Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite.

Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP), an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs) through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of airway remodeling in chronic allergen-induced asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extracts for up to 5 consecutive weeks. We showed that repeated respiratory exposure to HDM caused significant airway eosinophilic inflammation, peribronchial collagen deposition, goblet cell hyperplasia, and airway hyperreactivity (AHR) to methacholine. These effects were accompanied with a salient Th2 response that was characterized by the upregulation of Th2-typed cytokines, such as IL-4 and IL-13, as well as the transcription factor GATA-3. Moreover, the levels of TSLP and transforming growth factor beta 1 (TGF-ß1) were also increased in the airway. We further demonstrated, using the chronic HDM-induced asthma model, that the inhibition of Th2 responses via neutralization of TSLP with an anti-TSLP mAb reversed airway inflammation, prevented structural alterations, and decreased AHR to methacholine and TGF-ß1 level. These results suggest that TSLP plays a pivotal role in the initiation and persistence of airway inflammation and remodeling in the context of chronic allergic asthma.

[The role of serum leptin in infants with wheezing after respiratory syncytial virus infected].

OBJECTIVE: To determine the role of serum leptin in infants with wheezing after respiratory syncytial virus infected. METHODS: 43 infants infected with RSV were given blood samples to detect leptin concentration with radioimmunoassays (RIA) within 24 hours after admission into hospital, discharged and 12 weeks later. Then, they were followed up for 2 years. 10 healthy children of the same age served as controls. RESULTS: 41.9% infants developed asthma after infected with RSV. Compared to control group, the serum level of leptin in the asthma group and non-asthma group were significantly higher before treatment (t = 3.41 and 2.64 respectively, P < 0.05). When they were discharged, the serum level of leptin in the asthma group was significantly higher than that in non-asthma group and control group (t = 5.74 and 6.23, respectively, P < 0.05). 12 weeks later, the serum level of leptin in the asthma group was still significantly higher than that in non-asthma group and control group (t = 6.32 and 6.11, respectively, P < 0.05), but there were no difference between non-asthma group and control group (t = 0.81, P > 0.05). CONCLUSION: The serum level of leptin in infants with asthma after RSV infected was higher than that in healthy and non-asthma children. Persistent higher level of leptin may play an important role in infants with asthma after RSV infected.

[Effects of Dermatophagoides pteronyssinus allergen-specific immunotherapy on the prognosis of asthmatic children].

OBJECTIVE: To investigate the effects of Dermatophagoides pteronyssinus allergen-specific immunotherapy (SIT) on the prognosis of asthmatic children. METHODS: Sixty-five children with established diagnosis of allergic asthma to dust mite were enrolled in this study, of whom 42 children received treatment with standardized SIT for 12 month and the other 23 served as the control group with inhaled corticosteroids according to Global Initiative for Asthma (GINA). The serum levels of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) were detected and the pulmonary functions examined before and after the one-year treatment in all the patients. RESULTS: After the one-year treatment with SIT, the asthmatic children showed obviously reduced serum levels of IL-4, significantly increased IFN-gamma levels and the IFN-gamma/IL-4 ratio (P<0.05), and markedly improved pulmonary functions (FVC, pre-FEV1% and pre-PEF%) (P<0.05). In the control group, the children exhibited significantly increased IFN-gamma levels and IFN-gamma/ IL-4 ratio (P<0.05) without obvious reduction of serum IL-4 levels or pulmonary function improvement (P>0.05). With comparable basic pulmonary functions in the two groups before the treatment, the children in SIT group showed significantly greater improvement in the pulmonary functions than those in the control group after the one-year treatment. CONCLUSION: The one-year treatment with SIT can significantly improve the pulmonary functions of children with allergic asthma, and this effect is attributed to the regulation of Th1/Th2 cell balance and inhibition of asthmatic airway remodeling by SIT.

Effects of dermatophagoides pteronyssinus allergen-specific immunotherapy on the serum interleukin-13 and pulmonary functions in asthmatic children.

BACKGROUND: Airway remodeling is the specific pathological characteristics of asthma, which is related to the clinical symptoms, pulmonary function, and airway hyperreactivity. This study aimed at exploring the effects of dermatophagoides pteronyssinus allergen-specific immunotherapy (SIT) on the serum interleukin (IL)-13 and pulmonary functions in asthmatic children. METHODS: Fifty-eight pediatric asthma patients allergic to dust mite participated in this study. Thirty-five children received SIT with a standardized dermatophagoides pteronyssinus extract for one year (SIT group), and the other 23 children treated with inhaled corticosteroids (ICS group) according to the Global Initiative for Asthma (GINA) for one year. Serum levels of IL-13, IL-4 and interferon (IFN)-gamma were examined and the pulmonary functions were checked before and after the treatment. RESULTS: After the treatment, the number of emergency visiting for asthma attack in SIT group was significantly less than that in ICS group. The serum levels of IL-4 and IL-13 were clearly reduced, IFN-gamma and the ratio of IFN-gamma/IL-4 were significantly increased, the pulmonary functions (forced vital capacity (FVC), forced expiratory volume in one second percentage (FEV(1)%) and peak expiratory flow percentage (PEF%) were significantly improved in the SIT group. Meanwhile, IFN-gamma and the ratio of IFN-gamma/IL-4 were greatly increased, but serum levels of IL-4 and IL-13 had less changes, the pulmonary functions (FVC, FEV(1)% and PEF%) were poorly improved in ICS group. The basic pulmonary functions in both groups were at the same level, which had made more improvement in SIT group than in ICS group one year later. CONCLUSIONS: One year of dermatophagoides pteronyssinus SIT can significantly reduce the frequencies of emergency visiting for asthma attack and improve the pulmonary functions of children with allergic asthma, and that is attributed to SIT, which can reduce the levels of IL-4 and IL-13 and regulate the imbalance of the Th1/Th2 cells in asthmatic children. All of these might be effective in preventing the asthmatic airway from remodeling.

[Significance of changes of T lymphocytes subsets in children with infectious mononucleosis and the effects of different interventions].

OBJECTIVE: To investigate changes of T lymphocytes subsets in children with infectious mononucleosis (IM) and the effects of different interventions. METHODS: Forty-eight children with IM were enrolled, 28 cases were assigned to the group treated with intravenous immunoglobulin (IVIG) 400 mg/(kg x d) for 5 continuous days or IVIG 1 g/(kg x d) for 2 continuous days, the remaining 20 cases were treated with ganciclovir (GCV) 5-10 mg/(kg x d) for 5 consecutive days. All these children were given general supportive therapies. Twenty healthy children from healthcare clinic serviced as control group. RESULTS: CD4 (%), CD8 (%) and the CD4/CD8 ratio in healthy control group were (34.12 +/- 3.53)%, (26.22 +/- 4.43)% and (1.41 +/- 0.3), in IVIG group were (24.2 +/- 4.3)%, (36.4 +/- 6.8)% and (0.72 +/- 0.12), and in GCV group were (23.7 +/- 5.1)%, (37.3 +/- 7.8)% and (0.67 +/- 0.13), respectively. CD4 (%), CD8 (%) and the ratio CD4/CD8 in the control group were significantly different from those in both groups with IM (P < 0.05). Compared with pre-treatment levels, the 28 cases treated with IVIG had significant improvement, the CD4 (%) increased, CD8 (%) decreased and the ratio of CD4/CD8 increased after treatment (P < 0.05). However, 20 cases in GCV treatment group made less changes (P > 0.05) . Meanwhile, the clinical symptoms and signs in the IVIG group were improved faster than that in the GCV group (P < 0.05). The rate of remission in IVIG group was 88.7% vs. 59.2% of GCV group (P < 0.05); the hospital days in IVIG group were (9.2 +/- 4.3) days vs. (13.8 +/- 5.1) days in the GCV (P < 0.05). CONCLUSION: It is indicated that the subsets of T lymphocytes in peripheral blood are obviously abnormal in children with IM caused by EBV infection in acute phase. IVIG can regulate the immunological derangements of T lymphocytes subsets, on which anti-viral therapy alone may have little impact.

[Efficacy of pulmicort suspension plus salbutamol and ipratropium bromide for management of acute asthma exacerbation in children: a comparative study].

OBJECTIVE: To evaluate the efficacy of 3 commonly used protocols for management of acute exacerbation of asthma in children. METHODS: Totally 113 asthmatic children were randomized into 3 groups. In group A (53 cases), the children were treated with inhalation of nebulized budesonide suspension plus salbutamol and ipratropium bromide twice daily for 5 days; in group B (41 cases), budesonide plus salbutamol and ipratropium aerosol was administered, and in group C (29 cases), dexathmisone plus aminophylline injection was given once daily for 5 days. All the children received basic treatment with fluid infusion, antibiotics or/and anti-virus medications. RESULTS: The children in both groups A and C showed effectively controlled asthma attack, with significant differences in the therapeutic effects (P>0.05). In contrast, only a few children showed improvement in group B, suggesting the ineffectiveness of the treatment. CONCLUSION: Nebulized medicine is one of the best means for management of acute asthma exacerbation in children, and inhalation of budesonide suspension plus salbutamol and ipratropium bromide can effectively relieve the asthmatic symptoms in these children with good compliance and convenient administration.

[Effects of BCG-PSN injection on immune and lung function of asthmatic children complicated with allergic rhinitis].

OBJECTIVE: To investigate the effect of polysaccharide nucleic acid of BCG (BCG-PSN) injection on immune and pulmonary function in asthmatic children complicated with allergic rhinitis. METHODS: Thirty-seven cases were separated at random into two groups, the BCG-PSN group (17 cases) was treated with BCG-PSN plus inhaled glucocortisteriods, and the control group (20 cases) was treated with inhaled glucocortisteriods only. The children in both groups were followed up for 6 months to record their lung function, allergic rhinitis scores, frequency of asthmatic attacks and respiratory infection. The levels of interleukin (IL)-4, interferon-gamma (IFN-g) and plasma total IgE were detected by using double antibody sandwich ELISA at the beginning and the end of treatment. RESULTS: In comparison with the control group, after treatment, the levels of IFN-g and the ratio of IFN-g/IL4 in the BCG-PSN group significantly increased, whereas the level of IL-4 and the plasma total IgE significantly decreased (P less than 0.05), while those of the control group had no significant change. The lung function of both groups had significant improvement (p less than 0.05). The frequencies of asthmatic attacks in BCG-PSN and control groups were 0.81 +/- 0.20 vs. 1.72 +/- 0.80, and the difference was statistically significant. The frequencies of respiratory tract infection in BCG-PSN and control groups were 1.15 +/- 0.55 vs. 3.21 +/- 0.73, the difference was significant. CONCLUSION: BCG-PSN may be able to correct the imbalance of Th1/Th2 and improve the lung function of children with asthma complicated with allergic rhinitis, which suggest that the immune adjusting treatment should be emphasized besides anti-inflammation therapy.

[Immunoregulants improves the prognosis of infants with wheezing].

OBJECTIVE: To assess the value of immunoregulants in improving the prognosis of infants with wheezing. METHODS: Forty-three infants with wheezing with given oxygen support, injection or inhalation of glucocorticosteroids or bronchodilatator to relieve the symptoms. Of these infants, 24 received immunoregulant treatment with bronchovaxom at the daily dose of 3.5 mg for 10 days every a month for a treatment course of 3 months. The other 19 infants were managed with budesonide aerosol at 200 microg once or twice daily for 3 months (basic treatment group). All the infants were followed up for 1 year to record the number of wheezing episode and infections. Ten healthy infants were also included in this study as the control group. RESULTS: In infants with bronchovaxom treatment, 25% reported more than 3 wheezing episodes within the 1-year follow-up, a rate significantly lower than that in the control group (63.2%, Chi(2)=6.344, P<0.05). The episodes of respiratory infection were similar between bronchovaxom group and the healthy control group (t=0.72, P>0.05), but significantly higher in the basic treatment group than in bronchovaxom and the healthy control group (t=3.11 and 3.92, respectively. P<0.05). CONCLUSIONS: Bronchovaxom can effectively reduce the recurrence of wheezing and respiratory infections in the infants with wheezing attack to reduce the risks of asthma development.

[Effect of leukotriene receptor antagonist on the levels of Th1 and Th2 cytokines in sera of infants with respiratory syncytial virus pneumonia].

OBJECTIVE: To investigate the effects of leukotriene receptor antagonist on the levels of Th1 and Th2 cytokines and the serum cysteinyl leukotrenes (CysLTs) in infants and young children with respiratory syncytial virus (RSV) pneumonia. METHODS: Thirty-seven infants and young children with RSV pneumonia were divided into two groups after discharge. The cases in group 1 (n=24) were treated with a leukotriene receptor antagonist, Singulair 4 mg once daily for 12 weeks; the cases in group 2 (n=13) were treated with budesonide aerosol 200 ug once or twice daily for 12 weeks. The serum CysLTs, IFN-gamma and IL-4 were detected with enzyme_linked immunosorbent assays (ELISA) for all the 37 cases, and 10 healthy infants of the same age served as controls. RESULTS: The serum CysLTs level in the cases with RSV pneumonia was significantly higher than that in controls (P<0.05). There was an imbalance in expression of Th1 and Th2 cytokines (IFN-gamma and IL-4 ) in these cases. Both Singulair and budesonide aerosol could correct the imbalance of Th1 and Th2 cytokines. The serum CysLTs level declined after treatment with Singulair in 24 cases, but no significant change occurred after treatment with budesonide aerosol in the remaining 13 cases. CONCLUSIONS: The serum CysLTs level in children with RSV pneumonia was higher than that in healthy children, and there was an imbalance of Th1 and Th2 cytokines in these infants, which was similar to those with asthma. Leukotriene receptor antagonist may be effective in preventing children with RSV pneumonia from evolving into asthma.

[Detection of serum Th1 and Th2 cytokines and its significance in neonates with cytomegalovirus pneumonia].

OBJECTIVE: To investigate changes in the levels of Th2 cytokine interleukin-4 (IL-4), Th1 cytokine interferon-gamma (IFN-gamma), and TNF-alpha in serum of newborn infants with cytomegalovirus (CMV) pneumonia. METHODS: Twenty-five neonatal cases who were positive for serum IgM antibody to CMV by ELISA were divided into IVIG intervention group and ganciclovir intervention group, and 15 healthy neonates were enrolled into the control group. The levels of IL-4, IFN-gamma, and TNF-alpha were detected by using double antibody ELISA for the control group and the intervention groups at the beginning and end of treatment. RESULTS: The levels of IFN-gamma and TNF-alpha in patients with CMV pneumonia were higher than that in the healthy neonates, while the levels of IL-4 were lower(t= 2.65 and 3.16, p less than 0.05). The level of IL-4 in patients with CMV pneumonia was significantly lower than that of the healthy neonates (t= 2.49, p less than 0.05). There was no significant difference in the levels of IFN-gamma, IL-4 and TNF-alpha between IVIG intervention group and ganciclovir intervention group at the beginning of treatment (t= 1.85, 1.71, 1.76, p greater than 0.05). In IVIG intervention group, the levels of IFN-gamma and TNF-alpha significantly decreased after treatment (t=3.98, 5.16, p less than 0.01), the level of IL-4 in this group was higher than that before treatment (t= 2.55, p less than 0.05). In ganciclovir group, the level of IFN-gamma and TNF-alpha did not change after treatment (t=1.75, 1.16, p greater than 0.05), the level of IL-4 in this group was higher than that before treatment (t= 2.39, p less than 0.05). CONCLUSION: There seems to be an imbalance of Th1 and Th2 cytokines secretion in the infants with CMV pneumonia and, which may lead to immune-inflammation injury. IVIG can regulate imbalanced Th1/Th2 activities, therefore, immunomodulatory treatment should be applied besides antiviral therapy.

[Correlation of reticular basement membrane thickness and airway wall remolding in asthma patients].

OBJECTIVE: To investigate the correlation between the reticular basement membrane thickness and the airway wall remolding in asthma patients. METHODS: Lung tissues were obtained from 5 patients who died from asthma, 3 males and 2 females, aged 45 +/- 16 (fatal asthma group), 5 asthmatics who died of diseases unrelated to asthma, 3 males and 2 females, aged 47 +/- 13, (non-fatal asthma group), and 5 dead patients without asthma, 3 males and 2 females, aged 24 +/- 14 (control group) to select 41, 38, and 43 transverse sections of tracheae respectively. The samples of tracheae were divided into cartilaginous and membranous airways by light microscopy (x100). The thickness of reticular basement membrane and the dimensions of the airway wall, including the smooth muscle area, submucosal gland area, inner and outer wall areas, and lumen area were measured. The correlations of reticular basement membrane thickness with the airway changes were analyzed. RESULTS: The reticular basement membrane was significantly thicker in both cartilaginous and membranous airways in the fatal and non-fatal asthma groups than in the control group (all P < 0.05). The submucosal gland area of the fatal asthma group was significantly larger than those of the non-fatal asthma group and control group (both P < 0.05). The inner wall area of the cartilaginous airway of the fatal asthma group was significantly larger than that of the non-fatal asthma group (P < 0.05); however, the inner wall area of the membranous airway of the fatal asthma group was not significantly different from that of the non-fatal asthma group. The outer wall areas of cartilaginous and membranous airways of the fatal asthma group were both significantly larger than those of the other 2 groups (all P < 0.05). There was no significant difference in the lumen areas of cartilaginous and membranous airways between the fatal and non-fatal asthma groups. The reticular basement membrane thickness was correlated with the smooth muscle area (P < 0.05), submucosal gland area (P < 0.05), and inner wall area (P < 0.01) of the corresponding bronchi in regard to the cartilaginous airway; and was correlated with the smooth muscle area (P < 0.05) and inner wall area (P < 0.01) of the corresponding bronchi in regard to the membranous airway, but was not correlated with the airway size, lumen area, and outer wall area in regard to the 2 kinds of airways. CONCLUSION: The reticular basement membrane thickness of central airway reflects the airway remolding of the central airway and the changes of smooth muscle and inner wall of the peripheral airway. It is worthwhile to do end bronchial biopsy to measure the reticular basement membrane thickness so as to assess the pathology of the airway and to conduct long-term follow-up among the asthma patients.

Airway remodeling: a comparison between fatal and nonfatal asthma.

BACKGROUND: Airway remodeling has been recently one of the main goals in asthma research because it has been implicated to influence airway behavior and evolution of asthma; hence, important in long-term followup of asthmatic patients. METHODS: Airways of fatal asthma (n=3), non-fatal asthma (n=3) and control cases (n=4) were studied using morphometry and immunohistochemical and H&E staining. RESULTS: The basement membrane was thicker in the cartilaginous and membranous airways of fatal and non-fatal asthma groups compared to the control group (p<0.05). Smooth muscle shortening was greater in airways of fatal asthma cases while submucosal gland area and mucus plug occupying ratio were greater in fatal asthma large airways compared to the two other groups (p<0.01). Increased intact and degranulated mast cells were observed in smooth muscle and in submucosal gland of fatal asthma airways (p<0.01) and were associated with greater degree of smooth muscle shortening and larger submucosal gland area, respectively. Eosinophil and EG2+ cell infiltrations were greatest in lamina propria of airways of fatal asthma than in nonfatal and control cases (p<0.01), but were not associated with any airway structural change. CONCLUSION: Increased infiltration of eosinophils in the lamina propria and mast cells in smooth muscle and submucosal glands may have a role in airway remodeling of fatal asthma airways but needs further investigation. Moreover, mast cells in cartilaginous airways may participate in the regulation of smooth muscle tone and mucous gland secretion and hyperplasia.

[Clinical investigation on the treatment of HCMV hepatitis in children].

OBJECTIVE: To investigate the effective therapeutic method of human cytomegalovirus (HCMV) hepatitis in children. METHODS: Twenty-five children with HCMV hepatitis were randomly assigned to a treated group (n=13) or a control group (n=12). Both groups were treated with prednisone, glucurone, luminal and Xiaoyanlidanpian. But the treated group was given ganciclovir (GCV) + intravenous immunoglobulin (IVIG) in addition. Each infant of the two groups was checked for blood routine, liver function and HCMV copy numbers on admission and before discharge. They were seen at the third, sixth and ninth month after discharge. On each visit blood specimens were collected for HCMV copy numbers (fluorescence quantitative PCR, FQ-PCR). RESULTS: The viral load of the treated group decreased significantly. A significant difference in viral copy numbers was found between the two groups on admission, discharge, and third, sixth and ninth month after discharge (P less than 0.001). The number of HCMV DNA copy fell to 10(3) copies/ml on discharge while that of the control group fell to the same level after the third month. The differences between the two groups in the length of hospitalization, time of initial jaundice disappearance and complete disappearance were statistically significant (P less than 0.05). The need for transfusion in the treated group was significantly less than that in the control group (chi-square=4.012, P less than 0.05). CONCLUSION: Combination of GCV with a high dosage of IVIG to treat HCMV active infection could decrease viral load remarkably; The duration of disease, severity of symptoms, degree of anemia and the need for blood transfusion were reduced. No adverse effects related to the combination of GCV with IVIG therapy were observed.

Clinical applications of real-time PCR for diagnosis and treatment of human cytomegalovirus infection in children.

There are many methods of detecting human cytomegalovirus (HCMV) infection. So far, the quantitative polymerase chain reaction (PCR) has been very useful not only in aiding in the diagnosis of HCMV but also in determining the severity and predicting HCMV infection. However, it is time-consuming and labor intensive. Real-time PCR (RT-PCR) is an exception, for it allows rapid quantification of HCMV DNA load. Our group used this method for detecting and monitoring HCMV and compared it with the diagnostic criterion recommended by the Pediatric Branch of Chinese Medical Association, in 45 children suspected of having HCMV infection. The response to two types of antiviral treatment on HCMV DNA load was also monitored in HCMV hepatitis cases. RT-PCR was positive in 30 cases while the diagnostic criterion, which includes enzyme-linked immunosorbent assay (ELISA) and/or conventional PCR, was positive in 32 cases. The decrease in the HCMV DNA load was achieved earlier in the modified treatment group compared with the conventional treatment group. A 10(3) copies/ml of HCMV DNA load of is a useful cut-off value in predicting patients who will have symptoms of the disease. RT-PCR can be used not only in detecting HCMV but also in monitoring response to antiviral treatment and risk of having symptoms of the disease.

IgE binding to raw and boiled shrimp proteins in atopic and nonatopic patients with adverse reactions to shrimp.

BACKGROUND: Characterization of seafood allergens is important to understand the immune response to these allergens. Moreover, a detailed comparison between atopic and nonatopic patients with adverse reactions to shrimp has never been reported. METHODS: Raw and boiled shrimp extracts were analyzed by immunoblotting using sera from 9 atopic and 7 nonatopic patients with a history of adverse reactions to shrimp, and 13 control subjects. Total IgE, specific IgE and skin prick tests (SPT) to shrimp were also investigated. RESULTS: The level of specific IgE to shrimp was higher in atopic patients than nonatopic patients (p<0.05). Symptoms, SPT results and major allergens involved were similar in atopic and nonatopic patients. The 16.5-kD protein had the highest frequency of IgE binding followed by the 40-kD protein in these patients. Other minor IgE-binding proteins were observed at the 20-, 22-, 54-, 72-, 129- and 140-kD regions. Patients who had binding to the 16.5-kD protein had either positive (25% raw/31% cooked) or negative (13% raw/cooked) CAP-FEIA-RAST, while patients who recognized the 40-kD protein all had positive (31% raw/19% cooked) CAP-FEIA-RAST. All control subjects had negative immunoblots for these two proteins. CONCLUSION: The 16.5-kD protein was the most frequent protein identified regardless of CAP-FEIA-RAST results, while the 40-kD protein was only present in patients with positive CAP-FEIA-RAST. Therefore, 16.5-kD protein may be an important allergen that is clinically relevant in both atopic and nonatopic patients with adverse reactions to shrimp even if it is not detected by the CAP-FEIA-RAST system.