Advances and Challenges of Antibody Therapeutics for Severe Bronchial Asthma

Asthma is a disease that consists of three main components: airway inflammation, airway hyperresponsiveness, and airway remodeling. Persistent airway inflammation leads to the destruction and degeneration of normal airway tissues, resulting in thickening of the airway wall, decreased reversibility, and increased airway hyperresponsiveness. The progression of irreversible airway narrowing and the associated increase in airway hyperresponsiveness are major factors in severe asthma. This has led to the identification of effective pharmacological targets and the recognition of several biomarkers that enable a more personalized approach to asthma. However, the efficacies of current antibody therapeutics and biomarkers are still unsatisfactory in clinical practice. The establishment of an ideal phenotype classification that will predict the response of antibody treatment is urgently needed. Here, we review recent advancements in antibody therapeutics and novel findings related to the disease process for severe asthma.

Vascular Endothelial Growth Factor as a Putative Biomarker of Depression in Asthmatics with Reversible Airway Narrowing

The vascular endothelial growth factor (VEGF) plays a pivotal role in process of angiogenesis in adults. If angiogenesis is not properly controlled, its deregulation may implicate it in various psychosomatic diseases states. The aim of our study was to reveal possible correlation between severity of depression in asthmatics with different degrees of airway narrowing and serum vascular endothelial growth factor levels. The study population included a total of 122 adult subjects: 82 patients with asthma (among them 42 patients with irreversible bronchoconstriction and 40 patients with reversible bronchoconstriction) and 40 healthy participants as a control group. The standardized Beck Depression Inventory (BDI) was used to estimate the depression symptoms. Enzyme-linked immunosorbent assay (ELISA) was used to assess the VEGF serum concentration in all participants. There was a significant difference in depression symptoms in asthmatics with reversible (p = 0.0432) and irreversible airway obstruction (p = 0.00005) in comparison to control group and between these two subgroups of asthmatics (p = 0.0233). Obtained results revealed significant correlation between level of depression and mean VEGF serum concentration in asthmatics with reversible airway obstruction (p = 0.0202). There was no difference between enhanced depression symptoms and VEGF serum concentration in patients with irreversible airway obstruction nor in the total group of asthmatics (in both p > 0.05). The relationship between asthma severity and depression symptoms seems to be certain. VEGF might be considered as a putative biomarker of depression in asthmatics, mainly those with reversible airway narrowing.

Much Ado about Sleep: Current Concepts on Mechanisms and Predisposition to Pediatric Obstructive Sleep Apnea

Obstructive Sleep Apnea (OSA) is a form of sleep-disordered breathing characterized by upper airway collapse during sleep resulting in recurring arousals and desaturations. However, many aspects of this syndrome in children remain unclear. Understanding underlying pathogenic mechanisms of OSA is critical for the development of therapeutic strategies. In this article, we review current concepts surrounding the mechanism, pathogenesis, and predisposing factors of pediatric OSA. Specifically, we discuss the biomechanical properties of the upper airway that contribute to its primary role in OSA pathogenesis and examine the anatomical and neuromuscular factors that predispose to upper airway narrowing and collapsibility.

Positive Expiratory Pressure: A Potential Therapy to Mitigate Acute Bronchoconstriction in the Asthma of Obesity

Late-onset non-allergic (LONA) asthma in obesity is characterized by increased peripheral airway closure secondary to abnormally collapsible airways. We hypothesized that positive expiratory pressure (PEP) would mitigate the tendency to airway closure during bronchoconstriction, potentially serving as rescue therapy for LONA asthma of obesity. The PC20 dose of methacholine was determined in 18 obese participants with LONA asthma. At each of 4 subsequent visits, we used oscillometry to measure input respiratory impedance (Zrs) over 8 minutes; participants received their PC20 concentration of methacholine aerosol during the first 4.5 minutes. PEP combinations of either 0 or 10 cmH2O either during and/or after the methacholine delivery were applied, randomized between visits. Parameters characterizing respiratory system mechanics were extracted from the Zrs spectra. In 18 LONA asthma patients (14 females, BMI: 39.6±3.4 kg/m2), 10 cmH2O PEP during methacholine reduced elevations in the central airway resistance, peripheral airway resistance and elastance, and breathing frequency was also reduced. During the 3.5 min following methacholine delivery, PEP of 10 cmH2O reduced Ax and peripheral elastance compared to no PEP. PEP mitigates the onset of airway narrowing brought on by methacholine challenge, and airway closure once it is established. PEP thus might serve as a non-pharmacologic therapy to manage acute airway narrowing for obese LONA asthma.

Asthma as a Developmental Disorder

Asthma is the most common disorder in childhood, affecting six million children in the United States. Asthma is a heterogeneous disease, but most cases either start in early life or have their roots in events occurring in utero or during the preschool years. Protective or harmful exposures, including to environmental microbes, occurring during critical developmental windows determine patterns of immune responses that often persist for a lifetime. Air pollution, tobacco smoke, and prematurity can cause congenital airway narrowing, and newborns with decreased airway function are at risk for having asthma symptoms up to adulthood. Effects of environmental exposures are modified by common genetic variations and may also be mediated by prenatal changes in the epigenetic structure of the genome. Based on this evidence, we have postulated that asthma should be considered a developmental disorder, and this concept may be applicable to other chronic medical conditions affecting both children and adults. Expected final online publication date for the Annual Review of Developmental Psychology, Volume 3 is December 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Airway Abnormalities in Adult Mucopolysaccharidosis and Development of Salford Mucopolysaccharidosis Airway Score

(1) Background: Mucopolysaccharidoses (MPS) are a heterogeneous group of lysosomal storage disorders caused by the absence of enzymes required for degradation of glycosaminoglycans (GAGs). GAGs deposition in tissues leads to progressive airway narrowing and/or tortuosity. Increased longevity of patients has posed newer problems, especially the airway. This study aims to characterise various airway abnormalities in adult MPS from a regional centre and proposes a method to quantify the severity of the airway disease. (2) Methods: Retrospective analysis by case notes review, clinical examination, endoscopy, cross-sectional imaging, 3-dimensional reconstruction, and physiological investigations were used to assess the airway abnormalities. Quantitative assessment of the airway severity was performed a validated questionnaire of 15 parameters to derive Salford Mucopolysaccharidosis Airway Score (SMAS). (3) Results: Thirty-one adult MPS patients (21M/ 9F; median 26.7 years; range 19–42 years) were reviewed. There were 9 MPS I, 12 MPS II, 2 MPS III, 5 MPS IV, 2 MPS VI, and 1 MPS VII. Airway abnormalities in each MPS type are described. Patients scoring more than 35 on SMAS had some form of airway intervention. The area under curve of 0.9 was noted at a score of 25, so SMAS more than 25 may predict a difficult airway and potential to have complications. Pearson’s correlation between SMAS and height, weight, BMI were poor (p < 0.05). (4) Conclusions: Airway abnormalities in adult MPS are varied and complex. Assessment of the airway should be holistic and include multiple parameters. An objective multidimensional score such as SMAS may help to predict and manage difficult airways warranting further investigation and validation.

Imaging ventilation using 19F perfluorinated gas magnetic resonance imaging: strategies for imaging collateral ventilation

Collateral Ventilation (CV) has become an important clinical issue with the increasing use of bronchoscopic lung volume reduction (BLVR) using endobronchial valve surgery in patients with severe COPD. The endobronchial valve BLVR procedure often uses one way valves to occlude segmental bronchi in lung regions with severe overinflation resulting from airway narrowing and collapse during exhalation. For BLVR to succeed, CV to the treated region must be minimal or absent. Current approaches to evaluating CV for both planning and follow-up of BLVR procedures involve CT imaging to assess fissure closure. Current techniques to assess regional lung function (including CV) are limited. Standard pulmonary function testing involving analysis of inert gas wash-in/wash-out can only provide statistical distributions without anatomic correlates. Herein we propose the use of fluorine magnetic resonance imaging of biologically inert perfluorinated gas mixed with oxygen to evaluate regional ventilation, in particular, interlobar collateral ventilation. We have evaluated normal subjects and subjects diagnosed with chronic obstructive pulmonary disease and have observed gas transfer at lobar fissures consistent with collateral ventilation.

EFFECT OF HAREETAKYADI YOGA IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE – PRE TEST-POST TEST DESIGN

Chronic Obstructive Pulmonary Disease (COPD) is a lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing, which is progressive and is not fully reversible. COPD includes chronic bronchitis and emphysema. Symptoms of COPD are well explained in Ayurveda in the context of Kasa and Swasa among which chronic bronchitis can be better correlated to Vataja and Kaphaja kasa and emphysema to Tamaka swasa. COPD is characterized by mucous hyper secretion, airway narrowing, fibrosis and destruction of lung parenchyma. Even though the existing conventional management is excellent, Ayurveda provides additional benefits such as improvement in quality of life. The study drug Hareetakyadi yoga is mentioned in Prakarana of kasa in Chikitsa manjari. The objective of the study was to evaluate the Effect of Hareetakyadi yoga in Chronic Obstructive Pulmonary Disease. The Study includes 10 subjects of age group 40-70 years of both gender, diagnosed clinically and as per investigations satisfying COPD, stage 1 & 2 as per GOLD criteria of spirometry attending department of Kayachikitsa, Government Ayurveda College, Thiruvananthapuram. A protocol from Deepana to Virechana were done as preparatory phase before administering drug. Hareetakyadi yoga having the properties of Kapha vata hara, Agni deepana and Rasayana property seems to be effective in the management of this disease.

Differential effects of intense exercise and pollution on the airways in a murine model

Background Exercise-induced bronchoconstriction (EIB) is a transient airway narrowing, occurring during or shortly after intensive exercise. It is highly prevalent in non-asthmatic outdoor endurance athletes suggesting an important contribution of air pollution in the development of EIB. Therefore, more research is necessary to investigate the combination of exercise and pollutants on the airways. Methods Balbc/ByJ mice were intranasally challenged 5 days a week for 3 weeks with saline or 0.2 mg/ml diesel exhaust particles (DEP), prior to a daily incremental running session or non-exercise session. Once a week, the early ventilatory response was measured and lung function was determined at day 24. Airway inflammation and cytokine levels were evaluated in bronchoalveolar lavage fluid. Furthermore, innate lymphoid cells, dendritic cells and tight junction mRNA expression were determined in lung tissue. Results Submaximal exercise resulted in acute alterations of the breathing pattern and significantly improved FEV0.1 at day 24. DEP exposure induced neutrophilic airway inflammation, accompanied with increased percentages of CD11b+ DC in lung tissue and pro-inflammatory cytokines, such as IL-13, MCP-1, GM-CSF and KC. Occludin and claudin-1(Cldn-1) expression were respectively increased and decreased by DEP exposure. Whereas, exercise increased Cldn-3 and Cldn-18 expression. Combining exercise and DEP exposure resulted in significantly increased SP-D levels in the airways. Conclusion DEP exposure induced typical airway neutrophilia, DC recruitment and pro-inflammatory cytokine production. Whereas, intensive exercise induced changes of the breathing pattern. The combination of both triggers resulted in a dysregulation of tight junction expression, suggesting that intensive exercise in polluted environments can induce important changes in the airway physiology and integrity.

Neck swelling and airway narrowing as an initial manifestation of giant cell arteritis

Giant cell arteritis can result in a wide range of symptoms due to the extensive distribution of the external carotid artery. Face and neck swelling and trismus are under-recognised features of giant cell arteritis and can present as the initial symptom prior to the development of classical temporal tenderness and jaw claudication. The lack of awareness of the less common symptoms may result in a late diagnosis of giant cell arteritis, leading to irreversible vision loss. In this paper, we present a case of neck swelling and airway narrowing as the initial manifestation of giant cell arteritis.