The impact of the COVID-19 pandemic on 397 631 elective dental admissions among the under-25s in England: a retrospective study.

BACKGROUND: COVID-19 caused widespread disruptions to health services worldwide, including reductions in elective surgery. Tooth extractions are among the most common reasons for elective surgery among children and young people (CYP). It is unclear how COVID-19 affected elective dental surgeries in hospitals over multiple pandemic waves at a national level. METHODS: Elective dental tooth extraction admissions were selected using Hospital Episode Statistics. Admission trends for the first 14 pandemic months were compared with the previous five years and results were stratified by age (under-11s, 11-16s, 17-24s). RESULTS: The most socioeconomically deprived CYP comprised the largest proportion of elective dental tooth extraction admissions. In April 2020, admissions dropped by >95%. In absolute terms, the biggest reduction was in April (11-16s: -1339 admissions, 95% CI -1411 to -1267; 17-24s: -1600, -1678 to -1521) and May 2020 (under-11s: -2857, -2962 to -2752). Admissions differed by socioeconomic deprivation for the under-11s (P < 0.0001), driven by fewer admissions than expected by the most deprived and more by the most affluent during the pandemic. CONCLUSION: Elective tooth extractions dropped most in April 2020, remaining below pre-pandemic levels throughout the study. Despite being the most likely to be admitted, the most deprived under-11s had the largest reductions in admissions relative to other groups.

Impact of the COVID-19 pandemic on the clinical management trends for acute appendicitis among the under-25s: a retrospective study.

OBJECTIVE: To describe the COVID-19 pandemic's impact on acute appendicitis management on children and young people (CYP). DESIGN: Retrospective cohort study. SETTING: All English National Health Service hospitals. PATIENTS: Acute appendicitis admissions (all, simple, complex) by CYP (under-5s, 5-9s, 10-24s). EXPOSURE: Study pandemic period: February 2020-March 2021. Comparator pre-pandemic period: February 2015-January 2020. MAIN OUTCOME MEASURES: Monthly appendicectomy and laparoscopic appendicectomy rate trends and absolute differences between pandemic month and the pre-pandemic average. Proportions of appendicitis admissions comprising complex appendicitis by hospital with or without specialist paediatric centres were compared. RESULTS: 101 462 acute appendicitis admissions were analysed. Appendicectomy rates fell most in April 2020 for the 5-9s (-18.4% (95% CI -26.8% to -10.0%)) and 10-24s (-28.4% (-38.9% to -18.0%)), driven by reductions in appendicectomies for simple appendicitis. This was equivalent to -54 procedures (-68.4 to -39.6) and -512 (-555.9 to -467.3) for the 5-9s and 10-24s, respectively. Laparoscopic appendicectomies fell in April 2020 for the 5-9s (-15.5% (-23.2% to -7.8%)) and 10-24s (-44.8% (-57.9% to -31.6%) across all types, which was equivalent to -43 (-56.1 to 30.3) and -643 (-692.5 to -593.1) procedures for the 5-9s and 10-24s, respectively. A larger proportion of complex appendicitis admissions were treated within trusts with specialist paediatric centres during the pandemic. CONCLUSIONS: For CYP across English hospitals, a sharp recovery followed a steep reduction in appendicectomy rates in April 2020, due to concerns with COVID-19 transmission. This builds on smaller-sized studies reporting the immediate short-term impacts.

Lateral flow test performance in children for SARS-CoV-2 using anterior nasal and buccal swabbing: sensitivity, specificity, negative and positive predictive values.

OBJECTIVE: To determine if the sensitivity of the lateral flow test is dependent on the viral load and on the location of swabbing in the respiratory tract in children. DESIGN: Phase 1: Routinely performed reverse transcriptase PCR (RT-PCR) using nose and throat (NT) swabs or endotracheal (ET) aspirates were compared with Innova lateral flow tests (LFTs) using anterior nasal (AN) swabs. Phase 2: RT-PCR-positive children underwent paired AN RT-PCR and LFT and/or paired AN RT-PCR and buccal LFT. SETTING: Tertiary paediatric hospitals. PATIENTS: Children under the age of 18 years. Phase 1: undergoing routine testing, phase 2: known SARS-CoV-2 positive. RESULTS: Phase 1: 435 paired swabs taken in 431 asymptomatic patients resulted in 8 positive RT-PCRs, 9 PCR test failures and 418 negative RT-PCRs from NT or ET swabs. The test performance of AN LFT demonstrated sensitivity: 25% (4%-59%), specificity: 100% (99%-100%), positive predictive value (PPV): 100% (18%-100%) and negative predictive value (NPV): 99% (97%-99%).Phase 2: 14 AN RT-PCR-positive results demonstrated a sensitivity of 77% (50%-92%) of LFTs performed on AN swabs. 15/16 paired buccal LFT swabs were negative. CONCLUSION: The NPV, PPV and specificity of LFTs are excellent. The sensitivity of LFTs compared with RT-PCR is good when the samples are colocated but may be reduced when the LFT swab is taken from the AN. Buccal swabs are not appropriate for LFT testing. Careful consideration of the swabbing reason, the tolerance of the child and the requirements for test processing (eg, rapidity of results) should be undertaken within hospital settings. TRIAL REGISTRATION NUMBER: NCT04629157.

Impact of rectal dissection technique on primary-school-age outcomes for a British and Irish cohort of children with Hirschsprung disease.

BACKGROUND: This prospective cohort study compared primary-school-aged outcomes between children with Hirschsprung disease (HD) following Soave, Duhamel or Swenson procedures. METHODS: Children with histologically proven HD were identified in British/Irish paediatric surgical centers (01/10/2010-30/09/2012). Parent/clinician outcomes were collected when children were 5-8 years old and combined with management/early outcomes data. Propensity score/covariate adjusted multiple-event-Cox and multivariable logistic regression analyses were used. RESULTS: 277 (91%) of 305 children underwent a pull-through (53% Soave, 37% Duhamel, 9% Swenson). Based upon 259 children (94%) with complete operative data, unplanned reoperation rates (95% CI) per-person year of follow-up were 0.11 (0.08-0.13), 0.34 (0.29-0.40) and 1.06 (0.86-1.31) in the Soave/Duhamel/Swenson groups respectively. Adjusted Hazard Ratios for unplanned reoperation compared with the Soave were 1.50 (95% CI 0.66-3.44, p = 0.335) and 7.57 (95% CI 3.39-16.93, p < 0.001) for the Duhamel/Swenson respectively. Of 217 post-pull-through children with 5-8 year follow-up, 62%, 55%, and 62% in Soave/Duhamel/Swenson groups reported faecal incontinence. In comparison to Soave, Duhamel was associated with lower risk of faecal incontinence (aOR 0.34,95%CI 0.13-0.89,p = 0.028). Of 191 children without a stoma, 42%, 59% and 30% in Soave/Duhamel/Swenson groups required assistance to maintain bowel movements; compared to Soave, the Duhamel group were more likely to require assistance (aOR 2.61,95% CI 1.03-6.60,p = 0.043). CONCLUSIONS: Compared with Soave, Swenson was associated with increased risk of unplanned reoperation, whilst Duhamel was associated with reduced risk of faecal incontinence, but increased risk of constipation at 5-8 years of age. The risk profiles described can be used to inform consent discussions between surgeons and parents. LEVEL OF EVIDENCE: Level II.

Impact of COVID-19 on primary care contacts with children and young people in England: longitudinal trends study 2015-2020.

BACKGROUND: The NHS response to COVID-19 altered provision and access to primary care. AIM: To examine the impact of COVID-19 on GP contacts with children and young people (CYP) in England. DESIGN AND SETTING: A longitudinal trends analysis was undertaken using electronic health records from the Clinical Practice Research Datalink (CPRD) Aurum database. METHOD: All CYP aged <25 years registered with a GP in the CPRD Aurum database were included. The number of total, remote, and face-to-face contacts during the first UK lockdown (March to June 2020) were compared with the mean contacts for comparable weeks from 2015 to 2019. RESULTS: In total, 47 607 765 GP contacts with 4 307 120 CYP were included. GP contacts fell 41% during the first lockdown compared with previous years. Children aged 1-14 years had greater falls in total contacts (≥50%) compared with infants and those aged 15-24 years. Face-to-face contacts fell by 88%, with the greatest falls occurring among children aged 1-14 years (>90%). Remote contacts more than doubled, increasing most in infants (over 2.5-fold). Total contacts for respiratory illnesses fell by 74% whereas contacts for common non-transmissible conditions shifted largely to remote contacts, mitigating the total fall (31%). CONCLUSION: During the COVID-19 pandemic, CYP's contact with GPs fell, particularly for face-to-face assessments. This may be explained by a lower incidence of respiratory illnesses because of fewer social contacts and changing health-seeking behaviour. The large shift to remote contacts mitigated total falls in contacts for some age groups and for common non-transmissible conditions.

Which children and young people are at higher risk of severe disease and death after hospitalisation with SARS-CoV-2 infection in children and young people: A systematic review and individual patient meta-analysis.

BACKGROUND: We aimed to describe pre-existing factors associated with severe disease, primarily admission to critical care, and death secondary to SARS-CoV-2 infection in hospitalised children and young people (CYP), within a systematic review and individual patient meta-analysis. METHODS: We searched Pubmed, European PMC, Medline and Embase for case series and cohort studies published between 1st January 2020 and 21st May 2021 which included all CYP admitted to hospital with ≥ 30 CYP with SARS-CoV-2 or ≥ 5 CYP with PIMS-TS or MIS-C. Eligible studies contained (1) details of age, sex, ethnicity or co-morbidities, and (2) an outcome which included admission to critical care, mechanical invasive ventilation, cardiovascular support, or death. Studies reporting outcomes in more restricted groupings of co-morbidities were eligible for narrative review. We used random effects meta-analyses for aggregate study-level data and multilevel mixed effect models for IPD data to examine risk factors (age, sex, comorbidities) associated with admission to critical care and death. Data shown are odds ratios and 95% confidence intervals (CI).PROSPERO: CRD42021235338. FINDINGS: 83 studies were included, 57 (21,549 patients) in the meta-analysis (of which 22 provided IPD) and 26 in the narrative synthesis. Most studies had an element of bias in their design or reporting. Sex was not associated with critical care or death. Compared with CYP aged 1-4 years (reference group), infants (aged <1 year) had increased odds of admission to critical care (OR 1.63 (95% CI 1.40-1.90)) and death (OR 2.08 (1.57-2.86)). Odds of death were increased amongst CYP over 10 years (10-14 years OR 2.15 (1.54-2.98); >14 years OR 2.15 (1.61-2.88)).The number of comorbid conditions was associated with increased odds of admission to critical care and death for COVID-19 in a step-wise fashion. Compared with CYP without comorbidity, odds ratios for critical care admission were: 1.49 (1.45-1.53) for 1 comorbidity; 2.58 (2.41-2.75) for 2 comorbidities; 2.97 (2.04-4.32) for ≥3 comorbidities. Corresponding odds ratios for death were: 2.15 (1.98-2.34) for 1 comorbidity; 4.63 (4.54-4.74) for 2 comorbidities and 4.98 (3.78-6.65) for ≥3 comorbidities. Odds of admission to critical care were increased for all co-morbidities apart from asthma (0.92 (0.91-0.94)) and malignancy (0.85 (0.17-4.21)) with an increased odds of death in all co-morbidities considered apart from asthma. Neurological and cardiac comorbidities were associated with the greatest increase in odds of severe disease or death. Obesity increased the odds of severe disease and death independently of other comorbidities. IPD analysis demonstrated that, compared to children without co-morbidity, the risk difference of admission to critical care was increased in those with 1 comorbidity by 3.61% (1.87-5.36); 2 comorbidities by 9.26% (4.87-13.65); ≥3 comorbidities 10.83% (4.39-17.28), and for death: 1 comorbidity 1.50% (0.00-3.10); 2 comorbidities 4.40% (-0.10-8.80) and ≥3 co-morbidities 4.70 (0.50-8.90). INTERPRETATION: Hospitalised CYP at greatest vulnerability of severe disease or death with SARS-CoV-2 infection are infants, teenagers, those with cardiac or neurological conditions, or 2 or more comorbid conditions, and those who are obese. These groups should be considered higher priority for vaccination and for protective shielding when appropriate. Whilst odds ratios were high, the absolute increase in risk for most comorbidities was small compared to children without underlying conditions. FUNDING: RH is in receipt of a fellowship from Kidney Research UK (grant no. TF_010_20171124). JW is in receipt of a Medical Research Council Fellowship (Grant No. MR/R00160X/1). LF is in receipt of funding from Martin House Children's Hospice (there is no specific grant number for this). RV is in receipt of a grant from the National Institute of Health Research to support this work (grant no NIHR202322). Funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript.

Deaths in children and young people in England after SARS-CoV-2 infection during the first pandemic year.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is rarely fatal in children and young people (CYP, <18 years old), but quantifying the risk of death is challenging because CYP are often infected with SARS-CoV-2 exhibiting no or minimal symptoms. To distinguish between CYP who died as a result of SARS-CoV-2 infection and those who died of another cause but were coincidentally infected with the virus, we undertook a clinical review of all CYP deaths with a positive SARS-CoV-2 test from March 2020 to February 2021. The predominant SARS-CoV-2 variants were wild-type and Alpha. Here we show that, of 12,023,568 CYP living in England, 3,105 died, including 61 who were positive for SARS-CoV-2. Of these deaths, 25 were due to SARS-CoV-2 infection (mortality rate, two per million), including 22 due to coronavirus disease 2019-the clinical disease associated with SARS-CoV-2 infection-and 3 were due to pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. In total, 99.995% of CYP with a positive SARS-CoV-2 test survived. CYP older than 10 years, Asian and Black ethnic backgrounds and comorbidities were over-represented in SARS-CoV-2-related deaths compared with other CYP deaths. These results are important for guiding decisions on shielding and vaccinating children. New variants might have different mortality risks and should be evaluated in a similar way.

Effectiveness and tolerability of mirabegron in children with overactive bladder: A retrospective pilot study.

AIMS: Mirabegron has promising results for OAB symptoms in adults, although the potential for cardiovascular side effects has caused concern. Efficacy and tolerability in children have not been extensively studied. Effectiveness, tolerability, and side effects of Mirabegron are reported in children with refractory OAB. METHODS: A retrospective review of children receiving Mirabegron between February 2014 and November 2018 was completed. Frequency, urgency, nocturnal (NE), and daytime incontinence (DI) were analyzed at baseline and 6 months. RESULTS: 70 children (50 females), median age 15 [range 8-16] years, commenced Mirabegron 25 mg (n = 29) or 50 mg (n = 41). 37 (53%) were still receiving treatment at 6 months: monotherapy n = 30, and combination therapy n = 7 (Solifenacin n = 4, Desmopressin n = 2, both n = 1). Where undertaken, blood pressure monitoring and ECGs were normal. For patients on monotherapy, 6 of 17 (35%) had improvement in NE, 11 of 19 (58%) in DI, 12 of 20 (60%) in frequency, and 8 of 21 (38%) in urgency symptoms. For patients receiving combination therapy, 2 of 6 (33%) had improvement in NE, 2 of 4 in DI (50%), 2 of 4 (50%) in frequency, and 4 of 6 (67%) had improvement in urgency. Reasons for treatment discontinuation (entire cohort) were: ineffectiveness (n = 28), worse symptoms (n = 4) and/or adverse reactions (n = 7), including dry mouth (n = 2), headaches (n = 4), dizziness (n = 1), nausea/vomiting (n = 3), increased seizures (n = 1), and rash (n = 1). CONCLUSION: Mirabegron improved symptoms in 70% of patients with refractory OAB. A prospective RCT should be the next step to establish the role of Mirabegron for the treatment of OAB in children. LEVEL OF EVIDENCE: Level II.

Surgical management of genitourinary lichen sclerosus et atrophicus in boys in England: A 10-year review of practices and outcomes.

INTRODUCTION: Circumcision has long been the mainstay of management for genitourinary lichen sclerosus et atrophicus (LS); however, there has been growing interest in surgical techniques that preserve the foreskin. OBJECTIVE: The aim of this study was to assess population-based surgical management of LS in England and determine surgical outcomes. STUDY DESIGN: Cases of LS treated in English NHS trusts (2002-2011) were extracted from the Hospital Episode Statistics (HES) Database. Cases were identified by both an ICD-10 code for LS and either an OPCS4.6 code for circumcision or preputioplasty (with/without injection of steroid). Subsequent admissions were analysed for related complications/procedures. Data are presented as median (interquartile range) unless otherwise stated. RESULTS: 7893 patients had surgery for LS, of whom 7567 (95.8%) underwent circumcision (Table). Primary preputioplasty was performed in 326 (4.1%) in 44/130 centres; of these 151/326 had concomitant injection of steroid. Age at surgical intervention was 9 (6-11) years. There were no postoperative bleeds following preputioplasty. Of those treated with preputioplasty, 74 (22%) had subsequent circumcision at a median of 677 (277-1203) days post operation. Concomitant steroid injection reduced the risk of subsequent circumcision (21/151 (14%) vs. 53/175 (30%), p < 0.001). More children underwent a second operative procedure following preputioplasty than those having had a primary circumcision (27.9% vs. 7.9%, p < 0.001). CONCLUSION: Although circumcision is the predominant treatment for LS, these data suggest that preputioplasty is a valid option in management, albeit with a higher re-intervention rate. Selection bias may play a role and a randomized controlled trial is needed. Preputioplasty combined with steroid injection appears to reduce the chance of completion circumcision.

Population-level surgical outcomes for infantile hypertrophic pyloric stenosis.

OBJECTIVES: Determine national outcomes for pyloromyotomy; how these are affected by: (i) surgical approach (open/laparoscopic), or (ii) centre type/volume and establish potential benchmarks of quality. METHODS: Hospital Episode Statistics data were analysed for admissions 2002-2011. Data presented as median (IQR). RESULTS: 9686 infants underwent pyloromyotomy (83% male). Surgery was performed in 22 specialist (SpCen) and 39 nonspecialist centres (NonSpCen). The proportion treated in SpCen increased linearly by 0.4%/year (r=0.76, p=0.01). Annual case volume in SpCen vs. NonSpCen was 40 (24-53) vs. 1 (0-3). Time to surgery was shorter in SpCen (1day [1, 2] vs. 2 [1-3]), but total stay equal (4days [3-6]). 137 (1.4%) had complications requiring reoperation (wound problem 0.6%; repeat pyloromyotomy 0.5% and perforation, bleeding or obstruction 0.2%): pooled rates were similar between SpCen and NonSpCen (1.4% vs. 1.6%, p=0.52). Three NonSpCen had >5% reoperations (within 99.8% C.I. as small denominators). There was no relationship between reoperation and centre volume. Laparoscopic pyloromyotomy had increased risk of repeat pyloromyotomy (OR 2.28 [1.14-4.57], p=0.029). CONCLUSIONS: Pyloric stenosis surgery shifted from centres local to patients, but outcomes were unaffected by centre type/volume. Modest reported benefits of laparoscopy appear offset by increased reoperations. Quality benchmarks could be set for reoperation <4%. TYPE OF STUDY: Treatment Study. LEVEL OF EVIDENCE: Level III.

Hypospadias surgery in England: Higher volume centres have lower complication rates.

INTRODUCTION: Hypospadias surgery has progressed steadily over recent years. There remains considerable variation in the operative management of boys with hypospadias in the UK, and it is therefore difficult to identify acceptable standards with regards to reoperation rates. OBJECTIVE: To determine the frequency of reoperations and complications from all centres performing hypospadias surgery in England and to identify variables that influence outcome. METHODS: All children undergoing NHS hypospadias surgery in England between 1999 and 2009 were identified using the Hospital Episode Statistics database. Patient demographics, centre type, and associated diagnostic (ICD-10) and treatment codes (OPCS4.6) were collected for both primary repairs and postoperative complications. Centres were classed as high volume if they performed an average of 20 or more operations a year. Operative complications were split into revisions (repeat repairs), repairs of urethral fistulae, repairs of meatal stenosis, or urethral stricture repairs. Statistical analysis included logistic regression, Spearman's correlation, and Mann-Whitney U for non-parametric data, with p < 0.05 taken as significant. Data are presented as median (interquartile range) unless otherwise stated. RESULTS: children underwent a total of 23,962 operations at 75 centres in England during the study period. The median age at primary repair was 21 (15-38) months. The overall complication rate was 18.1%. The median complication rate for individual centres was 20.0% (13.9-27.4%) overall; 10.8% (4.7-15.9%) for revision procedures, 8.1% (5.5-11.7%) for urethral fistulae, 2.3% (1.1-3.7%) for meatal stenosis repairs, and 1.8% (0-2.8%) for urethral strictures. High volume centres had significantly lower complication rates than low volume centres (17.5% vs. 25%, p = 0.01) (Figure), and this was proven to be an independent predictor of outcomes (p = 0.01). Staged repairs were associated with more complications (p < 0.001); however, patient age and centre type were not. Median time to repair of complication was 13 (8-22) months. DISCUSSION: This national population-based study used hospital episode statistics data. While accuracy is high and it has been validated for use in research, it has intrinsic limitations which affect our study. We are unable to fully account for the severity of hypospadias or the number of operating surgeons within institutions. CONCLUSIONS: This study has found a clear relationship between caseload volume and complications following hypospadias surgery. Furthermore, there is significant variability between centres in terms of their surgical outcomes. Taken together these results suggest that surgeons, particularly those in centres with small caseloads should assess their results against such benchmarks when evaluating the service they provide.

Isolation of Enteric Nervous System Progenitor Cells from the Aganglionic Gut of Patients with Hirschsprung's Disease.

Enteric nervous system progenitor cells isolated from postnatal human gut and cultured as neurospheres can then be transplanted into aganglionic gut to restore normal patterns of contractility. These progenitor cells may be of future use to treat patients with Hirschprung's disease, a congenital condition characterized by hindgut dysmotility due to the lack of enteric nervous system ganglia. Here we demonstrate that progenitor cells can also be isolated from aganglionic gut removed during corrective surgery for Hirschsprung's disease. Although the enteric nervous system marker calretinin is not expressed in the aganglionic gut region, de novo expression is initiated in cultured neurosphere cells isolated from aganglionic Hirschsprung bowel. Furthermore, expression of the neural markers NOS, VIP and GFAP also increased during culture of aganglionic gut neurospheres which we show can be transplantation into cultured embryonic mouse gut explants to restore a normal frequency of contractility. To determine the origin of the progenitor cells in aganglionic region, we used fluorescence-activated cell sorting to demonstrate that only p75-positive neural crest-derived cells present in the thickened nerve trunks characteristic of the aganglionic region of Hirschsprung gut gave rise to neurons in culture. The derivation of enteric nervous system progenitors in the aganglionic gut region of Hirschprung's patients not only means that this tissue is a potential source of cells for future autologous transplantation, but it also raises the possibility of inducing the differentiation of these endogenous cells in situ to compensate for the aganglionosis.

Early cholecystectomy in children with gallstone pancreatitis reduces readmissions.

BACKGROUND: Multiple guidelines exist in adult practice regarding the timing of cholecystectomy for gallstone pancreatitis. Current evidence to support their application to pediatric practice is minimal. This study sought to determine the effect of timing of cholecystectomy for gallstone pancreatitis in children on the risk of readmission. METHOD: All patients younger than 19years of age presenting to an acute NHS trust in England with a diagnosis of gallstone pancreatitis between 1 January 1999 and 31st December 2009 were included. Patient level data were extracted from the English Hospital Episode Statistic Database. ICD10, OPCS4.6 and hospital administrative data were used to determine: diagnosis, age, associated comorbidities and subsequent procedures performed. RESULTS: 670 cases of gallstone related pancreatitis were recorded in younger than 19 years old between 1999 and 2009 resulting in 3 deaths during this period. The majority (534/670) underwent a cholecystectomy which was performed less than two weeks from primary admission in 33% (174/534) of cases. Cholecystectomy within two weeks provides an actual risk reduction (ARR) of readmission of 57.5% (95% CI 50.1 to 64.4%, p<0.0001, NNT 2). No significant difference was identified in operative complications or mortality following early cholecystectomy in this group (p>0.05). CONCLUSIONS: Readmissions can be significantly reduced in this population by performing a cholecystectomy within two weeks with no apparent rise in surgical complications.

Symptomatic ureteric triplex in a child.

We describe a case of a triplex system in a 4-year-old girl that was associated with a ureterocele and vesicoureteric reflux and causing symptomatic culture-proven urinary tract infections. Undetected on preoperative ultrasound imaging and micturating cystourethrogram, this was discovered at the time of a planned left heminephrectomy. The redundant system having been removed the patient is now asymptomatic.

Hemophagocytic lymphohistiocytosis mimicking surgical symptoms and complications: lessons learned from four cases.

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is a severe immunological disorder that leads to a massive inflammatory reaction that may prove rapidly fatal. We show that HLH may present by masquerading as surgical disease or as a postoperative complication leading to delays in diagnosis and treatment. STUDY DESIGN: A case series of four children with acute surgical presentation and prolonged unexplained postoperative sepsis, who were diagnosed with HLH. RESULTS: Four children with different clinical presentations (1. neonatal abdominal distension, 2. ileostomy closure and Hirschsprung's disease, 3. iatrogenic sigmoid perforation and Crohn's disease, and 4. streptococcal toxic shock syndrome with primary peritonitis) were diagnosed with HLH at our regional pediatric surgical centre in the last two years. All developed signs of prolonged postoperative sepsis with hepatosplenomegaly and pancytopenia, requiring intensive care support. In the absence of explanation for their symptoms and deteriorating clinical condition, a total of six 'negative' exploratory laparotomies were performed. Eventually, HLH was diagnosed with bone marrow aspiration after an average of 23 days (range 17-40), following the finding of significantly elevated ferritin (up to 293150 ng/ml) and triglyceride levels. All children improved with initiation of high-dose steroid treatment followed by etoposide and cyclosporin. CONCLUSION: HLH may rarely present with symptoms and signs of surgical disease or complicate post-operative recovery. This diagnosis should be considered in children with unexplained prolonged fever, hepatosplenomegaly and pancytopenia, especially if associated with high ferritin levels. HLH can prove rapidly fatal without appropriate treatment.

Stem cells derived from neonatal mouse kidney generate functional proximal tubule-like cells and integrate into developing nephrons in vitro.

We have recently shown that kidney-derived stem cells (KSCs) isolated from the mouse newborn kidney differentiate into a range of kidney-specific cell types. However, the functionality and integration capacity of these mouse KSCs remain unknown. Therefore, the main objectives of this study were (1) to determine if proximal tubule-like cells, generated in vitro from KSCs, displayed absorptive function typical of proximal tubule cells in vivo, and (2) to establish whether the ability of KSCs to integrate into developing nephrons was comparable with that of metanephric mesenchyme (MM), a transient population of progenitor cells that gives rise to the nephrons during kidney organogenesis. We found that proximal tubule-like cells generated in vitro from mouse KSCs displayed megalin-dependent absorptive function. Subsequently, we used a chimeric kidney rudiment culture system to show that the KSCs could generate proximal tubule cells and podocytes that were appropriately located within the developing nephrons. Finally, we compared the ability of KSCs to integrate into developing kidneys ex vivo with that of metanephric mesenchyme cells. We found that KSCs integrated into nascent nephrons to a similar extent as metanephric mesenchyme cells while both were excluded from ureteric bud branches. Our analysis of the behavior of the two cell types shows that some, but not all KSC characteristics are similar to those of the MM.

Regulation of progenitor cell proliferation and neuronal differentiation in enteric nervous system neurospheres.

Enteric nervous system (ENS) progenitor cells isolated from mouse and human bowel can be cultured in vitro as neurospheres which are aggregates of the proliferating progenitor cells, together with neurons and glial cells derived from them. To investigate the factors regulating progenitor cell proliferation and differentiation, we first characterised cell proliferation in mouse ENS neurospheres by pulse chase experiments using thymidine analogs. We demonstrate rapid and continuous cell proliferation near the neurosphere periphery, after which postmitotic cells move away from the periphery to become distributed throughout the neurosphere. While many proliferating cells expressed glial markers, expression of the neuronal markers ß-tubulin III (Tuj1) and nitric oxide synthase was detected in increasing numbers of post-mitotic cells after a delay of several days. Treatment of both mouse and human neurospheres with the γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) reduced expression of the transcription factors Hes1 and Hes5, demonstrating inhibition of Notch signaling. DAPT treatment also inhibited progenitor cell proliferation and increased the numbers of differentiating neurons expressing Tuj1 and nitric oxide synthase. To confirm that the cellular effects of DAPT treatment were due to inhibition of Notch signaling, siRNA knockdown of RBPjκ, a key component of the canonical Notch signaling pathway, was demonstrated both to reduce proliferation and to increase neuronal differentiation in neurosphere cells. These observations indicate that Notch signaling promotes progenitor cell proliferation and inhibits neuronal differentiation in ENS neurospheres.

Future therapies for Hirschsprung's disease.

The current management of Hirschsprung's disease (HSCR) is still associated with significant long-term morbidities despite on-going refinements in surgical care. Over the course of the past 20 years, significant inroads have been made in our understanding of the development of the enteric nervous system and what factors are responsible for the development of HSCR. This has prompted increased interest in the possibility of using this knowledge to develop new alternative and adjunctive therapies for HSCR. The aim of this review is to provide an overview of the current progress being made toward the development of future therapies to improve the outcome for children with HSCR.