TFEB regulates dendritic cell antigen presentation to modulate immune balance in asthma.

OBJECTIVE: Asthma stands as one of the most prevalent chronic respiratory conditions in children, with its pathogenesis tied to the actived antigen presentation by dendritic cells (DCs) and the imbalance within T cell subgroups. This study seeks to investigate the role of the transcription factor EB (TFEB) in modulating the antigen presentation process of DCs and its impact on the differentiation of T cell subgroups. METHODS: Bone marrow dendritic cells (BMDCs) were activated using house dust mites (HDM) and underwent RNA sequencing (RNA-seq) to pinpoint differentially expressed genes. TFEB mRNA expression levels were assessed in the peripheral blood mononuclear cells (PBMCs) of both healthy children and those diagnosed with asthma. In an asthma mouse model induced by HDM, the TFEB expression in lung tissue DCs was evaluated. Further experiments involved LV-shTFEB BMDCs co-cultured with T cells to explore the influence of TFEB on DCs' antigen presentation, T cell subset differentiation, and cytokine production. RESULTS: Transcriptomic sequencing identified TFEB as a significantly differentially expressed gene associated with immune system pathways and antigen presentation. Notably, TFEB expression showed a significant increase in the PBMCs of children diagnosed with asthma compared to healthy counterparts. Moreover, TFEB exhibited heightened expression in lung tissue DCs of HDM-induced asthmatic mice and HDM-stimulated BMDCs. Silencing TFEB resulted in the downregulation of MHC II, CD80, CD86, and CD40 on DCs. This action reinstated the equilibrium among Th1/Th2 and Th17/Treg cell subgroups, suppressed the expression of pro-inflammatory cytokines like IL-4, IL-5, IL-13, and IL-17, while augmenting the expression of the anti-inflammatory cytokine IL-10. CONCLUSION: TFEB might have a vital role in asthma's development by impacting the antigen presentation of DCs, regulating T cell subgroup differentiation, and influencing cytokine secretion. Its involvement could be pivotal in rebalancing the immune system in asthma. These research findings could potentially unveil novel therapeutic avenues for treating asthma.

Long-chain acyl-CoA synthetase 4-mediated mitochondrial fatty acid metabolism and dendritic cell antigen presentation.

OBJECTIVE: This study aims to investigate the role of Acyl-CoA synthetase 4 (ACSL4) in mediating mitochondrial fatty acid metabolism and dendritic cell (DC) antigen presentation in the immune response associated with asthma. METHODS: RNA sequencing was employed to identify key genes associated with mitochondrial function and fatty acid metabolism in DCs. ELISA was employed to assess the levels of fatty acid metabolism in DCs. Mitochondrial morphology was evaluated using laser confocal microscopy, structured illumination microscopy, and transmission electron microscopy. Flow cytometry and immunofluorescence were utilized to detect changes in mitochondrial superoxide generation in DCs, followed by immunofluorescence co-localization analysis of ACSL4 and the mitochondrial marker protein COXIV. Subsequently, pathological changes and immune responses in mouse lung tissue were observed. ELISA was conducted to measure the levels of fatty acid metabolism in lung tissue DCs. qRT-PCR and western blotting were employed to respectively assess the expression levels of mitochondrial-associated genes (ATP5F1A, VDAC1, COXIV, TFAM, iNOS) and proteins (ATP5F1A, VDAC1, COXIV, TOMM20, iNOS) in lung tissue DCs. Flow cytometry was utilized to analyze changes in the expression of surface antigens presented by DCs in lung tissue, specifically the MHCII molecule and the co-stimulatory molecules CD80/86. RESULTS: The sequencing results reveal that ACSL4 is a crucial gene regulating mitochondrial function and fatty acid metabolism in DCs. Inhibiting ACSL4 reduces the levels of fatty acid oxidases in DCs, increases arachidonic acid levels, and decreases A-CoA synthesis. Simultaneously, ACSL4 inhibition leads to an increase in mitochondrial superoxide production (MitoSOX) in DCs, causing mitochondrial rupture, vacuolization, and sparse mitochondrial cristae. In mice, ACSL4 inhibition exacerbates pulmonary pathological changes and immune responses, reducing the fatty acid metabolism levels within lung tissue DCs and the expression of mitochondria-associated genes and proteins. This inhibition induces an increase in the expression of MHCII antigen presentation molecules and co-stimulatory molecules CD80/86 in DCs. CONCLUSIONS: The research findings indicate that ACSL4-mediated mitochondrial fatty acid metabolism and dendritic cell antigen presentation play a crucial regulatory role in the immune response of asthma. This discovery holds promise for enhancing our understanding of the mechanisms underlying asthma pathogenesis and potentially identifying novel targets for its prevention and treatment.

The effects of delayed appropriate antimicrobial therapy on children with Staphylococcus aureus blood infection.

Early appropriate antimicrobial therapy plays a critical role for patients with Staphylococcus aureus bloodstream infection (SAB). We aim to determine the optimal time-window for appropriate antimicrobial therapy and evaluate the effects of delayed therapy on adverse clinical outcomes (in-hospital mortality, sepsis, and septic shock) in children with SAB by propensity score matching (PSM) analysis. Receiver-operating characteristic was used to determine the cut-off point of the time to appropriate therapy (TTAT), the patients were divided into timely and delayed appropriate antimicrobial therapy (delayed therapy) groups accordingly. The PSM was used to balance the characteristics between the two groups, controlling the effects of potential confounders. Kaplan-Meier methods and Cox proportional hazards regression were applied to the matched groups to analyze the association between delayed therapy and clinical outcomes. Inverse probability of treatment weighting and propensity score covariate adjustment were also performed to investigate the sensitivity of the results under different propensity score-based approaches. In total, 247 patients were included in this study. The optimal cut-off point of TTAT was identified as 6.4 h, with 85.0% sensitivity and 69.2% specificity (AUC 0.803, 95% confidence interval 0.702-0.904). Eighty-seven (35.22%) of the 247 patients who received delayed therapy (TTAT ≥ 6.4 h) had higher in-hospital mortality (19.54% vs 1.88%, p < 0.001), higher incidences of sepsis (44.83% vs 15.00%, p < 0.001) and septic shock (32.18% vs 6.25%, p < 0.001) when compared to timely therapy (TTAT < 6.4 h) patients. After PSM analysis, a total of 134 episodes (67 in each of the two matched groups) were further analyzed. No statistically significant difference was observed in in-hospital mortality between delayed and timely -therapy groups (log-rank test, P = 0.157). Patients with delayed therapy had a higher incidence of sepsis or septic shock than those with timely therapy (log-rank test, P = 0.009; P = 0.018, respectively). Compared to the timely-therapy group, the hazard ratio and 95% confidence interval in delayed-therapy group were 2.512 (1.227-5.144, P = 0.012) for sepsis, 3.109 (1.166-8.290, P = 0.023) for septic shock.    Conclusion: Appropriate therapy delayed 6.4 h may increase the incidence of sepsis and septic shock, with similar in-hospital mortality in patients with SAB. What is Known: • Staphylococcus aureus (S. aureus) is a major cause of bloodstream infections in children. Undoubtedly, early antimicrobial application plays a critical role in the treatment of children with Staphylococcus aureus bloodstream infections (SAB). • However, rapid, and aggressive administration of antimicrobials may lead to the overuse of these drugs and the emergence of multidrug-resistant microorganisms. Therefore, it is crucial to determine the optimal time-window for appropriate antimicrobial administration in children with SAB. Unfortunately, the optimal time-window for appropriate antimicrobial administration in children with SAB remains unclear. What is New: • Determining the optimal time-window for appropriate antimicrobial administration in patients with matched data variables is particularly important. The Propensity score matching (PSM) analysis effectively controls for confounding factors to a considerable extent when assessing the impact of treatment, thereby approximating the effects observed in randomized controlled trials. • To our knowledge, this is the first study using PSM method to assess the effects of delayed appropriate antimicrobial therapy on adverse outcomes in children with SAB. In low-risk populations with SAB, a delay of 6.4 h in appropriate therapy might increase the occurrence rate for sepsis and septic shock; however, no correlation has been found between this delay and an increased risk for hospital mortality.

Defining RSV epidemic season in southwest China and assessing the relationship between birth month and RSV infection: A 10-year retrospective study from June 2009 to May 2019.

Respiratory syncytial virus (RSV) is one of the most common causes of lower respiratory tract infections (LRTI). However, only limited information is available regarding its seasonality and its relationship with birth month. A retrospective hospital-based study was carried out from June 2009 to May 2019 in Chongqing, southwest of China. LRTI cases under 5 years were enrolled in this study and PCR was used to detect 8 respiratory viruses. RSV seasonality was determined using "average annual percentage" (AAP) and "percent positivity" method. A total of 6991 cases were enrolled in this study, with an RSV positivity of 34.5%. From June 2009 to May 2019, we analyzed RSV epidemic season during 10 RSV epidemic years in Chongqing using two methods. The result of AAP method was similar to that of percent positivity method with a 30% threshold, which showed an epidemic season of roughly October to March in the subsequent year, with a small peak in June. On average, the RSV epidemic season in RSV-A dominant years typically started earlier (week 42 for RSV-A vs. week 46 for RSV-B), ended earlier (week 12 for RSV-A vs. week 14 for RSV-B), lasted longer (24 weeks for RSV-A vs. 22 weeks for RSV-B), and reached its peak earlier (week 2 for RSV-A vs. week 3 for RSV-B) than in RSV-B dominant years. The proportion of severe LRTI was higher in cases of single infection with RSV-A compared to those of single infection with RSV-B (26.3% vs. 22.3%, p = 0.024). Among infants under 1 year, those born in May and August through December were more likely to be infected with RSV. Infants born 1-2 months before the epidemic season were relatively more susceptible to RSV infection. In Chongqing, the RSV epidemic was seasonal and usually lasted from October to March of next year with a small peak in summer. Infants born 1-2 months before the epidemic season were relatively more susceptible to RSV infection and this population should be targeted while developing RSV immunization strategies.

Dysregulation of iron homeostasis in airways associated with persistent preschool wheezing.

BACKGROUND: Currently, there are no reliable clinical tools available to identify persistent asthma symptoms among preschool children with recurrent wheezing. We investigated iron homeostasis in the airways of preschoolers with recurrent wheezing and assessed whether iron homeostasis-related indices may reliably predict persistent wheezing. METHODS: Iron levels and mRNA expression levels of iron homeostasis molecules were examined in bronchoalveolar lavage samples from 89 preschoolers with recurrent wheezing and 56 controls, with a 12-month follow-up conducted. Risk factors for persistent wheezing were identified using least absolute shrinkage and selection operator and multivariate logistic regression. The addition of predictive values of iron indices to the modified Asthma Predictive Index (mAPI) or clinical predictors was determined using area under receiver operating characteristic curves (AUC). RESULTS: Preschoolers with recurrent wheezing had reduced iron levels in their airways, associated with significantly decreased expression of iron export molecule SLC40A1 and increased expression of iron intake factor TFR1 and iron storage factors FTH and FTL. Risk factors for persistent wheezing included mAPI positivity, iron predictors (lower expression of SLC40A1 and higher expression of FTL), and clinical predictors (aeroallergen sensitivity, shorter breastfeeding duration, and earlier age of first wheezing episode). The addition of information on iron predictors significantly enhanced the power of clinical predictors (AUC: 84%, increase of 12%) and mAPI (AUC: 81%, increase of 14%). CONCLUSIONS: Iron homeostasis is altered in the airways of preschoolers with recurrent wheezing. Adding information on iron-related indices to clinical information significantly improves accurate prediction of persistent wheezing in preschool-aged children.

Prognostic accuracy of SOFA and qSOFA for mortality among children with infection: a meta-analysis.

BACKGROUND: Age-adjusted Sequential Organ Failure Assessment (SOFA) and age-adjusted quick SOFA (qSOFA) scores have been developed to predict poor outcomes in children with infection. We investigated the prognostic performance of age-adjusted SOFA and age-adjusted qSOFA scores and compared them with the systemic inflammatory response syndrome (SIRS) criteria for predicting mortality in children with infection. METHODS: A bivariate random-effects regression model was used for synthesis of diagnostic test data. RESULTS: A total of 14 studies invoing 70,194 participants were included. The pooled sensitivity for age-adjusted SOFA, age-adjusted qSOFA, and SIRS were 0.82 (95% CI, 0.74-0.88), 0.46 (95% CI, 0.22-0.71), and 0.79 (95% CI, 0.66-0.88), respectively. The pooled specificity for age-adjusted SOFA, age-adjusted qSOFA, and SIRS were 0.62 (95% CI, 0.45-0.77), 0.90 (95% CI, 0.66-0.98), and 0.39 (95% CI, 0.26-0.54), respectively. The area under the summary receiver operating characteristic curve (AUSROC) for age-adjusted SOFA, age-adjusted qSOFA, and SIRS were 0.82 (95% CI, 0.79-0.85), 0.66 (95% CI, 0.62-0.70), and 0.64 (95% CI, 0.60-0.68), respectively. Different baseline populations, different SOFA adaptation methods and different cut-offs used for age-adjusted SOFA may be potential sources of heterogeneity. CONCLUSIONS: Age adjusted SOFA score is a useful tool for predicting mortality in children with sepsis/suspected sepsis. IMPACT: First study to investigate the prognostic performance of age-adjusted sequential organ failure assessment (SOFA) and age adjusted quick SOFA (qSOFA) scores in comparison to the systemic inflammatory response criteria (SIRS) for the prediction of mortality in children with sepsis. The age-adjusted SOFA score predicts poor outcomes with high sensitivity in children with sepsis Low sensitivity limits the utility of age-adjusted qSOFA as a simple predictive tool for adverse outcomes. Developing another enhanced or modified bedside tool with higher sensitivity may be necessary.

A multicentre study on the incidence of respiratory viruses in children with community-acquired pneumonia requiring hospitalization in the setting of the zero-COVID policy in China.

BACKGROUND: Stringent nonpharmaceutical interventions (NPIs) have been implemented worldwide to combat the COVID-19 pandemic, and the circulation and seasonality of common respiratory viruses have subsequently changed. There have been few multicentre studies or comparisons of the prevalence of respiratory viruses accounting for community-acquired pneumonia (CAP) in hospitalized children between the pre-COVID period and the period after community and school reopening in the setting of the zero-COVID policy. METHODS: We included 1543 children with CAP who required hospitalization from November 1, 2020 to April 30, 2021 (period 1), and 629 children with the same conditions from November 1, 2018, to April 30, 2019 (period 2), in our study. All respiratory samples from these patients were screened for six respiratory viruses (respiratory syncytial virus [RSV], adenovirus [ADV], influenza A virus [Flu A], influenza B virus [Flu B], parainfluenza virus type 1 [PIV1], and parainfluenza virus type 3 [PIV3]) using a multiplex real-time PCR assay. RESULTS AND CONCLUSIONS: The median ages of the enrolled patients at the time of diagnosis were 1.5 years and 1.0 years for period 1 and period 2, respectively. In period 1, viral pathogens were detected in 50.3% (776/1543) of the enrolled patients. The most frequently identified viral pathogen was RSV (35.9%, 554/1543), followed by PIV3 (9.6%, 148/1543), PIV1 (3.6%, 56/1543), ADV (3.4%, 52/1543), Flu A (1.0%, 16/1543), and Flu B (0.8%, 13/1543). The total detection rates of these six viruses in the peak season of CAP were at the pre-COVID level. The prevalence of Flu A decreased dramatically, and circulation activity was low compared to pre-COVID levels, while the incidence of PIV3 increased significantly. There were no significant differences in the detection rates of RSV, ADV, Flu B, and PIV1 between the two periods. Our results showed that respiratory viruses accounted for CAP in hospitalized children at pre-COVID levels as communities and schools reopened within the zero-COVID policy, although the prevalence aetiology spectrum varied.

Inappropriate empirical antibiotic therapy was an independent risk factor of pediatric persistent S. aureus bloodstream infection.

Persistent S. aureus bloodstream infection (PSBSI) increased the incidence of metastatic infection and mortality. We aimed to clarify its risk factors and correlation with metastatic infection and septic shock in children. This retrospective and observational study enrolled children with S. aureus bloodstream infection who admitted to Children's Hospital of Chongqing Medical University between January 2016 and December 2021. The logistic regression model was used for multivariable analyses to determine independent factors associated with PSBSI and clarify the effect of persistent S. aureus bloodstream infection and other factors on metastatic infection and septic shock. One hundred and twenty-seven children were included in this study retrospectively. There were thirty-two cases in the persistent S. aureus bloodstream infection group and ninety-five children in the non-persistent infection group. Multivariate logistic regression analysis indicated that inappropriate empirical antibiotic therapy (OR, 7.26; 95%CI, 2.48-21.30; P<0.01) was an independent risk factor of persistent S. aureus bloodstream infection. Persistent S. aureus bloodstream infection (OR, 6.40; 95%CI, 2.08-19.70; P<0.01) and community-acquired S. aureus bloodstream infection (OR, 4.75; 95%CI, 1.34-16.89; P=0.02) were independent predictors of metastatic infection. Pittsburgh bacteremia scores ≥ 2 (OR, 28.81; 95%CI, 5.26-157.99; P<0.01), hypoalbuminemia (OR, 13.34; 95%CI, 2.43-73.28; P<0.01) and persistent S. aureus bloodstream infection (OR, 5.48; 95%CI, 1.13-26.54; P=0.04) were independent risk factors of septic shock. CONCLUSION: Inappropriate empirical antibiotic therapy was an independent risk factor of pediatric persistent S. aureus bloodstream infection. Pediatric persistent S. aureus bloodstream infection was associated with metastatic infection and septic shock. WHAT IS KNOWN: • Pathogenic features such as Methicillin-resistant S. aureus and sources of infection such as central venous catheter related infection were risk factors of PSBSI in adults. • PSBSI increased the incidence of metastatic infection and mortality in adults. WHAT IS NEW: • Inappropriate empirical antibiotic therapy was an independent risk factor of pediatric persistent S. aureus bloodstream infection. • Pediatric persistent S. aureus bloodstream infection was associated with metastatic infection and septic shock.

The role of small airway function parameters in preschool asthmatic children.

BACKGROUND: Small airways are the major sites of inflammation and airway remodeling in all severities of asthma patients. However, whether small airway function parameters could reflect the airway dysfunction feature in preschool asthmatic children remain unclear. We aim to investigate the role of small airway function parameters in evaluating airway dysfunction, airflow limitation and airway hyperresponsiveness (AHR). METHODS: Eight hundred and fifty-one preschool children diagnosed with asthma were enrolled retrospectively to investigate the characteristics of small airway function parameters. Curve estimation analysis was applied to clarify the correlation between small and large airway dysfunction. Spearman's correlation and receiver-operating characteristic (ROC) curves were employed to evaluate the relationship between small airway dysfunction (SAD) and AHR. RESULTS: The prevalence of SAD was 19.5% (166 of 851) in this cross-sectional cohort study. Small airway function parameters (FEF25-75%, FEF50%, FEF75%) showed strong correlations with FEV1% (r = 0.670, 0.658, 0.609, p<0.001, respectively), FEV1/FVC% (r = 0.812, 0.751, 0.871, p<0.001, respectively) and PEF% (r = 0.626, 0.635, 0.530, p<0.01, respectively). Moreover, small airway function parameters and large airway function parameters (FEV1%, FEV1/FVC%, PEF%) were curve-associated rather than linear-related (p<0.001). FEF25-75%, FEF50%, FEF75% and FEV1% demonstrated a positive correlation with PC20 (r = 0.282, 0.291, 0.251, 0.224, p<0.001, respectively). Interestingly, FEF25-75% and FEF50% exhibited a higher correlation coefficient with PC20 than FEV1% (0.282 vs. 0.224, p = 0.031 and 0.291 vs. 0.224, p = 0.014, respectively). ROC curve analysis for predicting moderate to severe AHR showed that the area under the curve (AUC) was 0.796, 0.783, 0.738, and 0.802 for FEF25-75%, FEF50%, FEF75%, and the combination of FEF25-75% and FEF75%, respectively. When Compared to children with normal lung function, patients with SAD were slightly older, more likely to have a family history of asthma and airflow obstruction with lower FEV1% and FEV1/FVC%, lower PEF% and more severe AHR with lower PC20 ( all p<0.05). CONCLUSION: Small airway dysfunction is highly correlated with large airway function impairment, severe airflow obstruction and AHR in preschool asthmatic children. Small airway function parameters should be utilized in the management of preschool asthma.

[Clinical characteristics of plastic bronchitis and risk factors for recurrence in children]. / å„¿ç«¥å¡‘åž‹æ€§æ”¯æ°”ç®¡ç‚Žä¸´åºŠç‰¹å¾åŠå¤å‘å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To study the clinical characteristics of plastic bronchitis (PB) in children and investigate the the risk factors for recurrence of PB. METHODS: This was a retrospective analysis of medical data of children with PB who were hospitalized in Children's Hospital of Chongqing Medical University from January 2012 to July 2022. The children were divided into a single occurrence of PB group and a recurrent PB group and the risk factors for recurrence of PB were analyzed. RESULTS: A total of 107 children with PB were included, including 61 males (57.0%) and 46 females (43.0%), with a median age of 5.0 years, and 78 cases (72.9%) were over 3 years old. All the children had cough, 96 children (89.7%) had fever, with high fever in 90 children. Seventy-three children (68.2%) had shortness of breath, and 64 children (59.8%) had respiratory failure. Sixty-six children (61.7%) had atelectasis and 52 children (48.6%) had pleural effusion. Forty-seven children (43.9%) had Mycoplasma pneumoniae infection, 28 children (26.2%) had adenovirus infection, and 17 children (15.9%) had influenza virus infection. Seventy-one children (66.4%) had a single occurrence of PB, and 36 cases (33.6%) had recurrent occurrence of PB (≥2 times). Multivariate logistic regression analysis showed that involvement of ≥2 lung lobes (OR=3.376) under bronchoscopy, continued need for invasive ventilation after initial removal of plastic casts (OR=3.275), and concomitant multi-organ dysfunction outside the lungs (OR=2.906) were independent risk factors for recurrent occurrence of PB (P<0.05). CONCLUSIONS: Children with pneumonia accompanied by persistent high fever, shortness of breath, respiratory failure, atelectasis or pleural effusion should be highly suspected with PB. Involvement of ≥2 lung lobes under bronchoscopy, continued need for invasive ventilation after initial removal of plastic casts, and concomitant multi-organ dysfunction outside the lungs may be risk factors for recurrent occurrence of PB.

[Clinical and bronchoscopy features of tracheobronchial tuberculosis in children]. / å„¿ç«¥æ°”ç®¡æ”¯æ°”ç®¡ç»“æ ¸çš„ä¸´åºŠåŠæ”¯æ°”ç®¡é•œä¸‹ç‰¹å¾åˆ†æž.

OBJECTIVES: To study the clinical and bronchoscopic characteristics of tracheobronchial tuberculosis (TBTB) in children and to identify factors influencing residual airway obstruction or stenosis. METHODS: The clinical data of children with TBTB were retrospectively collected. The children were divided into two groups based on the last bronchoscopic result within one year of follow-up: a group with residual airway obstruction or stenosis (n=34) and a group without residual airway obstruction or stenosis (n=58). A multivariate logistic regression analysis was used to identify the factors influencing residual airway obstruction or stenosis in children with TBTB. Receiver operating characteristic (ROC) curves were used to analyze the predictive value of the factors influencing residual airway obstruction or stenosis in children with TBTB. RESULTS: A total of 92 children with TBTB were included, and the main symptoms were cough (90%) and fever (68%). In children under 1 year old, the incidence rates of dyspnea and wheezing were significantly higher than in other age groups (P<0.008). Chest CT findings included mediastinal or hilar lymph node enlargement (90%) and tracheobronchial stenosis or obstruction (61%). The lymphatic fistula type was the main type of TBTB observed bronchoscopically (77%). All children received interventional treatment, and the effective rate was 84%. During one year of follow-up, 34 children had residual airway obstruction or stenosis. The TBTB diagnostic time and the initiation of interventional treatment were significantly delayed in the group with residual airway obstruction or stenosis compared with the group without residual airway obstruction or stenosis (P<0.05). The multivariate logistic regression analysis showed that the TBTB diagnostic time was closely related to residual airway obstruction or stenosis in children (P<0.05). ROC curve analysis showed that at the cut-off value of 92 days of TBTB diagnostic time, the area under the curve for predicting residual airway obstruction or stenosis in children with TBTB was 0.707, with a sensitivity of 58.8% and a specificity of 75.9%. CONCLUSIONS: The clinical manifestations of TBTB are nonspecific, and symptoms are more severe in children under 1 year old. TBTB should be suspected in children with tuberculosis and chest imaging indicating airway involvement. Delayed diagnosis of TBTB is associated with the development of residual airway obstruction or stenosis.

Methodology and experiences of rapid advice guideline development for children with COVID-19: responding to the COVID-19 outbreak quickly and efficiently.

BACKGROUND: Rapid Advice Guidelines (RAG) provide decision makers with guidance to respond to public health emergencies by developing evidence-based recommendations in a short period of time with a scientific and standardized approach. However, the experience from the development process of a RAG has so far not been systematically summarized. Therefore, our working group will take the experience of the development of the RAG for children with COVID-19 as an example to systematically explore the methodology, advantages, and challenges in the development of the RAG. We shall propose suggestions and reflections for future research, in order to provide a more detailed reference for future development of RAGs. RESULT: The development of the RAG by a group of 67 researchers from 11 countries took 50 days from the official commencement of the work (January 28, 2020) to submission (March 17, 2020). A total of 21 meetings were held with a total duration of 48 h (average 2.3 h per meeting) and an average of 16.5 participants attending. Only two of the ten recommendations were fully supported by direct evidence for COVID-19, three recommendations were supported by indirect evidence only, and the proportion of COVID-19 studies among the body of evidence in the remaining five recommendations ranged between 10 and 83%. Six of the ten recommendations used COVID-19 preprints as evidence support, and up to 50% of the studies with direct evidence on COVID-19 were preprints. CONCLUSIONS: In order to respond to public health emergencies, the development of RAG also requires a clear and transparent formulation process, usually using a large amount of indirect and non-peer-reviewed evidence to support the formation of recommendations. Strict following of the WHO RAG handbook does not only enhance the transparency and clarity of the guideline, but also can speed up the guideline development process, thereby saving time and labor costs.

Potentially effective drugs for the treatment of COVID-19 or MIS-C in children: a systematic review.

The purpose of this systematic review is to evaluate the efficacy and safety of using potential drugs: remdesivir and glucocorticoid in treating children and adolescents with COVID-19 and intravenous immunoglobulin (IVIG) in treating MIS-C. We searched seven databases, three preprint platform, ClinicalTrials.gov, and Google from December 1, 2019, to August 5, 2021, to collect evidence of remdesivir, glucocorticoid, and IVIG which were used in children and adolescents with COVID-19 or MIS-C. A total of nine cohort studies and one case series study were included in this systematic review. In terms of remdesivir, the meta-analysis of single-arm cohort studies have shown that after the treatment, 54.7% (95%CI, 10.3 to 99.1%) experienced adverse events, 5.6% (95%CI, 1.2 to 10.1%) died, and 27.0% (95%CI, 0 to 73.0%) needed extracorporeal membrane oxygenation or invasive mechanical ventilation. As for glucocorticoids, the results of the meta-analysis showed that the fixed-effect summary odds ratio for the association with mortality was 2.79 (95%CI, 0.13 to 60.87), and the mechanical ventilation rate was 3.12 (95%CI, 0.80 to 12.08) for glucocorticoids compared with the control group. In terms of IVIG, most of the included cohort studies showed that for MIS-C patients with more severe clinical symptoms, IVIG combined with methylprednisolone could achieve better clinical efficacy than IVIG alone. CONCLUSIONS: Overall, the current evidence in the included studies is insignificant and of low quality. It is recommended to conduct high-quality randomized controlled trials of remdesivir, glucocorticoids, and IVIG in children and adolescents with COVID-19 or MIS-C to provide substantial evidence for the development of guidelines. WHAT IS KNOWN: • The efficacy and safety of using potential drugs such as remdesivir, glucocorticoid, and intravenous immunoglobulin (IVIG) in treating children and adolescents with COVID-19/MIS-C are unclear. WHAT IS NEW: • Overall, the current evidence cannot adequately demonstrate the effectiveness and safety of using remdesivir, glucocorticoids, and IVIG in treating children and adolescents with COVID-19 or MIS-C. • We are calling for the publication of high-quality clinical trials and provide substantial evidence for the development of guidelines.

Guidelines for the prevention and management of children and adolescents with COVID-19.

Children are the future of the world, but their health and future are facing great uncertainty because of the coronavirus disease 2019 (COVID-19) pandemic. In order to improve the management of children with COVID-19, an international, multidisciplinary panel of experts developed a rapid advice guideline at the beginning of the outbreak of COVID-19 in 2020. After publishing the first version of the rapid advice guideline, the panel has updated the guideline by including additional stakeholders in the panel and a comprehensive search of the latest evidence. All recommendations were supported by systematic reviews and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Expert judgment was used to develop good practice statements supplementary to the graded evidence-based recommendations. The updated guideline comprises nine recommendations and one good practice statement. It focuses on the key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin (IVIG) for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health. CONCLUSION: This updated evidence-based guideline intends to provide clinicians, pediatricians, patients and other stakeholders with evidence-based recommendations for the prevention and management of COVID-19 in children and adolescents. Larger studies with longer follow-up to determine the effectiveness and safety of systemic glucocorticoids, IVIG, noninvasive ventilation, and the vaccines for COVID-19 in children and adolescents are encouraged. WHAT IS KNOWN: • Several clinical practice guidelines for children with COVID-19 have been developed, but only few of them have been recently updated. • We developed an evidence-based guideline at the beginning of the COVID-19 outbreak and have now updated it based on the results of a comprehensive search of the latest evidence. WHAT IS NEW: • The updated guideline provides key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.

Time to appropriate antimicrobial therapy serves an independent prognostic indicator in children with nosocomial Klebsiella pneumoniae bloodstream infection.

We tend to investigate the connection between time to appropriate therapy (TTAT) and prognosis in pediatric patients with nosocomial Klebsiella pneumoniae (K. pneumoniae) bloodstream infection, and find the optimal cutoff point for the empirical administration of antimicrobials. This retrospective study was conducted in Children's Hospital of Chongqing Medical University, and inpatients with nosocomial K. pneumoniae bloodstream infection were finally enrolled. We applied the Classification and Regression Tree (CART) analysis to find the TTAT cutoff point and the Logistic Regression analysis to evaluate prognostic indicators. The incidence of septic shock and mortality was 17.91% (12/67) and 13.43% (9/67), respectively. The CART-derived TTAT cutoff point was 10.7 h. The multivariate logistic regression analysis indicated delayed therapy (TTAT ≥ 10.7 h), pediatric risk of mortality (PRISM) III scores ≥ 10, time to positivity (TTP) ≤ 13 h, and requiring for invasive mechanical ventilation were independently associated with the incidence of septic shock (Odds ratio [OR] 9.87, 95% Confidence interval [CI] 1.46-66.59, P = 0.019; OR 9.69, 95% CI 1.15-81.39, P = 0.036; OR 8.28, 95% CI 1.37-50.10, P = 0.021; OR 6.52, 95% CI 1.08-39.51, P = 0.042; respectively) and in-hospital mortality (OR 22.19, 95% CI 1.25-393.94, P = 0.035; OR 40.06, 95% CI 2.32-691.35, P = 0.011; OR 22.60, 95% CI 1.78-287.27, P = 0.016; OR 12.21, 95% CI 1.06-140.67, P = 0.045; respectively).Conclusions: TTAT is an independent predictor of poor outcomes in children with nosocomial K. pneumoniae bloodstream infection. Initial appropriate antimicrobial therapy should be administrated timely and within 10.7 h from the onset of bloodstream infection is recommended.

Guideline for the management of pediatric off-label use of drugs in China (2021).

BACKGROUND: The "Law on Doctors of the People's Republic of China," which was officially implemented on March 1, 2022, emphasizes the requirements for rational drug use and the necessity for appropriate management of off-label drug use. The safety and ethical considerations related to off-label drug use are different in children than in adults. There is so far no management guideline for pediatric off-label use of drugs in China, and the applicability of foreign guidelines is limited. Establishing a localized evidence-based management guideline for pediatric off-label use of drugs to support the national legislation and clinical practice is of critical importance. METHODS: We established a guideline working group, including experts from a broad range of disciplines and developed recommendations following the guidance of the World Health Organization Handbook and the Chinese Medical Association. The following themes were identified by questionnaires and expert interviews to be of great concern in the management of off-label drug use in children: general principles and characteristics of management of pediatric off-label drug use; establishment of expert committees; evidence evaluation; risk-benefit assessment; informed consent; monitoring and assessment of the risk; and monitoring and patient education. Two rounds of Delphi surveys were organized to determine the final recommendations of this guideline. We graded the recommendations based on the body of evidence, referring to the evaluation tool of the Evidence-based management (EBMgt) and the Oxford Center for Evidence-Based Medicine: Level of Evidence (March 2009). RESULTS: We developed the first guideline for the management of pediatric off-label use of drugs in China. CONCLUSIONS: The guideline is to offer guidance for pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on how to manage off-label drug use in pediatrics and to provide recommendations for Chinese healthcare policy in the future.

[The Effect of Interventional Treatment with Bronchoscopy in 10 Children with Acquired Subglottic Stenosis].

OBJECTIVE: To explore the effects of interventional therapy with bronchoscopy in children with acquired subglottic stenosis (SGS). METHODS: The clinical data of ten pediatric inpatients with acquired SGS who were admitted to Children's Hospital of Chongqing Medical University, as well as their follow-up information obtained 1 week, 1 month, 3 months and 6 months after the procedure was done.were retrospectively analyzed to examine the effect of interventional bronchoscopic therapies, including balloon dilatation, holmium laser, and cryotherapy, in pediatric patients with acquired SGS. RESULTS: Among the 10 patients with acquired SGS, there were 5 boys and 5 girls aged between 1 month and 6 years and 5 months, with a median age of 11 months and 1 day. Among the 5 patients with acute acquired SGS, two were treated with balloon dilatation only, with one cured and one showing clinical improvement, while three received comprehensive interventional therapy combining balloon dilatation, holmium laser, and cryotherapy, with two cured and one showing improvement. Among the 5 patients with chronic acquired SGS, four cases were cured with comprehensive interventional therapy, while one case suffered from aggravated upper airway obstruction 4 + hours after balloon dilatation. The patient was subsequently put on invasive mechanical ventilation for 4 days, but was unable to be extubated. The parents signed do-not-resuscitate order and the patient died afterwards. Bronchoscopy performed 1 week, 1 month and 3 months after the procedure was done showed that the SGS was improved to varying degrees. CONCLUSION: Bronchoscopy intervention is an effective therapy for acquired SGS in children.

The Impact of Weather and Air Pollution on Viral Infection and Disease Outcome Among Pediatric Pneumonia Patients in Chongqing, China, from 2009 to 2018: A Prospective Observational Study.

BACKGROUND: For pediatric pneumonia, the meteorological and air pollution indicators have been frequently investigated for their association with viral circulation but not for their impact on disease severity. METHODS: We performed a 10-year prospective, observational study in 1 hospital in Chongqing, China, to recruit children with pneumonia. Eight commonly seen respiratory viruses were tested. Autoregressive distributed lag (ADL) and random forest (RF) models were used to fit monthly detection rates of each virus at the population level and to predict the possibility of severe pneumonia at the individual level, respectively. RESULTS: Between 2009 and 2018, 6611 pediatric pneumonia patients were included, and 4846 (73.3%) tested positive for at least 1 respiratory virus. The patient median age was 9 months (interquartile range, 4‒20). ADL models demonstrated a decent fitting of detection rates of R2 > 0.7 for respiratory syncytial virus, human rhinovirus, parainfluenza virus, and human metapneumovirus. Based on the RF models, the area under the curve for host-related factors alone was 0.88 (95% confidence interval [CI], .87‒.89) and 0.86 (95% CI, .85‒.88) for meteorological and air pollution indicators alone and 0.62 (95% CI, .60‒.63) for viral infections alone. The final model indicated that 9 weather and air pollution indicators were important determinants of severe pneumonia, with a relative contribution of 62.53%, which is significantly higher than respiratory viral infections (7.36%). CONCLUSIONS: Meteorological and air pollution predictors contributed more to severe pneumonia in children than did respiratory viruses. These meteorological data could help predict times when children would be at increased risk for severe pneumonia and when interventions, such as reducing outdoor activities, may be warranted.

GITRL on dendritic cells aggravates house dust mite-induced airway inflammation and airway hyperresponsiveness by modulating CD4+ T cell differentiation.

BACKGROUND: Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) plays an important role in tumors, autoimmunity and inflammation. However, GITRL is not known to modulate the pathogenesis of allergic asthma. In this study, we investigated whether regulating GITRL expressed on dendritic cells (DCs) can prevent asthma and to elucidate its mechanism of action. METHODS: In vivo, the role of GITRL in modulating house dust mite (HDM)-induced asthma was assessed in adeno-associated virus (AAV)-shGITRL mice. In vitro, the role of GITRL expression by DCs was evaluated in LV-shGITRL bone marrow dendritic cells (BMDCs) under HDM stimulation. And the direct effect of GITRL was observed by stimulating splenocytes with GITRL protein. The effect of regulating GITRL on CD4+ T cell differentiation was detected. Further, GITRL mRNA in the peripheral blood of asthmatic children was tested. RESULTS: GITRL was significantly increased in HDM-challenged mice. In GITRL knockdown mice, allergen-induced airway inflammation, serum total IgE levels and airway hyperresponsiveness (AHR) were reduced. In vitro, GITRL expression on BMDCs was increased after HDM stimulation. Further, knocking down GITRL on DCs partially restored the balance of Th1/Th2 and Th17/Treg cells. Moreover, GITRL stimulation in vitro inhibited Treg cell differentiation and promoted Th2 and Th17 cell differentiation. Similarly, GITRL mRNA expression was increased in the peripheral blood from asthmatic children. CONCLUSIONS: This study identified a novel role for GITRL expressed by DCs as a positive regulator of CD4+ T cells responses in asthma, which implicates that GITRL inhibitors may be a potential immunotherapy for asthma.

[Epidemiological characteristics of respiratory syncytial virus in hospitalized children with acute lower respiratory tract infection in Chongqing, China, from 2013 to 2018: an analysis of 2 066 cases].

OBJECTIVE: To study the detection rate, epidemic pattern, and clinical features of respiratory syncytial virus (RSV) in hospitalized children with acute lower respiratory infection (ALRI). METHODS: Nasopharyngeal aspirates were collected from children with ALRI, aged < 2 years, who were hospitalized in Children's Hospital of Chongqing Medical University from June 2013 to May 2018. Multiplex PCR was used to detect 16 common respiratory viruses. The epidemiological characteristics of RSV were analyzed. RESULTS: A total of 2 066 hospitalized children with ALRI were enrolled. Among the children, 1 595 (77.20%) tested positive for virus and 826 (39.98%) tested positive for RSV [410(49.6%) positive for RSV-A, 414 (50.1%) positive for RSV-B, and 2 (0.2%) positive for both RSV-A and RSV-B]. RSV-B was the main subtype detected in 2013-2014 and 2016-2017, while RSV-A was the main subtype in 2014-2015 and 2017-2018, and these two subtypes were prevalent in 2015-2016. The highest detection rate of RSV was noted in winter. RSV + human rhinovirus was the most common combination of viruses and was detected in 123 children. These children were more likely to develop wheezing than those with single RSV detected (P=0.030). A total of 298 samples were detected with single RSV, 148 were detected with RSV mixed with other viruses, 389 were detected with other viruses, and 241 were detected negative for viruses. Compared with the other viruses and negative virus groups, the single RSV group had a significantly younger age and significantly higher incidence rates of dyspnea, respiratory failure, and severe lower respiratory tract infection (P < 0.0083). The RSV-A positive group had a significantly higher proportion of boys than the RSV-B positive group (P=0.004), but there were no significant differences in clinical manifestations between the two groups. CONCLUSIONS: In Chongqing in 2013-2018, RSV-A and RSV-B not only can predominate alternately, but also can co-circulate during a season. RSV is the major viral pathogen of hospitalized children with ALRI and can cause severe lower respiratory tract infection. There are no differences in clinical manifestations between children with RSV-A infection and those with RSV-B infection, but boys are more susceptible to RSV-A infection.