Vitamin D3 and deconvoluting a rash.

BACKGROUNDAdverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODSSkin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTSCholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSIONHigh-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATIONclinicaltrials.gov (NCT02968446).FUNDINGNIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).

Incorporation of Telehealth Into Multidisciplinary Clinics: Visits Via Video Offer Advantages for Team and Families.

ABSTRACT: Shelter in place orders in the coronavirus disease 2019 (COVID-19) pandemic necessitate changes in how medical care is delivered. We describe our method for team telemedicine visits for California Children's Services, a state insurance for children requiring multidisciplinary care, to demonstrate how such visits can be efficiently conducted. Although the physical distance provides some obstacles, telemedicine visits can also improve some elements of the team visit.

Cutaneous Chronic Graft Versus Host Disease in a Symmetric Distribution.

Graft-versus-host disease (GVHD) is a common complication following patients who have undergone allogenic hematopoietic stem cell transplantation (allo-HSCT). While GVHD has been previously sub-categorized through a temporal relationship upon transplantation, revisions from the National Institutes of Health have modified the diagnosis criteria to be more involved with specific signs and symptoms. Chronic classifications of GVHD include non-sclerotic and sclerotic forms, and the sclerotic form can be further classified based on morphologies such as lichen-sclerosis-like, sclerodermoid or morphea-like plaques. Generalized morphea can have similar histopathological findings but in order to be diagnosed, certain diagnostic criteria must be met. Herein, we report a patient with linear and inflammatory morphea morphology of chronic GVHD, which presents symmetrically on both lower extremities.

Somatic mutations and clonal hematopoiesis in congenital neutropenia.

Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis. An average of 3.6 ± 1.2 somatic mutations per exome was identified in HSPCs from patients with SCN compared with 3.9 ± 0.4 for healthy controls (P = NS). Clonal hematopoiesis due to mutations in TP53 was present in 48% (13/27) of patients with SDS but was not seen in healthy controls (0/17, P < .001) or patients with SCN (0/40, P < .001). Our SDS cohort was young (median age 6.3 years), and many of the patients had multiple TP53 mutations. Conversely, clonal hematopoiesis due to mutations of CSF3R was present in patients with SCN but was not detected in healthy controls or patients with SDS. These data show that hematopoietic stress, including granulocyte colony-stimulating factor, do not increase the mutation burden in HSPCs in congenital neutropenia. Rather, distinct hematopoietic stressors result in the selective expansion of HSPCs carrying specific gene mutations. In particular, in SDS there is enormous selective pressure to expand TP53-mutated HSPCs, suggesting that acquisition of TP53 mutations is an early, likely initiating event, in the transformation to myelodysplastic syndrome/acute myeloid leukemia in patients with SDS.

Aquagenic urticaria: diagnostic and management challenges.

Aquagenic urticaria (AU) is a rare inducible form of physical urticaria, which occurs in response to cutaneous exposure to water, including sweat and tears. Patients present with characteristic 1-3 mm folliculocentric wheals with surrounding 1-3 cm erythematous flares within 20-30 minutes following skin contact with water. In rare cases, there are concomitant systemic symptoms, such as wheezing or shortness of breath. The pathogenesis of AU is poorly understood at this time, and it appears to be mediated in both a histamine-dependent and independent manner. Diagnosis is based on eliciting a thorough clinical history combined with a water challenge test. Some patients may need to undergo further testing to exclude other physical urticarias. Rarely, multiple physical urticarias can be present in one patient, which can complicate diagnosis and treatment. Currently, the first-line therapy for AU is an oral administration of nonsedating, second-generation H1 antihistamines, but many patients may require further interventions to have adequate symptomatic control. In this review, we discuss the diagnostic and management challenges of AU. We review the key diagnostic features that differentiate AU from other physical urticarias. We additionally describe a therapeutic ladder for the treatment of AU and the rationale supporting these treatments.

Challenges in meeting fellowship procedural guidelines in pediatric therapeutic endoscopy and liver biopsy.

OBJECTIVE: The aims of this study were to assess the opportunities for therapeutic endoscopy, liver biopsies, and percutaneous endoscopic gastrostomy (PEG) placements available to fellows during a 3-year pediatric gastroenterology fellowship, and to evaluate access to ancillary procedural-training opportunities. METHODS: Data were collected from 12 pediatric gastroenterology fellowship programs in the United States. Procedures completed in the years 2009-2011 were queried using CPT codes and endoscopy databases. The maximal opportunity for procedures was based on the total procedures performed by the institution in 3 years divided by the total number of fellows in the program. The centers completed a questionnaire regarding ancillary opportunities for endoscopic training. RESULTS: There is significant variability in pediatric endoscopic training opportunities in specialized gastrointestinal (GI) procedures. Under the 1999 guidelines, no centers were able to meet the thresholds for polypectomy and control of nonvariceal bleeding. The 2013 guidelines allowed the number of programs reaching polypectomy thresholds to increase by 67% but made no difference for control of bleeding despite a decrease in the threshold. Training in PEG placement was not available in 42% of the surveyed centers. Elective ancillary procedural training is offered by 92% of the surveyed centers. CONCLUSIONS: Most training programs do not have the volume of therapeutic endoscopy procedures for all of the fellows to meet the training guidelines. Training in therapeutic endoscopy, PEG placement, and liver biopsy in pediatric GI fellowships should be supplemented using all of the possible options including rotations with adult GI providers and hands-on endoscopy courses. A shift toward evaluating competency via quality measures may be more appropriate.

Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.

OBJECTIVES: To determine if interventions during the pre-hemolytic uremic syndrome (HUS) diarrhea phase are associated with maintenance of urine output during HUS. DESIGN: Prospective observational cohort study. SETTINGS: Eleven pediatric hospitals in the United States and Scotland. PARTICIPANTS: Children younger than 18 years with diarrhea-associated HUS (hematocrit level <30% with smear evidence of intravascular erythrocyte destruction), thrombocytopenia (platelet count <150 × 10³/mm³), and impaired renal function (serum creatinine concentration > upper limit of reference range for age). INTERVENTIONS: Intravenous fluid was given within the first 4 days of the onset of diarrhea. OUTCOME MEASURE: Presence or absence of oligoanuria (urine output ≤ 0.5 mL/kg/h for >1 day). RESULTS: The overall oligoanuric rate of the 50 participants was 68%, but was 84% among those who received no intravenous fluids in the first 4 days of illness. The relative risk of oligoanuria when fluids were not given in this interval was 1.6 (95% confidence interval, 1.1-2.4; P = .02). Children with oligoanuric HUS were given less total intravenous fluid (r = -0.32; P = .02) and sodium (r = -0.27; P = .05) in the first 4 days of illness than those without oligoanuria. In multivariable analysis, the most significant covariate was volume infused, but volume and sodium strongly covaried. CONCLUSIONS: Intravenous volume expansion is an underused intervention that could decrease the frequency of oligoanuric renal failure in patients at risk of HUS.

Deer sausage: a newly identified vehicle of transmission of Escherichia coli O157:H7.

Five Missouri patients infected with Escherichia coli O157:H7 were studied for an epidemiologically plausible association. Case isolates, case interviews, and pathogen and meat XbaI pulsed field electrophoresis patterns were consistent with the common source being contaminated, fermented deer sausage, a previously unrecognized mode of transmission for Escherichia coli O157:H7.

Laboratory values for children with newly diagnosed inflammatory bowel disease.

OBJECTIVE: The goal was to determine how often common laboratory tests yield normal results at the time of diagnosis for children with inflammatory bowel disease. METHODS: Data were obtained from a registry of children with newly diagnosed inflammatory bowel disease who were enrolled prospectively in 18 US/Canadian centers. Laboratory values investigated included hemoglobin level, platelet count, albumin level, and erythrocyte sedimentation rate. Disease severity was categorized by physician global assessment. RESULTS: A total of 526 children (mean age: 11.6 years; 58% male; 392 with Crohn disease and 134 with ulcerative colitis) were studied. All 4 values were normal for 21% of patients with mild Crohn disease and 54% with mild ulcerative colitis. In contrast, only 3.8% of children with moderate/severe Crohn disease and 4.3% with moderate/severe ulcerative colitis had normal results for all 4 tests. The erythrocyte sedimentation rate was least likely to be normal; overall, 26% of patients with inflammatory bowel disease had a normal erythrocyte sedimentation rate, including 18% with moderate/severe disease. Hemoglobin levels were normal for 32%, platelet counts for 50%, and albumin levels for 60%. There was no clear association between Crohn disease location and either severity or number of normal laboratory values. In contrast, there were direct correlations between ulcerative colitis disease severity and both the extent of bowel inflammation and the number of abnormal laboratory tests. CONCLUSION: The presence of normal screening laboratory studies should not dissuade clinicians from considering a diagnosis of inflammatory bowel disease.

Health-related quality of life in the first year after a diagnosis of pediatric inflammatory bowel disease.

BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is of increasing importance in the evaluation of new therapies for inflammatory bowel disease (IBD). Available data concerning HRQOL in pediatric patients are sparse and uniformly cross-sectional. The aim of this study was to describe HRQOL and influential factors in newly diagnosed pediatric patients with Crohn's disease and ulcerative colitis during the first 12 months after diagnosis. MATERIALS AND METHODS: Participants were drawn from a large, prospectively derived observational IBD registry of pediatric patients studied through 18 U.S. and Canadian centers. Patients who had completed a baseline IMPACT questionnaire and for whom there were 12 months of follow-up data available were included. In addition to description of cohort, factors that were believed to influence HLQOL were assessed during the course of the year from diagnosis. RESULTS: Two hundred eighteen children met inclusion criteria (77% Crohn's disease, 23 % ulcerative colitis, mean age 12.7 +/- 1.9 years). Mean total IMPACT score at baseline was 154, 181 at 6 months, and 191 at 1 year (possible range 0-238, with increasing scores representing better quality of life). Repeated measures analysis showed that age and disease severity significantly negatively affected the IMPACT scores during the course of the year. CONCLUSIONS: In this large prospective pediatric IBD cohort, significant improvement in HRQOL is noted during the year from diagnosis. Mean IMPACT scores varied significantly depending on the disease severity and also decreased with increasing age.