Case Report: Rotavirus Vaccination and Severe Combined Immunodeficiency in Japan.

Severe combined immunodeficiency (SCID) is an inborn error of immunity that occurs in approximately 1 in 50,000 births, mainly due to impaired lymphocyte differentiation. Without curative treatment, such as hematopoietic cell transplantation (HCT) or gene therapy, severe infection in the first year of life could make this condition fatal. The results of HCT are poor when patients have active infections, thus requiring early diagnosis before onset of infection. In five cases of SCID diagnosed in Japan, the oral rotavirus vaccine had been administered before diagnosis. In this study, we demonstrated that the rotavirus from their stools was a vaccine-derived strain. In some cases, severe gastroenteritis triggered the diagnosis of SCID. However, newborn screening for SCID is available before the first rotavirus vaccination using assays for the detection of T-cell receptor excision circles (TRECs). Therefore, to improve the prognosis of patients with SCID in Japan, we should establish a screening system of TRECs for newborns throughout Japan.

Leucine-rich alpha-2-glycoprotein 1 and angiotensinogen as diagnostic biomarkers for Kawasaki disease.

OBJECTIVE: Kawasaki disease (KD) is a systemic vasculitis in childhood that can lead to coronary artery lesions (CALs). Although early diagnosis and treatment is important for preventing KD patients from development of CALs, diagnosis depends on the clinical features of KD. We studied the usefulness of leucine-rich alpha-2-glycoprotein 1 (LRG1) and angiotensinogen (AGT), previously reported as KD-related proteins, for KD diagnosis and estimation of intravenous immunoglobulin (IVIG) efficacy. METHODS: We undertook a prospective cohort study with patients having two or more KD symptoms in multiple centers in Japan, between July 2017 and February 2019. RESULTS: Two hundred forty-two patients were included. In multivariable analysis, one unit increase in LRG1 was associated with higher odds of KD diagnosis (Odds ratio [OR] 1.02 [95% confidence interval (CI) 1.001-1.03]). Double-positivity for AGT (≥ 26 µg/mL) and LRG1 (≥ 123.5 µg/mL) was an independent biomarker for KD diagnosis in both the total cohort and the subgroup of patients with two to four KD symptoms (OR 5.01 [95% CI 1.86-13.50] and 3.71 [95% CI 1.23-11.16], respectively). There was no association between LRG1/AGT and IVIG efficacy. CONCLUSION: Double-positivity for LRG1 and AGT is an biomarker for KD diagnosis, especially useful in diagnosing incomplete KD from non-KD. Future studies with larger cohorts should seek to determine whether LRG1 and AGT are valuable as definitive data referred at the diagnosis of KD and for estimating the risk of CALs.

Association between Immunoglobulin M and Steroid Resistance in Children with Nephrotic Syndrome: A Retrospective Multicenter Study in Japan.

Background: The prognosis of steroid-resistant nephrotic syndrome (SRNS) in children is poorer than steroid-sensitive cases. Diagnosis of SRNS is made after observing the response to the initial 4-week corticosteroid therapy, which might be accompanied by side effects. However, predictive indicators at initial diagnosis remain unknown. We aimed to investigate whether selectivity index (SI) and other indicators at initial diagnosis-for example, serum IgM and total serum protein-albumin ratio (TA ratio, total serum protein level over albumin level)-can predict SRNS. Methods: A total of 80 children were enrolled from seven hospitals in Japan between January 2008 and December 2019 (mean age, 4.7 years; 65% male). Of the children enrolled, 13 (16%, M/F=5:8) had been diagnosed as steroid resistant after initial treatment with steroids. The association between serum IgM (tertile categories: low, 24-133; middle, 134-169; and high, 169.1-510 mg/dl), SI (<0.2 or ≥0.2), and TA ratio (tertile categories: low, 1.8-2.6; middle, 2.62-3.75; and high, 3.8-15.3) at initial diagnosis and steroid resistance was evaluated with logistic regression, adjusting for age and sex. Results: Low levels of serum IgM were significantly associated with steroid resistance (adjusted odds ratio, 6.94; 95% CI, 1.12 to 43.11). TA ratio and SI were not significantly associated with steroid resistance. Conclusions: Low levels of serum IgM at initial diagnosis might predict steroid resistance among Japanese children with idiopathic nephrotic syndrome.

New-onset diabetes after renal transplantation in a patient with a novel HNF1B mutation.

CAKUT are the most frequent causes of ESRD in children. Mutations in the gene encoding HNF1B, a transcription factor involved in organ development and maintenance, cause a multisystem disorder that includes CAKUT, diabetes, and liver dysfunction. Here, we describe the case of a patient with renal hypodysplasia who developed NODAT presenting with liver dysfunction. The NODAT was initially thought to be steroid and FK related. However, based on the patient's clinical features, including renal hypodysplasia and recurrent elevations of transaminase, screening for an HNF1B mutation was performed. Direct sequencing identified a novel splicing mutation of HNF1B, designated c.344 + 2T>C. Because CAKUT is the leading cause of ESRD in children and HNF1B mutations can cause both renal hypodysplasia and diabetes, HNF1B mutations may account for a portion of the cases of NODAT in pediatric patients who have undergone kidney transplantation. NODAT is a serious and major complication of solid organ transplantation and is associated with reduced graft survival. Therefore, for the appropriate management of kidney transplantation, screening for HNF1B mutations should be considered in pediatric patients with transplants caused by CAKUT who develop NODAT and show extra-renal symptoms.

[Case of a 14-year-old boy with chronic tubulointerstitial nephritis first diagnosed as acute focal bacterial nephritis].

A 14-year-old boy was admitted to a general hospital because of prolonged fever of unknown origin. After Enterococcus feacalis was detected from his urine and abdominal contrast enhanced computed tomography and 99m-Tc dimercaptosuccinic acid scintigram showed multiple focal defects, he was diagnosed as acute focal bacterial nephritis (AFBN). His condition recovered as a result of Ampicillin (ABPC)and Cefotaxime infusion. There was no specific finding in voiding cystography. Six months later, his fever recurred and he was diagnosed as refractory AFBN because Enterococcus feacalis was detected in his urine again. He was treated with ABPC and Meropenem (MEPM) infusion, but the fever persisted and his renal function deteriorated. He was transferred to our hospital for intensive treatment. On admission, blood examination showed findings of inflammation (WBC 14,400/µL, CRP 3.7 mg/dL, erythrocyte sedimentation rate : 69 mm/h, IgG : 2,107 mg/dL) and renal impairment (Cr : 1.8 mg/dL, cystatin C : 2.0 mg/L). Although neither pyuria nor pathogenic bacteria were detected in his urine, Enterococcusfeacalis was detected at the hospital where he had been treated previously, hence we started treatment for AFBN with ABPC, MEPM, Levofloxacin, then Linezolid. However, the fever persisted and his renal function deteriorated (Cr 2.0 mg/dL). Kidney-specific accumulation was found in Ga scintigraphy, which suggested chronic inflammation. Clinical course and laboratory findings showed no symptoms of bacterial, viral, fungal, or tuberculous infections nor collagen disease. Although renal biopsy revealed no glomerular abnormality, tubulointerstitial edema, fibrosis and tubulitis were observed. Rupture of the tubular basal membrane and non-caseating granulomas also existed. Pathological findings did not match those of renal sarcoidosis. Ophthalmological screening negated the existence of tubulointerstitial nephritis with uveitis syndrome. After methylprednisolone pulse therapy, the fever recovered immediately and his renal impairment imroved gradually (Cr 1.49 mg/dL). He continues to undergo treatment as an outpatient. Although tubulointerstitial nephritis is rare in children, some patients have a poor renal prognosis. It is important to determine the existence of tubulointerstitial nephritis on treating a patient with renal impairment.