Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease.

PURPOSE: Diarrhea lasting longer than 14 days which fails to respond to conventional management is defined as severe and protracted diarrhea and might overlap with inflammatory bowel disease (IBD). METHODS: The prevalence, associated pathogens, and prognosis of severe and protracted diarrhea without IBD (SD) and with monogenetic IBD (mono-IBD) in primary immunodeficiency patients (PID) were investigated in Taiwan. RESULTS: A total of 301 patients were enrolled between 2003 and 2022, with predominantly pediatric-onset PID. Of these, 24 PID patients developed the SD phenotype before prophylactic treatment, including Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG1 (one each), CVID (two), and SCID (one) without identified mutations. The most detectable pathogens were pseudomonas and salmonella (six each), and all patients improved after approximately 2 weeks of antibiotic and/or IVIG treatments. Six (25.0%) mortalities without HSCT implementation were due to respiratory failure from interstitial pneumonia (3 SCID and 1 CGD), intracranial hemorrhage (WAS), and lymphoma (HIGM). In the mono-IBD group, seventeen patients with mutant TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), LRBA (1), TTC37 (3), IL10RA (1), STAT1 (1), ZAP70 (1), PIK3CD (1), and PIK3R1 (1) genes failed to respond to aggressive treatments. Nine mono-IBD patients with TTC7A (2), FOXP3 (2), NEMO (2), XIAP (2), and LRBA (1) mutations were fatal in the absence of HSCT. The mono-IBD group had a significantly earlier age of diarrhea onset (1.7 vs 33.3 months, p = 0.0056), a longer TPN duration (34.2 vs 7.0 months, p < 0.0001), a shorter follow-up period (41.6 vs 132.6 months, p = 0.007), and a higher mortality rate (58.9 vs 25.0%, p = 0.012) compared with the SD group. CONCLUSION: When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.

Tight junction protein ZO-1 in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a form of systemic febrile vasculitis that is complicated with coronary artery lesions (CAL). The tight junctions that maintain the intestinal barrier also play a role in systemic inflammatory diseases. Serum zonula occludens-1 (ZO-1) expression was found to be significantly lower in asthmatic patients, and another study reported that elevated systemic ZO-1 was positively correlated with inflammation in cirrhotic patients. A murine model of KD vasculitis demonstrated that vasculitis depended on intestinal barrier dysfunction, which is maintained by tight junctions. In this study, we aimed to investigate the role of the tight junction zonula occludens-1 (ZO-1) in the treatment response of intravenous immunoglobulin (IVIG) and the occurrence of CAL formation in KD patients. METHODS: We enrolled 40 KD patients, 12 healthy controls, and 12 febrile controls in this study. The serum levels of tight junction ZO-1 were determined by enzyme-linked immunosorbent assay. RESULTS: The serum ZO-1 level was higher in the fever control group but did not reach a statistical significance. KD patients who received a second dose of IVIG treatment due to initial IVIG unresponsiveness had a higher serum levels of tight junction ZO-1, but without statistical significance (2.15 ± 0.18 vs. 2.69 ± 0.31 ng/mL, p = 0.058). KD patients who developed a CAL demonstrated a significant lower serum tight junction ZO-1 levels than KD without CAL formation (1.89 ± 0.16 vs. 2.39 ± 0.15 ng/mL, p = 0.027). After multiple logistic regression analysis, ZO-1 levels [(95% confidence interval (CI): 0.058 ~ 0.941, odds ratio (OR) = 0.235, p = 0.041)] showed as the risk factor for CAL formation. CONCLUSION: Serum levels of tight junction ZO-1 levels were lower in KD patients than fever controls and associated with CAL formation.

Overlap Syndrome Involving Systemic Lupus Erythematosus and Autoimmune Hepatitis in Children: A Case Report and Literature Review.

Background: The diagnosis of overlap syndrome involving systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) is not easily established because of its similar clinical presentations and biochemical features to those of lupus hepatitis. The term overlap syndrome is usually used in the context of overlap of autoimmune hepatitis with PSC (primary sclerosing cholangitis) or PBC (primary biliary cholangitis). Few cases of AIH complicated by SLE have been reported in the literature, and the condition is even rarer in childhood. Case presentation: Here we report the case of a 16-year-old girl with SLE who initially presented with autoimmune (cholestatic) hepatitis. According to American Association for the Study of Liver Diseases practice guidelines, the diagnosis was made based on aggregated scores including female (+2); ALP:AST (or ALT) ratio <1.5(+2); elevated serum IgG level(+3); ANA > 1:80 (+3); negative hepatitis viral markers and drug history (+3, +1); average alcohol intake <25 g/day (+2); and histological interface hepatitis features (+3). She then developed a malar rash, ANA positivity, anti-double-stranded DNA (anti-dsDNA) antibodies, and a low complement level. She met 4 of 17 Systemic Lupus International Collaborating Clinics classification criteria (1) for SLE. Our patient responded very well to corticosteroid at an initial dose of methylprednisolone 40 mg Q12H for 4 days tapering to 1 mg/kg/day according to liver function test results and bilirubin level. No relapse occurred during the 3-year follow-up course. Conclusions: Overlapping of SLE and AIH should be suspected when children with SLE have impaired liver function or AIH patients present with a malar or other skin rash. Liver biopsy plays an important role in establishing the differential diagnosis of SLE with liver impairment or overlap with AIH. The prompt diagnosis and adequate further treatment plans can improve disease outcomes.

Corrigendum: Overlap Syndrome Involving Systemic Lupus Erythematosus and Autoimmune Hepatitis in Children: A Case Report and Literature Review.

[This corrects the article DOI: 10.3389/fped.2019.00310.].

Postnatal high-fat diet sex-specifically exacerbates prenatal dexamethasone-induced hypertension: Mass spectrometry-based quantitative proteomic approach.

Hypertension can originate from pre- and post-natal insults. High-fat (HF) diet and prenatal dexamethasone (DEX) exposure are both involved in hypertension of developmental origins. We examined whether postnatal HF diet sex-specifically increases the vulnerability to prenatal DEX exposure-induced programmed hypertension in adult offspring. Additionally, we sought to identify candidate proteins involved in programmed hypertension through a mass spectrometry-based quantitative proteomic approach. Male and female offspring were studied separately: control, DEX, HF, and DEX + HF (n=8/group). Pregnant Sprague-Dawley rats received dexamethasone (0.1 mg/kg body weight) or vesicle from gestational day 16-22. Offspring received high-fat diet (D12331, Research Diets) or regular diet from weaning to 4 months of age. Rats were sacrificed at 4 months of age. We found that postnatal HF diet increased vulnerability of prenatal DEX-induced hypertension in male but not in female adult offspring. Additionally, HF and DEX elicited renal programming in a sex-specific fashion. In males, DEX + HF increased renal parvalbumin (PVALB) and carbonic anhydrase III (CA III) protein levels. While prenatal DEX down-regulated PVALB and CA III protein abundance in female offspring kidneys. Moreover, DEX + HF increased renal protein level of type 3 sodium hydrogen exchanger (NHE3) in males but not in females. In conclusion, postnatal HF diet and prenatal DEX exposure synergistically induced programmed hypertension in male-only offspring. DEX + HF induced sex-specific alterations of protein profiles in offspring kidneys. By identifying candidate proteins underlying sex-specific mechanisms, our results could lead to novel offspring sex-specific interventions to prevent hypertension induced by antenatal corticosteroids and postnatal HF intake in both sexes.