Managing asthma in adolescents and adults 2020 asthma guideline update From the National Asthma Education and Prevention Program

Asthma is a major public health problem worldwide and is associated with excess morbidity, mortality, and economic costs associated with lost productivity. The National Asthma Education and Prevention Program has released the 2020 Asthma Guideline Update with updated evidence-based recommendations for treatment of patients with asthma. To report updated recommendations for 6 topics for clinical management of adolescents and adults with asthma: (1) intermittent inhaled corticosteroids (ICSs); (2) add-on long-acting muscarinic antagonists; (3) fractional exhaled nitric oxide; (4) indoor allergen mitigation; (5) immunotherapy; and (6) bronchial thermoplasty. The National Heart, Lung, and Blood Advisory Council chose 6 topics to update the 2007 asthma guidelines based on results from a 2014 needs assessment. The Agency for Healthcare Research and Quality conducted systematic reviews of these 6 topics based on literature searches up to March-April 2017. Reviews were updated through October 2018 and used by an expert panel (n = 19) that included asthma content experts, primary care clinicians, dissemination and implementation experts, and health policy experts to develop 19 new recommendations using the GRADE method. The 17 recommendations for individuals aged 12 years or older are reported in this Special Communication. From 20 572 identified references, 475 were included in the 6 systematic reviews to form the evidence basis for these recommendations. Compared with the 2007 guideline, there was no recommended change in step 1 (intermittent asthma) therapy (as-needed short-acting ß2-agonists [SABAs] for rescue therapy). In step 2 (mild persistent asthma), either daily low-dose ICS plus as-needed SABA therapy or as-needed concomitant ICS and SABA therapy are recommended. Formoterol in combination with an ICS in a single inhaler (single maintenance and reliever therapy) is recommended as the preferred therapy for moderate persistent asthma in step 3 (low-dose ICS-formoterol therapy) and step 4 (medium-dose ICS-formoterol therapy) for both daily and as-needed therapy. A short-term increase in the ICS dose alone for worsening of asthma symptoms is not recommended. Add-on long-acting muscarinic antagonists are recommended in individuals whose asthma is not controlled by ICS-formoterol therapy for step 5 (moderate-severe persistent asthma). Fractional exhaled nitric oxide testing is recommended to assist in diagnosis and monitoring of symptoms, but not alone to diagnose or monitor asthma. Allergen mitigation is recommended only in individuals with exposure and relevant sensitivity or symptoms. When used, allergen mitigation should be allergen specific and include multiple allergen-specific mitigation strategies. Subcutaneous immunotherapy is recommended as an adjunct to standard pharmacotherapy for individuals with symptoms and sensitization to specific allergens. Sublingual immunotherapy is not recommended specifically for asthma. Bronchial thermoplasty is not recommended as part of standard care; if used, it should be part of an ongoing research effort. Asthma is a common disease with substantial human and economic costs globally. Although there is no cure or established means of prevention, effective treatment is available. Use of the recommendations in the 2020 Asthma Guideline Update should improve the health of individuals with asthma.

Proteomic analysis of serum and sputum analytes distinguishes controlled and poorly controlled asthmatics.

BACKGROUND: A major goal of asthma therapy is to achieve disease control, with maintenance of lung function, reduced need for rescue medication, and prevention of exacerbation. Despite current standard of care, up to 70% of patients with asthma remain poorly controlled. Analysis of serum and sputum biomarkers could offer insights into parameters associated with poor asthma control. OBJECTIVE: To identify signatures as determinants of asthma disease control, we performed proteomics using Olink proximity extension analysis. METHODS: Up to 3 longitudinal serum samples were collected from 23 controlled and 25 poorly controlled asthmatics. Nine of the controlled and 8 of the poorly controlled subjects also provided 2 longitudinal sputum samples. The study included an additional cohort of 9 subjects whose serum was collected within 48 hours of asthma exacerbation. Two separate pre-defined Proseek Multiplex panels (INF and CVDIII) were run to quantify 181 separate protein analytes in serum and sputum. RESULTS: Panels consisting of 9 markers in serum (CCL19, CCL25, CDCP1, CCL11, FGF21, FGF23, Flt3L, IL-10Rß, IL-6) and 16 markers in sputum (tPA, KLK6, RETN, ADA, MMP9, Chit1, GRN, PGLYRP1, MPO, HGF, PRTN3, DNER, PI3, Chi3L1, AZU1, and OPG) distinguished controlled and poorly controlled asthmatics. The sputum analytes were consistent with a pattern of neutrophil activation associated with poor asthma control. The serum analyte profile of the exacerbation cohort resembled that of the controlled group rather than that of the poorly controlled asthmatics, possibly reflecting a therapeutic response to systemic corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomic profiles in serum and sputum distinguished controlled and poorly controlled asthmatics, and were maintained over time. Findings support a link between sputum neutrophil markers and loss of asthma control.

Effect of obesity on sinonasal disease in asthma.

OBJECTIVE: Sinonasal disease can contribute to poor asthma control. There are reports that link obesity with an increased prevalence of sinonasal disease, but no studies evaluating the severity of sinonasal disease in obese asthmatics, and how this impacts asthma control. The purpose of the current study was to determine if obesity is associated with increased severity of sinonasal disease, and/or affects response to nasal corticosteroid treatment in asthma. METHODS: This study included 236 adults participating in a 24-week randomized, double-masked, placebo-controlled study of nasal mometasone for the treatment of poorly controlled asthma. Sinonasal disease severity was assessed using validated questionnaires, and compared in participants of differing BMIs. Eosinophilic inflammation was assessed using markers in nasal lavage, serum and exhaled nitric oxide. Response to treatment was compared in different BMI groups. RESULTS: Obesity had no effect on the severity of sinonasal disease symptoms in asthmatics (Sino-Nasal Outcome Test 22 (SNOT 22) score [mean ± SD] 35.4 ± 18.5, 40.2 ± 22.8, and 39.1 ± 21.7, p = 0.43, in lean, overweight and obese participants), nor on nasal, bronchial or systemic markers of allergic inflammation. Nasal steroids had some limited effects on symptoms, lung function and inflammatory markers in lean participants, but no detectable effect was found in obese patients. CONCLUSIONS: Obesity does not affect severity of sinonasal disease in patients with asthma; the association of sinonasal disease symptoms with increased asthma severity and markers of Type 2 inflammation are consistent across all BMI groups. The response of obese patients to nasal corticosteroids requires further study.

Obesity and symptoms of depression contribute independently to the poor asthma control of obesity.

UNLABELLED: Obesity is a major risk factor for poorly controlled asthma, but the reasons for poor asthma control in this patient population are unclear. Symptoms of depression have been associated with poor asthma control, and increase with higher body mass index (BMI). The purpose of this study was to assess whether depressive symptoms underlie poor asthma control in obesity. METHODS: We determined the relationship between BMI, psychological morbidity and asthma control at baseline in a well-characterized patient population participating in a clinical trial conducted by the American Lung Association-Asthma Clinical Research Centers. RESULTS: Obese asthmatic participants had increased symptoms of depression (Center for Epidemiologic Studies Depression Scale score in lean 10.1 ± 8.1, overweight 10.0 ± 8.1, obese 12.4 ± 9.9; p = 0.03), worse asthma control (Juniper Asthma Control Questionnaire score in lean 1.43 ± 0.68, overweight 1.52 ± 0.71, obese 1.76 ± 0.75; p < 0.0001), and worse asthma quality of life (scores in lean 5.21 ± 1.08, overweight 5.08 ± 1.05, obese 4.64 ± 1.09; p < 0.0001). Asthmatics with obesity and those with symptoms of depression both had a higher risk of having poorly controlled asthma (adjusted odds ratio of 1.83 CI 1.23-3.52 for obesity, and 2.08 CI 1.23-3.52 for depression), but there was no interaction between the two. CONCLUSION: Obesity and symptoms of depression are independently associated with poor asthma control. As depression is increased in obese asthmatics it may be an important co-morbidity contributing to poor asthma control in this population, but factors other than depression also contribute to poor asthma control in obesity.

The many faces of asthma in obesity.

Obesity is a major risk factor for the development of asthma, and causes severe, uncontrolled disease that responds poorly to therapy. The obese state alters early onset allergic asthma, and leads to the development of a novel form of late onset asthma secondary to obesity. The presentation of early onset allergic asthma is altered through effects on immune function. Factors such as mechanical loading, effects of adipokines on airways, altered diet, insulin resistance and altered metabolism of nitric oxide likely all contribute to increased airway reactivity in obesity, causing late onset asthma in obesity. Obesity also alters responses to environmental factors such as ozone and particulate matter. Focused studies to understand the importance of these factors in the pathogenesis of airway disease in obesity will be essential to develop therapies to intervene in this new epidemic of airway disease.

Adherence of adoptively transferred alloreactive Th1 cells in lung: partial dependence on LFA-1 and ICAM-1.

T helper type 1 (Th1) cells are important effectors in a number of immune-mediated lung diseases. We recently described a murine model of lung injury induced by adoptive transfer of cloned alloreactive Th1 cells. To investigate mechanisms that result in injury to the lung, we studied the in vivo distribution of (51)Cr-labeled Th1 cells. One hour after intravenous administration, >85% of injected radioactivity was left in the lung, and at 24 h, 40% of radioactivity was left in the lung. Adherence of Th1 cells in the lung was significantly inhibited by neutralizing antibody to lymphocyte function-associated antigen-1. Th1 cell adherence also was decreased in lungs of mice deficient in intercellular adhesion molecule-1 (ICAM-1). Th1 cell transfer further induced expression of ICAM-1 and vascular cell adhesion molecule-1 in the lung. Vascular cell adhesion molecule-1-immunoreactive protein was markedly induced in lung endothelium by alloreactive Th1 cells. These findings indicate that Th1 cells localize in normal lung by a mechanism involving lymphocyte function-associated antigen-1 and ICAM-1. Alloreactive cells further induce endothelial adhesion molecules that may facilitate recruitment of inflammatory cells to the lung and amplify Th1 cell-induced lung injury.

Chemokine expression in Th1 cell-induced lung injury: prominence of IFN-gamma-inducible chemokines.

Proinflammatory responses generated by T helper type 1 (Th1) cells may contribute significantly to immune-mediated lung injury. We describe a murine model of Th1 cell-induced lung injury in which adoptive transfer of alloreactive Th1 cells produces pulmonary inflammation characterized by mononuclear cell vasculitis, alveolitis, and interstitial pneumonitis. To investigate the link between activation of Th1 cells in the lung and inflammatory cell recruitment, we characterized cytokine and chemokine mRNA expression in Th1 cells activated in vitro and in lung tissue after adoptive transfer of Th1 cells. Activated Th1 cells per se express mRNA for interferon (IFN)-gamma and several members of the tumor necrosis factor family as well as the C-C chemokine receptor-5 ligands regulated on activation normal T cells expressed and secreted and macrophage inflammatory protein-1alpha and -1beta. Additional chemokine genes were induced in the lung after Th1 cell administration, most notably IFN-gamma-inducible protein (IP-10) and monokine induced by IFN-gamma (MIG). Remarkable increases in IP-10- and MIG-immunoreactive proteins were present in inflammatory foci lung and identified in macrophages, endothelium, bronchial epithelium, and alveolar structures. The findings suggest that IFN-gamma-inducible chemokines are an important mechanism for amplifying inflammation initiated by Th1 cells in the lung.

Neutralization of tumor necrosis factor-alpha action delays but does not prevent lung injury induced by alloreactive T helper 1 cells.

BACKGROUND: Lung injury occurs frequently after allogeneic bone marrow transplantation in association with graft-versus-host disease, an immune response that involves both cellular and cytokine components. In a murine model, we recently showed that cloned alloreactive T helper (Th)1 cells can cause lung injury associated with increased production of tumor necrosis factor (TNF)-alpha by alveolar macrophages (J Immunol 1998; 161: 1913). METHODS: To evaluate the role of TNF-alpha in this model, we injected in vitro-activated Th1 cells into the following: (1) recipients deficient in receptors for TNF; (2) C57BL/6 control mice; (3) C57BL/6 mice, pretreated with soluble TNFRIIFc (a dimorphic high-affinity TNF antagonist); (4) mice expressing TNFRIIFc transgene under control of the surfactant apoprotein C promoter (SPCTNFRIIFc); and (5) wild-type littermate controls (C57BL/6) (n=3-6 mice/group). RESULTS: At 1 and 3 days after i.v. Th1 cell transfer, recipients were killed for analysis of lung histology, bronchoalveolar lavage (BAL) protein, and BAL cell counts. Control mice (wild type) at day 1 after injection had a mild to moderate mononuclear perivasculitis and increased interstitial cellularity. At day 3, lesions were more severe and perivasculitis also involved larger veins. TNFR-deficient mice had normal lung or minimal lung inflammation at day 1. At day 3, perivasculitis of medium-sized vessels was present, but there was no apparent involvement of larger veins. Results in mice treated with soluble TNFRIIFc and transgenic mice (SPCsTNFRIIFc) were similar to controls. BAL protein and BAL cell counts did not differ between any of the experimental groups. CONCLUSIONS: We conclude that lung inflammation induced by Th1 cells may be only delayed when TNF-alpha action is blocked. The persistence of abnormalities indicates that other proinflammatory pathways are involved in injury caused by these cells.

A scanning beam time-resolved imaging system for fingerprint detection.

A highly sensitive confocal scanning-beam system for time-resolved imaging of fingerprints is described. Time-resolved imaging is a relatively new forensic procedure for the detection and imaging of latent fingerprints on fluorescent substrates such as paper, cardboard, and fluorescent paint. Ordinary fluorescent imaging of latent fingerprints on these surfaces results in poor contrast. Instead, the specimens are treated with a phosphorescent dye that preferentially adheres to the fingerprint which allows time-resolved discrimination between the fingerprint phosphorescence and the background fluorescence. Time resolved images are obtained by synchronizing the digital sampling of the specimen luminescence with the on-off cycle of the chopped illumination beam. The merit of this technique is illustrated with high contrast images of fingerprints obtained from the fluorescent painted surface of a Coke can.

Marital status, marital satisfaction, and body image dissatisfaction.

OBJECTIVE: This study examined whether married individuals have comparable body image disturbance to nonmarried individuals and whether the quality of a marital relationship is significantly related to body image disturbance in a sample of dieters. METHOD: Measures of marital status, marital satisfaction, and body dissatisfaction were administered to a sample of 16,377 subjects who had tried to lose weight at least once within the previous 3 years. RESULTS: Marital status was not associated with increased body dissatisfaction. Marital satisfaction was significantly related to body dissatisfaction when controlling for age, body mass index, self-esteem, and gender. DISCUSSION: Body dissatisfaction occurs at comparable levels among married and single individuals and the study of marital functioning among eating-disordered individuals represents a large gap in the literature.

Imaging electrophoretic gels with a scanning beam laser macroscope.

A scanning beam laser macroscope has been developed which scans an area of 7.5 x 7.5 cm in 5 s. This new imaging system is examined as a potential tool for scanning electrophoretic gels. A specially-designed telecentric, f* theta laser scan lens is used in the instrument to achieve a linear scan and a flat focal plane. The laser scan lens focuses the incoming beam from a laser to a 10 microns spot inside the gel. A raster scan is performed across the gel and the signal is detected with a photomultiplier, forming a 512 x 512 digital image stored as a computer file. Silver-stained protein polyacrylamide gels have been imaged in transmission and double-transmission, while DNA agarose gels (stained with ethidium bromide) have been imaged in fluorescence with better than 25 pg sensitivity. The macroscope has the advantage that it is not tied to the electrophoresis system as are end-of-line scanners, and the scan is rapid, so that several gels can be scanned in a very short time.

Clinical improvement following dermabrasion of photoaged skin correlates with synthesis of collagen I.

BACKGROUND AND DESIGN: The ability of superficial dermabrasion to improve clinical features of photoaged skin is well known, but the specific biological mechanisms involved are poorly understood. The so-called repair zone, as visualized by routine histologic examination, has been attributed to new collagen formation within the papillary dermis and may be responsible for clinical improvement following dermabrasion. We investigated molecular and histologic events occurring in dermabraded skin and correlated them with clinical improvement. Ten photoaged patients (mean age, 59 years) underwent facial dermabrasion to the level of the papillary dermis. Clinical severity of photoaging was graded in a blinded manner at baseline and 12 weeks after dermabrasion. Biopsy specimens obtained at baseline and 3 and 12 weeks after dermabrasion were analyzed histologically and by in situ hybridization for fibroblast procollagen I mRNA, immunohistologically and by Western blotting with a monoclonal antibody specific for the aminoterminal cleavage site of procollagen I. RESULTS: Masson's trichrome staining demonstrated an increase in collagen from baseline (as an upper dermal band in the dermabrasion "repair zone") at 3 and 12 weeks' postdermabrasion. Immunohistologic examination demonstrated papillary dermal fibroblast staining for procollagen I at baseline that increased by threefold at 3 weeks' postdermabrasion and by 1.5-fold at 12 weeks' postdermabrasion. Western blotting demonstrated an average-fold increase in pN collagen I of 4.2 +/- 1.5 at 3 weeks and of 2.7 +/- 0.7 at 12 weeks. By in situ hybridization, baseline levels of procollagen I mRNA in papillary dermal fibroblasts increased sixfold at weeks 3 and 12 postdermabrasion. Increase in procollagen I mRNA correlated with clinical improvement, ie, reduction in wrinkling. CONCLUSION: Superficial dermabrasion clinically improves photoaged skin, and this improvement correlates strongly with increased collagen I gene expression.

Single-pinhole confocal differential phase contrast microscopy.

A new technique for obtaining confocal differential phase contrast is outlined. It is shown that this method involving a single pinhole and a split detector is easier to align and calibrate than the standard method of two pinholes and two detectors. Experimental calibration curves, which show that this arrangement does perform differential phase contrast imaging and that it can be used to measure surface height variations of the order of λ/600 per micrometer, are presented. Confocal scanning-beam reflection and transmission differential phase contrast images are presented.

Surface-profile reconstruction using reflection differential phase-contrast microscopy.

The use of optical differential phase-contrast microscopy to obtain the surface profile of samples is outlined. The range of accurate feature height determination was calculated as a function of steepness of the side of the feature. Heights of thin features (height <0.1 microm) were accurately determined experimentally. Sample tilting and oblique stage scanning were required in order to determine the heights of thicker samples. Reconstructed profile heights were measured as a function of defocus.

Physiological adaptation to the environment.

The ability of an animal to cope with new environments arises from its capacity to respond to environmental variables and maintain body equilibrium (homeostasis). Each compensating mechanism depends on, and is a part of, a physiological feedback process. The severity (intensity and duration) of an environmental change relative to the animal's capacity to respond determines the potential disruption to the animal's equilibrium and the resources that must be invested to regain homeostasis. However, an environmental change sufficient to seriously challenge one individual may be insufficient to produce a measurable response in another. The principles behind the responses occurring in animals as a consequence of a change in their physical environment are illustrated in this review by examples drawn from responses of animals to cold stress. Behavioral opportunities sometimes are constrained in farm animals, and internal metabolic responses tend to become more prominent in such situations. Furthermore, as a disturbing factor persists, the immediate defensive responses are replaced by longer-term and adaptive mechanisms that reduce the burden on the animal. As we gain greater understanding of the environment-animal interface and the sensitivity and response of animals to disruption, we will be better able to establish and maintain suitable environments for our farm animals.

Multiple symmetrical lipomatosis in a patient with Hürthle cell carcinoma of the thyroid: a case report.

Multiple symmetrical lipomatosis is a rare disorder of fat distribution which generally affects middle age men of Mediterranean origin. Hürthle cell carcinoma is an uncommon variety of follicular carcinoma which invades locally and metastasizes hematogenously to bone, lung, and other distant organs. This report describes a patient who developed multiple symmetrical lipomatosis after undergoing total thyroidectomy for Hürthle cell carcinoma of the thyroid. Type IV hyperlipidemia, hyperuricemia, frequent ethanol usage, and macrocytosis were features previously associated with multiple symmetrical lipomatosis which were present in this patient. Fourteen years after the initial surgery, metastatic Hürthle cell carcinoma was detected in the superior mediastinum. The location of the metastasis and the long disease free interval are unusual features of this case. A possible association between Hürthle cell carcinoma and multiple symmetrical lipomatosis is considered.