A novel anti-IL4Rα nanoparticle efficiently controls lung inflammation during asthma

Drug resistance and the harmful side effects accompanying the prolonged corticosteroid treatment of chronic pulmonary diseases prompted the development of more specific anti-inflammatory approaches. Several strategies aiming to block IL4Rα, the receptor for a key pro-inflammatory pathway, were investigated. However, their efficiency was limited, mostly due to the systemic or subcutaneous route of administrations. In this paper, we examined the ability of an intranasal treatment with biocompatible nanoparticles targeting IL4Rα to control lung inflammation in ovalbumin (OVA)-sensitized mice. OVA-sensitized mice were treated with anti-IL4Rα-conjugated nanoparticles. The levels of pro-inflammatory cytokines in the lungs and broncho-alveolar lavage fluid (BALF) were determined using a cytokine array assay. The effects of nanoparticle treatment on the activation of lung inflammatory cells and their ability to proliferate and produce cytokines were determined using fluorescence-activated cell sorting (FACS) analysis. Lung inflammation was also monitored using immunohistochemical staining. Treatment with the anti-IL4Rα nanoparticles significantly decreased pro-inflammatory cytokine expression and release in BALF and airway lung tissue in mice. The numbers of lung tissue lymphocytes, neutrophils and eosinophils were also decreased. Interestingly, anti-IL4Rα nanoparticles deactivated CD4 and CD8 T cells in lung tissue and inhibited their ability to produce pro-inflammatory cytokines to a significantly lower level than the treatment with free anti-IL4Rα. Moreover, they induced a sustained low level of lung inflammation for 1 week following the last instillation compared with the treatment with free anti-IL4Rα antibodies. Together, this data suggested that the enhanced tissue penetrability and sustainability of these nanoparticles improved the strength and durability of the immunosuppressive effects of anti-IL4Rα.

Poor asthma education and medication compliance are associated with increased emergency department visits by asthmatic children

Acute exacerbations of bronchial asthma remain a major cause of frequent Emergency Department [ED] visits by pediatric patients. However, other factors including psychosocial, behavioural and educational, are also reportedly associated with repetitive ED visits. Therefore, it is necessary to determine whether such visits are justifiable. The objective of this cross-sectional study was to identify risk factors associated with visits to ED by asthmatic children. Asthmatic children [n= 297] between 1-17 years old were recruited and information collected at the time of visiting an ED facility at two major hospitals. Asthmatic patients visited the ED 3.9 3.2 times-per-year, on average. Inadequately controlled asthma was perceived in 60.3% of patients. The majority of patients [56.4%] reported not receiving education about asthma. Patients reflected misconceptions about the ED department, including the belief that more effective treatments are available [40.9%], or that the ED staff is better qualified [27.8%]. About half of patients [48.2%] visited the ED because of the convenience of being open 24 hours, or because they are received immediately [38.4%]. Uncontrolled asthma was associated with poor education about asthma and/or medication use. Patients educated about asthma, were less likely to stop corticosteroid therapy when their symptoms get better [OR:0.55; 95% CI:0.3-0.9;P= 0.04]. This study reports that most patients had poor knowledge about asthma and were using medications improperly, thus suggesting inefficient application of management action plan. Unnecessary and frequent visits to the ED for asthma care was associated with poor education about asthma and medication use. Potential deficiencies of the health system at directing patients to the proper medical facility were uncovered and underline the necessity to improve education about the disease and medication compliance of patients and their parents/guardians

IL-4 receptor alpha single-nucleotide polymorphisms rs1805010 and rs1801275 are associated with increased risk of asthma in a Saudi Arabian population

The IL-4 receptor alpha subunit [IL-4Ralpha], when associated with the common gamma chain receptor, or the IL-13Ralpha1 subunit, transduces signals to STAT6 in response to IL-4 and IL-13 stimulations. This results in a number of cell-specific responses including Th2 differentiation, lymphocyte proliferation and IgE production. Given the prominent role of IL-4Ralpha in allergic disorders, several single-nucleotide polymorphisms [SNPs] have been found associated with asthma and other atopic disorders, including rs1805010 [I75V] and rs1801275 [Q576R] SNPs; however, lack of significant association have also been reported for some ethnic groups. The objective of this study was to determine whether IL-4Ralpha rs1805010 and rs1801275 polymorphisms are associated with asthma in patients from Saudi Arabia. One hundred and ninety severe asthmatic patients [11-70 years old] and 194 healthy subjects of equivalent age range were recruited for blood donation. DNA was purified and genotyping for rs1801275 and rs1805010 polymorphisms in the IL-4Ralpha gene was performed by PCR amplification, followed by cycle sequencing of the purified PCR fragments using BigDye chain terminator and capillary electrophoresis. Pearson's Chi-square tests showed that the minor alleles, G, for both rs1805010 and rs1801275 SNPs, were significantly more frequent in asthmatics than in the healthy group [Yates' P < 0.05]; conversely, the major alleles, A, were significantly more frequent in healthy than in asthmatics [P < 0.05]. Concerning association analysis, odds for A/G-G/G genotypes were significantly higher to be associated with asthma predisposition [rs1801275: OR = 2.12; 95% CI = 1.39-3.22; P < 0.001*; rs1805010: OR = 1.6; 95% CI = 1.01-2.53; P < 0.05*; dominant model]. Analysis of gender-genotype interactions, with genders nested within A/G-G/G, indicated higher odds for females than males of significant association with asthma [rs1801275: OR = 5.19, 95% CI = 2.09-12.94*; rs1805010: OR = 3.73, 95% CI = 2.06-6.74*]. Rs1805010 and rs1801275 were in linkage disequilibrium [D' = 0.27; P < 0.0004*], with G-G haplotype being more frequent in asthmatics than in healthy subjects [OR = 2.43, 95% CI = 1.59-3.71*].The risk alleles, G, of IL-4Ralpha rs1805010 and rs1801275 SNPs and corresponding A/G-G/G genotypes were significantly associated with asthma predisposition in asthmatics from Saudi Arabia.

T1 and T2 ADAM33 single nucleotide polymorphisms and the risk of childhood asthma in a Saudi Arabian population: a pilot study

Genetic association studies have demonstrated that over 100 variants in target genes [including ADAM33] are associated with airway remodeling and hyper-responsiveness in different ethnic groups; however, this has never been evaluated in Arabic populations. The objective of this study was to determine whether ADAM33 polymorphisms that are associated with asthma in a population of asthmatic children from Saudi Arabia. A cross-sectional pilot study comparing the polymorphisms of normal subjects and asthmatic patients from Saudi Arabia over a period of 1 year. One hundred and seven Saudi asthmatic children and 87 healthy Saudi children of 3-12 years old were assessed for allelic association of ADAM33 T1 [rs2280091], T2 [rs2280090], ST+4 [rs44707] and S1 [rs3918396] SNPs to asthma. Genotyping was done by real-time PCR, multiplex ARMS and PCR-RFLP. T1 and T2 SNP genotype frequencies in asthmatic children were significantly different compared to controls [P<.05], indicating allelic association with asthma. The T1 A/G and G/G and the T2 A/G and A/A genotypes [P=0.0013 and P=.008, respectively] but not S1 and ST+4, increased the risk of asthma when using the best fit dominant model. Strong linkage disequilibrium between T1 [rs2280091] and T2 [rs2280090] was observed [r2=0.83; D'=0.95; P<.001]. The haplotype G-A-A-C was significantly more frequent in asthmatics, thus supporting the association of T1 G-allele and T2 A-allele with increased predisposition to asthma [P=.007]. T1 A/G and T2 G/A ADAM33 polymorphisms, but not S1 or ST+4, were significantly associated with asthma development in Saudi children, like those reported for white and Hispanic population in the United States

Eosinophilic pneumonia: experience at two tertiary care referral hospitals in Saudi Arabia

Eosinophilic lung diseases are a diverse group of disorders characterized by pulmonary opacities associated with tissue or peripheral eosinophilia. A retrospective study conducted at two tertiary care hospitals from January 1999 to December 2009. All cases with the diagnosis of pulmonary eosinophilia were reviewed over a period of 10 years. Data on demographic, clinical, and radiologic characteristics were collected. Thirty-five patients with a mean age of 33.9 [16.2] years, of which 20 [57.1%] were male and meeting the criteria of eosinophilic lung disease were identified. Cough and dyspnea were the most frequent symptoms at presentation in 29 [82.9%] and 27 [77.1%] patients, respectively. Reticulonodular and airspace patterns were the most common radiographic findings in 17 [48.6%] and 15 [42.9%] patients, respectively. Peripheral eosinophilia was present in 33 [94.3%] patients. Twenty-four patients [68.6%] were labeled as having idiopathic pulmonary infiltrate with eosinophilia. Complete remission was achieved in 13 [54.2%] of 24 patients, while 10 [41.7%] patients relapsed within a few months of discontinuation of therapy. Specific therapy for a specific disease was administered in 8 patients: 2 patients for pulmonary tuberculosis, 2 for Churg-Strauss syndrome, 1 for lymphoma, 1 for schistosomiasis, 1 for acute eosinophilic pneumonia, and 1 for Wegener granuloma; 3 patients were treated as allergic bronchopulmonary aspergillosis. Pulmonary eosinophilia remains rare but challenging, and it can have the same diverse clinical and radiographic presentations seen with other common pulmonary conditions. Clinicians should be alert to these syndromes and must think of them in any lung disease differential diagnoses

Vitamin D levels in Saudi children with type 1 diabetes

To assess the prevalence of vitamin D deficiency in type 1 diabetic [T1DM] children. In this prospective cross-sectional study, we included 100 Saudi children with T1DM attending the Pediatric Endocrinology and Diabetes Clinics, and 100 healthy controls from the Department of Pediatrics, Security Forces Hospital, Riyadh, Kingdom of Saudi Arabia from June to September 2010. We measured serum 25-hydroxy vitamin D [25OHD], parathyroid hormone, calcium, phosphate, and alkaline phosphatase in these patients, and compared the results with age, gender, and ethnicity-matched control subjects. The mean levels of 25OHD were significantly lower in the T1DM children compared to the controls [36.7 +/- 14.3 nmol/l versus 44.8 +/- 14.1 nmol/l]. In the T1DM children, 64% were mildly, 16% were moderately, and 4% were severely vitamin D deficient as compared with 52% [mildly], 6% [moderately], and 1% [severely] in the control group. Overall, 84% of the T1DM children, and 59% of the healthy children were vitamin D deficient. There was no correlation between glycemic control and 25OHD level. Prevalence of vitamin D deficiency in diabetic children is relatively high. Therefore, screening for vitamin D deficiency and supplementation of children with low vitamin D levels should be warranted

Cytomegalovirus infections in unrelated cord blood transplantation in pediatric patients: incidence, risk factors, and outcomes

Stem cells from umbilical cord blood [CB] have increasingly become a viable alternate source of progenitor cells for hematopoietic cell transplantation [HSCT] Cytomegalovirus [CMV] is thought to contribute significantly to HSCT morbidity and mortality. Retrospective case-control study in patients at tertiary care center. We determined the incidence, risk factors and outcomes for CMV infection and disease after unrelated cord blood transplantation [UCBT] in children. Between 2003 and 2007, 73 pediatric patients underwent UCBT and 68% of recipients were CMV seropositive. The overall incidence of CMV infection, early and late CMV infection was 58.9% [43/73], 62.8% [27/43], and 37.4% [1 6/43], respectively. In patients with early CMV infection, 6 of 27 [22%] patients progressed to develop CMV end-organ disease including pneumonitis and retinitis. High levels CMV antigenemia >70 infected cells by pp65 antigenemia assay + PMNs, P-.237 were associated with a higher risk of progression to CMV disease. The development of CMV infections was higher in CMV-seropositive recipients [P<.001] and in those who developed graft-versus-host-diseases [GVHD] [P<.001]. Other risk factors for CMV infection include the use of high-dose corticosteroids [P<.001] and older age of the recipient at the time of transplant [P<.002]. Late CMV infection was strongly associated with a previous history of early CMV infection [P<.001]. CMV infection is a significant complication in UCBT recipients in pediatric patients and is associated with an increase in transplant-related morbidity and mortality. Risk factors for CMV infections after UCBT include GVHD, use of corticosteroids, underlying diseases [hematologic malignancies] and older age. Late CMV infection was strongly associated with a previous history of CMV infection

Human metapneumovirus and human coronavirus infection and pathogenicity in Saudi children hospitalized with acute respiratory illness

Human metapneumovirus [hMPV] and the Netherlands human coronavirus [HCoV-NL63] have been isolated from children with respiratory tract infection. The prevalence of these viruses has not been reported from Saudi Arabia. We sought to determine whether hMPV and HCoV-NL63 are responsible for acute respiratory illness and also to determine clinical features and severity of illness in the hospitalized pediatric patient population. Prospective hospital-based study from July 2007 to November 2008. Nasopharyngeal specimens from children less than 16 years old who were suffering from acute respiratory diseases were tested for hMPV and HCoV-NL63 by reverse transcriptase-polymerase chain reaction. Samples were collected from July 2007 to November 2008. Both viruses were found among Saudi children with upper and lower respiratory tract diseases during the autumn and winter of 2007 and 2008, contributing to 11,1% of all viral diagnoses, with individual incidences of 8.3% [hMPV] and 2.8% [HCoV-NL63] among 489 specimens. Initial symptoms included fever, cough, and nasal congestion. Lower respiratory tract disease occurs in immunocompromised individuals and those with underlying conditions. Clinical findings of respiratory failure and culture-negative shock were established in 7 children infected with hMPV and having hematologic malignancies, myelofibrosis, Gaucher disease, and congenital immunodeficiency; 2 of the 7 patients died with acute respiratory failure. All children infected with HCoV-NL63 had underlying conditions; 1 of the 4 patients developed respiratory failure. hMPV and HCoV-NL63 are important causes of acute respiratory illness among hospitalized Saudi children. hMPV infection in the lower respiratory tract is associated with morbidity and mortality in immunocompromised children. HCoV-NL63 may cause severe lower respiratory disease with underlying conditions