Fluorescence-Based Lateral Flow Immunoassay for Quantification of Infliximab: Analytical and Clinical Performance Evaluation.

BACKGROUND: Therapeutic drug monitoring of infliximab (IFX) can improve treatment outcomes; however, the temporal gap between drug concentration monitoring and subsequent availability restricts its practical application. To address this issue, an automated monitoring method, AFIAS IFX, was developed to rapidly and accurately analyze IFX concentration in blood. The analytical and clinical performances of this method were assessed to establish its clinical utility. METHODS: The analytical performance of AFIAS IFX was evaluated according to Clinical and Laboratory Standard Institute guidelines. For clinical validation, AFIAS IFX was compared with 3 established enzyme-linked immunosorbent assay kits (LISA TRACKER, RIDASCREEN, and ImmunoGuide) using 100 consecutive samples from 28 patients treated with IFX. Passing-Bablok regression and Bland-Altman analyses were performed to compare the methods. RESULTS: The detection and quantification limits of AFIAS IFX were 0.12 and 0.20 mcg/mL, respectively. Furthermore, AFIAS IFX analyzed samples within 10 minutes for concentrations up to 50 mcg/mL, exhibiting reproducibility (coefficient of variation [CV] ≤7.8%) and accuracy (recovery 98%-101%) with serum, plasma, and whole blood samples. Clinically, it exhibited a good correlation with the 3 established enzyme-linked immunosorbent assay kits. For patients treated with Remicade (IFX), the Passing-Bablok regression slope was 1.001-1.259, with a mean difference of -1.48 to 0.28 mcg/mL. For patients treated with CT-P13, the Passing-Bablok regression slope was 0.974-1.254, with a mean difference of -2.44 to 0.15 mcg/mL. CONCLUSIONS: AFIAS IFX, a novel fluorescence-based lateral flow assay, exhibited excellent performance in analyzing IFX trough levels and is a potentially powerful tool for therapeutic drug monitoring in clinical settings, with opportunities for further development.

Comparison of Ustekinumab Trough Concentrations Measured by 2 ELISA Kits and Evaluation of Clinical Response in Crohn's Disease.

BACKGROUND: Ustekinumab is a recently introduced biological agent for the treatment of Crohn's disease. The clinical use of the trough concentration of ustekinumab is not as standardized as that of infliximab. The authors aimed to introduce a measurement method and the results of trough concentrations of ustekinumab in clinical applications. METHODS: Thirty-two blood samples from 10 young adult patients diagnosed with Crohn's disease were analyzed. During the maintenance treatment, injection intervals were shortened from 12 weeks to 8 weeks in 4 patients who exhibited a loss of response. Ustekinumab trough concentrations were measured using 2 commercial ELISA kits, kit A and kit B. RESULTS: The median trough concentrations measured with kits A and B were 0.26 and 0.38 mcg/mL, respectively. In the case of kit A, low trough concentrations were undetected on many occasions and measured as zero, whereas kit B displayed their relative values even at low concentrations. Poor clinical parameters, elevated erythrocyte sedimentation rate, C-reactive protein, and calprotectin levels were significantly correlated with lower trough concentrations ( P < 0.05). The area under the receiver operating characteristics curve of kit B (0.921) was greater than that of kit A (0.744). The optimal cutoff values for prediction clinical responses were 0.17 and 0.41 mcg/mL for kit A and kit B, respectively. CONCLUSIONS: The trough concentration of ustekinumab measured by the 2 ELISA kits correlated with laboratory results that indicated the activity of Crohn's disease. Furthermore, kit B detected even minute changes in trough concentrations.

Vedolizumab Is Safe and Efficacious for the Treatment of Pediatric-Onset Inflammatory Bowel Disease Patients Who Fail a Primary Biologic Agent.

BACKGROUND: Vedolizumab (VDZ) is currently licensed for use in adults for the treatment of inflammatory bowel disease (IBD). We aimed to investigate the clinical course of pediatric-onset IBD following treatment with VDZ as more than a secondary biologic agent. We also evaluated factors associated with secondary loss of response (LOR) and durability of VDZ treatment. METHODS: Pediatric-onset IBD patients diagnosed at an age younger than 18 years who had received VDZ as more than a secondary biologic agent were included in this retrospective observational study conducted at the Department of Pediatrics of two centers in Korea. Comparative analysis was conducted between groups divided according to the development of secondary LOR during VDZ treatment. RESULTS: A total of 24 patients comprising 10 patients with Crohn's disease and 14 with ulcerative colitis were included. Of these, 19 were male and 5 were female. The mean age at diagnosis was 14.6 ± 2.5 years. The mean age at initiation of VDZ was 20.5 ± 2.8 years. Nine patients (37.5%) had received two or more biologic agents before starting VDZ. During a median of 0.9 years follow-up from VDZ initiation, 9 patients (37.5%) experienced LOR requiring interval shortening and 4 patients (16.7%) were changed to a different biologic agent. According to multivariate Cox proportional hazard regression analysis, administration of two or more biologic agents before VDZ treatment was the only factor positively associated with LOR (hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.026-30.56; P = 0.047), while LOR was the only factor negatively associated with VDZ durability (HR, 0.003; 95% CI, 0.00-0.08; P = 0.010). No adverse events were observed during treatment with VDZ. CONCLUSION: VDZ is safe and efficacious for the treatment of pediatric-onset IBD patients failing a primary biologic agent. The durability of VDZ may be enhanced by introducing VDZ earlier in the disease course. Further prospective studies in children are required in the future to validate these findings.

Therapeutic Drug Monitoring of Adalimumab During Long-term Follow-up in Paediatric Patients With Crohn Disease.

OBJECTIVES: We investigated the therapeutic drug monitoring of adalimumab (ADL) on clinical remission (CR) and mucosal healing (MH) rates in paediatric patients with Crohn disease (CD). Furthermore, long-term treatment efficacy of ADL in paediatric CD was evaluated through 3-year follow-up. METHODS: We conducted a prospective study of 31 patients with CD who received ADL maintenance therapy and underwent endoscopic evaluation of MH and pharmacokinetic analysis. Patients in CR were identified based on Paediatric Crohn Disease Activity Index (PCDAI) scores less than 10. Patients with MH were identified based on Simple Endoscopic Scores for Crohn Disease (SES-CD) of less than 2. RESULTS: At 4 months and 1 year of ADL treatment, 28 and 26 patients, respectively, were under CR; 13 and 17 patients, respectively, achieved MH. The median trough levels (TLs) of ADL were higher in patients in CR (7.6 ±â€Š3.5 µg/mL) than in patients with active disease (5.1 ±â€Š2.2 µg/mL). ADL TLs were significantly higher in patients who achieved MH than in those who did not (14.2 ±â€Š7.6 vs 7.8 ±â€Š5.2 µg/mL). The optimal cut-point for predicting MH at 1 year of ADL treatment was 8.18 µg/mL. During long-term follow-up, ADL TLs were stably maintained over 10 µg/mL; not only CR and MH but also histologic remission was obtained at a high rate. ADL administration maintained a positive effect on growth during the maintenance period. CONCLUSIONS: ADL TLs were significantly higher in paediatric patients with CD who achieved CR or MH. ADL treatment showed long-term stable efficacy and positive effects on growth indicators.

Individual approach for treatment of primary intestinal lymphangiectasia in children: single-center experience and review of the literature.

BACKGROUND: Intestinal lymphangiectasia is a rare disease. Thus, prospective studies are impossible, and therapy is still controversial. Several medicines are suggested for treatment but there are no existing indications for drug choice and treatment guidelines. We aimed to introduce the action mechanism of each drug and treatment overview in a single-center experience and a review of the literature on second-line therapy for primary intestinal lymphangiectasia. METHOD: Children under 18 years old diagnosed with intestinal lymphangiectasia from June 2000 to June 2020 were included and retrospectively reviewed in the study. Capsule endoscopy, MR lymphangiography, or whole-body MRI for investigating the extent of abnormal lymphatic vessels in addition to endoscopy and biopsy were conducted. The individual treatment approaches depended upon the lymphangiectasis locations involved. RESULTS: Only one patient showed a response to dietary therapy. One patient was successfully cured after two therapeutic lymphatic embolization. Octreotide was tried for two patients who had extensive lymphangiectasis. Lymphangiectasis recurred when octreotide was used for 3 months in one patient, and there was no effect in the other patient. Sirolimus was tried for four patients. Two of them had abnormal lymphatic lesions only in the intestine, and the others had extensive lymphangiectasis. The former group showed clinical improvement after 3-4 months of sirolimus treatment, whereas the latter group showed clinical improvement only after 1 month of sirolimus treatment. CONCLUSION: Surgery or embolization is a potential therapeutic option for patients with focal abnormal lymphatic lesions. Octreotide is not an optimal choice for patients with extensive lymphangiectasis. Sirolimus is an effective and safe drug and can be the first drug of choice for patients with extensive lymphangiectasis.

Development and Validation of the Mucosal Inflammation Noninvasive Index For Pediatric Crohn's Disease.

BACKGROUND & AIMS: Mucosal healing (MH) has become a goal of therapy for Crohn's disease (CD), but frequent endoscopies are not feasible. We aimed to develop and validate a non-invasive index to assess mucosal inflammation in children with CD. METHODS: We collected data from the multi-center prospective ImageKids study, in which children with CD underwent ileocolonoscopy with magnetic resonance enterography. We investigated the association of pediatric CD activity index (PCDAI) items and laboratory test results with the simple endoscopic score for CD (SESCD). We used these data in a blended mathematical judgmental clinimetric approach to develop a weighted categorized index to identify children with CD who have MH, which we called the MINI index. We validated the index using data from 3 independent patient cohorts. The derivation and validation cohorts included 154 and 168 children, respectively (age 14.1 ± 2.5 years and 14.2 ± 3.9 years), of whom 16% and 36% had MH (defined as SESCD<3). RESULTS: In multivariable models, the stooling item of the PCDAI, erythrocyte sedimentation rate, and level of fecal calprotectin were associated with SESCD (all P < .05). We added data on level of C-reactive protein to develop the MINI index. MINI scores below 8 identified children with MH with 88% sensitivity and 85% specificity in the derivation cohort and with 84% sensitivity and 87% specificity in the validation cohorts. Ninety percent of the patients in the validation cohort with scores of 8 or more had active mucosal inflammation, yet 78% of patients with scores below 8 had MH. Scores below 6 increase the positive predictive value to 86%. CONCLUSIONS: We developed an index to non-invasively assess mucosal inflammation in children with CD. This index, identifies children with MH with high sensitivity and specificity. The added benefit of MINI over measurement of fecal calprotectin was small but significant, especially for patients with concentrations of fecal calprotectin from 100 to 599 µg/g. ClinicalTrials.gov no: NCT01881490.

Potential Utility of Therapeutic Drug Monitoring of Adalimumab in Predicting Short-Term Mucosal Healing and Histologic Remission in Pediatric Crohn's Disease Patients.

BACKGROUND: Limited data exist regarding mucosal healing (MH) and therapeutic drug monitoring (TDM) in pediatric Crohn's disease (CD) patients treated with adalimumab (ADL). We aimed to investigate the associations between ADL trough levels (TLs) and MH, and between ADL TLs and histologic remission (HR) at 16 weeks from ADL treatment in pediatric CD patients. METHODS: This was a prospective study on moderate-to-severe luminal pediatric CD patients receiving ADL. Ileocolonoscopies and biopsies, as well as clinical activity assessments, laboratory examinations, including tests for ADL TLs and antibody to ADL, were performed 16 weeks after ADL initiation. MH was defined as a Simple Endoscopic Score for CD of 0. HR was defined as the complete absence of microscopic inflammation. RESULTS: Seventeen subjects (13 males, 4 females) were included. At 16 weeks from ADL initiation, 14 (82.4%), 8 (47.1%), and 4 (23.5%) patients achieved clinical remission, MH, and HR, respectively. ADL TLs were significantly higher in patients who achieved MH compared to those who did not (13.0 ± 6.5 vs. 6.2 ± 2.6 µ/mL, respectively; P = 0.023) and also significantly higher in patients who achieved HR compared to those who did not (17.9 ± 5.3 vs. 6.8 ± 2.5 µ/mL, respectively; P = 0.02). The optimal TL for predicting MH was 8.76 µ/mL. CONCLUSION: Serum ADL TLs at 16 weeks were significantly higher in pediatric patients with CD who achieved MH and HR, respectively. TDM may guide in optimizing treatment efficacy and better target MH in the era of treat-to-target.

Early US findings of biliary atresia in infants younger than 30 days.

PURPOSE: To investigate and compare ultrasound (US) findings for the diagnosis of biliary atresia (BA) in infants younger than 30 days with those of infants older than 30 days. MATERIALS AND METHODS: From 2000 to 2015, we reviewed hepatobiliary US images in 12 BA infants younger than 30 days (younger BA group) and 62 BA infants older than 30 days (older BA group) before Kasai procedure. Eight (67%) of younger BA group underwent follow-up US examinations before Kasai procedure. Our review of the images focused on triangular cord sign, gallbladder (GB) abnormalities, vascular changes, and signs of portal hypertension. RESULTS: The triangular cord sign was present in 17% of younger BA group and in 56% of older BA group (P=.024). GB abnormalities were commonly identified in both groups. The hepatic artery diameter was significantly smaller in younger BA group than in older BA group (P<.001). Signs of portal hypertension were less common in younger BA group (17%) than in older BA group (84%) (P<.001). Follow-up US of two infants in younger BA group showed a new appearance of the triangular cord sign. CONCLUSION: BA infants younger than 30 days showed atypical US findings compared with those older than 30 days. KEY POINTS: • BA infants younger than 30 days show atypical US findings. • GB abnormalities were common in both younger and older BA group. • Subsequent US examination may be helpful to diagnose BA in young infants.

NUDT15 genotype distributions in the Korean population.

Thiopurines have a narrow therapeutic range because of frequent toxicity (i.e. marrow suppression), which is only partly explained by TPMT genetic polymorphisms, especially within Asian populations. Recent studies have identified NUDT15 variation as another important factor affecting thiopurine metabolism. In this study, a total of four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal) were genotyped in 920 Korean individuals using direct sequencing of NUDT15 for the first time in a Korean population. The allele frequencies were 86.7% for NUDT15*1, and 4.4, 6.9, 0.4, 1.1, and 0.50% for *2, *3, *4, *5, and *6, respectively. The NUDT15 phenotypes based on diplotypes included normal activity (n=692), intermediate activity (n=209), and low activity (n=19), occurring in 75.2, 22.7, and 2.1% of the population, respectively. This study was the first to report NUDT15 variants other than NUDT15*3 in the Korean population and more individuals who were categorized as having intermediate or low NUDT15 activity in our study than in previously reported studies in the Korean population (24.8 vs. 19.4%, P<0.05). This study is useful for future clinical studies on thiopurine pharmacogenetics and dosage adjustment in the Korean population.

Baseline Wall Thickness Is Lower in Mucosa-Healed Segments 1 Year After Infliximab in Pediatric Crohn Disease Patients.

OBJECTIVES: We aimed to quantitatively investigate the therapeutic response to combined immunosuppression treatment by magnetic resonance enterography (MRE) in active luminal Crohn disease (CD) in the pediatric population. METHODS: Pediatric patients with moderate-to-severe luminal CD, who received scheduled infliximab and azathioprine, were included in this preliminary study. Ileocolonoscopy and MRE were performed at baseline and at 1 year, and Simple Endoscopic Score for Crohn's Disease (SES-CD) and Magnetic Resonance Index of Activity (MaRIA) scores were calculated. The correlation between SES-CD and MaRIA scores were investigated with analysis per person and per segment. RESULTS: A total of 167 segments from 17 patients were evaluated by both Ileocolonoscopy and MRE. SES-CD and MaRIA scores showed significant correlations on both per-person analysis (ρ = 0.699, P < 0.001) and per-segment analysis (ρ = 0.596, P < 0.001). Analysis according to ileocolonic location of each segment revealed that the correlation strength was strongest in the right colon (ρ = 0.653, P < 0.001), whereas the correlation in the rectum was statistically insignificant (ρ = 0.29, P = 0.096). A comparative analysis of MaRIA components revealed a significantly thinner bowel wall thickness at baseline in endoscopically healed segments (50/65) compared with unhealed segments (15/65) (median 4.3 vs 7.2 mm, P = 0.036). CONCLUSIONS: Therapeutic response to combined immunosuppression at 1 year assessed by MRE correlates with ileocolonoscopy in pediatric patients with CD. Bowel wall thickness of the involved segments at baseline may affect treatment response to combined immunosuppression.

De novo hepatitis b prophylaxis with hepatitis B virus vaccine and hepatitis B immunoglobulin in pediatric recipients of core antibody-positive livers.

The use of hepatitis B core antibody-positive (HBcAb+) grafts for liver transplantation (LT) has the potential to safely expand the donor pool, as long as proper prophylaxis against de novo hepatitis B (DNHB) is employed. The aim of this study was to characterize the longterm outcome of pediatric LT recipients of HBcAb + liver grafts under a prophylaxis regimen against DNHB using hepatitis B virus (HBV) vaccine and hepatitis B immunoglobulin (HBIG). From June 1996 to February 2013, 49 patients receiving pediatric LT at our center were from HBcAb + donors. Forty-one patients who received DNHB prophylaxis according to our protocol were included in this analysis. Our DNHB prophylaxis protocol consists of HBV vaccine intramuscular injections given intermittently to maintain anti-hepatitis B surface antibody (HBsAb) titers above 100 IU/L. HBIG was also used during the first posttransplant year with a target anti-HBsAb titer level above 200 IU/L. There were 19 boys and 22 girls. Median age was 1.0 year (range, 4 months to 16 years). Median follow-up time was 66 months after transplant. Median annual number of HBV vaccine injections was 0.8 per year (range, 0-1.8 per year). Four patients did not require any HBV vaccine injections during follow-up. One patient with DNHB was encountered during the follow-up period (1/41, 2.4%). DNHB was diagnosed at 3.5 years after transplant, when hepatitis B surface antigen was positive upon routine follow-up serologic testing. Anti-HBsAb titer was 101.5 IU/L at the time. No grafts were lost because of DNHB-related events. Overall survival of the 41 recipients of HBcAb + grafts who received DNHB prophylaxis was 92.3% at 10 years after transplant. In conclusion, longterm prophylaxis against DNHB with HBV vaccine in pediatric LT recipients of HBcAb + grafts was safe and effective in terms of DNHB incidence as well as graft and patient survival.

PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX: prevalence of deletion mutations.

BACKGROUND: Molecular diagnosis of glycogen storage diseases (GSDs) is important to enable accurate diagnoses and make appropriate therapeutic plans. The aim of this study was to evaluate the PHKA2 mutation spectrum in Korean patients with GSD type IX. METHODS: Thirteen Korean patients were tested for PHKA2 mutations using direct sequencing and a multiplex polymerase chain reaction method. A comprehensive review of the literature on previously reported PHKA2 mutations in other ethnic populations was conducted for comparison. RESULTS: Among 13 patients tested, six unrelated male patients with GSD IX aged 2 to 6 years at the first diagnostic work-up for hepatomegaly with elevated aspartate transaminase (AST) and alanine transaminase (ALT) were found to have PHKA2 mutations. These patients had different PHKA2 mutations: five were known mutations (c.537 + 5G > A, c.884G > A [p.Arg295His], c.3210_3212delGAG [p.Arg1072del], exon 8 deletion, and exons 27-33 deletion) and one was a novel mutation (exons 18-33 deletion). Notably, the most common type of mutation was gross deletion, in contrast to other ethnic populations in which the most common mutation type was sequence variant. CONCLUSIONS: This study expands our knowledge of the PHKA2 mutation spectrum of GSD IX. Considering the PHKA2 mutation spectrum in Korean patients with GSD IX, molecular diagnostic methods for deletions should be conducted in conjunction with direct sequence analysis to enable accurate molecular diagnosis of this disease in the Korean population.

Complete sequence-based screening of TPMT variants in the Korean population.

Thiopurine S-methyltransferase (TPMT) is a cytoplasmic enzyme involved in the metabolism of thiopurine drugs and its activity is largely influenced by polymorphisms of the TPMT gene. To date, more than 35 TPMT variants are known to be associated with reduced enzyme activity, but most studies on the TPMT genotype have included only common nonfunctional variants, such as TPMT*2 and TPMT*3. In this study, we carried out a complete sequencing analysis to screen all TPMT variants in Korean patients. A total of 900 Korean patients were genotyped for TPMT and 30 patients (3.3%) had the known TPMT variant alleles. TPMT*3C was found in 25 patients (2.8%): 24 patients with TPMT*1/*3 and one with TPMT*3/*3. Rare TPMT variants including TPMT*6, TPMT*16, and TPMT*32 were detected in five patients (0.6%) and a novel variant, TPMT*38 (c.514T>C, p.S172P), was identified in two patients. This is the first complete sequence-based screening study evaluating all TPMT variants in Asian populations.

Sustained linear growth and preserved renal function in 10-year survivors of pediatric liver transplantation.

The aim of this study was to characterize the clinical outcomes of children and adolescents who achieved survival of more than 10 years following liver transplantation (LT) in a single center in Korea. From June 1996 to October 2003, 57 pediatric LTs were performed. The medical records of 44 patients who had survived more than 10 years were reviewed retrospectively. Median age of patients at LT was 0.8 years. Forty-one patients received living donor LT, and three patients received deceased donor LT. Biliary atresia was the most common indication (65.9%). Thirty-five patients were on tacrolimus monotherapy at 10 years post-LT with a mean trough level of 2.73 ng/ml, and five patients were maintaining stable graft function without any immunosuppression. There were no patients receiving antihypertensive medication and one case of diabetes mellitus. Renal dysfunction was seen in two patients (4.5%), while none required renal replacement therapy. Mean height z-score prior to LT was -1.35 and at 10 years post-transplant was 0.05. Good linear growth was sustained in this cohort throughout the 10 years, approaching the 50th percentile. Also, there were remarkably low incidences of renal dysfunction and patients requiring medications for glycemic or hypertensive control, all hallmarks of continued use of immunosuppressive agents.

Infliximab "Top-Down" Strategy is Superior to "Step-Up" in Maintaining Long-Term Remission in the Treatment of Pediatric Crohn Disease.

OBJECTIVES: We aimed to compare the efficacy of remission maintenance between infliximab "top-down" and "step-up" strategies in moderate to severe pediatric Crohn disease during 3 years. We also aimed to determine prognostic factors that may influence the relapse-free rate in these patients. METHODS: The present study was a retrospective review of a prospective cohort, based on an infliximab treatment protocol for pediatric Crohn disease used at Samsung Medical Center. A total of 31 patients (group A) were treated with early infliximab induction ("top-down" strategy) and 20 patients (group B) refractory to conventional therapy underwent infliximab treatment ("step-up" strategy). The efficacy of infliximab treatment was assessed by relapse-free rate and remission period rate for 3 years. A total of 11 prognostic factors that may influence the relapse-free rate were further analyzed. RESULTS: The relapse-free rates at 3 years were 35.5% (95% confidence interval [CI] 0.194-0.519) in group A and 15.0% (95% CI 0.037-0.335) in group B (P = 0.0094). Overall remission period rate for 3 years also showed a significant difference between the 2 groups (92.1%  ± 7.2% vs 78.3%  ± 16.6%; P = 0.005). Multivariable analysis revealed that the duration from the initial diagnosis to infliximab infusion was the only factor associated with relapse-free remission for 3 years (hazard ratio = 1.077; 95% CI 1.025-1.131). CONCLUSIONS: "Top-down" strategy had a longer remission period compared with the "step-up" strategy in pediatric Crohn disease during a study period of 3 years, based on relapse-free rate and remission period rate. Earlier introduction of infliximab is recommended in pediatric patients with moderate to severe Crohn disease.

Sensory Processing Difficulties in Toddlers With Nonorganic Failure-to-Thrive and Feeding Problems.

OBJECTIVES: Failure-to-thrive is defined as an abnormally low weight and/or height for age. The term "nonorganic failure-to-thrive" (NOFT) has been used to describe "failure-to-thrive" without an obvious cause underlying the growth failure. The purpose of the present study was to compare sensory processing abilities between toddlers with NOFT and feeding problems and age-matched controls. METHODS: Toddlers with NOFT and feeding problems (N = 16) were recruited from the pediatric feeding clinic in a tertiary university hospital, and age-matched controls (N = 16) were recruited from community volunteers. They were evaluated for sensory processing ability using an Infant/Toddler Sensory Profile (ITSP), and for development of cognition, motor skills, and language using the Bayley Scales of Infant Development II and Sequenced Language Scale for Infants. Behavior at mealtime was evaluated using the Behavioral Pediatrics Feeding Assessment Scale. RESULTS: In the NOFT with feeding problems group, atypical performances were more frequently observed in 3 of 5 ITSP section items (tactile, vestibular, and oral) compared with those in the control group. Significant delayed development of cognition, motor skills, and language was observed in the NOFT with feeding problems group compared with that in the control group. In addition, children who showed 1 or more atypical performances in ITSP had delayed development in cognition, motor skills, and language. CONCLUSIONS: Sensory processing problems were more commonly observed in toddlers with feeding problems and growth deficiency. The present study could provide a preliminary evidence for a possible impact of the sensory processing problems on the feeding difficulties in toddlers with NOFT. Future large studies should be conducted to clarify the relation between sensory processing difficulties and feeding problems in toddlers.

A Bottom-Up Liquid Chromatography-Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Infliximab: Method Development, Comparison With 2 Enzyme-Linked Immunosorbent Assay Methods, and Evaluation of Anti-Drug Antibody Interference.

CONTEXT.­: Therapeutic drug monitoring is recommended to optimize infliximab use and improve outcome in chronic inflammatory disorders. OBJECTIVE.­: To describe a simple and affordable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to measure infliximab in serum. DESIGN.­: Infliximab was measured using winged stable isotope-labeled peptides as internal standards. Linearity, lower limit of measuring interval, limit of detection, precision, accuracy, carryover, and ion suppression were evaluated. Method comparison against 2 enzyme-linked immunosorbent assay (ELISA) methods (Remsima Monitor and IDKmonitor Infliximab) and anti-drug antibody (ADA) interference were evaluated using clinical specimens from inflammatory bowel disease patients (N = 237). RESULTS.­: Analytical run time and sample preparation time were 5 minutes per sample and 3 hours per batch, respectively. Analytical measurement interval and limit of detection were 0.50 to 50.0 µg/mL (R2 = 0.998) and 0.25 µg/mL, respectively. The intraday and interday imprecision percentage coefficients of variation were less than 6.1%. Accuracy was 94.2% to 98.7%. No significant ion suppression or carryover was observed. Infliximab concentrations measured by LC-MS/MS showed good agreement with those measured by Remsima Monitor (mean percentage difference, 5.7%; 95% CI, -1.2% to 12.6%) but were markedly lower than those measured by IDKmonitor (-32.6%; -35.8% to -29.4%), demonstrating significant bias between ELISAs. Although a good agreement between LC-MS/MS and ELISA was observed for ADA-negative samples (-3.5%; -12.8% to 5.9%), a significant bias was observed for ADA-positive samples (13.6%; 1.7% to 25.6%). CONCLUSIONS.­: This simple, fast, and affordable LC-MS/MS method for infliximab quantitation could improve standardization of infliximab quantitation and optimization of infliximab use in patients with high-titer ADA.

Long-term follow-up of de novo allergy in pediatric liver transplantation--10 yr experience of a single center.

We conducted a study to clarify the incidence, clinical course, and risk factors of de novo allergies after liver transplantation. Ninety-three patients who had been followed longer than one yr and who had no previous allergy history were included. Forty-two patients (45.2%) developed de novo allergy. Of them, food allergy developed in 35 (37.6%). Respiratory allergy was observed in three (3.2%), and a patient (1.1%) had drug allergy. Fifty-two (55.9%) of the 93 patients developed eosinophilia. The median age of patients with de novo allergy was 15 months (IR 11.3-20 months). De novo allergy developed five months after liver transplantation (IR 2.3-9.5 months) and lasted for 16 months (IR 8-34.5 months). Younger age at liver transplantation displayed statistically significant differences in development of allergy between allergy and non-allergy groups. Twenty-nine (69.0%) patients improved from allergy during the follow-up period. No patient with de novo gastrointestinal allergy progressed to any respiratory allergy such as asthma. Older age at transplantation, EBV non-risk, and CMV non-risk had statistical significance in allergy improvement. Younger age at transplant predisposes to the development of allergy, while improvement of allergy is achieved more in older age.

Pediatric liver transplantation outcomes in Korea.

Pediatric liver transplantation is the standard of care for treatment of liver failure in children. The aim of this study was to identify the characteristics of pediatric liver transplantation in centers located in Korea and determine factors that influence outcomes. This retrospective study was performed using data from between 1988 and 2010 and included all recipients 18 yr old and younger who underwent pediatric liver transplantation in Korea during that period. Our data sources were hospital medical records and the outcome measure was overall patient survival. Univariate and multivariate statistical analyses were undertaken using the Cox proportional hazards model. Five hundred and thirty-four pediatric liver transplantations were performed in 502 children. Median age and average pediatric end-stage liver disease (PELD) score were 20 months and 18 point, respectively. Biliary atresia (57.7%, 308/534) was the most common cause of liver disease. Eighty-two (15.3%) were deceased donor liver transplantations and 454 (84.7%) were living donor liver transplantations. Retransplantation was performed in 32 cases (6%). Overall, 1-, 5-, and 10-yr patient survival rates were 87.8%, 82.2%, and 78.1%, respectively. In multivariate analysis, independent significant predictors of poor patient survival were chronic rejection and retransplantation. This study presents the epidemiologic data for nearly all pediatric liver transplantation in Korea and shows that the independent prognostic factors in patient survival are chronic rejection and retransplantation.

Free antibodies-to-infliximab are biomarker for predicting the effect of dose intensification in pediatric Crohn's disease patients with secondary loss of response.

Background: Immunogenicity to antitumor necrosis factor alpha agents, such as infliximab (IFX), may lead to therapeutic failure. Objectives: This study evaluated the relationship between free and total antibodies-to-infliximab (ATIs), trough levels (TLs) of IFX, and the response to dose intensification. Design: We performed a prospective, observational study including pediatric patients with Crohn's disease (CD) receiving IFX maintenance therapy without dose intensification. Methods: We compared clinical and laboratory outcomes according to the presence of free and total ATIs. Factors associated with response to IFX dose intensification were investigated by analyzing IFX TLs and free and total ATIs. Results: Of the 98 patients, 9 patients had detectable free ATIs and 38 patients had total ATIs. Patients with free ATIs had significantly lower TLs (0.7 versus 5.1 µg/mL, p < 0.001) than patients without free ATIs. However, there was no difference in the IFX TLs according to the presence of total ATIs (p = 0.2523). Analysis of the 38 samples with total ATIs showed that response to dose intensification was significantly lower in patients with free ATIs than those without free ATIs (22.2% versus 65.5%, p < 0.001). In addition, free ATIs were the only factor with poor response to dose intensification [odds ratio (OR): 14.15, 95% confidence interval (CI): 1.31-151.97, p = 0.0140]. According to the receiver operating characteristic analysis, the optimal cutoff level indicating non-response to IFX dose intensification was 30.0 AU/mL for free ATIs concentration (area under curve, 0.792; 95% CI: 0.590-0.942; sensitivity, 60.0%; specificity, 96.7%; p = 0.0241). Conclusion: Free ATIs, but not total ATIs, have a negative impact on the course of CD. Free ATIs are potential reliable biomarker for predicting the effect of dose intensification in patients with loss of response to IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.