U.S National Institutes of Health stands with Asthma patients, families, advocates, researchers, and health care professionals

Today on @WorldAsthmaDay, the U.S National Institutes of Health stands with patients, families, advocates, researchers, and health care professionals to raise awareness about this common chronic respiratory disease, the people it affects, and the biomedical research that improves its prevention and treatment.

Asthma is a chronic lung disease that causes periods of wheezing, chest tightness, shortness of breath, and coughing. It is a major contributing factor to missed time from school and work, with severe attacks requiring emergency room visits and hospitalizations. Sometimes these asthma attacks can be fatal.

This year, we recognize that the coronavirus disease 2019 (COVID-19) pandemic is creating concern and uncertainty for many people around the globe, including those with asthma. The disease can affect the nose, throat, and lungs, cause an asthma attack, and possibly lead to pneumonia and acute respiratory disease. According to the Centers for Disease Control and Prevention(link is external), people with asthma should continue their current asthma medications and discuss any concerns with their healthcare provider. Researchers at NIH and elsewhere are working to learn more about COVID-19 and to develop specific treatments and vaccines.

Three NIH institutes support and conduct studies on asthma — the National Institute of Environmental Health Sciences (NIEHS); the National Heart, Lung, and Blood Institute (NHLBI); and the National Institute of Allergy and Infectious Diseases (NIAID). Institute scientists and grantees made several important advances in understanding, treating, and managing asthma in 2019. These findings and other highlights are featured in five topic areas below:

Relationship between asthma and COVID-19
Populations at risk of developing asthma
Potential new treatments
Genes involved in asthma
Asthma management

Relationship between asthma and COVID-19

NIAID is initiating a home-based study to assess the incidence of infection with SARS-CoV-2, the virus that causes COVID-19, in children and their caregivers and siblings. A key objective of this observational study will be to determine if infection rates or immune responses to SARS-CoV-2 infection differ in children who have asthma or other allergic conditions compared to those who have not been diagnosed with or treated for these conditions.

NIAID also is starting an observational study in patients hospitalized for COVID-19 to understand if specific characteristics of the immune response influence or reflect the severity of infection. This study may help determine whether underlying diseases, such as asthma, influence the body’s response to SARS-CoV-2 infection.
Populations at risk of developing asthma

Children

NIH scientists are making progress in understanding the underlying factors that contribute to the development of asthma in U.S. children. This year, an international collaboration led by NIEHS scientists reported that the presence of newly discovered novel epigenetic markers — or chemical tags that attach to DNA — may indicate a newborn’s risk of developing asthma. The data were generated by the Pregnancy and Childhood Epigenetics Consortium and may help researchers find asthma biomarkers, or molecular indicators of asthma, and identify at birth which children will eventually develop the condition.

At NHLBI, researchers discovered a link(link is external) between childhood asthma flare ups and changes in the lung microbiome, the communities of bacteria and other microorganisms that are normally present in the lung and usually do not cause symptoms. The scientists determined that children with mild to moderate asthma who experienced early signs of an upcoming asthma flare up tended to have higher levels of certain types of disease-causing bacteria in their lungs. The study could lead to a precision medicine approach for treating mild to moderate childhood asthma by altering the number and types of bacteria in a child’s airways.

Ongoing NIAID-funded clinical studies focus on interventions to prevent asthma development in children at high risk of developing the condition. One team of researchers studied a large group of children who were hospitalized as infants with bronchiolitis, a common early-life lung infection usually caused by a virus. The scientists found that recurrent wheezing by age 3 is at least three times more likely to occur in children whose bronchiolitis was associated with a rhinovirus C infection and who also had early signs of allergy to foods or inhaled allergens.

African Americans and people of African ancestry

Another group that bears a disproportionate burden of asthma is African Americans. In an NHLBI-funded study that is the largest genome-wide association study of asthma in African ancestry populations to date, researchers identified two novel regions on a specific chromosome that may be linked to asthma risk. The scientists theorize that a better understanding of the genetic risk factors for asthma in African ancestry populations will lead to development of better therapeutic interventions.
Potential new treatments

Using a mouse model of asthma, NIEHS researchers reported a possible treatment for neutrophilic asthma, a particularly severe form that responds poorly to the standard asthma therapy of corticosteroids. The orally available drug VTP-938 made it easier for the mice to breathe after they were exposed to house dust extracts. The results suggest that VTP-938 may be an innovative treatment for humans with this steroid-resistant form of asthma.
Genes involved in asthma

An NIAID-funded study sought to understand why some, but not all, colds lead to asthma attacks among children with asthma. The scientists obtained nasal washings from 106 children with severe asthma who experienced cold symptoms. Members of the research team compared samples from those who required corticosteroids after a cold-induced asthma attack and those who did not have an asthma attack following a cold. The research team found that colds that led to an asthma attack caused changes in the production of six families of genes that are associated with maintaining the function of the outermost layer of tissue lining the respiratory tract and with the responses of immune cells in close contact with this layer.

Variations in two genes — the aryl hydrocarbon receptor nuclear translocator (ARNT) and the protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) — are associated with immune-mediated diseases, such as asthma, in several ethnicities, according to NIEHS researchers and their collaborators. Because ARNT and PTPN22 are sensitive to environmental factors, this study is the first to demonstrate across ethnicities the combined role of these genes and environmental changes in the development of immune-related conditions like asthma.
Asthma management

NHLBI’s National Asthma Education Prevention Program is coordinating the 2020 focused updates to the 2007 Asthma Management Guidelines. These guidelines are designed to improve the care of people living with asthma as well as help primary care providers and specialists make decisions about asthma management. NHLBI released the updated focus areas of the guidelines for public comment, and the final recommendations for these areas are expected to be published later this year. They will address several priority topic areas listed below:

Using inhaled medications when needed
A new type of inhaled medication called long acting muscarinic antagonists
Treating allergies by exposure to low doses of allergens by mouth or with shots
Reducing indoor asthma triggers
A new procedure for asthma known as bronchial thermoplasty
A fractional exhaled nitric oxide test that may be helpful in diagnosing or managing asthma

Experts hope that these guidelines will help reduce the burden of asthma nationwide and improve the quality of life for those living with the condition.

Patient, Physician, and Health-System Factors Influencing the Quality of Antidepressant and Sedative Prescribing for Older, Community-Dwelling Adults.

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Patient, Physician, and Health-System Factors Influencing the Quality of Antidepressant and Sedative Prescribing for Older, Community-Dwelling Adults.

Health Serv Res. 2016 Dec 26;:

Authors: Extavour RM, Perri M

Abstract
OBJECTIVE: To identify determinants of potentially inappropriate (PI) antidepressant and anxiolytic/sedative prescribing for older, community-dwelling adults.
DATA SOURCES/STUDY SETTING: Office visits from the 2010 National Ambulatory Medical Care Survey.
STUDY DESIGN: A cross-sectional study measuring associations between various patient and physician factors and prescribing of PI antidepressants, and PI sedatives among elderly, using Beers 2012/2015 criteria, a clinical decision model, and multivariate logistic regressions.
DATA COLLECTION: Visits by older adults (?65 years) involving medications were extracted to identify visits with antidepressants and sedatives.
PRINCIPAL FINDINGS: Black race, asthma, depression, osteoporosis, payment type, consultation time, and computer systems with prescribing support were associated with reduced odds of PI antidepressant prescribing among users. Income, chronic renal failure, diabetes, and obesity were associated with reduced odds of PI sedative prescribing. Female sex, white race, depression, increasing number of medications, and physician specialty were associated with increased odds of PI sedative prescribing.
CONCLUSIONS: Various patient and health-system factors influence the quality of antidepressant and sedative prescribing for older community-dwelling adults. Longer consultations and the use of computer systems with prescribing support may minimize potentially inappropriate antidepressant prescribing. As medication numbers increase, exposure to PI sedatives is more likely, requiring medication review and monitoring.

PMID: 28024315 [PubMed – as supplied by publisher]

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Ponciretin attenuates ethanol-induced gastric damage in mice by inhibiting inflammatory responses.

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Ponciretin attenuates ethanol-induced gastric damage in mice by inhibiting inflammatory responses.

Int Immunopharmacol. 2016 Dec 22;43:179-186

Authors: Kang GD, Kim DH

Abstract
BACKGROUND: Poncirin (PO) and isosakuranetin (or ponciretin [PT]) are compounds found in fruits of the genus Citrus. They are frequently used in traditional Chinese medicine for the treatment of inflammation and asthma. Therefore, we examined their anti-gastritis effects in vitro and in vivo.
METHODS: The anti-inflammatory effects of PO and PT were examined using ethanol- or LPS-stimulated KATO III cells. Gastritis was induced in ICR mice via intragastric injection of absolute ethanol. Levels of inflammatory markers were measured by enzyme-linked immunosorbent assay, immunoblotting, and quantitative polymerase chain reaction.
RESULTS: Treatment with PT or PO inhibited the secretion of interleukin (IL)-8 and tumor necrosis factor (TNF) in ethanol- or LPS-stimulated KATO III cells. They also reduced the activation of nuclear factor kappa B (NF-?B). Pre-treatment with PT or PO significantly protected against ethanol-induced hemorrhagic gastritis, characterized by edema, tissue erosions, and mucosal friability in mice. Treatment with PT or PO suppressed ethanol-induced NF-?B activation and the release of TNF, IL-8, and IFN-?. The protective effect of PT was greater than that of PO and comparable to ranitidine, a positive control.
CONCLUSION: PT may attenuate ethanol-induced gastritis by inhibiting the infiltration of immune cells, including neutrophils, via the regulation of CXCL4 (or IL-8) secretion and the activation NF-?B.

PMID: 28013186 [PubMed – as supplied by publisher]

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Ventilation/perfusion ratio and right to left shunt in healthy newborn infants.

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Ventilation/perfusion ratio and right to left shunt in healthy newborn infants.

J Clin Monit Comput. 2016 Dec 23;:

Authors: Dassios T, Ali K, Rossor T, Greenough A

Abstract
Oxygenation impairment can be assessed non-invasively by determining the degree of right-to-left shunt and ventilation/perfusion (VA/Q) inequality. These indices have been used in sick newborn infants, but normative values have not been reported which are essential to determine the magnitude of the abnormality. We, therefore, aimed to measure the shunt and VA/Q in infants with no history of respiratory conditions and determine if there was any effect of supine or prone position and the reproducibility of the data. Data were analysed from infants who had undergone a hypoxic challenge and in a subset who had been assessed in the supine or prone position. Transcutaneous oxygen saturations (SpO2) were recorded at fractions of inspired oxygen (FIO2) of 0.21 and 0.15. Two independent raters used a computer software algorithm which analysed and fitted paired data for FIO2 and SpO2 and derived a curve which represented the best fit for each infant’s data and calculated the shunt and VA/Q. The raters ability to interpret the SpO2 value which corresponded to a given FIO2 was compared. The downwards displacement of the FIO2 versus SpO2 curve was used to estimate the degree of right-to-left shunt and the rightwards shift of the curve was used to calculate the VA/Q ratio. The mean (SD) gestational age of the 145 infants was 39 (1.6) weeks, their birth weight was 2990 (578) gms and median (range) postnatal age at measurement 3 (1-8) days. The mean (SD) VA/Q ratio was 0.95 (0.21). None of the infants had a right-to-left shunt. No significant differences were found in VA/Q in the supine compared to the prone position. The intraclass correlation coefficient of VA/Q between two independent raters was 0.968 (95% CI 0.947-0.980), p?<?0.001. Right-to-left shunt and VA/Q ratio in healthy newborn infants were similar in the prone compared to the supine position.

PMID: 28012013 [PubMed – as supplied by publisher]

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Allergic Sensitization at School Age is a Systemic Low-grade Inflammatory Disorder.

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Allergic Sensitization at School Age is a Systemic Low-grade Inflammatory Disorder.

Allergy. 2016 Dec 19;:

Authors: Chawes BL, Stokholm J, Schoos AM, Rahman N, Brix S, Bisgaard H

Abstract
BACKGROUND: Systemic low-grade inflammation has been demonstrated in a range of the frequent noncommunicable diseases (NCDs) proposing a shared mechanism, but is largely unexplored in relation to allergic sensitization. We therefore aimed to investigate the possible association with childhood allergic sensitization.
METHODS: High sensitivity C-reactive protein (hs-CRP), interleukin-1? (IL-1?), IL-6, tumor necrosis factor-? (TNF-?) and chemokine (C-X-C motif) ligand 8 (CXCL8) were measured in plasma at age 6mo (N=214) and 7yrs (N=277) in children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) birth cohort. Allergic sensitization against common inhalant and food allergens was determined longitudinally at age ½, 1½, 4 and 6yrs by specific-IgE assessments and skin prick tests. Associations between inflammatory biomarkers and sensitization phenotypes were tested with logistic regression and principle component analyses (PCA).
RESULTS: Adjusted for gender, recent infections and a CRP genetic risk-score, hs-CRP at 7yrs was associated with concurrent elevated specific-IgE against any allergen (adjusted OR (aOR) =1.40; 95% CI, 1.14-1.72; p=0.001), aeroallergens (aOR, 1.43; 1.15-1.77; p=0.001), food allergens (aOR, 1.31; 95% CI, 1.02-1.67; p=0.04), sensitization without any clinical allergy symptoms (aOR=1.40; 1.06-1.85; p=0.02), and with similar findings for skin prick tests. The other inflammatory markers were not univariantly associated with sensitization, but multi-parametric PCA suggested a specific inflammatory response among sensitized children. Inflammatory markers at age 6mo were not associated with subsequent development of sensitization phenotypes.
CONCLUSIONS: Elevated hs-CRP is associated with allergic sensitization in school-aged children suggesting systemic low-grade inflammation as a phenotypic characteristic of this early onset NCD. This article is protected by copyright. All rights reserved.

PMID: 27992959 [PubMed – as supplied by publisher]

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Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

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Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

Front Pharmacol. 2016;7:299

Authors: Thompson MD, Capra V, Clunes MT, Rovati GE, Stankova J, Maj MC, Duffy DL

Abstract
Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the ALOX5 gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the LTC4S gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the CYSLTR2 gene, encoding the Met201Val CYSLTR2 receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ?2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. In vitro work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca(2+) flux and inositol phosphate generation. In addition, the CYSLTR1 gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.

PMID: 27990118 [PubMed – in process]

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[Patient-related independent clinical risk factors for early complications following interventional pulmonology procedures].

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[Patient-related independent clinical risk factors for early complications following interventional pulmonology procedures].

Beijing Da Xue Xue Bao. 2016 Dec 18;48(6):1006-1011

Authors: Huang JJ, Zhang H, Zhang W, Wang X, Gong YH, Wang GF

Abstract
OBJECTIVE: To investigate the early complication rate and identify patient-related independent clinical risk factors for early complications in patients following interventional pulmonology procedures.
METHODS: In the period from December 2014 to December 2015, sufficient data of Peking University First Hospital Respiratory and Critical Care Medicine Department for analysis were identified in 218 subjects. Interventional pulmonology procedures were performed in all the patients. Early complications after the procedures were defined as newly respiratory failure, arrhythmia requiring treatment, severe hemoptysis, pneumothorax, pneumomediastinum, pulmonary edema, tracheoesophageal fistulae, bronchopleural fistulae, acute coronary syndrome, acute cerebrovascular accident, and death. Patient-related clinical risk factors were defined as coronary atherosclerotic heart disease, cerebral infarction, diabetes mellitus, cirrhosis, chronic kidney disease, arrhythmia, asthma, chronic obstructive pulmonary disease, hypertension, and previous interventional pulmonology treatment. The patient-related independent clinical risk factors which had close relations to the occurrence of early complications were analyzed by multivariate statistical analysis with Logistic regression.
RESULTS: There were 56.4% male and 43.6% female subjects in this study. There were 10.6% current smokers, 26.6% former smokers, and 62.8% non-smokers. The overall early complication rate was 8.3%. In all the subjects groups, the patient-related independent clinical risk factors for the early complication rate were coronary atherosclerotic heart disease (B=1.545, P=0.006, OR=4.686, 95% CI 1.568-14.006), chronic obstructive pulmonary disease (B=1.037, P=0.049, OR=2.820, 95% CI 1.675-11.790), and current smoking status (B=1.412, P=0.032, OR=4.139, 95% CI 1.134-15.109); for the newly respiratory failure rates were coronary atherosclerotic heart disease (B=2.207, P=0.004, OR=9.087, 95% CI 2.028-40.714), chronic obstructive pulmonary disease (B=1.646, P=0.048, OR=5.188, 95% CI 1.783-34.375), and lesions involving three central airways (B=1.899, P=0.032, OR=6.680, 95% CI 1.182-37.740). In the malignant group, the patient-related independent clinical risk factor for the early complication rate was current smoking status (B=2.953, P=0.006, OR=19.161, 95% CI 2.360-155.572). In the benign group, the patient-related independent clinical risk factor for the early complication rate was only coronary atherosclerotic heart disease (B=1.976, P=0.022, OR=7.214, 95% CI 1.324-39.298).
CONCLUSION: Closer monitoring of patients with identified clinical risk factors is advisable prior and immediately after interventional pulmonology procedures. In order to avoid or minimize early complications, special attention should be directed toward patients who are current smokers, or patients with lesions involving three central airways, or with coronary atherosclerotic heart disease or chronic obstructive pulmonary disease.

PMID: 27987505 [PubMed – in process]

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Optimization of substituted imidazobenzodiazepines as novel asthma treatments.

Optimization of substituted imidazobenzodiazepines as novel asthma treatments.

Eur J Med Chem. 2016 Nov 24;126:550-560

Authors: Jahan R, Stephen MR, Forkuo GS, Kodali R, Guthrie ML, Nieman AN, Yuan NY, Zahn NM, Poe MM, Li G, Yu OB, Yocum GT, Emala CW, Stafford DC, Cook JM, Arnold LA

Abstract
We describe the synthesis of analogs of XHE-III-74, a selective ?4?3?2 GABAAR ligand, shown to relax airway smooth muscle ex vivo and reduce airway hyperresponsiveness in a murine asthma model. To improve properties of this compound as an asthma therapeutic, a series of analogs with a deuterated methoxy group in place of methoxy group at C-8 position was evaluated for isotope effects in preclinical assays; including microsomal stability, cytotoxicity, and sensorimotor impairment. The deuterated compounds were equally or more metabolically stable than the corresponding non-deuterated analogs and increased sensorimotor impairment was observed for some deuterated compounds. Thioesters were more cytotoxic in comparison to other carboxylic acid derivatives of this compound series. The most promising compound 16 identified from the in vitro screens also strongly inhibited smooth muscle constriction in ex vivo guinea pig tracheal rings. Smooth muscle relaxation, determined by reduction of airway hyperresponsiveness with a murine ovalbumin sensitized and challenged model, showed that 16 was efficacious at low methacholine concentrations. However, this effect was limited due to suboptimal pharmacokinetics of 16. Based on these findings, further analogs of XHE-III-74 will be investigated to improve in vivo metabolic stability while retaining the efficacy at lung tissues involved in asthma pathology.

PMID: 27915170 [PubMed – as supplied by publisher]

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Association of interleukin-18 and asthma.

Association of interleukin-18 and asthma.

Inflammation. 2016 Dec 02;

Authors: Xu MH, Yuan FL, Wang SJ, Xu HY, Li CW, Tong X

Abstract
Cytokine-mediated immunity plays a dominant role in the pathogenesis of various immune diseases, including asthma. The recent identification of the family interleukin (IL)-1-related cytokine IL-18 now contributes to our understanding of the fine-tuning of cellular immunity. IL-18 can act as a cofactor for Th2 cell development and IgE production and also plays an important role in the differentiation of Th1 cells. Recent work identified an IL-18 association with the pathogenesis of asthma, wherein increased IL-18 expression was found in the serum of patients. Furthermore, IL-18 polymorphisms with susceptibility to asthma were reported, suggesting that IL-18 may be therapeutically relevant to asthma. In this review, we discuss the role of IL-18 in the pathogenesis of asthma and its therapeutic potential based on current research.

PMID: 27913952 [PubMed – as supplied by publisher]

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