Asthma biomarkers in the age of biologics.

The heterogeneous nature of asthma has been understood for decades, but the precise categorization of asthma has taken on new clinical importance in the era of specific biologic therapy. The simple categories of allergic and non-allergic asthma have given way to more precise phenotypes that hint at underlying biologic mechanisms of variable airflow limitation and airways inflammation. Understanding these mechanisms is of particular importance for the approximately 10% of patients with severe asthma. Biomarkers that aid in phenotyping allow physicians to "personalize" treatment with targeted biologic agents. Unfortunately, testing for these biomarkers is not routine in patients whose asthma is refractory to standard therapy. Scientific advances in the recognition of sensitive and specific biomarkers are steadily outpacing the clinical availability of reliable and non-invasive assessment methods designed for the prompt and specific diagnosis, classification, treatment, and monitoring of severe asthma patients. This article provides a practical overview of current biomarkers and testing methods for prompt, effective management of patients with severe asthma that is refractory to standard therapy.

Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: A placebo-controlled randomized trial.

BACKGROUND: Antibiotics are frequently used to treat wheezing children. Macrolides may be effective in treating bronchiolitis and asthma. METHOD: We completed a prospective, double-blinded, randomized placebo-control trial of azithromycin among pre-school children (12 to 60 months of age) presenting to the emergency department with wheeze. Patients were randomized to receive either five days of azithromycin or placebo. Primary outcome was time to resolution of respiratory symptoms after treatment initiation. Secondary outcomes included the number of days children used a Short-Acting Beta-Agonists during the 21 day follow-up and time to disease exacerbation during the following six months (unscheduled health care visit or treatment with an oral corticosteroid for acute respiratory symptoms). RESULTS: Of the 300 wheezing children recruited, 222 and 169 were analyzed for the primary and secondary outcomes, respectively. The treatment groups had similar demographics and clinical parameters at baseline. Median time to resolution of respiratory symptoms was four days for both treatment arms (interquartile range (IQR) 3,6; p = 0.28). Median number of days of Short-Acting Beta-Agonist use among those who received azithromycin was four and a half days (IQR 2, 7) and five days (IQR 2, 9; p = 0.22) among those who received placebo. Participants who received azithromycin had a 0.91 hazard ratio for time to six-month exacerbation compared to placebo (95% CI 0.61, 1.36, p = 0.65). A pre-determined subgroup analysis showed no differences in outcomes for children with their first or repeat episode of wheezing. There was no significant difference in the proportion of participants experiencing an adverse event. CONCLUSION: Azithromycin neither reduced duration of respiratory symptoms nor time to respiratory exacerbation in the following six months after treatment among wheezing preschool children presenting to an emergency department. There was no significant effect among children with either first-time or prior wheezing.

Adequate Vitamin D Intake but Low Serum Levels in Pediatric Asthma Patients: A Pilot Study, Alberta Children's Hospital.

Background. We assessed vitamin D intakes and serum 25(OH) vitamin D levels in pediatric asthma patients on moderate-to-high dose inhaled steroids and compared them to published findings of healthy children in our city. Methods. Parents and/or patients were interviewed to estimate the children's vitamin D intakes from foods and supplements (using an adapted validated food frequency questionnaire) and asthma duration and management. Vitamin D status: serum 25-hyroxy vitamin D (25(OH)D) was obtained from the medical records. Results. Vitamin D intakes from food and supplements of the asthma patients (n = 20, 742 ± 185 IU/day) were significantly higher compared to healthy Canadian children (n = 1442, 229 ± 121 IU/day). Despite higher vitamin D intakes, the children had nonsignificantly lower serum 25(OH) vitamin D levels compared to the comparison group. Serum 25(OH)D levels increased by 3.6 nmol/L with each 100 IU of vitamin D intake (95% Confidence interval = 2.0-4.0, R2 = 0.931, and p = 0.001). Conclusion. Since adequate vitamin D status in asthma patients is necessary to support bone mineral accretion, it is important to achieve adequate vitamin D status by checking serum 25(OH)D status and supplement accordingly.

Bronchiolitis obliterans organising pneumonia associated with anticonvulsant hypersensitivity syndrome induced by lamotrigine.

A 14-year-old girl who was known to have a seizure disorder and on lamotrigine treatment was admitted to the hospital, with a history of rash, fever and cough. Her condition deteriorated with clinical features suggestive of anticonvulsant hypersensitivity syndrome (ACHS) complicated with bronchiolitis obliterans organising pneumonia (BOOP). Her chest CT showed multifocal parenchymal opacities and lung biopsy was typical for BOOP. Initially, the lamotrigine was discontinued since the onset of the rash, then she was treated for pneumonia with antibiotics, which may have delayed the diagnosis. Eventually, BOOP was considered and she was treated with a high dose of corticosteroid. She improved clinically and her repeated chest CT showed a marked resolution of the lesions. This case illustrates the possible occurrence of BOOP as a complication of ACHS secondary to lamotrigine treatment.

Pediatric sand aspiration managed using bronchoscopy and extracorporeal membrane oxygenation.

Sand aspiration is a rare but potentially fatal occurrence to consider in near-drownings, accidental burials or cave-ins. Optimal management is not well defined.

The respiratory presentation of severe combined immunodeficiency in two Mennonite children at a tertiary centre highlighting the importance of recognizing this pediatric emergency.

Severe combined immunodeficiency (SCID) is considered to be a pediatric emergency, with respiratory distress being the most common presenting symptom. The authors present two cases of SCID in children <4 months of age with respiratory distress at a tertiary care centre due to a recently described homozygous CD3 delta mutation found only in the Mexican Mennonite population. Failure to respond to broad-spectrum antibiotics prompted investigation for possible SCID. Bronchial alveolar lavage fluid from both patients grew Pneumocystis jiroveci, and flow cytometry revealed absent T cells. The CD3 delta gene is believed to be important in T cell differentiation and maturation. The present article reminds pediatricians and pediatric respirologists that the key to diagnosing SCID is to have a high index of suspicion if there is poor response to conventional therapies.

Pulmonary Langerhans cell histiocytosis: a variable disease in childhood.

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is rare in childhood but occurs most commonly in children with multisystem (MS) LCH. In adults, by contrast, the lung is the most common and usually the sole organ affected. This retrospective study describes the clinical manifestation, course, and outcome of PLCH in children consecutively diagnosed at two Canadian institutions. PROCEDURE: The medical records of children (<18 years of age) consecutively diagnosed with LCH at the two institutions, were examined to ascertain the demographic details, pathological diagnosis, and organs involved. Further clinical details including, the clinical manifestation, details of therapy, course of lung disease, and clinical outcome were extracted for patients with PLCH. Initial and follow-up lung radiographs and CT scans were re-reviewed. RESULTS: Of the 178 patients with LCH, 40 (22.5%) presented with MS disease. Thirteen (7.3%) had PLCH, seven at initial diagnosis, and six at the time of disease progression. The median age was 10.1 months and mean was 11.9 months at diagnosis of PLCH. Lung involvement was always in the context of MS LCH, and half of the patients had no respiratory symptoms. Disease-free survival was around 70%, with a mean follow-up duration of 7 years. Of the four patients who died, three had other risk-organ involvement. Five of the nine surviving patients have had complete radiological resolution of PLCH. CONCLUSION: PLCH is seen in less than 10% of childhood LCH, but more than 30% of MS LCH. About half of children with PLCH may be asymptomatic, and the prognosis appears to depend on the presence or absence of other risk-organ involvement. The MS PLCH found in children appears to be a different disease from the single system (SS) PLCH seen in adults.

Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial.

BACKGROUND: We did a randomised, double-blind, controlled clinical trial to prospectively assess whether use of combination antibiotic susceptibility testing improved clinical outcomes in patients with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria. METHODS: 251 patients with cystic fibrosis who were chronically infected with multiresistant gram negative bacteria gave sputum at 3-month intervals for conventional culture and sensitivity tests and for combination antibiotic susceptibility tests using multiple combination bactericidal antibiotic testing (MCBT). Patients who developed an exacerbation of pulmonary disease were randomised to receive a 14-day course of any two blinded intravenous antibiotics chosen on the basis of either results from conventional sputum culture and sensitivity testing or the result of MCBT. The primary outcome was time from randomisation until the patient's next pulmonary exacerbation. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN60187870. FINDINGS: 132 patients had a pulmonary exacerbation and were randomised during the 4.5-year study period. The time to next pulmonary exacerbation was not prolonged in the MCBT-treated group (hazard ratio 0.86 in favour of the conventionally-treated group, 95% CI 0.60-1.23, p=0.40). There was no difference between the groups in treatment failure rate. After 14 days of intravenous antibiotic therapy, changes in lung function, dyspnoea, and sputum bacterial density were similar in both groups. INTERPRETATION: Antibiotic therapy directed by combination antibiotic susceptibility testing did not result in better clinical and bacteriological outcomes compared with therapy directed by standard culture and sensitivity techniques. The non-bactericidal effects of antibiotic therapy might play an important part in determining improvement in patients with cystic fibrosis pulmonary exacerbations.