Immunosuppression In Children Research Articles

Serum IgG and IgA level in children with acute lymphoblastic leukaemia and its relation with outcome in induction chemotherapy

Background: Immunosuppression in children with Acute Lymphoblastic Leukaemia (ALL) escalates vulnerability to severe infectious complications which leads to higher morbidity and mortality rates among patients. Immunoglobulins are important part of defence mechanism of the body contributing to the humoral immunity. Of all the immunoglobulins, IgG and IgA represents most common type of antibody in blood circulation and provides most long-lived antibody-based immunity against invading pathogens. In earlier years, studies have shown that, serum immunoglobulins are found to be decreased during chemotherapy and this reduction is related with severe sepsis and death in patients. Early identification of immune status can be much useful for assessment of severity and better risk stratification of the patients. Objective: Evaluation of serum IgG and IgA levels in children with ALL and its relationship with sepsis in induction phase of chemotherapy. Method: This prospective observational study was conducted in the Departments of Paediatric Haematology & Oncology and Department of General Paediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka. During January 2022 to December 2022, a total 60 paediatric patients of newly diagnosed ALL were included as study population. As control, 30 patients were included in this study from General paediatrics and Paediatric Haematology & Oncology, BSMMU to compare baseline immunoglobulin levels with the study group. Complete history and physical examination of all patients were undertaken, and all prior reports were collected. Serum IgG and IgA level assay was done before starting chemotherapy and at the end of induction chemotherapy in the study group. Patients diagnosed with ALL received chemotherapy modified UK-ALL 2003 protocol. History and data of any event of sepsis, along with the symptoms of complications were taken from all patients during the course of induction chemotherapy. Results: The mean age of the cases were 5.49±3.15 (mean ± SD) years, which ranged from 1.9 to 15 years. Among the cases, 41 patients (68.3%) were male and 19 (31.7%) females. Seven (11.7%) subjects expired during induction chemotherapy. In comparison to the control group the mean IgG level in the study group was lower at baseline and even lower at the end of induction and it was statistically significant (p<0.05). The mean IgG level was low in patients with septic events in comparison with the patients with no septic events. Difference of mean of IgG between septic and aseptic patients was significant only at the end of induction chemotherapy (p<0.05). The mean IgA level was low in study group in comparison with the control group and it was statistically significant (p<0.05) only at the end of induction chemotherapy. The mean IgA level was low in patients with septic events in comparison with the patients with no septic events. Difference of mean of IgA between septic and aseptic patients was significant (p<0.05). Based on the receiver-operator characteristic (ROC) curves of change of S. IgG, with a cut off value 50% decreased from baseline having 68.8% sensitivity and 29.7% specificity for prediction of sepsis. Considering change of S. IgA with a cut off value 50% decreased from baseline having 67.6% sensitivity and 27.5% specificity for prediction of sepsis. Conclusion: In our study, the mean IgG and IgA level of the cases were low in comparison to the control group. The mean IgG and IgA level of the patients were lower who had infectious complications, and it was more marked after induction chemotherapy. Therefore, evaluation of immunoglobulin profiles is recommended to be considered in patients with ALL in further studies.

Feasibility of discontinuing immunosuppression in children with idiopathic nephrotic syndrome.

Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed. This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded. Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8months (IQR 24.6-71.2months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006-4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944-0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use. Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants. Not applicable.

Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Due to a lack of evidence, treatment recommendations are based on expert opinion, resulting in variation. The aim of this study was to describe the clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy-proven IgAVN in order to identify prognostic risk factors and signals of treatment efficacy. Retrospective data were collected on 1148 children with biopsy-proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analysed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow-up. The median follow-up was 3.7 years (interquartile range 2-6.2). At last follow-up, 29% of patients had an eGFR <90mL/min/1.73 m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second-line immunosuppressive regimen being superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow-up. In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly, there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

261. Adaptive Immunosuppression in Children with Septic Shock

Abstract Background Septic children can develop a severe compensatory anti-inflammatory response, termed “immunoparalysis (IP)”, which is strongly associated with adverse outcomes. IP can be defined as a reduced ability of innate immune cells to produce TNFα when whole blood is stimulated ex vivo with LPS (a TNFα response &amp;lt; 200 pg/ml). Adaptive (lymphocyte-based) immune function is poorly understood in IP. We hypothesize that septic children with IP will also have suppressed lymphocyte cytokine production capacity and reduced lymphocyte populations. Methods Single-center, prospective, observational study of children (&amp;lt; 18 yrs) with septic shock. Subjects were enrolled and sampled &amp;lt; 48 hrs from shock onset. Ex vivo whole blood stimulation assays were used to evaluate innate (LPS-induced) and adaptive (PHA-induced) cytokine production capacities (Fig1). Cell populations were measured by flow cytometry (Fig2). Identical sampling and processing were done in a cohort of healthy control children. Data represent median (IQR).Figure 1.Ex-vivo stimulation assays TNFα production after lipopolysacharide (LPS) stimulation (innate immune response) is measured by chemiluminescence (Siemens Healthcare Diagnostics). Cytokine production after phytohemagglutinin (PHA) stimulation (adaptive immune response) is measured by multiplex assay (Biorad). Table 1 Whole blood was stained within 30 minutes of collection and included the cell populations shown above. Samples were acquired on the cytometer within a week of staining and analyzed using FlowJo 10.8.0 software. Results 30 children with septic shock (15 [8,16] yrs; 64% male, 3% mortality) and 11 healthy controls (6 [3,8] yrs; 54% male) were enrolled. Among septic subjects, length of stay was 5 [2,18] days in the ICU and 17 [6, 38] days in the hospital. Etiologies and sites of infection are shown in Fig3. Septic subjects had lower ex vivo PHA-induced cytokine production (Fig4), and relative lymphopenia by flow cytometry vs healthy controls, especially double negative-T cells (3.7% vs 8.4%; p=0.03) and γδ-T cells (2.9% vs 7.6%; p=0.03). 12 septic subjects had IP. Rates of viral detection (50% vs 11%; p=0.03) and viral-bacterial co-detection (63% vs 9%; p=0.04) were higher in the IP group vs non-IP septic subjects. Subjects with IP had lower monocyte HLA-DR expression but no differences in lymphocyte populations. PHA-induced production of Th1 cytokines was lower in those with IP, while production of Th2 cytokines was preserved (Fig5). *Subjects where included in analysis if treated as presumed bacterial infections. Abbreviations: PCR: Polymerase chain reaction; GI: Gastrointestinal; MSSA: Methicillin susceptible S aureus; MRSA: Methicillin resistant S aureus; Rh/E: Rhinovirus/Enterovirus; RSV: Respiratory Syncytial virus; PIV: Parainfluenza Virus.Figure 4.PHA-induced cytokine production capacity in sepsis vs healthy controls Comparisons done by Mann-Whitney U test. Asterisks represent p-value &amp;lt;0.05.Figure 5.PHA-induced cytokine production capacity in children with and without immunoparalysis (IP) Comparisons done by Mann-Whitney U test. Asterisks represent p-value &amp;lt;0.05. Conclusion Children with septic shock have early innate and adaptive immune suppression. Immunoparalysis was associated with skewing to a Th2 profile of cytokine production, and with the presence of viral infections. This approach has the potential to drive enrollment into clinical trials of personalized immunomodulation in this population. Disclosures Mark Hall, MD FCCM, Abbvie: Advisor/Consultant|Kiadis: Honoraria|Partner Therapeutics: complementary study drug Sobi for a clinical trial for which I am the Principal Investigator|Sobi: Complementary study drug for a clinical trial for which I am the Principal Investigator

Pediatric Kidney Transplantation-Can We Do Better? The Promise and Limitations of Epitope/Eplet Matching.

Kidney transplant is the optimal treatment for end-stage kidney disease as it offers significant survival and quality of life advantages over dialysis. While recent advances have significantly improved early graft outcomes, long-term overall graft survival has remained largely unchanged for the last 20 years. Due to the young age at which children receive their first transplant, most children will require multiple transplants during their lifetime. Each subsequent transplant becomes more difficult because of the development of de novo donor specific HLA antibodies (dnDSA), thereby limiting the donor pool and increasing mortality and morbidity due to longer time on dialysis awaiting re-transplantation. Secondary prevention of dnDSA through increased post-transplant immunosuppression in children is constrained by a significant risk for viral and oncologic complications. There are currently no FDA-approved therapies that can meaningfully reduce dnDSA burden or improve long-term allograft outcomes. Therefore, primary prevention strategies aimed at reducing the risk of dnDSA formation would allow for the best possible long-term allograft outcomes without the adverse complications associated with over-immunosuppression. Epitope matching, which provides a more nuanced assessment of immunological compatibility between donor and recipient, offers the potential for improved donor selection. Although epitope matching is promising, it has not yet been readily applied in the clinical setting. Our review will describe current strengths and limitations of epitope matching software, the evidence for and against improved outcomes with epitope matching, discussion of eplet load vs. variable immunogenicity, and conclude with a discussion of the delicate balance of improving matching without disadvantaging certain populations.

Targeting Calcineurin Inhibitor-Induced Arterial Hypertension in Liver Transplanted Children Using Hydrochlorothiazide.

Arterial hypertension (AH) is the most common toxic effect of calcineurin inhibitor (CNI)-based immunosuppression in children after liver transplantation (LT). Activation of the renal sodium chloride cotransporter (NCC) by CNIs has been described as a major cause of CNI-induced AH. Thiazides, for example, hydrochlorothiazide (HCTZ), can selectively block the NCC and may ameliorate CNI-induced AH after pediatric LT. From 2005 thru 2015 we conducted a retrospective, single-center analysis of blood pressure in 2 pediatric cohorts (each n = 33) with or without HCTZ in their first year after LT. All patients received CNI-based immunosuppression. According to AAP guidelines, AH was defined as stage 1 and stage 2. Cohort 1 received an HCTZ-containing regimen to target the CNI-induced effect on the NCC, leading to AH. Cohort 2 received standard antihypertensive therapy without HCTZ. In children who have undergone LT and been treated with CNI, AH overall was observed less frequently in cohort 1 vs cohort 2 (31% vs 44%; ns). Moreover, severe AH (stage 2) was significantly lower in cohort 1 vs 2 (1% vs 18%; p < 0.001). Multivariate analysis revealed HCTZ as the only significant factor with a protective effect on occurrence of severe stage 2 AH. While monitoring safety and tolerability, mild asymptomatic hypokalemia was the only adverse effect observed more frequently in cohort 1 vs 2 (27% vs 3%; p = 0.013). Targeting NCC by HCTZ significantly improved control of severe CNI-induced AH and was well tolerated in children who underwent LT. This effect may reduce the risk of long-term end-organ damage and improve quality of life.

P011 Sharing is caring: a regional service development project exploring secondary immunosuppression in children

Abstract Background/Aims The range of approved immunosuppressive and immunomodulatory (IM) agents has grown considerably with an increasing list of indications across paediatric specialties. At present, there is limited evidence supporting best practice for prescribing and monitoring of IM agents in children and young people (CYP). We present a staged service development project exploring cross-specialty prescribing and monitoring of IM agents at a tertiary children’s hospital (Great North Children’s Hospital, GNCH) and data sharing with local hospitals across northeast England. Methods In Phase 1, we searched pharmacy databases and surveyed specialty teams in GNCH to identify clinicians regularly prescribing IM agents to CYP over a twelve-month period. Phase 2 was a cross-specialty retrospective case-notes review of prescribing, monitoring and infection surveillance in a representative sample of CYP on IM agents. Phase 3 explored information sharing with six other hospitals in the region and acute presentations to these sites involving CYP on IM agents. Results Phase 1 identified 9 paediatric and 2 adult specialties prescribing IM agents to 416 CYP. 32 discrete IM therapies were prescribed with significant between-specialty overlap in drugs prescribed but a wide range of prescribing and monitoring practices. Phase 2 assessed 77 CYP on IM agents in detail - 57% were prescribed &amp;gt;1 IM agent, 100% had FBC measured at least once (range once only to weekly), 18% developed lymphopenia at least once and 40% were prescribed prophylactic antibiotics. Previous varicella exposure had been assessed in 70%. Phase 3 data are summarised in Table 1. P011 Table 1:Information sharing and acute presentations to regional hospitals local to immunosuppressed patientsTotal number of patients141Mean age in years (range)11 (2 - 17)NDiagnosisJIA without uveitis108JIA with uveitis9Uveitis alone8Systemic JIA4Period fever4Behçet’s disease2Juvenile dermatomyositis2Scleroderma1Juvenile systemic lupus erythematosus1Mixed connective tissue disease1Granulomatosis with polyangiitis1Immunosuppressive or immunomodulatory agent usedAdalimumab65Methotrexate42Tocilizumab22Mycophenolate mofetil10Etanercept10Infliximab5Sulfasalazine5Prednisolone4Abatacept4Leflunomide4Canakinumab2Colchicine2Anakinra2Rituximab2Cyclophosphamide1Number of immunosuppressive or immunomodulatory agents per patient3 agents52 agents441 agent92Number of acute presentations by diagnosis or presenting complaint (n = 19)Fever4Chickenpox4Viral upper respiratory tract infection2Joint pain2Abdominal pain2Rash2Eye infection1Tonsilitis1Wheeze1Yes (%)No (%)Named local consultant (n = 129)3763Correct diagnosis recorded locally (n = 130)8020Correct immunosuppressive or immunomodulatory agent recorded locally (n = 130)5050Open access for febrile illness (n = 116)4159Reviewed in past 2 years for acute illness (n = 109)1783Note: presented numbers for immunosuppressive or immunomodulatory agents are not mutually exclusive. JIA, juvenile idiopathic arthritis Conclusion IM agents are central to modern paediatric clinical care across a wide range of diseases. This staged project identified significant variation in IM prescribing and monitoring practice between specialties at GNCH. Communication between specialty and local teams is inadequate. Particular areas of concern include limited diagnostic, blood monitoring and medication information sharing and limited local information governing management of intercurrent illness and vaccination. Although different disease processes can necessitate different advice and prescribing practices, sharing examples of good practice will minimise unnecessary variation. We propose the development of a regional immunosuppression working group to improve quality and safety across our region. Disclosure J.L. Bennett: None. C. Tsilifis: None. A. Flinn: None. T. Altmann: None. N. Jansen: None. H. Tumelty: None. K. Aitken: None. S. Bhopal: None. E. Harrison: None. S. Ravenscroft: None. E. Sen: None. E. Williams: None. T. Flood: None. S. Sampath: None. A. Battersby: None. F. McErlane: None.

Immunization status and re-immunization of childhood acute lymphoblastic leukemia survivors

ABSTRACT Intensive chemotherapy can cause long-lasting immunosuppression in children who survived cancer. The immunosuppression varies according to the type of cancer, intensity of chemotherapy and age of the patient. A sufficient immune reconstruction when has been completed in childhood cancer survivors, the re-vaccination program can achieve sufficient antibody levels for some of the life-threatening vaccine-preventable infectious diseases. This study evaluates the serological status of pediatric acute lymphoblastic leukemia (ALL) cases before and after the intensive chemotherapy treatment. Antibodies against measles, mumps, rubella, varicella, hepatitis A and B were tested with the enzyme-linked immunosorbent assay (ELISA) method. Antibody titers were measured firstly at the leukemia diagnosis time when the chemotherapy was not started. The second evaluation of antibody titers was studied at 6 months after the cessation of chemotherapy for all patients. Forty-six patients with the mean age of 6.1 ± 4.5 years were participated in this study. Changing to seronegative after treatment was significantly different in measles, rubella, hepatitis A and hepatitis B (p < .05). Seventy-eight (28%) antibody levels in the patients were non-protective for all diseases. Only three (7%) patients had protective antibody levels for all diseases in the sixth month of chemotherapy cessation. There was a negative correlation between patient’s age and losing protective antibody levels for any vaccine-preventable disease (p < .05). Antibody levels against vaccine-preventable diseases have evident that reduced after ALL treatment at childhood. Pediatric ALL survivors must be re-vaccinated for vaccine-preventable diseases after achieving immune reconstruction.

Long-term renal survival and undetected risk factors of IgA nephropathy in Chinese children-a retrospective 1243 cases analysis from single centre experience.

The long-term renal outcome for IgA nephropathy (IgAN) in large cohorts of children remains unclear. IgAN is a progressive disease, to explore novel biomarkers is necessary for predicting the disease activity and progression of IgAN. In addition, there is a hot debate on when to treat with immunosuppression in children. We aimed to confirm the long-term renal survival, find some undetected risk factors and investigate when to treat with immunosuppression can benefit for renal outcome in Chinese children. 1243 Children with IgAN were enrolled and a follow-up of at least 1year after a biopsy from 2000 to 2017. Long-term renal survival, undetected risk factors and the renal survival of immunosuppressive and non-immunosuppressive therapy were evaluated. The primary endpoint of the study was a combined outcome of either ≥50% reduction in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD) or death. The median follow-up time were 86.8months (interquartile range 54.7-140.2months). The 5-, 10- and 15-year renal survival rates were 95.3%, 90.3% and 84%, respectively. Cox multivariate regression and Kaplan-Meier analysis showed that hypertension, hyperuricemia, high 24h urine protein (24h-UP) levels, lower initial eGFR, high urine C3 levels, high retinol-binding protein (RBP) levels, segmental glomerulosclerosis (S) and tubular atrophy and interstitial fibrosis (T) were associated with renal outcome. The statistically significant predictive perfect power for renal outcome was RBP≥0.7µg/ml (AUC = 0.899, sensitivity = 84.00%, specificity = 86.00%), 24h-UP ≥ 1g/24h (AUC = 0.722, sensitivity = 84.20%, specificity = 52.70%), eGFR<60ml/min/1.73m2 (AUC = 0.718, sensitivity = 81.30%, specificity = 39.20%) and S1 lesion (AUC = 0.703, sensitivity = 75.50%, specificity = 65.10%).Children with urinary RBP ≥0.7µg/ml were associated with a 2.513-fold risk than patients with urinary RBP<0.7µg/ml (P = 0.003). Our study suggested that immunosuppressive therapy may reduce the risk of progression in IgAN children had both eGFR>50ml/min/1.73m2 and proteinuria of at least 1g/day. This is the first report that the 15-year renal survival rate of children with IgAN in China was 84%. At the same time, this is the first study to reveal that urinary RBP≥0.7µg/ml may indicate a poor renal outcome. In addition, this study supports immunosuppressive therapy for IgAN children had both proteinuria≥1g/day and initial eGFR>50ml/min/1.73m2.

P1802EVALUATION OF THE GENETICAL FEATURES AFFECTING THE RENAL OUTCOMES IN CHILDREN WITH STEROID RESISTANT NEPHROTIC SYNDROME

Abstract Background and Aims Nephrotic syndrome in childhood is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Although most children respond to glucocorticoid therapy, approximately 10% of patients turn out to be steroid resistant (steroid-resistant nephrotic syndrome [SRNS]). Although several studies in children with SRNS have shown that mutations in genes encoding proteins in the podocyte skeleton may be responsible for the etiology in only one-third of cases, the genetic features related with renal prognosis and response to immunosuppressive agents are not fully recognized. The aim of this study was to investigate the genomic alterations associated with renal prognosis and resistance to immunosuppression in children with SRNS. Method The children with SRNS were enrolled in this study. Custom gene panel was designed for next-generation sequencing analysis of more than 20 target genes (ABCB1, ABCC2, CTLA4, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, FOXP3, GSTP1, IMPDH1, IMPDH2, NOS3, NR3C1, SLCO1B1, SLCO1B3, TPMT, UGT1A9, UGT2B7) and 200 single nucleotide variants (SNVs) which were reported as implicated in renal prognosis of nephrotic syndrome. The target gene panel was enriched for drug metabolism regulating transporters and enzymes. Results A total of 25 children, 16 boys (64%), median age at last visit 17.5 years (13-18 years), median age at diagnosis 7.5 years (2-15), median follow-up 9.58±4.54 years, were included in the study. All patients were diagnosed focal segmental glomerulosclerosis on renal biopsy.

Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy (POSITIVE Study): The Collaboration and Design of a National Transplant Precision Medicine Program.

BackgroundDespite age-related differences in biology, physiology, and behavior, transplant immunosuppression is not tailored by age. This likely contributes to high graft failure and posttransplant complications. We present the aims, design, and methods of the Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy Study aimed at personalizing posttransplant immunosuppression in children and young adults.MethodsIn this prospective observational cohort study, we recruited pediatric and young adult solid organ transplant, pediatric allogeneic hematopoietic stem cell transplant recipients, and matched living and deceased organ donors from 14 transplant centers across Canada. Clinical data, questionnaires, biospecimens, and pharmacy records were collected at serial time points: (1) to identify genetic and host immune factors that influence immunosuppression dose requirements across different ages and transplant types, (2) to identify viral-host interactions that increase susceptibility to Epstein-Barr virus infection, and (3) to define care processes and structures associated with medication adherence in adolescents and young adults.ResultsFrom 2015 to 2018, 1662 new and prevalent transplant recipients were screened, 1166 were recruited for the various aims, including 370 liver, 445 kidney, 277 heart, 19 lung, 19 multiple, and 36 hematopoietic stem cell transplant transplants. Twelve percent were younger than 2 years, 30% were 2 to 10 years, 42% were 10 to 18 years, and 16% were 18 to 24 years at enrollment. Nine hundred thirty-one consented to participation in aims 1 and 2 (90% consent rate), 287 to aim 3 (82% consent rate). Biospecimens collected included 898 for DNA, 276 for immunoassays, and 717 for biomarker studies. Seventy percent participants have completed follow-up; 30% are pending study completion.ConclusionsThe design of this national multicenter cross-organ network helped maximize recruitment of a large patient cohort for studying age and organ-related differences in immunosuppression needs that would not otherwise be feasible. Leveraging the unique clinical, biological, environmental, and behavioral characteristics of this cohort will help develop precision medicine strategies for individualizing posttransplant immunosuppression.

Characteristics of pediatric recurrent erythema multiforme.

Erythema multiforme (EM) is an acute condition characterized by distinctive target lesions of the skin often accompanied by mucosal ulcers. A subset of individuals experience frequent episodes of recurrent EM, which is rare and poorly understood, especially in children. To characterize clinical features, laboratory findings, and treatment responses of pediatric recurrent EM. A retrospective chart review was conducted at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin (2000-2015) and the Mayo Clinic in Rochester, Minnesota (1990-2015). Inclusion criterion was a diagnosis before age 18 years with recurrent EM, defined as a symmetrically distributed, fixed eruption, including target lesions, with or without mucous membrane involvement, occurring on at least three occasions. A literature review was conducted to include individuals who met the inclusion criterion. Twenty-six patients were included, of whom 16 (62%) were male. The median age of onset was 9.1years (range 0-15.7years). Nine patients (35%) required hospitalization. Herpes simplex virus testing was positive in 9 of 17 (65%) patients. Remission was achieved in 5 of 16 (31%) patients while taking suppressive antivirals. Eight patients received continuous anti-inflammatory treatment, two (25%) of whom experienced remission. This study of pediatric recurrent EM found a greater male predominance, more hospitalizations, fewer cases caused by herpes simplex virus, and alower response to immunosuppression in children than in the general population.

Immunosuppression in pediatric liver transplant recipients: Unique aspects.

Pediatric liver transplantation has experienced improved outcomes over the last 50 years. This can be attributed in part to establishing optimal use of immunosuppressive agents to achieve a balance between minimizing the risks of allograft rejection and infection. The management of immunosuppression in children is generally more complex and can be challenging when compared with the use of these agents in adult liver transplant patients. Physiologic differences in children alter the pharmacokinetics of immunosuppressive agents, which affects absorption, distribution, metabolism, and drug excretion. Children also have a longer expected period of exposure to immunosuppression, which can impact growth, risk of infection (bacterial, viral, and fungal), carcinogenesis, and likelihood of nonadherence. This review discusses immunosuppressive options for pediatric liver transplant recipients and the unique issues that must be addressed when managing this population. Further advances in the field of tolerance and accommodation are needed to relieve the acute and cumulative burden of chronic immunosuppression in children. Liver Transplantation 23 244-256 2017 AASLD.

Simple markers for the detection of severe immunosuppression in children with HIV infection in highly resource-scarce settings: experience from the Democratic Republic of Congo

Objectives:The decision to initiate the antiretroviral therapy in HIV-infected children living in poor countries is compromised by lack of resources. The objective of this study is to identify simple clinical and biological markers other than CD4+ count and viral load measurement that could help the decision to introduce antiretroviral treatment and to monitor patients.Methods:A cross sectional study was conducted between January and March 2005 in Kinshasa, Democratic Republic of Congo.Results:Eighty-four children infected with HIV were recruited. In this cohort, the lymphocytes (P = 0.001) and CD4 (P = 0.0001) were significantly lower in children with immunological stage 3 and viral load (P = 0.027) was significantly higher in children at the same immunological stage. Reticulocytes (r = +0.440), white blood cells count (r = +0.560), total lymphocytes (r = +0.675) and albumin (r = +0.381) showed positive significant correlations with CD4. Haemoglobin (r = − 0.372), Haematocrit (r = − 0.248), red blood cells (r = − 0.278) and CD4 (r = − 0.285) showed negative significant correlations with viral load. Neutropaenia (P = 0.02), enlarged nodes (P = 0.005) and oral candidiasis (P = 0.04) were associated with viral load >10 000 copies/ml. Oral candidiasis (P = 0.02) was associated with CD4 level < 15%.Conclusion:Oral candidiasis, enlarged nodes, total lymphocytes count, neutropaenia and albumin predict severe immunodepression. These clinical and biological markers may guide the clinician in making the decision to initiate antiretroviral therapy in highly resource-scarce settings.

Outcome after Discontinuation of Immunosuppression in Children with Autoimmune Hepatitis: A Population-Based Study

Outcome after Discontinuation of Immunosuppression in Children with Autoimmune Hepatitis: A Population-Based Study

Superior outcome using cyclosporin A alone versus cyclosporin A plus methotrexate for post-transplant immunosuppression in children with acute leukemia undergoing sibling hematopoietic stem cell transplantation.

The outcome of cyclosporin A (CSA) alone (n = 19) as graft-versus-host disease (GVHD) prophylaxis was compared to that of CSA combined with methotrexate (MTX) (n = 43) in children with acute leukemia who underwent hematopoietic stem cell transplantation. All respective donors were HLA-identical siblings. All patients received CSA at a dose of 3 mg/kg/day starting on day -1. A CSA level of 80-130 ng/ml was aimed for. The 43 patients in the historical control were given an additional 10 mg/m(2) dosage of MTX on days 1, 3, 6, and 11. Patients who received CSA alone had a significantly reduced cumulative incidence of relapse (5 vs. 40 %; p = 0.002), a significantly increased 5-year event-free survival (84 vs. 35 %; p = 0.001), and a significantly increased 5-year overall survival (84 vs. 42 %; p = 0.004). The incidence of acute GVHD grade II-IV and chronic GVHD in patients in the CSA group was equivalent to the CSA+MTX group (26 vs. 19 %; p = 0.440, and 32 vs. 23 %; p = 0.428). In conclusion, post-transplant immunosuppression consisting of CSA alone is well tolerated and may contribute to a superior outcome.

Effects of sublingual immunotherapy for Dermatophagoides farinae on Th17 cells and CD4+CD25+ regulatory T cells in peripheral blood of children with allergic asthma

Sublingual immunotherapy is becoming a more common treatment for allergic diseases, particularly in pediatric clinics. This type of treatment is highly effective for Dermatophagoides farinae allergy, but the mechanisms resulting in immune tolerance have not been investigated. We explored the effects of sublingual immunotherapy with D. farinae drops on populations of subsets of T immune cells, specifically Th17 cells and CD4(+) CD25(+) regulatory T cells (Treg cells), in peripheral blood of children with allergic asthma. We assessed immune cell populations in 60 patients allergic to D. farinae who were randomly divided into 2 groups: a treatment group (n = 30) and a control group (n = 30), treated with sublingual administration of D. farinae drops or placebo, respectively, for 48 weeks. Clinical symptoms of asthma were scored for each individual before and after treatment, and the percentages of Th17 cells and CD4(+) CD25(+) Treg cells in the peripheral blood were evaluated by flow cytometry at 12-week intervals beginning at baseline. Both the mean daily symptom scores and percentages of Th17 cells significantly declined in the treatment group throughout the study period (p < 0.05), and in the control group both declined but without significant differences between time points. In contrast, the percentages of Treg cells significantly increased in the treatment group throughout the study period (p < 0.05), but no statistical difference was observed among different sampling times. Sublingual administration of D. farinae drops alters T immune cell profiles and reduces asthma symptoms, likely resulting in enhanced immunosuppression in children with asthma.

Outcome after Discontinuation of Immunosuppression in Children with Autoimmune Hepatitis: A Population-Based Study

To assess sustained immunosuppression-free remission (SIFR) in children with autoimmune hepatitis (AIH). We retrospectively reviewed all children with AIH in the region between 1986 and 2011 using a population-based methodology. We identified 56 children with AIH (62.5% females; median age, 11.1years [IQR, 5.7-14.4years], followed for a median of 5.6years [IQR, 2.8-8.6years]). Liver disease was characterized by type II AIH in 8.9%, cirrhosis in 14.0%, and primary sclerosing cholangitis in 21.4%. Coexisting nonhepatic immune-mediated diseases occurred in 37.5%. Biochemical remission on immunosuppressive therapy was achieved in 76.4% of all patients with AIH at a median of 1.2years (IQR, 0.4-3.6years); 23.1% of these patients experienced a subsequent relapse. Discontinuation of all immunosuppressive medications was attempted in 16 patients and was successful in 14 patients (87.5%) with type 1 AIH (median age at discontinuation, 8.9years [IQR, 3.5-17.9years], treated for a median of 2.0years [IQR, 1.3-3.5years] after diagnosis), with SIFR occurring at a median of 3.4years (IQR, 2.6-5.8years) of follow-up. Excluding patients with inflammatory bowel disease who received immunosuppressive therapy independent of their liver disease, the probability of achieving SIFR within 5years of diagnosis of AIH was 41.6% (95% CI, 25.3%-62.9%). Baseline patient characteristics associated with an inability to achieve biochemical remission on immunosuppression or SIFR were elevated international normalized ratio, positive antineutrophil cytoplasmic antibody titer, cirrhosis, and a nonhepatic autoimmune disorder. We found a high rate of successful discontinuation of all immunosuppressive medications in carefully selected patients with AIH in a population-based cohort. SIFR is an achievable goal for children with AIH, particularly those with type I disease in stable biochemical remission on immunosuppressive therapy.

A contemporary analysis of induction immunosuppression in pediatric lung transplant recipients

There is an increasing trend in the use of induction immunosuppression in children undergoing lung transplantation (LTx). To evaluate the effect of this practice on survival, the United Network for Organ Sharing (UNOS) was queried from 1987 to 2012, restricting analysis to transplant patients 6-17 years old from 2001 to 2012, who received no induction (NONE) or induction (INDUCED) with the contemporary agents of basiliximab, alemtuzumab, thymoglobulin, antilymphocyte globulin (ALG), or antithymocyte globulin (ATG). Of 23 951 lung transplants, 330 met inclusion criteria with 177 (54%) being INDUCED. Of the INDUCED agents, 121 (68%) were basiliximab, 3 (2%) alemtuzumab, and 53 (30%) ALG/ATG/thymoglobulin. The mean patient age was 13.6 (SD = 3.2) and 14 (SD = 3.0) years for the INDUCED and NONE groups, respectively. The median survival in the INDUCED group was 77.4 months (95% CI: 46.1, 125.6) compared with 50.8 months (95% CI: 42.9, 61.3) for the NONE (log-rank P-value = 0.3601). The most common cause of death was due to allograft failure or pulmonary complications with only one patient dying from post-transplant lymphoproliferative disorder. The estimated hazard ratio for INDUCED versus NONE was 0.859 (95% CI: 0.620, 1.191; P = 0.3618); there were no significant confounders or effect modifiers among the demographic and clinical variables. In conclusion, antibody-based induction immunosuppression with contemporary agents had a trend toward a protective, but not statistically significant, effect in 6- to 17-year-old patients.

Non‐inflammatory centrilobular sinusoidal fibrosis in pediatric liver transplant recipients under tacrolimus withdrawal

We hypothesized that non-inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living-donor liver transplantation. In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow-up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed. In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant (P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 0-4). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF-improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non-improved patients (P = 0.0245). NICSF might be an indicator of inadequate immunosuppression in long-term followed recipients and its mechanism may be due to immune reactions including humoral immunity.