Occupational Asthma Reference

Thompson BR, Dysanapsis—Once Believed to be a Physiological Curiosity—Is Now Clinically Important, Am J Respir Crit Care Med, 2017;195:277-278,10.1164/rccm.201609-1959ED
(Plain text: Thompson BR, Dysanapsis-Once Believed to be a Physiological Curiosity-Is Now Clinically Important, Am J Respir Crit Care Med)

Keywords: Airflow obstruction, predicted lung function, dysanapsis, review

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In respiratory physiology, there is always the tension between what is part of the normal continuum and where to draw the line in the sand to define disease. The area of lung growth, and the pattern of growth, is no different. We assume that as the lung grows and matures, the length and diameter of the airways grow in similar proportions, making the resistance to airflow similar across individuals. For example, it does not really matter what an individual’s vital capacity is; they should be able to forcefully blow out roughly 80% of their vital capacity in 1 second—that is, the FEV1/FVC should be roughly 0.8. In reality, that is not necessarily the case, as the relationship between airway caliber and lung volume is not consistent. We have reference values (1) based on normal population data that determine what the FEV1, FVC, and FEV1/FVC should be. What happens, however, when the lung size (VC or FVC) and FEV1 are within normal limits, but there is clinically significant airflow obstruction (FEV1/FVC less than the lower limit of normal or using the fixed cut-off of FEV1/FVC?<?0.7 or 0.8)? Is this truly airflow obstruction or part of the normal continuum? Is it indeed a problem?

The concept of the disproportionate growth between lung size and airway caliber was termed “dysanaptic growth” by Green and colleagues in 1974 (2), who described the wide variations in maximum expiratory flows in normal subjects with similar lung size. They postulated that the differences in maximum expiratory flows noted were due to between-individual differences in airway caliber and geometry (caliber vs. length) and suggested that the proposed disconnect between lung size and airway size was indeed a normal variant and may have an embryological basis. Mead (3) continued with this work and demonstrated that there was no association between airway caliber (estimated as maximal expiratory flow/static recoil pressure at 50% vital capacity) and lung size. However, there were differences in airway caliber between male and female individuals with comparable lung volumes and, importantly, boys and men with comparable lung volumes. The work of Green and colleagues (2) and Mead (3) has been confirmed and further developed using more sophisticated techniques, such as acoustic reflectance and computed tomography–based techniques (4, 5).

This is all physiologically interesting; however, is it clinically important? In this edition of the Journal, Forno and colleagues (pp. 314–323) present a comprehensive study looking at the question of whether airway dysanapsis is associated with asthma morbidity in obese children (6). To do this, the authors used six large cohorts of subjects from separate childhood studies. They then looked for associations between obesity and dysanapsis in children with and without asthma and the association between dysanapsis and clinical outcomes. The results are compelling, and the authors clearly demonstrate that there was an association with airway dysanapsis and overweight or obese as children with or without asthma. Moreover, in overweight children with asthma, there was an association with airway dysanapsis and clinical outcomes.

A potential issue with this kind of analysis is determining the cutoffs that are going to be used to define disease. This is important as the definition can potentially force the results toward a preconceived notion. The physiological phenomenon described by Green and colleagues (2) and Mead (3) did not ever describe a line in the sand between normality and abnormality, but more that dysanapsis was a physiological description of why there is the variation in expiratory resistance to flow for a given lung size. Forward this work on 25 years, and Pellegrino and colleagues in the American Thoracic Society/European Respiratory Society lung function interpretation document (7) define dysanapsis as airflow obstruction (FEV1/FVC less than the lower limit of normal) in the presence of an FEV1 greater than or equal to 100% predicted normal. It is not clear where this definition came from, and following back the references they ended up with Green and colleagues (2) and Mead (3). Clearly, this definition could force the results. Furthermore, defining airflow obstruction either as a fixed cutoff or as a lower limit of normal (8) could also force the results. So there is a disconnect between the concept of “airflow obstruction” (FEV1/FVC less than the lower limit of normal) in the presence of a normal FEV1 and what Green and colleagues (2) and Mead (3) describe. The authors are well aware of this issue and used a sensitivity analysis to address it head on. No matter what definition (lower limit of normal or various percent predicted cutoffs) was used for FEV1/FVC, FEV1, and FVC to describe dysanapsis, the results were essentially the same. Clearly, in some definitions data were lost; however, this did not affect the main outcomes providing a very strong and robust message. Finally, the authors studied the relationships as a cross-section and longitudinally, and again the relationships hold.

It is sometimes interesting in science to look back over a journey. Some 42 years ago, a very interesting, well-conducted study posed the notion that there was no association between airway caliber and lung size. This was demonstrated to be the case over the years using more sophisticated techniques. However, there are differences in airway caliber between men and women, and there is incongruence of growth between airway caliber and lung parenchyma. Importantly, this so-called dysanapsis was the explanation of why airflow obstruction in the presence of a normal FEV1 and FVC is potentially a normal variant. The current data demonstrating that dysanapsis is related to obese/overweight children, and that in children who are obese/overweight dysanapsis is associated with symptoms, medication use, and exacerbations, provide a strong reason for us to suggest that dysanapsis is not normal. These are the sorts of data that will lead many to scramble to their computers and start interrogating their respiratory function databases to look for associations between dysanapsis and other respiratory diseases. The hitch is, if dysanapsis is a problem, what do we do about it? The next 40 years can sort that out.

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