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Changing roles of eosinophils in health and disease.

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eosinophils_OBJECTIVE: To review and highlight the unappreciated roles of eosinophils suggested by recent studies.

DATA SOURCES: The literature, unpublished observations, and insights by the authors.

STUDY SELECTIONS: Basic studies of mouse models and patient-based clinical studies of disease.

RESULTS: Eosinophils are often thought of as destructive end-stage effector cells primarily linked to parasite host defense and dysregulated immune responses associated with allergic diseases, such as asthma. However, recent studies (ie, research focused on mechanisms of action and translational studies examining disease/inflammatory pathways) are suggesting far more complex roles for eosinophils. The goal of this review is 3-fold. (1) The authors examine the dynamic history of eosinophils and how physicians over time used this information to formulate defining hypotheses. Particular emphasis is placed on recent studies challenging the parochial view of host defense in favor of roles maintaining homeostasis through immune modulation and tissue remodeling/repair. (2) They discuss diagnostic approaches to assess eosinophils in clinical settings as a means of disease identification and subsequently as a measurement of disease severity. (3) They examine how contemporary views of eosinophils and their perceived roles in diseases have led to specific therapeutic strategies. The emphasis is to review the successes and failures of these strategies as the basis of formulating future clinical studies targeting eosinophils as potential therapies of disease.

CONCLUSION: Despite the complexities of eosinophil-mediated activities and the less than overwhelming success of initial attempts targeting these cells, eosinophils remain a potentially important focal target of disease diagnosis and subsequent treatment strategies.

Nebulized Hypertonic Saline for Bronchiolitis: A Randomized Clinical Trial.

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Bronchiolitis is one of the most common and costly respiratory diseases in infants and young children. Previous studies have shown a potential benefit of nebulized hypertonic saline; however, its effect in the emergency department (ED) setting is unclear.

OBJECTIVE To compare the effect of nebulized 3% hypertonic saline vs 0.9% normal saline on admission rate and length of stay in infants with bronchiolitis.

DESIGN, SETTING, AND PARTICIPANTS We conducted a double-blind, randomized clinical trial during 3 consecutive bronchiolitis seasons from March 1, 2008, through April 30, 2011. We recruited a convenience sample of patients younger than 24 months with a primary diagnosis of viral bronchiolitis presenting to the ED of 2 urban free-standing tertiary children's hospitals. We excluded patients who were premature (gestational age, <34 weeks) or who had chronic pulmonary disease, immune deficiency, cardiac disease, or previous episodes of wheezing or inhaled bronchodilator use. Of eligible patients who were approached, 161 (26.6%) declined to participate. INTERVENTIONS Patients received 4 mL of 3% sodium chloride (hypertonic saline [HS group]) or 0.9% sodium chloride (normal saline [NS group]) inhaled as many as 3 times in the ED. Those admitted received the assigned medication every 8 hours until discharge. All treatment solutions were premedicated with albuterol sulfate.

MAIN OUTCOMES AND MEASURES Hospital admission rate, length of stay for admitted patients, and Respiratory Distress Assessment Instrument score.

RESULTS A total of 197 patients were enrolled in the NS group and 211 in the HS group. Admission rate in the 3% HS group was 28.9% compared with 42.6% in the NS group (adjusted odds ratio from logistic regression, 0.49 [95% CI, 0.28-0.86]). Mean (SD) length of stay for hospitalized patients was 3.92 (5.24) days for the NS group and 3.16 (2.11) days for the HS group (P = .24). The Respiratory Distress Assessment Instrument score decreased after treatment in both groups; however, we found no significant difference between groups (P = .35).

CONCLUSIONS AND RELEVANCE Hypertonic saline given to children with bronchiolitis in the ED decreases hospital admissions. We can detect no significant difference in Respiratory Distress Assessment Instrument score or length of stay between the HS and NS groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00619918.

Utility of Electrocardiogram in the Assessment and Monitoring of Pulmonary Hypertension (Idiopathic or Secondary to Pulmonary Developmental Abnormalities) in Patients ≤18 Years of Age.

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ECGElectrocardiograms have utility in disease stratification and monitoring in adult pulmonary arterial hypertension (PAH). We examined the electrocardiographic findings that are common in pediatric PAH and assessed for correlation with disease severity and progression.

We retrospectively identified patients aged ≤18 years followed at a single institution from January 2001 to June 2012 with catheterization-confirmed diagnosis of idiopathic PAH and PAH secondary to pulmonary developmental abnormalities. Patients with an electrocardiography performed within 60 days of catheterization were included. Primary and secondary outcomes are the prevalence of abnormal electrocardiographic findings at the time of catheterization and the association between electrocardiographic and hemodynamic findings and electrocardiographic changes with disease progression on follow-up catheterization, respectively.

Of the 100 electrocardiography-catheterization pairs derived from the 46 patients identified, 93% had an electrocardiographic abnormality: 78% had right ventricular hypertrophy (RVH) and 52% had right axis deviation (RAD) for age. In patients with idiopathic PAH, the presence of RVH and RAD correlated with pulmonary vascular resistance and transpulmonary gradient. RAD and RVH on baseline electrocardiogram was associated with an increased risk of disease progression on subsequent catheterization (odds ratio 11.0, 95% confidence interval 1.3 to 96.2, p = 0.03) after adjusting for PAH subgroup. The sensitivity, specificity, and positive and negative predictive values of RAD and RVH on baseline electrocardiogram for disease progression were 92%, 48%, 33%, and 95%, respectively.

In conclusion, electrocardiographic abnormalities are common in pediatric PAH. RAD and RVH on electrocardiogram were associated with worse hemodynamics, whereas their absence is suggestive of a lack of disease progression.

Pulmonary radiologic findings in common variable immunodeficiency: clinical and immunological correlations.

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CVIDIt remains unclear whether interstitial lung disease (ILD) in common variable immunodeficiency (CVID) is a consequence of chronic infection or a manifestation of dysregulated lymphoid proliferation found in those with this condition.

OBJECTIVE: To increase understanding of CVID-associated lung disease by comparing clinical and immunologic associations in those with bronchiectasis, ILD, or no lung disease observed on chest computerized tomography (CT).

METHODS: Retrospective review of electronic medical records of 61 patients with CVID was used to identify clinical and laboratory correlates of bronchiectasis, ground glass opacity, and pulmonary nodules on CT scan.

RESULTS: Significant clinical and immunologic associations were identified for common CT scan findings in CVID. Bronchiectasis was strongly correlated with a CD4(+) T-cell count lower than 700 cells/μL and was associated with a history of pneumonia and older age. Pulmonary nodular disease was correlated with increased CD4(+):CD8(+) T-cell ratios, a history of autoimmune hemolytic anemia or immune thrombocytopenic purpura, elevated IgM, and younger age. Ground glass opacity had similar clinical and laboratory characteristics as those for nodular lung disease but was associated with elevated monocyte counts and the presence of liver disease.

CONCLUSION: CT findings of bronchiectasis or ILD, including ground glass opacity and extensive pulmonary nodules, were correlated with selected clinical and laboratory characteristics. These results suggest divergent processes of CVID lung disease, with bronchiectasis more strongly associated with infection and T-cell lymphopenia and ILD more strongly linked with autoimmunity and lymphoproliferation.

Optimisation of Omalizumab Dosage in Patients with Severe Persistent Allergic Asthma Using recoveryELISA.

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omalizumabThe objective of this study was to investigate the suitability of recoveryELISA as a method to monitor treatment with therapeutic antibodies using the example of omalizumab.

METHODS: The recoveryELISA is a newly developed immunoassay technology that measures three parameters in one test: the free level of antigen, the level of therapeutic antibody and the specific dose-response interaction which represents the actual activity of the drug. A retrospective and observational analysis was performed on 197 serum samples from 17 patients (13 ± 4 years of age) with severe persistent allergic asthma who received add-on treatment with omalizumab.

RESULTS: The mean omalizumab serum level during antibody therapy was 59 ± 45 µg/mL; the kit's upper detection limit of 140 µg/mL was exceeded in 27 samples. Antibody concentrations between 50 and 140 µg/mL were found in 64 samples. Independent of the omalizumab dosage, nearly all measurements were in a range of absolute saturation as regards the IgE binding rate. Almost complete binding of IgE with a recovery of added labelled IgE of <1 % was reached within a maximum of 11 days.

CONCLUSIONS: The biochemical activity of therapeutic antibodies can be examined by recoveryELISA and their residual activity can be determined. Thus, further individualisation of therapy with biologics is possible using this test which seems to be suitable to diminish side effects and reduce costs.

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