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Background: Coronavirus disease 2019 (COVID-19) can lead to various complications, including multisystem inflammatory syndrome in children (MIS-C) and post-COVID-19 conditions (long COVID). This study aimed to determine the rates, risk factors and outcomes of MIS-C and long COVID in children previously diagnosed with COVID-19., Methods: This study was a combined retrospective and prospective cohort study. Patients 0-18 years of age diagnosed with COVID-19 or another respiratory virus infection were enrolled between October 2021 and April 2022. Demographic and clinical data were reviewed. Information on persisting symptoms and their impacts were recorded at 1-3, 3-6 and 6-12 months after infection. Laboratory investigations and chest imaging examinations were performed during follow-up. MIS-C and long COVID were defined according to the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) definitions., Results: A total of 618 patients were enrolled, comprising 437 (70.7%) with COVID-19 and 181 (29.3%) with another respiratory virus infection. At 1-3 months, the rate of persisting symptoms was 16.5% in patients with COVID-19, compared with 1.1% in patients with another respiratory virus infection. The rate of MIS-C was 0.7%. The rate of long COVID according to the CDC and WHO definitions were 20.4% and 13.0%, respectively. Respiratory systems were most affected in long COVID. Age 5-18 years, anosmia during COVID-19, history of pneumonia and infection during the delta and omicron waves were associated with long COVID in children., Conclusions: Long COVID after COVID-19 in children is uncommon. Children with anosmia and a history of pneumonia during COVID-19 require follow-up for long COVID., Competing Interests: The study was supported by the National Science and Technology Development Agency, Thailand, the Royal College of Pediatricians of Thailand and the Pediatric Society of Thailand. The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Vaccination can effectively prevent hepatitis B virus (HBV) infection. Vaccination with 3 doses of hexavalent HBV-containing vaccines led to a higher Hepatitis B surface antibody (anti-HBs) antibody level than vaccination with 3 doses of pentavalent HBV-containing vaccines. Whether the substitution of one dose of hexavalent HBV-containing vaccine in the pentavalent regimen could lead to a higher anti-HBs antibody level remains unknown., Methods: A randomized, open-label controlled trial was conducted. Infants 30-120 days of age were randomly assigned to either a combined hexavalent/pentavalent regimen (hexavalent HBV-containing vaccine at 2 months of age and pentavalent HBV-containing vaccine at 4 and 6 months of age) or a 3-dose pentavalent regimen (pentavalent HBV-containing vaccine at 2, 4, and 6 months of age). Anti-HBs antibody levels were measured 3-6 months after the last vaccination., Results: Seventy-six infants were enrolled, 38 in each group. The geometric mean of anti-HBs antibody levels in the combined hexavalent/pentavalent group was significantly higher than that of the 3-dose pentavalent group [316.2 mIU/mL (95% CI: 173.8-575.4 mIU/mL) versus 81.3 mIU/mL (95% CI: 38.9-169.8 mIU/mL), P = 0.006]. By multivariate analysis, the combined hexavalent/pentavalent regimen (coefficient 0.57; P = 0.003) was associated with higher anti-HBs antibody levels, while body weight <10th percentile (coefficient -0.85; P = 0.006) and receiving concomitant pneumococcal conjugated vaccines (coefficient -0.65; P = 0.001) were associated with lower anti-HBs antibody levels., Conclusion: Substituting the first dose with a hexavalent HBV-containing vaccine in the pentavalent regimen for HBV vaccination led to higher anti-HBs antibody levels in infants. Concomitant pneumococcal conjugated vaccine administration may have an adverse impact on anti-HBs antibody level., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Immune reconstitution (IR) kinetics of paediatric patients underwent haploidentical haematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PTCy) have not been extensively studied. We compared IR patterns of children receiving HSCT from haploidentical (n = 92) and HLA-matched donors (n = 36), and analysed risk factors for viral infection in these patients., Methods: We prospectively measured lymphocyte subset numbers before HSCT and at 1, 3, 6 and 12 months after HSCT. Blood cytomegalovirus (CMV), Epstein-Barr virus, adenovirus, BK virus (BKV) and urine adenovirus and BKV viral loads were measured at designated time points., Results: The median numbers of total T and T helper cells at 1 month were significantly lower in the haploidentical group compared with the HLA-matched group. Haploidentical HSCT recipients had significantly lower median numbers of several T cell subsets and B cells for 1 year after HSCT. The median NK cell count of the haploidentical group was lower at 1 month. BKV haemorrhagic cystitis, blood CMV and urine adenovirus reactivation were more frequently found in the haploidentical group. Post-haploidentical HSCT patients receiving anti-T lymphocyte globulin (ATG) had significantly lower median numbers of total T cells (at 1 month) and T helper cells (at 6 and 12 months) and higher rate of blood BKV reactivation compared with those without ATG., Conclusion: Paediatric patients who undergo haploidentical HSCT with PTCy are likely to have delayed IR and an increased risk of viral reactivation/infection compared with HLA-matched HSCT. The addition of ATG to PTCy delayed T cell recovery and increased risk of BKV reactivation., (© 2024 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Globally, cases of children's coronavirus disease 2019 (COVID-19) have been reported since the pandemic started. Most children have an asymptomatic or mild infection. Therefore, the incidence rate of COVID-19 in children might have been underestimated. This study aimed to determine (1) the seroprevalence (and seroconversion rates) of COVID-19, including associated risk factors, in pediatric patients visiting hospitals; and (2) the immunological responses to COVID-19. This was a prospective, cross-sectional study. Patients aged 0-18 years who visited the hospital from September 2020 to February 2022 were included. Demographic, clinical, and laboratory data were reviewed. A total of 1,443 pediatric patients were enrolled. Of these, 323 (22.6%) had a history of COVID-19. In the pre-Delta period, the seroprevalence increased from 4.1% to 70.6% in all included patients and from 0.5% to 10% in patients without a known history of COVID-19 compared with the Delta-Omicron period. The seroconversion rate was 6.8% (19 per 100 person-years) in pediatric patients with COVID-19. Risk factors for COVID-19 seropositivity were respiratory symptoms, being in an outpatient department setting, and infection during the Delta-Omicron period. Exposure to household members with confirmed COVID-19 was a risk factor for seropositivity and seroconversion. Infection during the Delta-Omicron period and testing conducted >2 weeks after the onset of symptoms was associated with spike immunoglobulin (Ig) M and spike and nucleocapsid IgG, respectively. High nucleocapsid IgG levels were associated with pneumonia in pediatric patients with COVID-19. Pediatric patients exposed to household members with COVID-19 and respiratory symptoms should be tested for COVID-19. Nucleocapsid IgG can be used as a surrogate marker to identify patients who may have experienced pneumonia from COVID-19 and as a screening tool for the COVID-19 outbreak, regardless of COVID-19 vaccination status., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pattanakitsakul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: Coronavirus disease 2019 (COVID-19) has become a global pandemic and led to increased mortality and morbidity. Vaccines against the etiologic agent; severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were approved for emergency use on different platforms. In the early phase of the pandemic, Thai healthcare workers (HCWs) received CoronaVac, an inactivated vaccine, as the first vaccine against SARS-CoV-2, followed by ChAdOx1 nCoV-19, a viral vector-based vaccine, or BNT162b2, an mRNA vaccine, as a booster dose. This preliminary study evaluated the immunogenicity of ChAdOx1 nCoV-19 and BNT162b2 as a booster dose in HCWs who previously received two doses of CoronaVac., Methods: Ten HCW participants received ChAdOx1 nCoV-19 and another 10 HCWs received BNT162b2 as a booster dose after two doses of CoronaVac. Anti-RBD IgG, neutralizing antibodies (NAb), and cellular immunity, including interferon-gamma (IFN-γ)-releasing CD4, CD8, double negative T cells, and NK cells, were measured at 3 and 5 months after the booster dose., Results: There was no significant difference in anti-RBD IgG levels at 3 and 5 months between the two different types of booster vaccine. The levels of anti-RBD IgG and NAb were significantly decreased at 5 months. HCWs receiving BNT162b2 had significantly higher NAb levels than those receiving ChAdOx1 nCoV-19 at 5 months after the booster dose. IFN-γ release from CD4 T cells was detected at 3 months with no significant difference between the two types of booster vaccines. However, IFN-γ-releasing CD4 T cells were present at 5 months in the ChAdOx1 nCoV-19 group only., Conclusion: ChAdOx1 nCoV-19 or BNT162b2 can be used as a booster dose after completion of the primary series primed by inactivated vaccine. Although the levels of immunity decline at 5 months, they may be adequate during the first 3 months after the booster dose., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.)

Hematopoietic stem-cell (HSC) transplantation using a donor with a homozygous mutation in the HIV co-receptor CCR5 (CCR5Δ32/Δ32) holds great promise as a cure for HIV-1. Previously, there were three patients that had been reported to be completely cured from HIV infection by this approach. However, finding a naturally suitable Human Leukocyte Antigen (HLA)-matched homozygous CCR5Δ32 donor is very difficult. The prevalence of this allele is only 1% in the Caucasian population. Therefore, additional sources of CCR5Δ32/Δ32 HSCs are required. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas) system is one method to mediate CCR5 knockout in HSCs that has been successfully employed as a gene editing tool in clinical trials. Additional anti-HIV-1 strategies are still required for broad-spectrum inhibition of HIV-1 replication. Here in this study, we combined an additional anti-HIV-1 therapy, which is C46, a cell membrane-anchored HIV-1 fusion inhibitor with the CRISPR/Cas9 mediated knockout CCR5. The combined HIV-1 therapeutic genes were investigated for the potential prevention of both CCR5 (R5)- and CXCR4 (X4)-tropic HIV-1 infections in the MT4CCR5 cell line. The combinatorial CRISPR/Cas9 therapies were superior compared to single method therapy for achieving the HIV-1 cure strategy and shows potential for future applications., (© 2024. The Author(s).)

Human immunodeficiency virus (HIV)-1 infection is an important public health problem worldwide. After primary HIV-1 infection, transcribed HIV-1 DNA is integrated into the host genome, serving as a reservoir of the virus and hindering a definite cure. Although highly active antiretroviral therapy suppresses active viral replication, resulting in undetectable levels of HIV RNA in the blood, a viral rebound can be detected after a few weeks of treatment interruption. This supports the concept that there is a stable HIV-1 reservoir in people living with HIV-1. Recently, a few individuals with HIV infection were reported to be probably cured by hematopoietic stem transplantation (HSCT). The underlying mechanism for this success involved transfusion of uninfected hematopoietic stem and progenitor cells (HSPCs) from CCR5-mutated donors who were naturally resistant to HIV infection. Thus, gene editing technology to provide HIV-resistant HSPC has promise in the treatment of HIV infections by HSCT. In this study, we aimed to find HIV-infected individuals likely to achieve a definite cure via gene editing HSCT. We screened for total HIV proviral DNA by Alu PCR in peripheral blood mononuclear cells (PBMCs) of 20 HIV-infected individuals with prolonged viral suppression. We assessed the amount of intact proviral DNA via a modified intact proviral DNA assay (IPDA) in purified peripheral CD34 + HSPCs. PBMCs from all 20 individuals were positive for the gag gene in Alu PCR, and peripheral CD34 + HSPCs were IPDA-negative for six individuals. Our results suggested that these six HIV-infected individuals could be candidates for further studies into the ability of gene editing HSCT to lead to a definite HIV cure., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: The incidence of coronavirus disease 2019 (COVID-19) in children has been increasing worldwide since the onset of the pandemic. This study examined the risk factors and characteristics of COVID-19 among pediatric patients compared to other respiratory viral infections., Methods: This was a prospective cross-sectional study. Patients aged 0-18 years presenting with respiratory symptoms from October 2020 to December 2021 were included. Demographic and clinical data were reviewed., Results: In total, 738 pediatric patients were enrolled. Of these, 48.5% had COVID-19, and 41.3% were infected with another respiratory virus. The COVID-19 incidence increased from 0.5% during the original strain outbreak (October 2020 to March 2021) to 56.5% and 73.4% during the alpha (April to June 2021) and delta (July to December 2021) periods, respectively. Children aged 6-18 years, being female, obesity, exposure to household members with COVID-19, and the delta period were risk factors for COVID-19. Being aged 1-5 years, obesity, shortness of breath, productive cough, and chest pain were associated with COVID-19 pneumonia. Children aged 5-18 years, underlying neurological disease, a history of COVID-19 pneumonia, and the delta period were associated with long COVID., Conclusions: Pediatric COVID-19 patients presenting with respiratory symptoms who are obese or have been exposed to household members with COVID-19 should be tested for COVID-19. COVID-19 patients who are obese, younger than five years old, or who present with shortness of breath, productive cough, or chest pain should be evaluated for pneumonia. COVID-19 patients with a history of COVID-19 pneumonia or underlying neurological disease should receive follow-up for long COVID., (© 2024 Japan Pediatric Society.)

Cytomegalovirus (CMV) infection is a major opportunistic infection after liver transplantation (LT) that necessitates monitoring. Because of the lack of studies in children, we aimed to investigate CMV-specific T cell immune reconstitution among pediatric LT recipients. The recipients were monitored for CMV infection and CMV-specific T cells from the start of immunosuppressive therapy until 48 weeks after LT. Clinically significant CMV viremia (csCMV) requiring preemptive therapy was defined as a CMV load of >2000 IU/mL. Peripheral blood CMV-specific T cells were analyzed by flow cytometry based on IFNγ secretion upon stimulation with CMV antigens including immediate early protein 1 (IE1) Ag, phosphoprotein 65 (pp65) Ag, and whole CMV lysate (wCMV). Of the 41 patients who underwent LT, 20 (48.8%) had csCMV. Most (17/20 patients) were asymptomatic and characterized as experiencing CMV reactivation. The onset of csCMV occurred approximately 7 weeks after LT (interquartile range: 4-12.9); csCMV rarely recurred after preemptive therapy. Lower pp65-specific CD8+ T cell response was associated with the occurrence of csCMV ( p = 0.01) and correlated with increased viral load at the time of csCMV diagnosis (ρ = -0.553, p = 0.02). Moreover, those with csCMV had lower percentages of IE1-specific CD4+ and wCMV-reactive CD4+ T cells at 12 weeks after LT ( p = 0.03 and p = 0.01, respectively). Despite intense immunosuppressive therapy, CMV-specific T cell immune reconstitution occurred in pediatric patients post-LT, which could confer protection against CMV reactivation.

Introduction: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV-specific immunity is associated with viral containment. This study investigated BKPyV-specific immunological factors among KT recipients., Methods: This prospective study in a single transplant center from January 2019 to August 2019 assessed associations between clinical and immunological characteristics, with a focus on BKPyV-cell-specific immunity and BKPyVAN, among KT recipients aged ≥15 years. The numbers of interferon-gamma (IFN-γ)-producing CD4 +  T, CD8 +  T, natural killer (NK), and natural killer T (NKT) cells were measured after stimulation with large T antigen and viral capsid protein 1 (VP1)., Results: In total, 100 KT recipients were included (mean age ± SD, 42 ± 11 years); 35% of the recipients were female patients, and 70% had received induction immunosuppressive therapy. The 1-year cumulative incidence of high-level BKPyV DNAuria (possible BKPyVAN) and (presumptive BKPyVAN) was 18%. Among 40 patients with immunological factor data, pre-KT %NK cells (hazard ratio [HR], 1.258; 95% confidence interval [CI], 1.077-1.469; p = .004) and %VP1-specific NK cells (HR, 1.209; 95% CI, 1.055-1.386; p = .006) were factors independently associated with possible and presumptive BKPyVAN. KT recipients with possible and presumptive BKPyVAN were more likely to exhibit significant mean coefficients of %NK, %VP1-specific NK, and %NKT cells at 1 month after KT than before KT (all p < .05)., Conclusion: Individuals with nonspecific and VP1-specific NK cells before KT and increasing numbers of these cells after KT may be at risk for high-level BKPyV DNAuria and presumptive BKPyVAN. Further studies are needed to determine the utility of BKPyV-specific innate immune surveillance in predicting the occurrence of BKPyVAN., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Cytomegalovirus (CMV) infection is the most common infection following pediatric liver transplantation (LT). Preemptive therapy (PET) is an approach to initiate antiviral treatment for asymptomatic early CMV viremia detected by surveillance testing. However, data on CMV infection after PET are scarce, and the optimal cut-off remains controversial. This study aimed to evaluate the incidence, risk factors, and consequences of CMV infection in pediatric LT using 2 different viral load (VL) cut-offs., Methods: We retrospectively reviewed patients aged 0-18 years who underwent LT at Ramathibodi Hospital between March 2001 and August 2020. Demographic data, CMV infection, CMV treatment, and consequences of CMV infection were collected. CMV viremia was monitored by a quantitative nucleic acid amplification test. Clinical outcomes were compared after starting antiviral therapy at a low (>400 but <2000 IU/mL) and a high VL cut-off (≥2000 IU/mL)., Results: A total of 126 patients were included. CMV infection was 71% (90/126), with an incidence rate of 5.5 per 1000 patient-day. Higher tacrolimus and prednisolone dosages were associated with CMV infection with an adjusted hazard ratio of 1.2 (95%CI 1.0-1.4, p = .02) and 2.4 (95%CI 1.9-3.4, p < .001), respectively. The consequences of CMV infection did not differ significantly for the low and high CMV VL cut-off groups., Conclusion: CMV infection in LT recipients is common and is associated with higher tacrolimus and corticosteroid dosage. Additionally, using the CMV VL cut-off at 2000 IU/mL to initiate antiviral therapy is practical and effective in preventing CMV disease., (© 2023 Wiley Periodicals LLC.)

Background: Pediatric patients with systemic lupus erythematosus (SLE) are at increased infectious risk caused by underlying immunologic dysregulation and immunosuppressive therapy. Hepatitis B virus (HBV) could be reactivated during the immunosuppressive treatment in patients with past HBV infections. Information on immunogenicity after hepatitis B (HB) immunization and reimmunization are still scarce., Methods: SLE patients 5-18 years of age who had completed a primary HB immunization were enrolled. Anti-HBs levels at enrollment and after each vaccine dose were determined. Patients with anti-HBs levels < 10 mIU/mL were administered 1 booster dose. After 1 booster dose, patients with negative anti-HBs levels were administered 2 more booster doses., Results: Ninety-three SLE patients were enrolled. The prevalence of seroprotection assessed by anti-HBs > 10 mIU/mL after completion of a primary HB immunization was 25.8% (95% CI: 17.2-34.4). Lupus nephritis was associated with unprotective anti-HBs levels [odds ratio (OR): 4.341; 95% CI: 1.044-18.040]. The anti-HBs seroconversion was 72.3% (95% CI: 61.5-83.0) after 1 booster dose and increased up to 93.4% (95% CI: 86.9-98.4) after 3 booster doses. SLE Disease Activity Index-2000 score ≥ 4 (OR: 4.625; 95% CI: 1.45-14.80) was significantly associated with nonseroconversion after the first booster dose. Hypocomplementemia before the first and second booster doses (OR: 27; 95% CI: 1.26-578.35) was significantly associated with nonseroconversion after 3 booster doses., Conclusions: All pediatric SLE patients should be evaluated for HBV serological status before immunosuppressive treatment. SLE patients with SLE Disease Activity Index-2000 score > 4 should need 3 booster doses if their anti-HBs level was < 10 mIU/mL., Competing Interests: The authors have conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Zinc plays essential roles in immune function and epithelial integrity. Patients undergoing hematopoietic stem cell transplantation (HSCT) often have low plasma zinc levels because of poor intake and diarrhea. We hypothesized that patients with zinc deficiency before HSCT had worse infectious complications after HSCT compared with patients with normal zinc levels. Citrulline, a marker of intestinal integrity, was also hypothesized to be lower in patients with zinc deficiency., Patients and Methods: Thirty patients undergoing HSCT at Ramathibodi Hospital during March 2020-September 2021 were enrolled. Blood samples for plasma zinc and citrulline were collected during the HSCT period. The 14- and 90-day outcomes after HSCT were prospectively recorded., Results: Twelve of 30 (40%) patients had zinc deficiency before HSCT. Zinc-deficient patients were younger (median (interquartile range): 6 (8.8) vs 13 (5.8) years old; p = 0.017). Zinc levels tended to increase after admission in both groups. Patients with zinc deficiency had lower citrulline levels than those with normal zinc levels. Citrulline levels decreased in both groups after stem cell infusion, and the level was not significantly different between the two groups. Zinc-deficient patients had a higher rate of bacterial infection within 90 days after HSCT than those with normal zinc levels (6 in 12 patients (50.0%) vs 1 in 18 patients (5.6%); odds ratio [OR]: 17.0; 95% confidence interval [CI]: 1.68-171.70; p = 0.016). This remained significant after adjustments for age (adjusted OR: 12.31; 95% CI: 1.084-139.92; p = 0.043)., Conclusion: The prevalence of zinc deficiency in pediatric patients undergoing HSCT was high. Zinc-deficient patients had lower citrulline levels and higher incidence of bacterial infection after HSCT. However, citrulline level was not different between patients with and without bacterial infections. It is worth to investigate whether zinc supplementation before HSCT can reduce bacterial infection after HSCT., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Suwanphoerung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Autoimmune hemolytic anemia (AIHA) can be induced by recent or concomitant infections. Many infectious agents are postulated to be associated with this condition. Treatment of infection induced AIHA still varies. This report describes a previously healthy Thai boy who developed AIHA associated with enterovirus-71 infection. He was successfully treated with oral prednisone., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Human pegivirus-1 (HPgV-1) is a lymphotropic human virus, typically considered nonpathogenic, but its infection can sometimes cause persistent viremia both in immunocompetent and immunosuppressed individuals. In a viral discovery research program in hematopoietic stem cell transplant (HSCT) pediatric patients, HPgV-1 was detected in 3 out of 14 patients (21.4%) using a target enrichment next-generation sequencing method, and the presence of the viruses was confirmed by agent-specific qRT-PCR assays. For the first time in this patient cohort, complete genomes of HPgV-1 were acquired and characterized. Phylogenetic analyses indicated that two patients had HPgV-1 genotype 2 and one had HPgV-1 genotype 3. Intra-host genomic variations were described and discussed. Our results highlight the necessity to screen HSCT patients and blood and stem cell donors to reduce the potential risk of HPgV-1 transmission.

Background: Thalassemic patients usually require regular blood transfusions; however, HSCT can provide a cure. Incidence of IBI in pediatric patients post-HSCT is still scant., Objectives: This study aimed to explore whether thalassemic patients had a different incidence of post-HSCT IBI compared with patients with other underlying diseases. Factors associated with IBI in the pediatric population undergoing HSCT were also investigated., Methods: In this retrospective cohort study, clinical data of pediatric patients who underwent HSCT during the period from 2011 to 2016 were reviewed and analyzed. The primary outcome was incidence of IBI within 1-year post-HSCT., Results: Of 123 patients, 53 were thalassemic. IBI was diagnosed in 23 patients within 1 year after HSCT (incidence: 19.5 episodes/1000 patients/month). The IBI incidence was lower in thalassemic patients than in patients with other underlying diseases (6.9 vs. 31.6 episodes/1000 patients/month). Having thalassemia as an underlying disease was the only factor associated with lower IBI in pediatric post-HSCT patients (hazard ratio: 0.245; 95% confidence interval, 0.080-0.748). In post-HSCT thalassemic patients, IBI mostly occurred within 100 days after HSCT, and most of these cases had catheter-related blood stream infection. The risk of IBI tended higher for haploidentical HSCT, but this difference was not statistically significantly different., Conclusion: The IBI incidence after HSCT was lower in thalassemic patients than in those with other underlying diseases. Catheter-related blood stream infection was the major IBI in these patients. IBI was not a major complication in thalassemic pediatric patients undergoing HSCT., (© 2021 Wiley Periodicals LLC.)

Objective: Juvenile-onset systemic lupus erythematosus (JSLE) is a complex and heterogeneous immune-mediated disease. Cellular components have crucial roles in disease phenotypes and outcomes. We aimed to determine the associations of lymphocyte subsets with clinical manifestations and long-term outcomes in JSLE patients., Methods: A cohort of 60 JSLE patients provided blood samples during active disease, of whom 34 provided further samples during inactive disease. In a longitudinal study, blood samples were obtained from 49 of the JSLE patients at 0, 3, and 6 months. The healthy control (HC) group consisted of 42 age-matched children. Lymphocyte subsets were analyzed by flow cytometry., Results: The percentages of CD4+ T, γδ T, and NK cells were significantly decreased in JSLE patients compared with HC, while the percentages of CD8+ T, NKT, and CD19+ B cells were significantly increased. The percentage of regulatory T cells (Tregs) was significantly lower in JSLE patients with lupus nephritis (LN) than in non-LN JSLE patients and HC. The patients were stratified into high and low groups by the median frequency of each lymphocyte subset. The γδ T cells high group and NK cells high group were significantly related to mucosal ulcer. The CD4+ T cells high group was significantly associated with arthritis, and the NKT cells high group was substantially linked with autoimmune hemolytic anemia. The CD8+ T cells low group was mainly related to vasculitis, and the Tregs low group was significantly associated with LN. The percentage of Tregs was significantly increased at 6 months of follow-up, and the LN JSLE group had a lower Treg percentage than the non-LN JSLE group. Predictors of remission on therapy were high Tregs, high absolute lymphocyte count, direct Coombs test positivity, and LN absence at enrollment., Conclusion: JSLE patients exhibited altered lymphocyte subsets, which were strongly associated with clinical phenotypes and long-term outcomes., Competing Interests: The authors have declared that no competing interests exist.

Hookworm infection is the most common human helminthic infection in the rural areas of southern Thailand. There is little information on the induced cellular immune responses in hookworm-infected children. The present study aimed to investigate the cellular immune responses, regulatory T cells (Tregs), Th1-type cytokines (interleukin (IL)-2 and interferon (IFN)-γ), a Th2-type cytokine (IL-5) and IL-10, which is one of the cytokines secreted by Tregs in hookworm-infected children. Twenty-nine schoolchildren diagnosed with hookworm infections and 28 healthy controls were enrolled in the study. CD4+ and CD8+ T cells and Tregs in whole blood were analyzed using flow cytometry. Plasma IL-2, IL-5, IL-10 and IFN-γ concentrations were quantified by enzyme-linked immunosorbent assay (ELISA). The median CD4+ T cell frequency was significantly higher in hookworm-infected children than healthy controls. Compared to healthy controls, hookworm-infected children had a significantly increased absolute number of Tregs. No differences in circulating CD8+ T cell median frequency or absolute numbers were observed among hookworm-infected children or healthy controls. Elevated IL-2 and IL-10 concentrations were found in hookworm-infected children. Moreover, the absolute number of Tregs was significantly positively correlated with the plasma IL-10 concentration (r s  = 0.406, P = 0.029). This study showed that hookworm-infected schoolchildren had significantly different immune responses than healthy controls, including an increase in the CD4+ T cell number, a significant induction of Tregs and significantly elevated circulating IL-10 levels. These alterations could be the mechanism underlying the immunomodulation that alleviates allergic diseases among hookworm-infected individuals., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pediatric liver transplant (LT) candidates often miss complete varicella-zoster virus (VZV) vaccination before LT. We aimed to evaluate the immunogenicity of two doses of VZV vaccines in pediatric LT candidates younger than 2 years and persistence of its immunogenicity after LT., Methods: Patients aged 9-24 months were enrolled before LT. The first dose of VZV vaccine was given at 9 months, and the second dose was given at between 1 to 3 months later, and at least 4 weeks before LT. Varicella-zoster IgG (VZG) was used to detect immunoglobulin G antibodies to VZV and was reported as a test value (TV). A test value ≥ 0.9 was considered as seropositive. TV was measured at enrollment, 1 month after the first and the second dose of VZV vaccine, before LT, and 3 and 6 months after LT., Results: Fourteen children were enrolled in this prospective cohort study. The median age at the first and the second dose of VZV vaccine was 11.5 months (IQR 9-12) and 13 months (IQR 12-33), respectively. The seroconversion rate was 66.7% (8/12) and 70% (7/10) after the first and second VZV vaccine doses, respectively. Seven of nine patients who underwent LT had two doses of VZV vaccine. Six patients were seropositive before LT, which persisted at 3 to 6 months after LT. Of two patients who received only one dose, TV was not detected after LT., Conclusions: The two doses of VZV vaccine appeared to be more immunogenic than one dose in pediatric LT candidates aged less than 2 years., (© 2021 Japan Pediatric Society.)

A false-positive anti-human immunodeficiency virus (HIV) test result can have devastating consequences. Sequential HIV serological testing is a strategy that could be applied in resource-limited settings to reduce false-positive results when a nucleic acid test is not affordable. We aimed to compare the results of sequential anti-HIV testing algorithms recommended by the national guidelines and our hospital algorithm in the setting of low HIV prevalence. We retrospectively reviewed individuals whose anti-HIV tested positive by Architect HIV Ag/Ab Combo with a signal/cut-off ratio of 1.00-20.00 between January 2015 and June 2016 at a university hospital in Bangkok, Thailand. A total of 111,224 samples were requested for anti-HIV tests during the study period. Sixty-six adults and nine children/adolescents met the inclusion criteria of this study. Compared to the national guidelines, our hospital HIV diagnosis algorithm could identify two individuals with false-positive anti-HIV tests and a reduction of inconclusive diagnoses from 45 to one adult cases ( p <.001). It also eliminated inconclusive diagnoses in four non-infected children with HIV-negative mothers. Our hospital HIV diagnosis algorithm can reduce the number of HIV misdiagnoses of serological tests in an area with low HIV prevalence. The sequential HIV serological test algorithms should be reviewed and evaluated in each institute.

Background: Drug utilization evaluation (DUE) is a systematic, criteria-based assessment of medicine that aims to optimize the appropriateness of antibiotic prescription. This study aimed to evaluate the performance of the DUE on prescriptions of two commonly used antibiotics in a pediatric population, cefepime and piperacillin/tazobactam, in a tertiary care hospital., Methods: This quasi-experimental study was conducted at the Department of Pediatrics, Ramathibodi Hospital, between March 2020 and August 2021. All hospitalized children aged 1 month to 20 years who received at least one dose of cefepime or piperacillin/tazobactam were enrolled. Before implementing the DUE, cefepime and piperacillin/tazobactam prescriptions were retrospectively evaluated using the DUE criteria. During the 6 month DUE implementation period, physicians voluntarily chose to use DUE to assess the prescriptions' appropriateness. Demographic data, antibiotic use, and clinical data were recorded., Results: There were 304 prescriptions of cefepime and piperacillin/tazobactam, with 108 empirical prescriptions (72 patients) in the DUE group and 158 prescriptions (138 patients) in the non-DUE group. The appropriateness of empirical prescriptions of cefepime and piperacillin/tazobactam was significantly higher in the DUE group (93.5% vs. 83.5%; P = 0.003). Drug utilization evaluation was significantly associated with appropriate empirical prescriptions (adjusted OR 5.32: 95% CI 1.80-15.73; P = 0.003). Prescriptions in critical care wards and urinary tract infections (UTIs) were associated with not fulfilling the DUE criteria for appropriateness., Conclusions: Drug utilization evaluation could improve the appropriateness of empirical use of cefepime and piperacillin/tazobactam in pediatric patients. Patients in critical care units and with UTIs appeared to be associated with inappropriate empirical treatment., (© 2022 Japan Pediatric Society.)

Background: Intensive care unit (ICU) settings typically have a high-volume prescription of carbapenems. Antimicrobial stewardship programs (ASPs) aim to promote appropriate antibiotic use. Handshake stewardship (HS) is adapted from ASPs but focuses on direct feedback to physicians who prescribed antibiotics regarding the appropriateness of antibiotic prescription. This study aimed to evaluate the impact and acceptability of HS on carbapenem consumption in pediatric critical care settings., Methods: This study was conducted over 18 months spanning pre-and post-implementation of HS. Carbapenem prescriptions were automatically discontinued during the pre-implementation period after 72 h if no indications existed. During the post-implementation, HS was performed by direct feedback to ICU physicians regarding the appropriateness of carbapenem prescriptions within 24 h. The primary outcome was the carbapenem consumption rate, defined as days of therapy (DOT)/1,000 patient-ICU days. Secondary outcomes were the acceptability of HS, length of critical care stay (LOCS), 30-day infection-related mortality rate, and the rate of carbapenem-resistant Enterobacteriaceae (CRE)., Results: There were 212 carbapenem prescriptions (163 patients) and 174 carbapenem prescriptions (110 patients) in the pre-and post-implementation periods, respectively. Carbapenem consumption decreased significantly from 667 to 369 DOT/1,000 patient-ICU days, with a median difference of 292 DOT/1,000 patient-ICU days (P < 0.001; 95% confidence interval: 175-408) after HS implementation. The acceptability of the HS was 95.4%. The LOCS, 30-day infection-related mortality, and CRE rate were not significantly different between pre-and post-implementation periods., Conclusions: Handshake stewardship significantly reduced carbapenem prescription in critically ill pediatric patients without negatively affecting patient outcomes., (© 2022 Japan Pediatric Society.)

Background: Adenovirus can cause severe diseases in post-hematopoietic stem cell transplant (HSCT) patients. Because these patients also have many other factors contributing to mortality, it remains controversial whether adenovirus infection itself contributes to increased mortality in these patients., Objective: To determine if adenovirus infection contributes to mortality in pediatric post-HSCT patients., Methods: This retrospective cohort study was performed in post HSCT patients, aged 0-18 years old, admitted at Ramathibodi Hospital from 2016 to 2020. Adenovirus infection was defined as the detection of adenovirus in blood or urine by polymerase chain reaction. Multivariate cox regression was used to identify factors associated with death., Results: The incidence of overall adenovirus infection (viremia or viruria) in this cohort was 20.8% (26 out of 125 enrolled patients). From the multivariate cox regression analysis, overall adenovirus infection was not significantly associated with death (hazard ratio [HR]: 2.41; 95% confidence interval [CI]: 0.96-6.06; p = .060). However, presence of viremia (HR: 3.90; 95% CI: 1.40-10.86; p = .009), having maximal serum viral load > 10 000 copies/ml (HR: 3.70; 95% CI: 1.20-11.38; p = .023), presence of end-organ diseases (HR: 3.44; 95% CI: 1.18-10.01; p = .023) were associated with mortality. Underlying diseases requiring long-term immunosuppressive drugs before HSCT, invasive fungal disease, invasive bacterial infection, cytomegalovirus infection, and longer engraftment time were also associated with mortality., Conclusion: Overall adenovirus infection does not appear to play a significant role in mortality in pediatric post-HSCT patients. However, more invasive forms of adenovirus infection were associated with mortality in these patients., (© 2021 Wiley Periodicals LLC.)

Background: Invasive fungal disease (IFD) is a major cause of morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT). Itraconazole has been used for prevention of IFD, but data related to incidence and associated factors of IFD in pediatric and adolescent patients on itraconazole prophylaxis remain scarce., Objectives: To identify incidence and risk factors associated with IFD among pediatric and adolescent patients receiving itraconazole prophylaxis after HSCT., Methods: Patients younger than 21 years who received itraconazole prophylaxis after HSCT from January 2007 to December 2016 were retrospectively enrolled. Incidence of IFD within 1 year and associated factors were analyzed., Results: All patients received itraconazole during the pre-engraftment period. Of 170 patients, 29 had IFD, with an incidence of 17.1% at 1 year. IFD at 1 year was significantly associated with increased mortality. Of 29 patients with IFD, only 9 developed IFD while on itraconazole prophylaxis (5.3%), all of whom had invasive pulmonary aspergillosis. No invasive candidiasis occurred during itraconazole prophylaxis. Prolonged neutropenia (hazard ratio [HR] = 1.08; 95% confidence interval [CI], 1.02-1.13), graft-versus-host disease within 100 days after transplantation (HR = 3.17; 95% CI, 1.17-8.57), and using etoposide in preconditioning regimens (HR = 21.60; 95% CI, 2.44-190.95) were significantly associated with IFD at 1 year. No patients had to discontinue itraconazole because of its adverse effects., Conclusions: Itraconazole proffered good efficacy for prevention of candidiasis during the pre-engraftment period. Most IFD episodes occurred after the engraftment period when itraconazole had been discontinued. During this period, patients with risk factors require appropriate fungal prophylaxis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Children and young adults undergoing hematopoietic stem cell transplantation (HSCT) typically lose their immunity to vaccine-preventable diseases, including Japanese encephalitis (JE). Revaccination against JE in this population has not been well characterized., Methods: This prospective study evaluated the immunogenicity of inactivated Vero cell culture-derived JE vaccine in children and young adults (<25 years of age) who had completed HSCT >1 year prior. Each patient received inactivated Vero cell culture-derived JE vaccine at enrollment and 1 month after enrollment, as well as a booster dose 13 months after enrollment. Serum JE plaque reduction neutralization test and JE-specific T lymphocyte count assay were performed at baseline, 1 month after the second dose, on the day of the booster dose, and 1 month after the booster dose., Results: Thirty-seven patients were enrolled. At baseline, 15 patients (40.5%) had plaque reduction neutralization titer >10, which is considered protective. Among 22 seronegative patients, 15 (68.2%) and 19 (86.4%) exhibited seroconversion after revaccination and booster dose, respectively. Median JE-specific T lymphocyte counts also increased. Twenty of 111 (18.0%) vaccination doses resulted in self-limiting side effects., Conclusions: The inactivated Vero cell culture-derived JE vaccine may be safe and effective for immunization against JE virus in children and young adults who have undergone HSCT., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Tuberculosis is a common cause of phlyctenular keratoconjunctivitis, especially for patients who live in a high endemic area of tuberculosis. We report a rare case of pediatric phlyctenular keratoconjunctivitis associated with primary sinonasal tuberculosis., Patient Concerns: A 7-year-old boy presented with a 5-month history of redness of the left eye accompanied by mild visual impairment. Physical examination revealed elevated pinkish-white nodules with a circumcorneal hypervascularized lesion on the left conjunctiva., Diagnosis: Computed tomography revealed an enhancing soft tissue mass in the left maxillary sinus with bone destruction. Histopathology of maxillary tissue showed chronic inflammation without granuloma. Special stain, culture and polymerase chain reaction for mycobacterium were initially negative. Left maxillary sinus tuberculosis was diagnosed by positive Mycobacterium tuberculosis polymerase chain reaction from formalin-fixed paraffin-embedded maxillary tissue., Interventions: Two month of oral isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by 10 months of oral isoniazid and rifampicin without topical eye drops agent were prescribed., Outcomes: Two months after initiation of treatment, the phlyctenular lesion had significantly improved. A follow-up computed tomography showed a significant reduction in the size of the maxillary sinus lesion and the extent of adjacent bone destruction., Lessons: Primary sinonasal tuberculosis is an uncommon cause of phlyctenular keratoconjunctivitis in children. When microbiological and histopathological evidences are absent, polymerase chain reaction analysis has a crucial role in the diagnosis of tuberculosis, especially in patient with uncommon presentation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Maraviroc, a C-C chemokine receptor 5 (CCR5) antagonist, has been used as an alternative antiretroviral drug in treatment-experienced adults and children infected by CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates. Prior to widespread use of this drug, rates of HIV-1 coreceptor tropism and factors associated with coreceptor tropism had to be determined., Methods: HIV-1-infected individuals aged <20 years with HIV-1 viral loads >1000 RNA copies/mL who were treatment-experienced or treatment-naive were enrolled. HIV-1 coreceptor tropism was determined using a genotypic test in which V3 sequences were analyzed with GENO2PHENO version 2.5 and a false discovery rate of 5%., Results: Fifty-two HIV-1-infected patients were recruited. The median age of participants was 14.9 years (interquartile range [IQR], 8.9-16.8 years). The median CD4 cell count was 396.0 cells/µL (IQR, 72.0-630.3 cells/µL). The median HIV-1 viral load was 43 339 RNA copies/mL (IQR, 8874-197 055 copies/mL). Thirty-nine patients (75%) were treatment-experienced. The most prevalent HIV-1 subtype in this population was CRF01&#95;AE (36 patients, 69.2%). Based on analyses of V3 loop sequences, 5 of 13 treatment-naive patients (38.5%) and 11 of 39 treatment-experienced patients (28.2%) were infected by R5 viruses, while 7 of 13 treatment-naive patients (53.8%) and 19 of 39 treatment-experienced patients (48.7%) were infected by X4 viruses. The only factor associated with the presence of X4 viruses was HIV-1 subtype CRF01&#95;AE., Conclusions: X4-tropic viruses are associated with the CRF01&#95;AE subtype. Hence, testing of HIV tropism should be performed before treatment with CCR5 inhibitors in children in areas where CRF01&#95;AE predominates., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bacterial infection has been identified as one of the most significant complications of liver transplantation (LT). Multidrug-resistant (MDR) gram-negative bacteria (GNB) infection remains problematic issue following LT in the adults. However, data in children are scarce. We aimed to examine the prevalence and associated factors of MDR-GNB infection among pediatric LT recipients.We performed a single-center retrospectively study of 118 children who underwent LT between January 2010 and December 2018. Data on the prevalence, clinical characteristics, types, and sites of MDR-GNB infection within 3 months after LT as well as the treatment outcomes were collected. Multidrug resistance was defined as acquired non-susceptibility to at least 1 agent in 3 or more antibiotic classes.In total, 64 (53.7%) patients developed 96 episodes of culture-proven bacterial infection with 93 GNB isolates. Moreover, there were 58 (62.4%) MDR-GNB isolates, with a predominance of Klebsiella pneumoniae (32.7%), Escherichia coli (31%), and Pseudomonas aeruginosa (10.3%). Interestingly, 10 (17.2%) isolates were determined to be carbapenem-resistant Enterobacteriaceae. The median time to MDR-GNB infection was 9 (interquartile range: 5-33) days. The most common type of infection was intra-abdominal infection (47.9%). In the multivariate analysis, the significant variables associated with post-LT MDR-GNB infection include exposure to third-generation cephalosporins (hazard ratio [HR]: 2.16, P = .023), operative time (hazard ratio [HR] 1.20, P = .009), and length of intensive care unit stay (HR 1.03, P = .049). With a focus on carbapenem-resistant Enterobacteriaceae infection, a pediatric end-stage liver disease score >21 was the only significant 6 variable in the multivariate analysis (HR 11.48, P = .024). The overall 3-month mortality rate was 6.8%.This study has highlighted the high prevalence rate of MDR-GNB infection after pediatric LT. Therefore, caution on the emergence of MDR-GNB infection should be paid in at-risk children. Moreover, knowledge regarding the prevalence of MDR-GNB infection and resistant patterns is essential for guideline development to prevent and minimize the risk of MDR-GNB infection in this group of patients.

Objective: Vitamin A is involved in maintenance of gut mucosal integrity and normal immune function. However, it is unclear whether these functions of vitamin A have any beneficial effects in patients undergoing hematopoietic stem cell transplantation (HSCT). In this study, we aimed to examine the potential protective effect of vitamin A supplementation on gastrointestinal (GI) mucosal integrity in HSCT recipients using plasma citrulline as a surrogate marker of intestinal integrity., Results: We performed a quasi-randomized trial in 30 pediatric patients undergoing HSCT. Half (n = 15) of the patients received a single high dose of vitamin A (200,000 IU) before the conditioning regimen was given, and half (n = 15) did not. Clinical data of patients who developed post-transplant complications were recorded for 60 days after HSCT. There were no significant differences in mean plasma citrulline levels on day 7 after HSCT between the treatment and control groups (5.8 vs. 5.9 µmol/L, respectively). The incidence of mucositis and other complications were not different between the two groups within 60 days of HSCT. Vitamin A supplementation prior to HSCT in pediatric patients had no clinical benefit in protecting GI mucosal integrity.

Background: Hematopoietic stem cell transplantation (HSCT) recipients require hepatitis B (HBV) revaccination. Hepatitis B surface antibody (anti-HBs) seroconversion rates after revaccination range from 64% to 79% in these patients. The seroconversion rate and factors associated with non-seroconversion have not been clearly elucidated in pediatric and young adult recipients after HSCT., Objectives: To evaluate anti-HBs seroconversion rates in pediatric and young adult patients revaccinated after HSCT, and to identify factors associated with non-seroconversion., Method: The current study was prospective and cross-sectional. Post-HSCT recipients aged ≤25 years who had completed a course of three HBV revaccinations were recruited, and their anti-HBs titers were assessed. Non-seroconverted patients were administered a fourth vaccination. Those who subsequently remained seronegative were administered two additional vaccinations. Those who remained seronegative after all six vaccinations were defined as non-responders., Results: A total of 118 patients were enrolled. The HBV-containing vaccines used included DTaP-IPV-HBV-Hib, DTwP-HBV-Hib, and monovalent vaccines. The anti-HBs seroconversion rate after three revaccinations was 82% (95% confidence interval [CI], 73.7-89.2). One patient (0.8%) was classified as non-responder. Factors associated with non-seroconversion after three revaccinations included cytomegalovirus (CMV) reactivation (odds ratio [OR] 10.63, 95% CI 1.16-97.00), anti-HBs seronegativity before HSCT (OR 7.01, 95% CI 1.55-31.78) and three DTwP-HBV-Hib revaccinations (OR 11.71, 95% CI 1.43-96.26)., Conclusion: In the current study the anti-HBs seroconversion rate after three HBV revaccinations was excellent. CMV reactivation, anti-HBs seronegativity before HSCT, and three DTwP-HBV-Hib revaccinations were associated with non-seroconversion, but the non-responder rate was low., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Volatile anesthetic agents used during surgery have immunomodulatory effects which could affect postoperative outcomes. Recognizing that regulatory T cells (Tregs) plays crucial roles in transplant tolerance and high peripheral blood Tregs associated with stable kidney graft function, knowing which volatile anesthetic agents can induce peripheral blood Tregs increment would have clinical implications. This study aimed to compare effects of desflurane and sevoflurane anesthesia on peripheral blood Tregs induction in patients undergoing living donor kidney transplantation., Methods: A prospective, randomized, double-blind trial in living donor kidney transplant recipients was conducted at a single center, tertiary-care, academic university hospital in Thailand during August 2015 - June 2017. Sixty-six patients were assessed for eligibility and 40 patients who fulfilled the study requirement were equally randomized and allocated to desflurane versus sevoflurane anesthesia during transplant surgery. The primary outcome included absolute changes of peripheral blood CD4 + CD25 + FoxP3 + Tregs which measured by flow cytometry and expressed as the percentage of the total population of CD4 + T lymphocytes at pre-exposure (0-h) and post-exposure (2-h and 24-h) to anesthetic gas. P-value < 0.05 denoted statistical significance., Results: Demographic data were comparable between groups. No statistical difference of peripheral blood Tregs between desflurane and sevoflurane groups observed at the baseline pre-exposure (3.6 ± 0.4% vs. 3.1 ± 0.4%; p = 0.371) and 2-h post-exposure (3.0 ± 0.3% vs. 3.5 ± 0.4%; p = 0.319). At 24-h post-exposure, peripheral blood Tregs was significantly higher in desflurane group (5.8 ± 0.5% vs. 4.1 ± 0.3%; p = 0.008). Within group analysis showed patients receiving desflurane, but not sevoflurane, had 2.7% increase in peripheral blood Treg over 24-h period (p < 0.001)., Conclusion: This study provides the clinical trial-based evidence that desflurane induced peripheral blood Tregs increment after 24-h exposure, which could be beneficial in the context of kidney transplantation. Mechanisms of action and clinical advantages of desflurane anesthesia based on Treg immunomodulation should be investigated in the future., Trial Registration: ClinicalTrials.gov, NCT02559297 . Registered 22 September 2015 - retrospectively registered.

T cells are classically recognized as distinct subsets that express αβ or γδ TCRs. We identify a novel population of T cells that coexpress αβ and γδ TCRs in mice and humans. These hybrid αβ-γδ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αβ TCR-mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs. They expressed high levels of IL-1R1 and IL-23R and secreted IFN-γ, IL-17, and GM-CSF in response to canonically restricted peptide antigens or stimulation with IL-1β and IL-23. Hybrid αβ-γδ T cells were transcriptomically distinct from conventional γδ T cells and displayed a hyperinflammatory phenotype enriched for chemokine receptors and homing molecules that facilitate migration to sites of inflammation. These proinflammatory T cells promoted bacterial clearance after infection with Staphylococcus aureus and, by licensing encephalitogenic Th17 cells, played a key role in the development of autoimmune disease in the central nervous system., Competing Interests: Disclosures: Dr. Edwards reported grants from Abbvie during the conduct of the study. Dr. Thomas reported a patent to PCT/US2016/064735 pending. Dr. Mills reported grants from Abbvie during the conduct of the study and personal fees from Pieris outside the submitted work. In addition, Dr. Mills had a patent on IL-17 inhibitors pending. No other disclosures were reported., (© 2020 Edwards et al.)

Background : In dengue infection, knowing time to platelet recovery is essential for optimal management. Aims : To determine a predictor for platelet recovery in patients with dengue infection. Methods : Platelet count and immature platelet fraction (IPF) from daily blood samples of patients with dengue infection during hospitalisation and 1-4 weeks after discharge were retrospectively analysed. The levels of patients' IPF were compared with normal controls recruited from healthy children with normal platelet counts. Results : A total of 244 EDTA blood samples were collected daily from 64 patients (45 males) with dengue infection (36 dengue fever, 28 dengue haemorrhagic fever) during hospitalisation and after discharge from the hospital. They did not receive any platelet concentrate transfusion. The median IPF among normal children was 3.6% with a 95 percentile of 9.9%. In dengue patients, an IPF of ≥10.0% after defervescence was associated with a subsequent platelet count of ≥60 × 10 9 /L within 72 hours. Conclusion : In patients with dengue infection, IPF ≥10.0% after defervescence is a predictor of subsequent platelet recovery to a haemostatic level ≥60 × 10 9 /L within 72 hours.

Background: Ethnicity and environmental factors can influence the percentages of lymphocyte subpopulations. This study aimed to assess the percentages of lymphocyte subpopulations according to age in Thai children., Methods: This was a cross-sectional study. The percentages of lymphocyte subpopulations were measured in umbilical cord blood and peripheral blood of healthy Thai children aged 1 month-15 years. The participants were stratified into five age groups: (a) cord blood; (b) age < 2 years; (c) age 2-5 years; (d) age 5-10 years; and (e) age 10-15 years., Results: Of 182 total samples, 32, 39, 41, 28, and 42 were from cord blood, children aged <2 years, children aged 2-5 years, children aged 5-10 years, and children aged 10-15 years, respectively. The percentages of most lymphocyte subpopulations including CD8 + T cells, CD19 + cells, γδ T cells, double-negative T cells, NK cells, and NK T cells increased significantly with age. Only the CD4+ T-cell percentage decreased in older children. Moderate correlations were observed between age and the percentages of CD4+ T cells, γδ T cells, NK cells, NK T cells, and double-negative T cells. Weak correlations were observed between age and the percentages of CD8+ T cells and CD19+ cells., Conclusion: Our study demonstrated age-related changes in the percentages of lymphocyte subpopulations in Thai children, which differed from those described in other countries. Therefore, the establishment of age-specific reference values for lymphocyte subsets in each country is recommended., (© 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background: The study aimed to develop dengue severity score to assess severe manifestations among hospitalized patients with dengue infection., Method: Children and adolescents with serologically confirmed dengue infection admitted at Ramathibodi Hospital from 2004 to 2018 and treated by an expert multidisciplinary team were recruited. Medical records were retrospectively reviewed and 14 items, related to clinical parameters and managements during hospitalization, were obtained daily as dengue severity score., Results: A total of 191 patients with a mean age of 10.7 years from 2004 to 2013 were recruited. They were classified as dengue fever (35), dengue hemorrhagic fever (DHF) I (53), II (50), III (37) and IV (16). The analysis of 593 daily records revealed the range of daily severity score among patients with DHF grades III (10-20) and IV (31-47) were significantly higher than those of other groups (dengue fever, 5-13; DHF I, 2-10; DHF II, 6-11) with P-values of 0.0001. Using a validity test, a total daily score of ≥12 was an assessment tool for dengue shock syndrome with sensitivity, 86% and specificity, 84%. An additional 51 hospitalized patients with DHF grades II, III and IV with similar ages from 2014 to 2018 were recruited. The number of patients with severe manifestations, having daily score of ≥12, was significantly higher than those without severe manifestations starting from Day -3 to Day +1 of illness., Conclusions: Daily dengue severity score of ≥12 was an accurate assessment tool for severe manifestations.

Background: Urinary tract infection (UTI) is a common cause of fever in children. Despite the increasing numbers of extended-spectrum beta-lactamase-producing organisms in the community, the empirical therapy of choice is still third-generation cephalosporins. This study was performed to investigate whether inappropriate empirical therapy (IAT) of community-onset UTI results in adverse clinical outcomes., Methods: We retrospectively studied a cohort of pediatric patients with first-episode community-onset UTI caused by Escherichia coli, Klebsiella pneumoniae and Proteus spp. at Ramathibodi Hospital from 2011 to 2017. The patients were classified into IAT and appropriate empirical therapy (AT) groups. Medical records were reviewed to assess clinical outcomes., Results: One hundred fifty-one eligible patients were enrolled in this study. The most common causative organism was E. coli (88.8% and 96.2% in the AT and IAT groups, respectively). Among the causative organisms, 19.8% were extended-spectrum beta-lactamase-producing organisms. There was no significant difference in clinical failure, microbiologic failure, relapse or time to defervescence between the 2 groups. No patients in either group developed sepsis after receiving empirical therapy. However, the length of hospital stay was significantly longer in the IAT than AT group [4.00 (4.50-6.00) vs. 7.00 (5.00-11.25) days, respectively; P = 0.000]., Conclusions: No significant difference in treatment outcomes was found between pediatric patients receiving AT and IAT for the treatment of UTI. In the era of increasing antimicrobial resistance, third-generation cephalosporins may still be a good choice as an empirical antimicrobial for children diagnosed with community-onset UTI.

Background: Immune reconstitution of T cells has been proven to be a protective factor against cytomegalovirus (CMV) reactivation in patients post-hematopoietic stem cell transplant. Recently, more evidence has suggested that natural killer (NK) cells also play role in the protection against CMV reactivation in these patients., Methods: CMV-specific T cells and CMV-reactive NK cells from pediatric patients undergoing hematopoietic stem cell transplant were examined by flow cytometry. These cells were defined as cells producing interferon gamma (IFNγ) upon stimulation with CMV antigens., Results: This study demonstrated that NK cells reactive to CMV do exist in pediatric patients after stem cell transplant. These cells vigorously responded to stimulation with CMV peptides (pp65 and IE1) and to a lesser extent to CMV whole lysate by secretion of IFNγ. Patients with CMV reactivation tended to have less CMV-reactive NK cells than those without., Conclusion: Reconstitution of CMV-reactive NK cells, together with CMV-specific T cells, may play a role in the control of CMV infections in patients after stem cell transplant., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Actinomyces species are gram-positive, facultative anaerobic bacilli. Infection caused by Actinomyces species is usually limited to cervicofacial, thoracic, and abdominopelvic regions. Infective endocarditis due to Actinomyces species is extremely rare with only 30 reported cases since 1939. We report a case of Actinomyces oris endocarditis in a 14-year-old boy who had a 2-week history of dyspnea on exertion without other constitutional signs. Transthoracic echocardiography was suggestive of perforation of the right coronary cusp of aortic valve. No organisms were isolated from blood cultures. The patient underwent surgical valve repair due to deteriorated cardiac function. Valve tissue culture did not initially identify the organism. However, the terminal subculture in a thioglycolate broth grew gram-positive bacilli. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was compatible with Actinomyces oris . After 6 weeks of intravenous ampicillin, the patient remained well with improved cardiac function. We reviewed all reported cases of infective endocarditis caused by Actinomyces species, commenting on clinical characteristics and factors associated with unfavorable outcomes in infective endocarditis due to Actinomyces species. Although infective endocarditis caused by Actinomyces spp is rare, it could be considered in a case of culture-negative endocarditis since the clinical features might be indistinguishable from other bacterial endocarditis. Additionally, MALDI-TOF MS is a useful diagnostic tool for the identification of Actinomyces spp to improve the accuracy of diagnosis.

Background: Adjustment of immunosuppression is the main therapy for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) after kidney transplantation (KT). Studies of BKPyV-specific T cell immune response are scarce. Here, we investigated BKPyV-specific T cell immunity in KT recipients diagnosed with BKPyVAN., Methods: All adult KT recipients with BKPyVAN diagnosed at our institution from January 2017 to April 2018 were included. Laboratory-developed intracellular cytokine assays measuring the percentage of IFN-γ-producing CD4 + and CD8 + T cells, after stimulation with large-T antigen (LT) and viral capsid protein 1 (VP1), were performed both at the time of diagnosis and after adjustment of immunosuppression., Results: We included 12 KT recipients diagnosed with BKPyVAN (7 proven, 4 presumptive, and 1 possible). Those with presumptive BKPyVAN had a median plasma BKPyV DNA load of 5.9 log10 copies/ml (interquartile range [IQR]: 4.9-6.1). Adjusted dosing of mycophenolic acid and tacrolimus with (86%) or without (14%) adjunctive therapies were implemented after diagnosis. There was a significantly higher median percentage of IFN-γ-producing CD4 + T cells to LT at a median of 3 (IQR: 1-4) months after adjustment of immunosuppression compared with at the time of diagnosis (0.004 vs. 0.015; p = 0.047). However, the difference between the median percentage of IFN-γ-producing CD4 + T cells to VP1 and CD8 + T cells to LT and VP1 did not reach statistical significance. Four (33%) patients achieved plasma BKPyV DNA clearance, and the remaining eight (67%) patients had persistent BKPyV DNAemia. Although eight (67%) patients developed allograft dysfunction, none required hemodialysis., Conclusions: We observed a marginal trend of BKPyV-specific CD4 + T cell recovery after adjustment of immunosuppression in KT recipients diagnosed with BKPyVAN. A further study would be benefited to confirm and better assess BKPyV-specific immune response after KT.

Background: Drug-resistant cytomegalovirus (CMV) infection has been increasingly recognized. However, there are limited data in pediatric patients. In this study, the prevalence and factors associated with CMV infection with UL97 mutations in pediatric patients treated with ganciclovir but not responding to treatment were evaluated., Methods: This retrospective study was conducted from January 2013 to December 2017. All patients who were suspected of having ganciclovir-resistant CMV infection and had never had ganciclovir prophylaxis were included. Genotypic assay for UL97 mutations in codons 460 and 520 conferring ganciclovir resistance was performed. Factors associated with the presence of UL97 mutations were analyzed., Results: Of 34 patients included, 10 patients (29.4%) had a genotypically confirmed UL97 mutation. The median age (interquartile range [IQR]) was 3 (0.85-8.68) years. Ganciclovir resistance was tested at a median time (IQR) of 22.5 (14.3-31) days after initiation of ganciclovir. All resistant isolates harbored a UL97 mutation in codon 460. Compared with patients infected with CMV without UL97 mutation, those infected with UL97 mutation strains were younger (median age [IQR], 3.02 [0.85-8.68] vs 10.45 [2.7-16.4] years) and had a higher maximum viral load (median [IQR], 5.06 [4.74-6.05] vs 4.42 [4.03-4.87] copies/mL). Six of 10 (60%) patients were successfully treated with high-dose ganciclovir (7.5 mg/kg twice daily)., Conclusions: UL97 mutation ganciclovir-resistant CMV infection was not uncommon in the pediatric population. Screening for this mutation should be considered in patients experiencing virological worsening while ganciclovir is given, even if patients have not previously received ganciclovir prophylaxis., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We assessed the effectiveness of an antibiotic stewardship program (ASP) on antibiotic prescriptions for acute respiratory tract infection (ARTI) in a medical school. Our ASP included delivering an antibiotic use guideline via e-mail and LINE (an instant messaging app) to faculty staff, fellows, and residents, and posting of the guideline in examination rooms. Medical records of pediatric patients diagnosed with ARTI were reviewed to assess the appropriateness of antibiotic prescription. ASP could increase the rate of appropriateness from 78% (1979 out of 2553 visits) to 83.4% (2449 out of 2935 visits; P < .001). The baseline of appropriateness was higher in residents (95%) compared with fellows (82%) and faculty staff (75%). The ASP significantly increased the appropriateness only in faculty staff, especially in semiprivate clinics (75% to 83%, P < .001). In conclusion, our ASP increased appropriateness of antibiotic prescriptions for ARTI, with the greatest impact among faculty staff in semiprivate clinics.

Objective: Capillary blood has been increasingly used in point-of-care setting for clinical monitoring in immunology and infectious diseases. We explored whether percentages of lymphocyte subsets (T-cells; CD3+, helper T-cells; CD4+, cytotoxic T-cells; CD8+, B-cells; CD19+, NK cells; CD56+, gamma delta T-cells, and regulatory T-cells) with regard to total lymphocyte count from capillary and venous blood of healthy volunteers were in good agreement., Results: All percentages of lymphocyte subsets with regard to total lymphocyte count from capillary blood were significantly correlated with those from venous blood (r ≥ 0.9 for every cell type). However, Bland-Altman plots showed high agreement between capillary and venous samples only in those of CD3+, CD4+, and CD8+ cells (limit of agreement percentages from mean venous blood < 20%). However, the agreement of percentages of other lymphocyte subsets from venous and capillary blood was mediocre. We concluded that capillary blood could be used as an alternative for venous blood to determine percentages of CD3+, CD4+, and CD8+ cells with regard to total lymphocyte count.

Introduction: Human adenovirus (HAdV) infection can cause substantial morbidity in kidney transplant (KT) recipients. Cell-mediated immunity plays an important role in controlling HAdV infection after KT., Methods: We prospectively (January 2015 to June 2018) investigated the absolute lymphocyte count (ALC) and interferon-γ-producing CD4 + and CD8 + T cells at diagnosis and at viral clearance by an intracellular cytokine assay after stimulating with HAdV whole lysate, hexon, and penton proteins. HAdV infection was defined as the presence of HAdV DNA load in plasma or clinical specimens measured by the polymerase chain reaction assay., Results: Eighteen adult KT recipients were diagnosed with HAdV infection at a median of 16 months (interquartile range [IQR], 2-39) after KT. The majority (94%) had HAdV-associated hemorrhagic cystitis. The median ALC at viral clearance was significantly higher compared with diagnosis (2257 cells/mm 3 [IQR, 1544-3078] vs 1001 cells/mm 3 [IQR, 641-1385]; P < 0.001). Eleven patients underwent measurement of the HAdV-specific T-cell response. The median numbers of CD4 + and CD8 + T cells at viral clearance were significantly higher compared with diagnosis (448 cells/mm 3 [IQR, 248-651] vs 215 cells/mm 3 [IQR, 159-272], P = 0.02; and 623 cells/mm 3 [IQR, 242-772] vs 235 cells/mm 3 [IQR, 129-266], P < 0.01), respectively. The median percentages of penton-specific CD4 + and hexon-specific CD8 + T cells at viral clearance were significantly higher compared with diagnosis (0.012% vs 0%, P = 0.03%; and 0.136% vs 0.016%, P = 0.003, respectively)., Conclusions: Our findings suggest a trend of ALC and HAdV-specific T-cell immune restoration in KT recipients who achieve successful HAdV clearance., (© 2019 Wiley Periodicals, Inc.)

The third-party umbilical cord blood (UCB)-derived regulatory T cells (Treg) are an alternative to donor-derived Treg as cellular therapy of graft-versus-host disease following hematopoietic stem cell transplantation. However, their suppressive characteristics against autologous and allogeneic T effector cells (Teff) have rarely been documented. The exact role of UCB-Treg in hematologic malignancies is also uncertain. Here, we investigated the direct effects of UCB-Treg on the proliferation of autologous Teff, as compared with allogeneic Teff, and also determined cellular fates of lymphoblasts after UCB-Treg co-culture. UCB-Treg were isolated from 8 UCB samples using 2-step immunomagnetic bead sorting. After 10-day ex vivo expansion, up to 60-fold increase in cell number with 76.7%±4.9% of CD4CD25CD127FoxP UCB-Treg was obtained. Further characterization showed that ex vivo-expanded UCB-Treg contained a higher proportion of CD95CD45RACCR4Treg-B subpopulation compared with the CD95CD45RACCR4Treg-A subpopulation (13.0%±4.8% vs. 0.8%±0.7%; P<0.05), along with the detecting of substantial amounts of secretory IL-10 (57.7±17.8 pg/mL) and TGF-β1 (196.5±29.7 pg/mL) in culture supernatants. After 4 days co-culture with UCB-Treg (at the ratio of 1:1), the proliferation of autologous and allogeneic Teff was decreased comparably (43.6%±17.5% vs. 37.6±17.7%; P=0.437). Suppression was independent of HLA-A, B, and DRB1 compatibility between UCB-Treg and Teff. UCB-Treg co-culture with various lymphoblasts showed proliferative suppression of Jurkat T lymphoblasts (45.4%±20.5% at the ratio of 1:1), but not Namalwa and Raji B lymphoblasts. All lymphoblasts had no significant cell apoptosis or death after co-culture. In conclusion, the ex vivo-expanded UCB-Treg had no difference in autologous and allogeneic Teff suppression. UCB-Treg therapy in patients with graft-versus-host disease who have a primary disease of T-cell leukemia may have additional benefits in the prevention of relapsed disease.

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality in the posttransplant setting; however, it is increasingly recognized in pediatric leukemia during chemotherapy. This study assessed the prevalence and associated factors of CMV infection in pediatric non-transplant leukemia patients.This was a cross-sectional study of 50 pediatric acute lymphoblastic leukemia (ALL) patients receiving chemotherapy at Ramathibodi Hospital from December 2015 to December 2016. CMV viral load quantified by DNA polymerase chain reaction (PCR) was monitored in different phases of chemotherapy: enrolment, post-induction, post-consolidation, post-intensification, and maintenance.One hundred forty one blood tests were evaluated from 50 patients. Overall prevalence of CMV DNAemia (≥20 copies/mL) and high-level CMV DNAemia (≥1000 copies/mL) was 52% (26 of 50) and 16.0% (8 of 50), respectively. All patients with high-level CMV DNAemia were in the maintenance phase of chemotherapy. One patient had CMV retinitis, while the rest had no end-organ CMV diseases. Increased lymphocyte count was significantly associated with protection from high-level CMV DNAemia (odds ratio 0.997, P = .02). Receiver operating characteristic curve identified a cut-off value of 798 cells/mm of absolute lymphocyte count (ALC) as a discriminator for the presence of high-level CMV DNAemia (area under the curve 0.756, 95% CI 0.645-0.867, P = .001) with 88.9% sensitivity and 50.4% specificity.CMV infection predominantly occurred during maintenance chemotherapy. Low ALC was significantly associated with high-level CMV DNAemia. CMV infection surveillance by quantitative CMV DNA PCR during maintenance chemotherapy in patients with ALC <800 cells/mm may be considered.

Compared to adults, infants suffer higher rates of hospitalization, severe clinical complications, and mortality due to influenza infection. We found that γδ T cells protected neonatal mice against mortality during influenza infection. γδ T cell deficiency did not alter viral clearance or interferon-γ production. Instead, neonatal influenza infection induced the accumulation of interleukin-17A (IL-17A)-producing γδ T cells, which was associated with IL-33 production by lung epithelial cells. Neonates lacking IL-17A-expressing γδ T cells or Il33 had higher mortality upon influenza infection. γδ T cells and IL-33 promoted lung infiltration of group 2 innate lymphoid cells and regulatory T cells, resulting in increased amphiregulin secretion and tissue repair. In influenza-infected children, IL-17A, IL-33, and amphiregulin expression were correlated, and increased IL-17A levels in nasal aspirates were associated with better clinical outcomes. Our results indicate that γδ T cells are required in influenza-infected neonates to initiate protective immunity and mediate lung homeostasis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: B cells play an essential role during dengue viral infection. While a major expansion of antibody secreting cells (ASCs) was observed, the importance of these increased frequencies of ASCs remains unclear. The alteration of B cell subsets may result from the expression of tissue specific homing molecules leading to their mobilization and distribution to different target organs during acute dengue viral infection., Methods: In this study, whole blood samples were obtained from thirty pediatric dengue-infected patients and ten healthy children and then stained with fluorochrome-conjugated monoclonal antibodies against CD3, CD14, CD19, CD20, CD21, CD27, CD38, CD45, CD138 and homing molecules of interest before analyzed by polychromatic flow cytometry. B cell subsets were characterized throughout acute infection period., Results: Data shows that there were no detectable differences in frequencies of resting, activated and tissue memory cells, whereas the frequency of ASCs was significantly increased and associated with the lower frequency of naïve cells. These results were found from patients with both dengue fever and dengue hemorrhagic fever, suggesting that such change or alteration of B cells was not associated with disease severity. Moreover, several homing molecules (e.g., CXCR3 and CCR2) were found in ASCs, indicating that ASCs may distribute to inflamed tissues and various organs., Conclusions: Findings from this study provide insight into B cell subset distribution. Furthermore, organ mobilization according to homing molecule expression on different B cell subsets during the course of dengue viral infection also suggests they are distributed to inflamed tissues and various organs.