Showing papers by "Atul Gupta published in 2012"

Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines

Abstract: Background The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood. Objectives We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the T H 2 cytokines IL-4, IL-5, and IL-13. Methods Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen T H 2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation. Results Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P P P P + and IL-13 + cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid T H 2 cytokines had significantly lower lung function than those with undetectable BAL fluid T H 2 cytokines. Conclusions STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the T H 2 mediators that are thought to drive allergic asthma were mostly absent.

The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells

Abstract: 1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4+ T cells Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3+ regulatory T (Treg) cells 1α25VitD3 increased the frequency of both Foxp3+ and IL-10+ CD4+T cells in vitro However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules The Foxp3+ and IL-10+ T-cell populations showed comparable suppressive activity We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10 1α25VitD3 enables the selective expansion of Foxp3+ Treg cells over their Foxp3− T-cell counterparts Equally, 1α25VitD3 maintains Foxp3+ expression by sorted populations of human and murine Treg cells upon in vitro culture A positive in vivo correlation between vitamin D status and CD4+Foxp3+ T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10+ and Foxp3+ Treg cells In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells

Long-term effectiveness of a staged assessment for paediatric problematic severe asthma

Abstract: To the Editors: The recently proposed term “problematic severe asthma” (PSA) [1] describes children with persistent symptoms and/or severe exacerbations despite high dose treatment [2]. They suffer significant morbidity and consume a disproportionate amount of healthcare resources. Children with PSA are heterogeneous with respect to lung function [3] and asthma phenotype [4] and warrant careful evaluation. PSA [5] encompasses 1) wrong diagnosis; 2) significant comorbidities; 3) difficult asthma with potentially reversible factors such as poor inhaler technique, ongoing allergen exposure or poor adherence to treatment [6]; and 4) severe therapy-resistant asthma (STRA) that is refractory to maximal treatment despite optimised standard management [7]. PSA children were enrolled in a staged assessment protocol to differentiate difficult asthma from STRA [6]. The different stages were as follows. Stage 1: a detailed re-evaluation of the child including a nurse-led outpatient assessment with evaluation of inhaler device and technique, psychosocial questionnaire, a home and school visit, an assessment of adherence including prescription uptake check and a final multidisciplinary team discussion to decide whether the child had difficult asthma or STRA [6]. Stages 2 and 3: children identified as STRA progressed to invasive investigations including bronchoscopy and assessment of steroid response [7]. Differentiating difficult asthma from STRA is important to avoid unnecessary invasive procedures and side effects from additional treatments such as methotrexate. Furthermore, the healthcare costs of these approaches cannot be justified if simply improving basic management may improve asthma control. There have been no longitudinal studies that have assessed the long-term efficacy of a staged assessment of paediatric PSA. We hypothesised that the stage 1 assessment distinguishes difficult asthma from STRA and results in …

1α,25-Dihydroxyvitamin D3 promotes CD200 expression by human peripheral and airway-resident T cells

Abstract: Background CD200, a cell-surface immunoglobulin-like molecule expressed by immune and stromal cells, dampens the pro-inflammatory activity of tissue-resident innate cells via its receptor, CD200R This interaction appears critical for peripheral immune tolerance, particularly in the airways where excessive inflammation is undesirable Vitamin D contributes to pulmonary health and promotes regulatory immune pathways, therefore its influence on CD200 and CD200R was investigated Methods CD200 and CD200R expression were assessed by qPCR and immunoreactivity of human lymphoid, myeloid and epithelial cells following 1α,25-dihydroxyvitamin D3 (1α,25VitD3) exposure in vitro and in peripheral T cells following 1α,25VitD3 oral ingestion in vivo The effect of 1α25VitD3 was also assessed in human airway-resident cells Results 1α25VitD3 potently upregulated CD200 on peripheral human CD4+ T cells in vitro, and in vivo there was a trend towards upregulation in healthy, but not asthmatic individuals CD200R expression was not modulated in any cells studied CD200 induction was observed to a lesser extent in CD8+ T cells and not in B cells or airway epithelium T cells isolated from the human airway also responded strongly to 1α25VitD3 to upregulate CD200 Conclusions The capacity of 1α,25-dihydroxyvitamin D3 to induce CD200 expression by peripheral and respiratory tract T cells identifies an additional pathway via which vitamin D can restrain inflammation in the airways to maintain respiratory health

The trachea with an air‐fluid level: A rare and bizarre radiological sign

Abstract: We report three children with an unusual radiological sign: "trachea with an air fluid level" We suggest this is related to paucity of cough leading to recurrent chest infections Voluntary cough suppression as a cause of chronic lower respiratory tract infection is recorded in adults (The Lady Windermere Syndrome) but has not previously been reported in children We propose that in these children impaired airway mucus clearance may be also be caused by voluntary cough suppression However, the complex physiology of coughing means it is difficult to distinguish between true voluntary cough suppression and paucity of cough due to a subtle neurological deficit In two patients, the cycle has led to permanent lung damage with bronchiectasis and reduced lung function In the third, early diagnosis and multidisciplinary intervention has so far delayed progression to bronchiectasis With greater awareness of this phenomenon in children, there is potential for effective early intervention with medical, physical, and psychological therapies

Fungal sensitisation in children with severe therapy resistant asthma

Abstract: Adults with severe asthma with fungal sensitisation (SAFS) have reduced lung function and increased morbidity [Am J Respir Care Med 2009;179:11-8]. We hypothesized that fungal sensitisation in children with severe, therapy-resistant asthma (STRA) is associated with increased morbidity. Methods: All children had STRA having had basic management optimized [Lancet 2010;376:814-25]. There were 166 patients (11.7 years [4-17]; 61% boys). SAFS (n=76) was defined as specific IgE (spIgE) or skin prick test (SPT) positivity to Aspergillus fumigatus, Alternaria alternata or Cladosporium herbarum. Non-sensitised patients (n=90) had negative spIgE and SPT. Age, atopy, symptoms, medication, lung function and airway inflammation were assessed. Results: SAFS children were mainly boys (57/76(75%) vs 43/90(48%), p Conclusions: Children with STRA and SAFS had earlier asthma onset, more atopy and bronchodilator reversibility, and were more often given prednisolone. We need a randomised controlled trial of antifungal therapy in paediatric SAFS.

A run too far

Abstract: As medical professionals we are taught the theory of medical practice and procedures, yet for most the greatest learning comes from patients that we see. The following case highlights an interesting and valuable learning point for a commonly performed procedure. A previously well 13-year-old developed right-sided chest pain towards the closing stages of a cross-country running race. He presented to Accident and Emergency the following day. He was tachypneic at 20 breaths per minute, oxygen saturations (SpO2) 98% in room air with decreased breath sounds on the right side of his chest on auscultation. Chest X-ray (CXR) confirmed a large right-sided pneumothorax and complete collapse of his right lung. A chest drain was inserted at the local hospital. During the procedure, the patient became acutely unwell, desaturating to SpO2 70%. A repeat CXR showed extensive unilateral, right-sided pulmonary edema (Fig. 1). He was given high flow oxygen but required no other support. The pulmonary edema gradually resolved over the next 24 hr and his oxygen requirement disappeared. Re-expansion pulmonary edema (REPO) is a rare but potentially life threatening complication of rapid unilateral lung expansion. There are many reports of REPO in adults with incidence between 0% and 1% following pneumothorax and effusion, but very few reports in children. REPO is believed to arise from rapidly changing intra-thoracic pressures during drainage of the thoracic cavity. There is increased risk of developing REPO following a prolonged period of lung collapse, rapid lung re-expansion and following suction applied to the chest tube. Other contributing factors include loss of surfactant, pulmonary vasculature pressure changes, and airway obstruction. Contralateral pulmonary edema has also been described following pneumothorax of the ipsilateral lung. The mechanism of this is not well understood but may be due to changes in pulmonary vasculature following lung re-expansion in a patient with mediastinal shift. Treatment of REPO is largely supportive. Some may require ventilatory support, with positive end expiratory pressure and hemodynamic support. Chest physiotherapy and positioning may reduce shunting and improve oxygenation. In summary, REPO is a rare but potentially serious complication of a commonly performed procedure. Pediatricians performing chest tube insertion should aware of this complication and how to treat it.