[Activated phosphoinositide 3-kinase delta syndrome: report of seven cases]. / PI3Kδ过度活化综合征7例报道.

OBJECTIVES: To summarize the clinical data of 7 children with activated phosphoinositide 3-kinase delta syndrome (APDS) and enhance understanding of the disease. METHODS: A retrospective analysis was conducted on clinical data of 7 APDS children admitted to Hunan Provincial People's Hospital from January 2019 to August 2023. RESULTS: Among the 7 children (4 males, 3 females), the median age of onset was 30 months, and the median age at diagnosis was 101 months. Recurrent respiratory tract infections, hepatosplenomegaly, and multiple lymphadenopathy were observed in all 7 cases. Sepsis was observed in 5 cases, otitis media and multiple caries were observed in 3 cases, and diarrhea and joint pain were observed in 2 cases. Lymphoma and systemic lupus erythematosus were observed in 1 case each. Fiberoptic bronchoscopy was performed in 4 cases, revealing scattered nodular protrusions in the bronchial lumen. The most common respiratory pathogen was Streptococcus pneumoniae (4 cases). Six patients had a p.E1021K missense mutation, and one had a p.434-475del splice site mutation. CONCLUSIONS: p.E1021K is the most common mutation site in APDS children. Children who present with one or more of the following symptoms: recurrent respiratory tract infections, hepatosplenomegaly, multiple lymphadenopathy, otitis media, and caries, and exhibit scattered nodular protrusions on fiberoptic bronchoscopy, should be vigilant for APDS. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(5): 499-505.

Integrated UPLC-MS, network pharmacology, and intestinal flora analysis to determine the treatment effect of Qiangzhi decoction on comorbid Tourette syndrome and RRTI.

Background: Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics. Recurrent respiratory tract infection (RRTI), a commonly occurring disease in childhood, correlates with recurrent and severe course of tic symptoms. Qiangzhi decoction (QZD) is a traditional Chinese medicine that can alleviate TS symptoms while reducing the recurrence of RRTI. However, the mechanism of QZD on TS and RRTI remains unclear. This study aimed to determine the treatment effect of QZD on comorbid TS and RRTI by integrating ultrahigh-performance liquid chromatography mass spectrometry (UPLC-MS), network pharmacology, and intestinal flora analysis. Methods: The components of QZD were first identified by UPLC-quadrupole (Q)-orbitrap-MS/MS. The mechanism of QZD on comorbid RRTI and TS was investigated by a series of network pharmacological methods, including target prediction and bioinformatics analysis. Finally, a comorbid TS and RRTI rat model was established by intraperitoneal injection of 3,3-iminodipropionitrile (IDPN), cyclophosphamide (CTX), and lipopolysaccharide (LPS). Alteration of gut microbiota in the alleviation of TS and RRTI by QZD was investigated via intestinal flora analysis. Results: The results of UPLC-Q-orbitrap-MS/MS showed that QZD had 96 types of chemical components. The network pharmacology results demonstrated that targets of QZD involved in the treatment of TS and RRTI involved 1045 biological processes (BPs), 109 cellular components (CCs), and 133 molecular functions (MFs), including synaptic and transsynaptic signaling, chemical synaptic transmission, neurotransmitter receptor activity, G protein-coupled amine receptor activity, and serotonin receptor activity, among others. Firmicutes, Bacteroidetes, Coprococcus, and Lachnospiraceae played crucial roles in gut microbiota of a QZD-treated comorbid TS and RRTI model. Conclusions: Our results revealed QZD provided a multicomponent, multitarget, and multipathway synergistic treatment of comorbid TS and RRTI.

A Case-Control Study on the Changes in Natural Killer Cell Activity following Administration of Polyvalent Mechanical Bacterial Lysate in Korean Adults with Recurrent Respiratory Tract Infection.

Polyvalent mechanical bacterial lysate (PMBL) is used for the treatment and prevention of recurrent respiratory tract infections. Although PMBL is an immunostimulant, it remains unknown whether treatment with PMBL influences natural killer cell activity (NKA). Hence, this case-control study compared the changes in IFN-γ levels (surrogate index for NKA) following PMBL treatment or time passing between the PMBL-treated group and controls. The treatment group included adults who had a PMBL prescription for three months against recurrent respiratory tract infection from an outpatient clinic, while the control group had healthy adults visiting the health promotion center for periodic health check-ups. The control group (N = 506) showed no change in IFN-γ levels, while the treatment group (N = 301) showed a significant increase in mean from 462.8 to 749.3 pg/mL after PMBL treatment. In the subgroup with IFN-γ <500 pg/mL, IFN-γ levels significantly increased in both groups. However, the change in the treatment group (287 ± 822 pg/mL) was greater than that in the control group (58 ± 809 pg/mL), and the interaction between the visit and case/control was significant (p = 0.030) in a generalized estimating equation model. In conclusion, NKA increased in the subjects with recurrent respiratory tract infections with PMBL treatment.

Study on the mechanism of the Modified Ginseng-Schisandra Decoction (MGSD) in the treatment of recurrent respiratory tract infection (RRTI) based on network pharmacology.

BACKGROUND: The aim of this study was to investigate the mechanism of Modified Ginseng-Schisandra Decoction in the treatment of recurrent respiratory tract infection (RRTI) using network pharmacology. METHODS: To screen the active ingredients of A Modified Ginseng-Schisandra Decoction, TCMSP, TCMID, Batman-TCM and PubChem database were applied. To predict the targets of active ingredients on RRTI, TCMSP, Pubmed, OMIM, Drug Bank, GAD and TTD database were used. The compounds-therapeutic target network was constructed with Cytoscape 3.7.2 software. The STRING database was used to construct a protein-protein interaction (PPI) network, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to identify potential signal pathways. RESULTS: The 3 main active ingredients of Modified Ginseng-Schisandra Decoction obtained by screening were quercetin, kaempferol, and isoflavone; the main therapeutic targets were PTGS2, ESR1, AR, PPARG, NOS2, and others. Based on the PPI network, we found that the targets of Modified Ginseng-Schisandra Decoction were significantly enriched in (FDR <0.01) cancer pathway, tumor necrosis factor (TNF) signaling pathway, hypoxia-inducible factor (HIF-1) signaling pathway, and others. CONCLUSIONS: Modified Ginseng-Schisandra Decoction can treat RRTI primarily through acting in the signal transduction of some key nodes of cancer pathway and TNF pathway. It exerts a direct or indirect influence on multiple signaling pathways, and has the characteristics of multicomponent, multitarget, and multichannel action.

Clinical observation of the effect of modified Ginseng-Schisandra decoction (MGSD) on trace elements and immune function in children with spleen deficiency syndrome after recurrent respiratory tract infection (RRTI): a randomized controlled trial.

BACKGROUND: Recurrent respiratory tract infection (RRTI) is common disease in childhood, and the incidence rate is increasing in China. The cause is complex, which is related to the physiological characteristics of children's respiratory system and the immature immune function, lack of trace elements and environmental pollution. Immunomodulators and antibiotics are often used to treat RRTI, but the clinical efficacy still needs to be improved. Chinese medicine has unique advantages in the treatment of RRTI. In the clinical treatment of RRTI, the authors often use modified Ginseng-Schisandra decoction (MGSD). In order to study the clinical effect of MGSD on serum trace elements and immune function in children with spleen deficiency syndrome after RRTI, we conducted this clinical observation. METHODS: This is a single-center randomized trial with two parallel groups. Eighty children who developed spleen deficiency syndrome following RRTI were randomly and equally divided into a control group and an observation group. The control group was given Medilac-vita and the observation group was given MGSD. The participants, care givers, and those assessing the outcomes were blinded to group assignment. The treatment course was 4 weeks. Clinical efficacy, traditional Chinese medicine (TCM) syndrome scores, humoral immunity, and trace element index values before and after treatment were compared between the two groups of children. RESULTS: The trial was finished. The total effective rate of the observation group (n=40, 95%) was significantly higher than control group (n=40, 65%) (P<0.05). After treatment, the TCM syndrome scores of the two groups were reduced compared to those before treatment, while the serum immunoglobulin A and G levels were increased (P<0.05); however, the observation group had significantly lower TCM syndrome scores than the control group. Significant improvements in serum immunoglobulins (IgA and IgG) levels, T lymphocyte subsets (CD3+, CD4+, and CD4+/CD8+), and trace elements (Zn and Fe) indicators were observed in the observation group compared to the control group (P<0.05). CONCLUSIONS: The application of MGSD in the treatment of children with spleen deficiency syndrome after RRTI has a definite clinical effect. MGSD can effectively improve the immune function of the patients and the content of the trace elements iron and zinc, and thus has potential value for promotion and application. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100047128.

Acupoint Herbal Patching for Long-Term Immune Function in Children with Recurrent Respiratory-Tract Infections: A Systematic Review of Real-World Data.

Objective: Acupoint herbal patching (AHP) has been used for the prevention and treatment of recurrent respiratory-tract infections (RRTIs) in children. some studies have suggested relevance to immune function as AHP's mechanism. This study was conducted to evaluate the long-term effects of AHP on immune function in pediatric patients with RRTIs based on real-world data from more than 1-year of follow-up. Materials and Methods: Eleven English-, Korean-, and Chinese-language databases were searched comprehensively up to January 2020. Real-world clinical data assessing AHP for children with RRTI and reporting long-term immune function-related biomarkers as outcomes were included. Descriptive analyses of the details of the participants, interventions, and outcomes were conducted. The risk of bias was assessed, using the ROBINS-I [Risk of Bias in Non-randomized Studies-of Interventions] tool. Results: Four observational studies with 399 pediatric participants were included. Two studies reported salivary secretory immunoglobulin (Ig) A (sIgA) as an immune function-related biomarker and 2 reported serum levels of IgA, IgG, and IgM. sIgA levels showed inconsistent results at 1 year after AHP. However, IgA, IgG, and IgM levels were increased significantly at both 1 and 2 years after AHP. The frequency and duration of respiratory infections were also reduced significantly after AHP. Most studies had high risks of bias, especially lack of consideration of confounding factors. Conclusions: Current evidence suggested that AHP might be connected to immune function-related biomarker levels and symptoms in pediatric patients with RRTIs in the long-term. Further well-designed, large-size, long-term registries are needed to investigate the effects of AHP on immune function in pediatric patients with RRTIs.

Acupoint herbal patching for children with recurrent respiratory tract infection: A systematic review and meta-analysis.

BACKGROUND: Acupoint herbal patching (AHP) has been used for recurrent respiratory tract infection (RRTI) in children. This systematic review aimed to analyze the safety and efficacy of AHP in pediatric RRTI. METHODS: Eleven databases were comprehensively searched up to January 2020. Randomized controlled trials (RCTs) using AHP as a monotherapy or adjunctive therapy in pediatric patients with RRTI were included. RESULTS: Twenty-two RCTs with 3579 participants were included. Meta-analyses showed that outbreaks and disease duration of respiratory tract infection (RTI) per year significantly decreased in the AHP group compared with the placebo group, when follow-up was conducted after 1, 2, or 3 years. Moreover, AHP as a monotherapy or adjunctive therapy significantly decreased outbreaks and disease duration of RTI without serious adverse events. CONCLUSION: This review provides promising evidence that AHP may reduce the frequency and duration of RTI and improve immune function in pediatric patients with RRTI.

Intestinal microbiota dysbiosis in children with recurrent respiratory tract infections.

BACKGROUND: The impact of the gut microbiota on recurrent respiratory tract infection (RRTI) remains to be fully elucidated. METHODS: To characterize the gut microbiota in patients with RRTI, fecal samples from 26 patients with RRTI and 23 healthy volunteers were profiled using the Illumina MiSeq platform. Beta diversity (Principal Component Analysis (PCA), Principal Co-ordinates Analysis (PCoA), Non-metric multidimensional scaling (NMDS)) analysis showed that the bacterial community structure segregated differently between the RRTI and control groups. RESULTS: Results from alpha diversity analysis revealed lower microbiota diversity in samples from RRTI patients than in normal controls. Taxonomic analysis illustrated that the abundance of six phyla (Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Verrucomicrobia, Tenericutes) and four genera (Enterococcus, Faecalibacterium, Bifidobacterium, Eubacterium were significantly different between these two groups. In addition, Enterococcus (P < 0.001) was more enriched in the RRTI group, whereas the abundances of Eubacterium (P < 0.001), Faecalibacterium (0.01 < P < 0.05) and Bifidobacterium (0.01 < P < 0.05) were reduced in the RRTI group compared to those in the normal control group. The performance of the model was assessed using ROC analysis, and Enterococcus, Eubacterium and Bifidobacterium achieved AUC values of 0.860, 0.820, and 0.689, respectively. CONCLUSIONS: These results provide fundamental evidence in support of intestinal microbiota dysbiosis in children with RRTI.

Pidotimod in the treatment of pediatric recurrent respiratory tract infection.

OBJECTIVE: To observe the clinical efficacy of pidotimod in the treatment of recurrent respiratory tract infection in children. METHODS: One hundred thirty-two patients with recurrent respiratory tract infection who received treatment in Tianan City Central Hospital were selected and divided into an observation group and a control group using random number table, 66 in each group. Patients in the control group were given conventional treatment, while patients in the observation group were given conventional treatment and pidotimod treatment; the clinical efficacy of the two therapies was compared. The levels of IgG and IgM were measured after treatment. RESULTS: The vital signs and the content of inflammatory mediator and Th1/Th2 in serum before and after treatment were compared, and the clinical efficacy of the two groups was evaluated. The fever, pulmonary rale, cough and antiadoncus of patients in the observation group disappeared earlier than those in the control group (P<0.05). The onset duration of respiratory tract infection and days of antibiotic application of the observation group were shorter than those of the control group after treatment (P<0.05). The times of infection of the observation group were less than that of the control group (P<0.05). Before treatment, the two groups had no significant difference in the content of inflammatory mediators and Th1/Th2 in the serum (P>0.05). The serum content of tumor necrosis factor (TNF)-α and interleukin (IL)-4 of the two groups one week after treatment was lower than that before treatment, and the content of interferon (IFN)-γ and IFN-γ/IL-4 were higher than that before treatment; moreover the observation group had lower serum content of TFN-α and IL-4 and lower content of IFN-γ and IFN-γ/IL-4 compared to the control group (P<0.05). The overall response rate of the observation group was 92.4%, much higher than 81.8% in the control group (P<0.05). CONCLUSION: Pidotimod has a remarkable efficacy in the treatment of pediatric recurrent respiratory tract infection because it can effectively inhibit the infection and optimize Th1/Th2 immune function.

A randomized, placebo-controlled, double-blinded, single-centre, phase IV trial to assess the efficacy and safety of OM-85 in children suffering from recurrent respiratory tract infections.

BACKGROUND: Over many years, OM-85, a lysate of 21 common bacterial respiratory pathogens, has been demonstrated to prevent respiratory recurrences in children. However, further studies are needed to explore the true importance of OM-85 in the prevention of respiratory tract infections (RTIs) in children. This study was planned to further contribute to the evaluation of the role played by OM-85 in prevention of recurrent RTIs in children. METHODS: This study was a randomized (3:3:1), placebo-controlled, double-blind, single-centre, phase IV trial carried out in Italy to assess the efficacy of OM-85 (Broncho-Vaxom®; Vifor Pharma; Meyrin 2/Geneva, Switzerland) in reducing the number of new RTI episodes in 288 children aged 1 to 6 years with a history of recurrent RTIs and to compare the efficacy of the standard 3-month regimen with that of administration of OM-85 for 6 months during a 6-month study period. RESULTS: The number of RTIs and of children who experienced at least one RTI were significantly lower among patients receiving OM-85 for 3 months than among those given placebo (33% vs 65.1%, p < 0.0001). Differences were statistically significant for upper RTIs (i.e., common cold/viral pharyngitis and acute otitis media; p < 0.0001 and p = 0.006, respectively). Days of absence from day-care for children and working days lost by parents were significantly lower in the group with children treated with OM-85 for 3 months than in the placebo group (p = 0.007 and p = 0.004, respectively). No difference was seen between children who received OM-85 for 3 and those who received OM-85 for 6 months. The prevalence of atopy as well as the history of recurrent wheezing and age of the study child did not influence the results. Benefit was maximally evident among children with a history of frequent recurrences. OM-85 was well tolerated and safe, even in children who received an influenza vaccination. CONCLUSIONS: The use of OM-85 for 3 months in 3 series of 10 consecutive days each time reduces the risk of recurrent RTIs in children, with a favourable safety profile. The greater effect observed in children prone to several respiratory episodes than in non-prone children seems to indicate that this lysate should be administered especially to children with a proven high susceptibility to RTIs.

Recurrent respiratory tract infections in children - analysis of immunological examinations.

BACKGROUND: Paediatric respiratory tract infections are among the most common reasons for preschool and school absences and visits to physicians. The disease mainly involves the upper respiratory tract and is associated with fever, cough, sore throat, and running nose. Children with recurrent respiratory infections (RRI), which are defined as more than six serious diseases a year, are a difficult diagnostic challenge. The aim of this study was to assess immunological deviations in laboratory tests performed in children with RRI. MATERIAL AND METHODS: In the retrospective study 25 children suffering from recurrent respiratory tract infection, aged 4.1 ±2.3 years, 13 boys and 12 girls, were involved. For all children chemiluminescence of granulocytes and immunophenotyping of lymphocytes from peripheral blood were examined. An immunophenotype of peripheral blood lymphocytes involved evaluation of T cell, B cells, and NK cells, examined with flow cytometry. RESULTS: Eleven of the studied children had decreased chemiluminescent response to stimulants, normal response was found for nine children, and five children had an increased result of the test. Five of the 25 children had decreased B cells number, and five had decreased number of T cells including decrease of CD4, as well as CD8 positive cells. Children with decreased chemiluminescence had more frequent neutropaenia than children with normal or increased chemiluminescent response, p < 0.05 (exact Fisher test). CONCLUSIONS: Recurrent respiratory tract infection could be associated with improper neutrophils response to pathogens, and immunological examination should be performed to find the reason for the increased number of infections in a year.

Meta-analysis of Zn, Cu and Fe in the hair of Chinese children with recurrent respiratory tract infection.

Trace elements play an important role in maintaining the normal metabolic and immune function. The onset of recurrent respiratory tract infection (RRI) is associated with the immune function, genetic factors and nutritional status. However, the association between the levels of trace elements and RRI remains inconclusive. We aimed to investigate the alterations of hair levels of zinc (Zn), copper (Cu) and iron (Fe) in Chinese children with RRI by performing a meta-analysis. A predefined electronic databases search was performed to identify eligible studies for the analysis of hair Zn, Cu or Fe levels in Chinese children with RRI. Thirteen studies were included. RRI patients displayed significantly lower levels of hair Zn (13 studies, random effects SMD: - 1.215, 95% CI: - 1.704 to - 0.725, p < 0.0001), Cu (11 studies, random effects SMD: - 0.384, 95% CI: - 0.717 to - 0.052, p = 0.023) and Fe (12 studies, random effects SMD: - 0.569, 95% CI: - 0.827 to - 0.312, p < 0.0001) compared with controls. No evidence of publication bias was observed. Sensitivity analysis did not change the results significantly. In conclusion, the deficiency of Zn, Cu and Fe may be contributing factors for the susceptibility of RRI in Chinese children. However, more studies in different ethnicities should be performed in the future.

Impact of a mixed bacterial lysate (OM-85 BV) on the immunogenicity, safety and tolerability of inactivated influenza vaccine in children with recurrent respiratory tract infection.

It is known that the immunogenicity and efficacy of conventional inactivated influenza vaccines (IIVs) are not completely satisfactory in children. The aim of this prospective, randomised, single-blind study was to compare the immune response to, and the effectiveness and safety of, an IIV (Fluarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) administered to 68 children aged 36-59 months affected by recurrent respiratory tract infections (RRTIs) who were vaccinated with (n=33) or without (n=35) the mixed bacterial lysate OM-85 BV (Broncho-vaxom, Vifor Pharma, Geneva, Switzerland). OM-85 BV had no effect on seroconversion or seroprotection rates, geometric mean titres, or dendritic cells, which were not significantly different between the two groups. Moreover, OM-85 BV did not significantly increase the pool of the memory B cells that produce IgG and IgM antibodies against the influenza antigens. However, respiratory morbidity was significantly lower in the children treated with OM-85 BV (p<0.05), thus confirming its positive effect on the incidence of RRTIs. There was no difference in the incidence of adverse events between the two groups. These findings show that the immune response of children to influenza vaccine is not significantly influenced by the administration of OM-85 BV. However, the use of OM-85 before and at the same time as IIV seems to reduce respiratory morbidity, and seems to be safe and well tolerated.

Role of Kasahara Dashemani Vati in Kasa and Vyadhikshamatva in children with special reference to recurrent respiratory tract infections.

The present single-centered randomized control trial (RCT) was carried out with the prime aim of assessing the effect of Kasahara Dashemani Vati (trial drug) on Kasa and Vyadhikshamatva in the children suffering from recurrent respiratory tract infections and comparing it with the efficacy of Indukanta Vati. The clinical trial included 40 patients belonging to age group of 3-12 years. The drugs were administered in a daily dose fixed as per "Clark's Rule" along with honey for duration of 60 days. The effect of treatment on the signs and symptoms of Kasa was assessed on the 15(th) day, whereas the effect on Vyadhikshamatva was assessed on the 60(th) day. The patients were under follow-up for a period of 60 days after completing the treatment course for evaluation of any recurrence. Effect of the therapy on the individual signs and symptoms of Kasa, laboratory parameters, immunoglobulin (Ig) biomarkers, status of Atura Bala, and prevention of recurrence during follow-up period were the parameters used to assess the overall effect of therapy. The observed data were subjected to appropriate statistical analysis for testing the statistical significance. Kasahara Dashemani provided relief in all symptoms of Kasa irrespective of Doshic involvement and on the parameters of Atura Bala. All the changes were statistically highly significant. The control group also showed similar effects which were statistically highly significant. The trial group was found to have a direct influence on serum Ig status. No patient has reported any adverse drug reactions during the treatment and follow-up periods.