The relationship of aeroallergen sensitization phenotypes to asthma control in primarily Hispanic asthmatic children.

OBJECTIVE: The purpose of this study was to determine whether aeroallergen sensitization phenotypes could predict maintenance of well-controlled asthma. METHODS: Asthmatic children age 2-18 years who enrolled in the CHOC Children's Breathmobile™ program from April 2002 to December 2011 were included in this retrospective analysis if they had been skin tested to a panel of indoor and outdoor aeroallergens and had returned for follow-up care within 6 months of their baseline visit. The study observation period encompassed all year one visits. Asthma severity and control were defined by NHLBI EPR-3 Guidelines criteria. RESULTS: In the 1627 primarily Hispanic children evaluated, those with persistent asthma were more likely than those with intermittent disease to be sensitized to each aeroallergen tested and to have more total sensitizations. Children with intermittent, but not persistent, asthma at baseline who were sensitized to pollen2 (trees or weeds) were less likely to maintain well-controlled asthma at follow-up visits. Whereas, sensitization to dander (cat, dog or feather) showed a protective effect to maintenance of well-controlled asthma in patients with persistent, but not intermittent, baseline disease severity. CONCLUSIONS: Our data suggest that both indoor and outdoor aeroallergens should be assessed regardless of baseline asthma severity, including those with intermittent asthma.

The benefits of specific immunoglobulin E testing in the primary care setting.

A common link among allergic diseases remains the many allergens that can provoke symptoms. The National Institutes of Health Guidelines for the Diagnosis and Management of Asthma and Guidelines for the Diagnosis and Management of Food Allergy support the use of in vivo (skin prick) or in vitro (blood) specific immunoglobulin E (IgE) testing, along with a detailed clinical history and physical examination, to document an allergy diagnosis. The initial responsibility of diagnosing allergic diseases falls principally on primary care providers, for whom skin prick testing is impractical. Access to in vitro testing provides a valuable diagnostic tool, in conjunction with patient history, for comprehensive allergy and asthma management, which can result in significant clinical and economic benefits and improved patient outcomes. Identification of specific allergens in patients enhances management through education, targeted allergen avoidance, pharmacotherapy, and immunotherapy. The utilization of specific IgE in vitro allergy testing may also drive efficient and effective utilization of healthcare resources. Testing can facilitate a close collaboration between the primary care provider and the allergy specialist, who is experienced in interpreting allergy tests and correlating them with clinical history, conducting food and drug challenges, educating about environmental controls, and managing chronic or recurrent conditions where allergy is not easily recognized. As healthcare reimbursement moves from fee-for-service to fee-for-outcomes, cooperative, comprehensive, and outcome-based patient management will gain in importance.

Residential Proximity to Freeways is Associated with Uncontrolled Asthma in Inner-City Hispanic Children and Adolescents.

Background. Proximity to heavy traffic has been linked to increased asthma severity. However, it is unknown whether exposure to heavy traffic is associated with the ability to maintain asthma control. Objectives. This study examines whether exposure to heavy traffic is associated with the ability to maintain asthma control in inner-city children. Methods. 756 inner-city asthmatic Hispanic children were followed for one year in a pediatric asthma management program (Breathmobile). At each scheduled visit, asthma specialist tracked patients' asthma severity and managed their asthma based on the NAEPP guidelines. The patients' residential distance from the nearest freeway was calculated based on residential address at study entry. Distance to nearest freeway was used as a surrogate marker for high exposure from traffic-related air pollutants. Results. Patients who lived near a freeway were significantly more likely to have asthma that was not well controlled (P = .03). Patients with intermittent and mild baseline severity have a two-fold increased risk of having asthma that is uncontrolled if they lived <2 miles from a freeway (OR = 2.2, P = .04). Conclusion. In children with asthma, residential proximity to freeways is associated with uncontrolled asthma.

Cyclic adenosine monophosphate induces plasminogen activator inhibitor-1 expression in human mast cells.

Plaminogen activator inhibitor-1 (PAI-1), the key physiological inhibitor of the plasmin fibrinolytic system, plays important roles in the pathogenesis of asthma. Mast cells (MCs) are crucial effector cells and a major source of PAI-1 for asthma. Cyclic adenosine monophosphate (cAMP) is the important regulator of MCs; however, its effects on PAI-1 expression in MCs remain unknown. We reported cAMP/protein kinase A pathway positively regulates PAI-1 expression through cAMP-response element binding protein binding to hypoxia response element-1 at -158 to -153bp of human PAI-1 promoter in human MCs. Moreover, cAMP synergistically augments PAI-1 expression with ionomycin- or IgE receptor cross-linking-mediated stimulation.

Pimecrolimus induces apoptosis of mast cells in a murine model of cutaneous mastocytosis.

BACKGROUND: Cutaneous mastocytosis (CM) is a common type of mastocytosis. Current treatment of CM is generally symptomatic. Pimecrolimus has been demonstrated as an effective anti-inflammatory drug for the treatment of inflammatory skin diseases, but whether it treats CM remains unknown. METHODS: The murine model of CM was induced by subcutaneous injection of 100 µg/kg recombinant murine stem cell factor (rmSCF) for a total of 17 days in Balb/c mice. Beginning on the 8th day, treatment with pimecrolimus 1% cream or vehicle was performed topically and daily for 10 days. The clinical signs of CM were scored, and pathological analysis was performed with toluidine blue staining and hematoxylin and eosin staining. The in situ apoptotic mast cells (MCs) were studied by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. The cutaneous histamine level was measured by ELISA. RESULTS: In the rmSCF-treated mice, the clinical signs of CM, including erythema, wheal after rubbing lesion skins, and increased thickness of skin, were obvious compared to control mice, and were reduced after pimecrolimus treatment. The numbers of cutaneous MCs and neutrophils were significantly greater in mice with CM than in control mice, and pimecrolimus treatment decreased the numbers of MCs but not neutrophils. Extensive apoptosis of cutaneous MCs was observed in pimecrolimus-treated mice. The cutaneous histamine level was elevated in the mice with CM compared with healthy controls, and was lowered after treatment with pimecrolimus. CONCLUSIONS: Pimecrolimus effectively treats CM by reducing the density of cutaneous MCs and the subsequent histamine production through inducing MCs apoptosis.

Loss of asthma control in inner city children with asthma after withdraw of asthma controller medication.

To determine what percentage of inner-city children with asthma would lose asthma control when taken off asthma controllers, a retrospective analysis was performed on inner-city asthmatic children who achieved asthma control in an asthma specific disease management program. Once disease control was achieved patients had stepwise reduction of asthma controllers based on the National Asthma Education and Prevention Program (NAEPP) Expert Review Panel (EPR) 2 guidelines. In patients who were taken off all controllers, probability of maintaining asthma control at the first visit after cessation of these medications was significantly lower compared to patients kept on inhaled corticosteroids. We conclude that cessation of asthma controllers in previously well controlled inner-city asthmatic children results in loss of asthma control in a significant number of these patients. Data support recommendations from national asthma guidelines to step down controller therapy, but clinical monitoring is important to reduce impairment due to loss of control.

Mesodermal deletion of transforming growth factor-beta receptor II disrupts lung epithelial morphogenesis: cross-talk between TGF-beta and Sonic hedgehog pathways.

In vertebrates, Sonic hedgehog (Shh) and transforming growth factor-beta (TGF-beta) signaling pathways occur in an overlapping manner in many morphogenetic processes. In vitro data indicate that the two pathways may interact. Whether such interactions occur during embryonic development remains unknown. Using embryonic lung morphogenesis as a model, we generated transgenic mice in which exon 2 of the TbetaRII gene, which encodes the type II TGF-beta receptor, was deleted via a mesodermal-specific Cre. Mesodermal-specific deletion of TbetaRII (TbetaRII(Delta/Delta)) resulted in embryonic lethality. The lungs showed abnormalities in both number and shape of cartilage in trachea and bronchi. In the lung parenchyma, where epithelial-mesenchymal interactions are critical for normal development, deletion of mesenchymal TbetaRII caused abnormalities in epithelial morphogenesis. Failure in normal epithelial branching morphogenesis in the TbetaRII(Delta/Delta) lungs caused cystic airway malformations. Interruption of the TbetaRII locus in the lung mesenchyme increased mRNA for Patched and Gli-1, two downstream targets of Shh signaling, without alterations in Shh ligand levels produced in the epithelium. Therefore, we conclude that TbetaRII-mediated signaling in the lung mesenchyme modulates transduction of Shh signaling that originates from the epithelium. To our knowledge, this is the first in vivo evidence for a reciprocal and novel mode of cross-communication between Shh and TGF-beta pathways during embryonic development.

Asthma control and future asthma-related morbidity in inner-city asthmatic children.

BACKGROUND: Asthma guidelines recommend routine evaluation of asthma control, which includes measurements of impairment and risk. It is unclear whether rigorous asthma control changes risk of asthma morbidity. OBJECTIVE: To examine whether the degree of asthma control in inner-city asthmatic children results in differential risk reduction of future asthma-related morbidity. METHODS: This retrospective observational study examines 960 inner-city children with asthma who were highly engaged in an asthma-specific disease management program for a minimum of 2 years. Degree of asthma control was determined during the first year of enrollment and was categorized as well controlled (> or = 80% of visits in control), moderately controlled (50%-79% of visits in control), or difficult to control (< 50% of visits in control). Risk and probability of asthma-related morbidity at each visit were determined during the second year of enrollment and included self-reported asthma exacerbations requiring systemic corticosteroid rescue and emergency department visits or hospitalizations. RESULTS: Increasing the degree of asthma control measured during the first year of enrollment led to statistically significant incremental reductions in risk of acute asthma exacerbations and emergency department visits or hospitalizations during the second year of enrollment. CONCLUSIONS: Achieving and maintaining asthma control in inner-city children with asthma results in significant reductions in asthma-related morbidity. Systematic assessments of asthma control may be useful for predicting future risk in children with asthma.

Improvement of asthma control with omalizumab in 2 obese pediatric asthma patients.

BACKGROUND: Dosing of the anti-IgE antibody (omalizumab) in the treatment of allergic asthma depends on serum IgE concentration and body weight. It is unclear whether omalizumab is therapeutically effective in obese patients with difficult-to-control asthma whose body weights fall outside dosing guidelines. OBJECTIVE: To report the efficacy of omalizumab in 2 obese pediatric patients with severe persistent asthma whose high body weights placed them outside current dosing guidelines. METHODS: Omalizumab was given at maximum doses to both patients. Standard asthma therapy was continued throughout the treatment period. Multiple parameters of asthma disease activity were followed at every health encounter for approximately 1 year during and before omalizumab treatment. These parameters included asthma disease severity and activity, pulmonary functions, daily inhaled corticosteroid requirements, systemic steroid rescue, and urgent care and emergency department visits and hospitalizations. RESULTS: While receiving omalizumab, both patients had improvements in asthma disease activity and reduction in systemic steroid requirements. One patient required fewer daily inhaled corticosteroids and achieved total asthma control. CONCLUSION: Patients with difficult-to-treat asthma may benefit from receiving omalizumab even if they fall outside current dosing guidelines because of high body weight.

Validation of a single survey that can be used for case identification and assessment of asthma control: the Breathmobile Program.

BACKGROUND: Underdiagnosis of asthma and underrecognition of disease severity in lower socioeconomic populations continue to be significant health care concerns despite national efforts to better educate health care providers. OBJECTIVE: To validate a 1-page survey as a point-in-time tool identifying uncontrolled vs controlled asthma and moderate-to-severe disease activity in an urban, lower-socioeconomic pediatric population. METHODS: A previously validated survey (the Breathmobile Case Identification Survey) was evaluated as a point-in-time tool for identifying children with poorly controlled disease. Clinical validation was achieved in children (n = 1,826) presenting to a school-based asthma program for either an initial (n = 666) or a follow-up (n = 1,170) visit. Responses were compared with a comprehensive evaluation by a physician specialist as the gold standard. Response patterns were used to construct multimodel tiered scoring algorithms for baseline and follow-up visits that identify children with uncontrolled asthma, and children are likely to have moderate-to-severe disease activity at that time. RESULTS: Surveys scored using the developed algorithms identified children with uncontrolled asthma (sensitivity: baseline, 77.0%; follow-up, 71.6%; specificity: baseline, 72.7%; follow-up, 71.5%) and detected moderate-to-severe disease activity (sensitivity: baseline, 69.2%; follow-up, 77.4%; specificity: baseline, 70.2%; follow-up, 70.3%). CONCLUSIONS: The Breathmobile Case Identification Survey can be used in lower-socioeconomic, urban populations as a point-in-time tool for identifying children with uncontrolled vs controlled asthma and moderate-to-severe disease activity.

School absenteeism in children with asthma in a Los Angeles inner city school.

OBJECTIVE: To investigate the pattern of school absenteeism in asthmatic children within a Los Angeles inner city school. STUDY DESIGN: Five hundred twenty-eight students of predominant Hispanic ethnicity, from a Los Angeles inner city school were divided into 3 groups: known asthma, high probability of asthma, and low probability of asthma using a previously validated instrument. Attendance records of these students were analyzed to determine total and respiratory absences over a year. School records were compared to the corresponding answers on 513 surveys to determine the accuracy of parental responses in regard to their children's absenteeism. RESULTS: Children with known asthma missed on average 2 more days of school than children with low probability of asthma and high probability of asthma. This was only significant in the younger age groups. Survey responses were found to have a 45.6% agreement with school attendance records. Underestimation occurred more often when school-recorded absentee rates were highest. Overestimation occurred more by parents of children with known asthma or a high probability of asthma. CONCLUSION: In a Los Angeles inner city population, younger children with known asthma miss more days of school than those with no asthma. Survey-reported absenteeism is less accurate than school attendance records.