Mark Avdalovic

The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations

Asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a commonly encountered yet loosely defined clinical entity. ACOS accounts for approximately 15–25% of the obstructive airway diseases and patients experience worse outcomes compared with asthma or COPD alone. Patients with ACOS have the combined risk factors of smoking and atopy, are generally younger than patients with COPD and experience acute exacerbations with higher frequency and greater severity than lone COPD. Pharmacotherapeutic considerations require an integrated approach, first to identify the relevant clinical phenotype(s), then to determine the best available therapy. The authors discuss the array of existing and emerging classes of drugs that could benefit those with ACOS and share their therapeutic approach. A consensus international definition of ACOS is needed to design prospective, randomized clinical trials to evaluate specific drug interventions on important outcomes such as lung function, acute exacerbations, quality of life and mortality.

Bidirectional Relationship between Cognitive Function and Pneumonia

RATIONALE Relationships between chronic health conditions and acute infections remain poorly understood. Preclinical studies suggest crosstalk between nervous and immune systems. OBJECTIVES To determine bidirectional relationships between cognition and pneumonia. METHODS We conducted longitudinal analyses of a population-based cohort over 10 years. We determined whether changes in cognition increase risk of pneumonia hospitalization by trajectory analyses and joint modeling. We then determined whether pneumonia hospitalization increased risk of subsequent dementia using a Cox model with pneumonia as a time-varying covariate. MEASUREMENTS AND MAIN RESULTS Of the 5,888 participants, 639 (10.9%) were hospitalized with pneumonia at least once. Most participants had normal cognition before pneumonia. Three cognition trajectories were identified: no, minimal, and severe rapid decline. A greater proportion of participants hospitalized with pneumonia were on trajectories of minimal or severe decline before occurrence of pneumonia compared with those never hospitalized with pneumonia (proportion with no, minimal, and severe decline were 67.1%, 22.8%, and 10.0% vs. 76.0%, 19.3%, and 4.6% for participants with and without pneumonia, respectively; P < 0.001). Small subclinical changes in cognition increased risk of pneumonia, even in those with normal cognition and physical function before pneumonia (β = -0.02; P < 0.001). Participants with pneumonia were subsequently at an increased risk of dementia (hazard ratio, 2.24 [95% confidence interval, 1.62-3.11]; P = 0.01). Associations were independent of demographics, health behaviors, other chronic conditions, and physical function. Bidirectional relationship did not vary based on severity of disease, and similar associations were noted for those with severe sepsis and other infections. CONCLUSIONS A bidirectional relationship exists between pneumonia and cognition and may explain how a single episode of infection in well-appearing older individuals accelerates decline in chronic health conditions and loss of functional independence.

Asthma/Allergic Airways Disease : Does Postnatal Exposure to Environmental Toxicants Promote Airway Pathobiology?

The recent, dramatic increase in the incidence of childhood asthma suggests a role for environmental contaminants in the promotion of interactions between allergens and the respiratory system of young children. To establish whether exposure to an environmental stressor, ozone (O3), and an allergen, house dust mite (HDMA), during early childhood promotes remodeling of the epithelial-mesenchymal trophic unit (EMTU) of the tracheobronchial airway wall by altering postnatal development, infant rhesus monkeys were exposed to cyclic episodes of filtered air (FA), HDMA, O3, or HDMA plus O3. The following alterations in the EMTU were found after exposure to HDMA, O3, or HDMA plus O3: (1) reduced airway number; (2) hyperplasia of bronchial epithelium; (3) increased mucous cells; (4) shifts in distal airway smooth muscle bundle orientation and abundance to favor hyperreactivity; (5) interrupted postnatal basement membrane zone differentiation; (6) modified epithelial nerve fiber distribution; and (7) reorganization of the airway vascular and immune system. Conclusions: cyclic challenge of infants to toxic stress during postnatal lung development modifies the EMTU. This exacerbates the allergen response to favor development of intermittent airway obstruction associated with wheeze. And, exposure of infants during early postnatal lung development initiates compromises in airway growth and development that persist or worsen as growth continues, even with cessation of exposure.

Ozone Exposure During thE Early Postnatal Period Alters the Timing and Pattern of Alveolar Growth and Development in Nonhuman Primates

Exposure to oxidant air pollutants in early childhood, with ozone as the key oxidant, has been linked to significant decrements in pulmonary function in young adults and exacerbation of airway remodeling in asthma. Development of lung parenchyma in rhesus monkeys is rapid during the first 2 years of life (comparable to the first 6 years in humans). Our hypothesis is that ozone inhalation during infancy alters alveolar morphogenesis. We exposed infant rhesus monkeys biweekly to 5, 8hr/day, cycles of 0.5 ppm ozone with or without house dust mite allergen from 1 to 3 or 1 to 6 months of age. Monkeys were necropsied at 3 and 6 months of age. A morphometric approach was used to quantify changes in alveolar volume and number, the distribution of alveolar size, and capillary surface density per alveolar septa. Quantitative real time PCR was used to measure the relative difference in gene expression over time. Monkeys exposed to ozone alone or ozone combined with allergen had statistically larger alveoli that were less in number at 3 months of age. Alveolar capillary surface density was also decreased in the ozone exposed groups at 3 months of age. At 6 months of age, the alveolar number was similar between treatment groups and was associated with a significant rise in alveolar number from 3 to 6 months of age in the ozone exposed groups. This increase in alveolar number was not associated with any significant increase in microvascular growth as measured by morphometry or changes in angiogenic gene expression. Inhalation of ozone during infancy alters the appearance and timing of alveolar growth and maturation. Understanding the mechanism involved with this altered alveolar growth may provide insight into the parenchymal injury and repair process that is involved with chronic lung diseases such as severe asthma and COPD. Anat Rec, 2012.

In Utero and Postnatal Exposure to Environmental Tobacco Smoke (ETS) Alters Alveolar and Respiratory Bronchiole (RB) Growth and Development in Infant Monkeys

The direct effect of environmental tobacco smoke (ETS) exposure in utero on the development of the lung parenchyma is not known. We used design-based stereologic methods to evaluate in utero and postnatal ETS exposure on alveolar and respiratory bronchiole (RB) development in the rhesus macaque. Methods Timed-pregnant rhesus macaques and their offspring were exposed to filtered air or various amounts of ETS during the prenatal and postnatal period. The left cranial lobe from necropsied infants was evaluated by design-based stereological methods and general pathological review. Results Infants in the in utero and six-month ETS groups had an 18% and 17% relative decrease, respectively, in alveolar number and a 57% and 33% increase, respectively, in alveolar size compared to filtered air (FA) monkeys. Lung volume positively correlated with alveolar number in the FA and six-month ETS group and negatively correlated in the in utero ETS group. The distribution of alveolar size was much more variable in the in utero group. Overall, RB volume was significantly increased in the six-month ETS group (p < .04). Conclusions Taken together, these results indicate that in utero and postnatal ETS exposure is associated with altered parenchymal lung development.

Epoprostenol in pregnant patients with secondary pulmonary hypertension: Two case reports and a review of the literature

Women who present with pulmonary hypertension during gestation have traditionally been persuaded to terminate their pregnancy. Historically, the mortality associated with this group is very high. Certain patients with a secondary cause of pulmonary hypertension are believed to share similar pathophysiology with primary pulmonary hypertension patients. Recently, new treatments have become available that have slowed disease progression. We present the successful treatment of two patients who presented during late gestation with moderate pulmonary hypertension. Both patients were managed with intravenous vasodilators and anticoagulants without complication. Each patient successfully delivered a healthy child via spontaneous vaginal delivery. The review of the historical management of similar patients including new insights into the etiology of pulmonary arterial hypertension is also included. It highlights the complexity involved in managing such patients and the requirement of a multidisiplinary team approach.

Asthma: a comparison of animal models using stereological methods

Asthma is a worldwide health problem that affects 300 million people, as estimated by the World Health Organization. A key question in light of this statistic is: “what is the most appropriate laboratory animal model for human asthma?” The present authors used stereological methods to assess airways in adults and during post-natal development, and their response to inhaled allergens to compare rodents and nonhuman primates to responses in humans. An epithelial–mesenchymal trophic unit was defined in which all of the compartments interact with each other. Asthma manifests itself by altering not only the epithelial compartment but also other compartments (e.g. interstitial, vascular, immunological and nervous). All of these compartments show significant alteration in an airway generation-specific manner in rhesus monkeys but are limited to the proximal airways in mice. The rhesus monkey model shares many of the key features of human allergic asthma including the following: 1) allergen-specific immunoglobulin (Ig)E and skin-test positivity; 2) eosinophils and IgE+ cells in airways; 3) a T-helper type 2 cytokine profile in airways; 4) mucus cell hyperplasia; 5) subepithelial fibrosis; 6) basement membrane thickening; and 7) persistent baseline hyperreactivity to histamine or methacholine. In conclusion, the unique responses to inhaled allergens shown in rhesus monkeys make it the most appropriate animal model of human asthma.

Accelerated structural decrements in the aging female rhesus macaque lung compared with males

Aging is associated with morphometric changes in the lung that lead to decreased lung function. The nonhuman primate lung has been shown to have similar architectural, morphological, and developmental patterns to that of humans. We hypothesized that the lungs of rhesus monkeys age in a pattern similar to human lungs. Thirty-four rhesus monkeys from the California National Primate Research Center were euthanized, necropsied, and the whole lungs sampled. Stereological analysis was performed to assess the morphological changes associated with age. The number of alveoli declined significantly from age 9 to 33 yr with a greater decline in females compared with males. Lungs of females contained roughly 20% more alveoli at age 9 yr than males, but by ∼30 yr of age, females had 30% fewer alveoli than males. The volume of alveolar air also showed a significant linear decrease in females relative to age, while males did not. The number-weighted mean volume of alveoli showed a significant positive correlation with age in females but not in males. The volume of alveolar duct showed a significant positive correlation with age in females, but not in males. Structural decrements due to aging in the lung were increased in the female compared with male rhesus monkey.

Non-cigarette tobacco and the lung.

Cigarette smoking is known to cause a wide range of damaging health outcomes; however, the effects of non-cigarette tobacco products are either unknown or perceived as less harmful than cigarettes. Smokeless tobacco, cigar smoking, and waterpipe smoking have increased in usage over the past few decades. Some experts believe that their use is reaching epidemic proportions. Factors such as a perception of harm reduction, targeted advertising, and unrecognized addiction may drive the increased consumption of non-cigarette tobacco products. In particular, the need for social acceptance, enjoyment of communal smoking activities, and exotic nature of waterpipe smoking fuels, in part, its popularity. The public is looking for “safer” alternatives to smoking cigarettes, and some groups advertise products such as smokeless tobacco and electronic cigarettes as the alternatives they seek. Though it is clear that cigar and waterpipe tobacco smoking are probably as dangerous to health as cigarette smoking, there is an opinion among users that the health risks are less compared to cigarette smoking. This is particularly true in younger age groups. In the cases of smokeless tobacco and electronic cigarettes, the risks to health are less clear and there may be evidence of a harm reduction compared to cigarettes. In this article, we discuss commonly used forms of non-cigarette tobacco products, their impacts on lung health, and relevant controversies surrounding their use.

Lung effects of inhaled corticosteroids in a rhesus monkey model of childhood asthma

The risks for infants and young children receiving inhaled corticosteroid (ICS) therapy are largely unknown. Recent clinical studies indicate that ICS therapy in pre‐school children with symptoms of asthma result in decreased symptoms without influencing the clinical disease course, but potentially affect postnatal growth and development. The current study employs a primate experimental model to identify the risks posed by ICS therapy.