresses inflammation, and promotes endothelial cell survival. Ang-2 binding promotes vascular activation, vascular inflammation, microvascular leakage, and neoangiogenesis. Therefore, Ang-2 and the Ang-2/Ang-1 ratio are markers of disease severity in sepsis, acute lung injury, acute respiratory distress syndrome, febrile neutropenia, malaria, Correspondence: Kazunari Kaneko, MD PhD, Department of Pediatrics, Kansai Medical University, 2-5-l Shin-machi, Hirakata-shi, Osaka 573 1010, Japan. Email: [email protected] Received 30 April 2020; revised 29 May 2020; accepted 8 June 2020. doi: 10.1111/ped.14345
A 12-year-old girl with hematuria and proteinuria in school urinary screening was referred to us.... more A 12-year-old girl with hematuria and proteinuria in school urinary screening was referred to us. Physical examination revealed no extrarenal lesions. Laboratory findings revealed impaired renal function and the elevation of serum MPO-ANCA (anti-neutrophil cytoplasmic antibody) level. Kidney biopsy showed necrotizing crescentic glomerulonephritis. From these findings, ANCA associated nephritis was made. Early remission was achieved with the combination treatment of methylprednisolone pulse therapy and rituximab. Long term remission without severe complications has been achieved with the maintenance treatment with the combination of prednisolone and azathioprine. Rituximab might be useful to achieve early remission in ANCA associated nephritis.
BACKGROUND: To evaluate the apoptosis inhibitor of macrophage (AIM) deposition patterns on the ki... more BACKGROUND: To evaluate the apoptosis inhibitor of macrophage (AIM) deposition patterns on the kidneys of children with IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) and to investigate the clinical usefulness of serum and/or urinary AIM levels as biomarkers for the disease activity. METHODS: Immunohistochemical study was performed in the kidneys of 37 patients with IgAN and 10 patients with HSPN. Serum and urinary AIM levels in the patients and 20 healthy controls (HCs) were quantified by enzyme-linked immunosorbent assay. The results were compared with clinical features. RESULTS: In patients with IgAN and HSPN, AIM expression was observed in various areas, including the glomerular mesangial and capillary areas, the proximal and distal tubular epithelial cells, and on infiltrating macrophages in the glomeruli and interstitial areas. Serum and urinary AIM levels were significantly elevated in these patients compared with the HCs. Urinary AIM levels were positively correlated with the histological severity and degree of proteinuria and hematuria as well as urinary β2 microglobulin and urinary N-acetyl-β-D-glucosaminidase levels. CONCLUSIONS: AIM plays an important role in the pathogenesis of IgAN and HSPN. Urinary AIM levels can potentially reflect active renal inflammation in these diseases and may represent a useful biomarker for disease activity.
This study was aimed at investigating the clinical significance of serum galactose-deficient IgA1... more This study was aimed at investigating the clinical significance of serum galactose-deficient IgA1 (Gd-IgA1) levels measured by a novel lectin-independent enzyme-linked immunosorbent assay (ELISA) using an anti-Gd-IgA1 monoclonal antibody (KM55) as a disease-specific biomarker for IgA nephropathy (IgAN) in children. Thirty-three children with IgAN, 40 with non-IgA glomerular diseases, and 38 age-matched healthy controls (HCs) were enrolled. Serum Gd-IgA1 levels were quantified by ELISA using KM55. Results were statistically compared with clinical features and pathological findings of IgAN. Serum Gd-IgA1 levels were significantly elevated in children with IgAN compared with children with non-IgA glomerular diseases and HCs. Serum Gd-IgA1 levels in children with IgAN were positively correlated with serum total IgA levels. However, the serum Gd-IgA1/total IgA ratio (Gd-IgA1/IgA) was also significantly elevated in children with IgAN. Serum Gd-IgA1 levels in children with IgAN increased i...
Please cite this article as: M. Takakura, M. Shimizu, H. Irabu, et al., Comparison of serum bioma... more Please cite this article as: M. Takakura, M. Shimizu, H. Irabu, et al., Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis, Clinical Immunology,
The present study aimed to assess the kinetics of cytokine release and compare the accuracy of se... more The present study aimed to assess the kinetics of cytokine release and compare the accuracy of serum biomarkers for the diagnosis of macrophage activation syndrome (MAS) associated with Kawasaki disease (KD). Serum neopterin, interleukin (IL)-18, IL-6 and soluble tumour necrosis factor receptor type I (sTNFR-I) and sTNFR-II levels were determined using enzyme-linked immunosorbent assay in 78 patients with KD, including five with MAS. Results were compared to the clinical features of MAS. Serum neopterin, IL-18, sTNFR-II levels and sTNFR-II/I ratio were significantly elevated in KD patients with MAS compared to those in the acute phase. Receiver operating characteristic curve analysis revealed areas under the curve and cutoff values of neopterin, IL-18, sTNFR-II levels and sTNFR-II/I ratio were 0.9750/30.0 nmol/L, 0.9813/1165 ng/mL, 0.9969/16,600 pg/mL and 0.9875/4.475, respectively. Serum sTNFR-II levels correlated positively with disease activity. These findings indicate that overproduction of interferon (IFN)-γ and TNF-α reflected by increased serum levels of neopterin and sTNFR-II are closely associated with the pathogenesis of MAS associated with KD. Serum sTNFR-II levels might be a useful marker to diagnose the transition to MAS.
Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and fatal autosomal recessive immune ... more Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and fatal autosomal recessive immune disorder characterized by uncontrolled activation of T and NK cells, macrophages, and overproduction of inflammatory cytokines. Early hematopoietic cell transplantation (HCT) is required for long-term survival. Current therapy is based on the HLH-94/2004 protocol, but is insufficient to fully control disease activity. This case report describes an infant with FHL type 3 who, despite initial therapy with dexamethasone and etoposide, showed aberrant cytokine levels, including interleukin-18 (IL-18), chemokine ligand 9 (CXCL9), soluble interleukin-2 receptor (sIL-2R), and soluble tumor necrosis factor receptor type II (sTNF-RII). The Janus kinase inhibitor ruxolitinib was therefore coadministered. The patient was treated with dose-adjusted ruxolitinib guided by cytokine profiles, and was successfully prepared for HCT. The results demonstrate the effectiveness and safety of dose-adjusted rux...
Trisomy 21 is sometimes complicated by congenital heart disease; however, comorbid type I diabete... more Trisomy 21 is sometimes complicated by congenital heart disease; however, comorbid type I diabetes mellitus and diseases involving autoantibodies such as Hashimoto's disease and Graves' disease are not uncommon. In contrast, autoinflammatory diseases such as Kawasaki disease and systemic juvenile idiopathic arthritis are rarely observed. We report a rare case of trisomy 21 with systemic juvenile idiopathic arthritis that responded well to the first course of methylprednisolone pulse therapy, but flared up and was complicated by macrophage activation syndrome (MAS). Subsequent methylprednisolone pulse therapy and cyclosporine resolved this condition. Cytokine analyses at several time points during the clinical course revealed that interleukin-18, interleukin-6, and chemokine ligand 9 levels were elevated even MAS onset in the patient with trisomy 21 once the clinical symptoms seemed to have settled down. Thus, in the future, early analysis of cytokine profiles should be performed for risk assessments of MAS and for determining the treatment intensity, even T21 patients.
Idiopathic systemic capillary leak syndrome, or Clarkson disease, is a life-threatening condition... more Idiopathic systemic capillary leak syndrome, or Clarkson disease, is a life-threatening condition characterized by repeated episodes of an acute increase in vascular permeability. This results in loss of protein-rich fluid into the interstitial compartment. Although the pathophysiology remains unknown, Xie et al. identified angiopoietin-2 (Ang-2) as one of the putative permeability mediators in adult patients. They found that serum Ang-2 levels were only elevated in episodic sera and that antibody-based inhibition of Ang-2 counteracted permeability induced by episodic sera. Clarkson disease primarily affects middle-aged adults, and only 32 pediatric cases (≤18 years) have been reported, including one Japanese girl. We present an infant with Clarkson disease who had a fatal outcome along with measurement of serum angiopoietin-1 (Ang-1) and Ang-2 levels. An 11-month-old boy presented with vomiting, diarrhea, and fever, which developed 1 day before admission. His critical condition, including disturbed consciousness, tachypnea (72 breaths/min), tachycardia (212 bpm), and hypotension (systolic blood pressure 70 mmHg), resulted in admission to intensive care. He was born prematurely, with a gestational age of 35 weeks and 3 days, and his birthweight was 2,100 g. His past medical history was remarkable. He had been treated for a milk allergy with an elemental diet. In addition, mild thrombocytopenia of unknown etiology, which did not require any specific treatment had been also noted. On admission, his weight was 6,960 g (7,710 g 1 week previously) and body temperature was 37.8 °C. He appeared pale and drowsy. The capillary refilling time was delayed (3 s). A complete blood count showed leukocytosis (white blood cell count: 2.3 9 10/lL), anemia (hemoglobin: 8.6 g/ dL), and thrombocytopenia (platelets: 5.3 9 10/lL). Abnormal renal function (serum creatinine: 0.91 mg/dL) and altered serum electrolytes (Na: 175 mEq/L, Cl: 145 mEq/L) were found. A slightly elevated C-reactive protein level (0.5 mg/ dL) was also observed. Cultures of blood and stool detected no significant pathogens. Rotavirus antigen could not be detected in his feces. From these findings, the diagnosis of severe hypernatremic dehydration due to acute gastroenteritis was made and rapid intravenous administration of saline (0.5 L/3 h) was performed. However, systolic blood pressure did not rise but dropped to 50 mmHg, and oliguria (0.4 mL/kg/h) persisted. Anasarca developed along with hemoconcentration (hemoglobin level rose from 8.6 to 10.7 g/dL) and hypoproteinemia (serum protein level dropped from 7.1 to 4.3 g/ dL). The diagnosis was then changed to Clarkson disease and inotropic agents with blood products, including packed red blood cells, platelets, fresh-frozen plasma, and albumin, were repeatedly administered. Intravenous immunoglobulin, theophylline, and corticosteroid were also infused. However, the patient did not respond and died of fatal ventricular fibrillation on the eighth day of illness. His maximum pediatric sequential organ failure assessment score during admission had been as high as 20 indicating a high risk of mortality . Subsequently, Ang-1 and Ang-2 levels were determined using pooled sera by commercial enzyme-linked immunosorbent assays (R&D Systems, Inc., Minneapolis, MN, USA). Ang-1 levels were decreased, while Ang-2 levels were extremely elevated on the 5th and 7th days of illness. Consequently, the Ang-2/Ang-1 ratio was extraordinarily high (Table 1). To the best of our knowledge, this is the second and youngest Japanese pediatric case of Clarkson disease. Importantly, this is the first report of dysregulation of Ang-1 and Ang-2 levels in a pediatric case. Ang-1 and Ang-2 are members of a family of vascular growth factors that play opposing physiological roles in endothelial activation and dysfunction. Ang-1 binding promotes vascular growth and stability, suppresses inflammation, and promotes endothelial cell survival. Ang-2 binding promotes vascular activation, vascular inflammation, microvascular leakage, and neoangiogenesis. Therefore, Ang-2 and the Ang-2/Ang-1 ratio are markers of disease severity in sepsis, acute lung injury, acute respiratory distress syndrome, febrile neutropenia, malaria, Correspondence: Kazunari Kaneko, MD PhD, Department of Pediatrics, Kansai Medical University, 2-5-l Shin-machi, Hirakata-shi, Osaka 573 1010, Japan. Email: [email protected] Received 30 April 2020; revised 29 May 2020; accepted 8 June 2020. doi: 10.1111/ped.14345
A 12-year-old girl with hematuria and proteinuria in school urinary screening was referred to us.... more A 12-year-old girl with hematuria and proteinuria in school urinary screening was referred to us. Physical examination revealed no extrarenal lesions. Laboratory findings revealed impaired renal function and the elevation of serum MPO-ANCA (anti-neutrophil cytoplasmic antibody) level. Kidney biopsy showed necrotizing crescentic glomerulonephritis. From these findings, ANCA associated nephritis was made. Early remission was achieved with the combination treatment of methylprednisolone pulse therapy and rituximab. Long term remission without severe complications has been achieved with the maintenance treatment with the combination of prednisolone and azathioprine. Rituximab might be useful to achieve early remission in ANCA associated nephritis.
BACKGROUND: To evaluate the apoptosis inhibitor of macrophage (AIM) deposition patterns on the ki... more BACKGROUND: To evaluate the apoptosis inhibitor of macrophage (AIM) deposition patterns on the kidneys of children with IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) and to investigate the clinical usefulness of serum and/or urinary AIM levels as biomarkers for the disease activity. METHODS: Immunohistochemical study was performed in the kidneys of 37 patients with IgAN and 10 patients with HSPN. Serum and urinary AIM levels in the patients and 20 healthy controls (HCs) were quantified by enzyme-linked immunosorbent assay. The results were compared with clinical features. RESULTS: In patients with IgAN and HSPN, AIM expression was observed in various areas, including the glomerular mesangial and capillary areas, the proximal and distal tubular epithelial cells, and on infiltrating macrophages in the glomeruli and interstitial areas. Serum and urinary AIM levels were significantly elevated in these patients compared with the HCs. Urinary AIM levels were positively correlated with the histological severity and degree of proteinuria and hematuria as well as urinary β2 microglobulin and urinary N-acetyl-β-D-glucosaminidase levels. CONCLUSIONS: AIM plays an important role in the pathogenesis of IgAN and HSPN. Urinary AIM levels can potentially reflect active renal inflammation in these diseases and may represent a useful biomarker for disease activity.
This study was aimed at investigating the clinical significance of serum galactose-deficient IgA1... more This study was aimed at investigating the clinical significance of serum galactose-deficient IgA1 (Gd-IgA1) levels measured by a novel lectin-independent enzyme-linked immunosorbent assay (ELISA) using an anti-Gd-IgA1 monoclonal antibody (KM55) as a disease-specific biomarker for IgA nephropathy (IgAN) in children. Thirty-three children with IgAN, 40 with non-IgA glomerular diseases, and 38 age-matched healthy controls (HCs) were enrolled. Serum Gd-IgA1 levels were quantified by ELISA using KM55. Results were statistically compared with clinical features and pathological findings of IgAN. Serum Gd-IgA1 levels were significantly elevated in children with IgAN compared with children with non-IgA glomerular diseases and HCs. Serum Gd-IgA1 levels in children with IgAN were positively correlated with serum total IgA levels. However, the serum Gd-IgA1/total IgA ratio (Gd-IgA1/IgA) was also significantly elevated in children with IgAN. Serum Gd-IgA1 levels in children with IgAN increased i...
Please cite this article as: M. Takakura, M. Shimizu, H. Irabu, et al., Comparison of serum bioma... more Please cite this article as: M. Takakura, M. Shimizu, H. Irabu, et al., Comparison of serum biomarkers for the diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis, Clinical Immunology,
The present study aimed to assess the kinetics of cytokine release and compare the accuracy of se... more The present study aimed to assess the kinetics of cytokine release and compare the accuracy of serum biomarkers for the diagnosis of macrophage activation syndrome (MAS) associated with Kawasaki disease (KD). Serum neopterin, interleukin (IL)-18, IL-6 and soluble tumour necrosis factor receptor type I (sTNFR-I) and sTNFR-II levels were determined using enzyme-linked immunosorbent assay in 78 patients with KD, including five with MAS. Results were compared to the clinical features of MAS. Serum neopterin, IL-18, sTNFR-II levels and sTNFR-II/I ratio were significantly elevated in KD patients with MAS compared to those in the acute phase. Receiver operating characteristic curve analysis revealed areas under the curve and cutoff values of neopterin, IL-18, sTNFR-II levels and sTNFR-II/I ratio were 0.9750/30.0 nmol/L, 0.9813/1165 ng/mL, 0.9969/16,600 pg/mL and 0.9875/4.475, respectively. Serum sTNFR-II levels correlated positively with disease activity. These findings indicate that overproduction of interferon (IFN)-γ and TNF-α reflected by increased serum levels of neopterin and sTNFR-II are closely associated with the pathogenesis of MAS associated with KD. Serum sTNFR-II levels might be a useful marker to diagnose the transition to MAS.
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