Site and nature of airway obstruction in chronic obstructive lung disease: 50 years on

It has been 50 years since Hogg, Macklem and Thurlbeck published the highly influential paper, The Site and Nature of Airway Obstruction in Chronic Obstructive Lung Disease¹ in the New England Journal of Medicine (NEJM). Their study demonstrated, for the first time, that the major site of increased airway resistance in obstructive lung disease was the small airways of the lung. This landmark paper changed our understanding of the pathophysiology of obstructive lung disease and ushered in intense study of small airway anatomy, physiology and pathology that continues to this day. To commemorate this important publication I have reviewed the events that led up to its publication and the subsequent investigations which have firmly established the small airways as the critical site of pathology in a variety of lung diseases.

The work described in the NEJM paper was part of James (Jim) Cameron Hogg’s PhD thesis project, Flow and Ventilation Distribution (McGill University 1969). Additional papers from that thesis included one more in the NEJM,² two in the Journal of Clinical Investigation^3,4 and one in the Journal of Applied Physiology.⁵ Jim was doing his PhD at McGill University jointly supervised by two giants in the field of lung physiology and pathology Peter T. Macklem and William (Whitey) Thurlbeck. He came under the mentorship of these individuals by a circuitous route. Jim spent his teenage years in Sioux Lookout Ontario, an isolated small community in North Western Ontario, which was a wonderful place for a boy to grow up. In the winter months and most of the rest of the year, he was preoccupied by hockey. He played left wing, could skate fast, shoot accurately and hold his own body checking. But he did not impress a former NHL player who was also the playing coach of the local senior men’s team who had invited him to play in a few games when they were shorthanded. When he asked the coach for a recommendation to try out with the Flin Flon Bombers, a high quality junior hockey team located on the Manitoba-Saskatchewan border, where many NHL players started their hockey career, the coach said no! His recovery from that disappointment led him, on a convoluted trajectory, to respiratory medicine and research and ultimately to a lifelong fascination with small airways’ disease. It also armed him for the many rejections faced by innovative researchers! Persistence became his most important trait.

Since a hockey career was not an option he chose to study medicine and this led him to the University of Manitoba in Winnipeg. During his physiology course, Jim was influenced by the legendary Joe Doupe (http://news.umanitoba.ca/lecture-honours-joe-doupe-the-man-who-revived-u-of-ms-medical-school/. Dr. Doupe stimulated students to think critically and his influence on Investigative Medicine in Canada has been profound. As for many before and after him, Doupe sparked in Jim an interest in research. Jim was also influenced by another giant in the Canadian Respiratory field Dr. Rueben Cherniack. Dr. Cherniack taught the Respiratory portion of the first year physiology course and gave lectures on clinical respiratory physiology in the second year. In addition, Jim did a clinical clerkship and a 2-month rotation during his internship on Chernicack’s service and Dr. Cherniack continued to serve as a mentor throughout his career.

Jim’s family was not wealthy and his mother, a nurse, was raising 4 children as a single mother because of the premature death of Jim’s father. To get through medical school, Jim enlisted with the Royal Canadian Airforce. The Air Force supported him for years 2–4 in medical school and during his rotating internship and committed him to serve 3 years with the RCAF. The first two of these he spent as a general medical Officer in Greenwood Nova Scotia, and the final year was spent at the Institute of Aviation Medicine in Toronto where he met the charismatic physician and physiologist Dr. Charlie Bryan who had completed his PhD at McGill studying the distribution of ventilation using trace amounts of radioactive Xenon gas.⁶

When Jim expressed an interest in further research study, Charlie arranged an interview with Dr. David Bates who was head of the combined Cardio-Pulmonary Division at the Royal Victoria Hospital at McGill University in Montreal. Initially, Jim was told there were no positions available, but when Jim mentioned that he also planned to get some training in Pathology, Bates called William (Whitey) Thurlbeck who immediately offered him a position to do a new project jointly supervised by himself and Peter Macklem. When Jim told Charlie about the offer, he strongly suggested that Jim go to Montreal and be under Peter Macklem's wing and “everything would be fine.” Good advice, as it turned out!

When Jim went to Montreal, Peter Macklem had recently returned from a post-doctoral fellowship at Harvard where he worked with Jere Mead. He and Jere were studying lung dynamics and mechanical properties, and Jere picked Peter up every day for the drive to the Laboratory in the Harvard School of Public Health. The commute was often the venue for intense physiological discussion, and one morning Peter remembered that as they were waiting at a red light, Jere Mead said, “Peter, I have an idea, and it is a good one!” His idea was a methodological innovation that allowed the measurement of a small airways’ resistance.

Until that time, it was widely believed that the small peripheral airways were the principle site of resistance to airflow in the human lung. This belief was related to some measurements and calculations performed by the great Swiss Physiologist Roher.^7,8 Roher had not measured the resistance, he calculated it. Mead’s great idea was to measure resistance using a unique “retrograde catheter.”⁹ The thin catheter was attached to the end of a piano wire, and the wire was treaded down the airway tree until it wedged in a small airway where it then perforated the lung and was drawn through the lung tissue until its slightly flared end was arrested in the lumen of the small airway it had perforated. By measuring the total lung resistance and the resistance from the catheter tip to the alveoli, lung resistance could be partitioned into central and peripheral components. Macklem and Mead made the measurements in excised canine lungs and found that the resistance beyond 2–3 mm diameter airways was less than 10% of total resistance. Roher had made both measurement and mathematical errors; he used calibrated bougies to estimate airway size. He wedged the bougies in the lung and then dissected along the airway in which they were wedged; however, he grossly underestimated the number and cross sectional area of these airways mainly because he made his measurements on collapsed lungs. The mathematical error resulted in him calculating that the flow in the airways would be purely laminar when in fact turbulent flow dominates in the larger airways.

That the small airways should provide little resistance to airflow in the human lung had been predicted only a few years earlier based on calculations done by Green.¹⁰ In 1963, Ewald Weibel published his now classic monograph¹¹ in which he made detailed morphometric measurements on an excised and inflated human lung. Green used these new data to repeat Rohrer’s calculations and found that the small airways should offer minimal resistance to airflow.

Jim was now poised to test this prediction. Through his relationship with Thurlbeck, he had access to human post mortem lungs and via Macklem, access to the technique to measure resistance. He measured central and peripheral resistance in a total of 29 human lungs, including 16 normal subjects of various ages who had died suddenly in accidents, as well 10 adults with chronic bronchitis and emphysema. He confirmed the findings in dogs and Green’s calculations; small airway resistance was less than 25% of total lower airway resistance. The startling finding was that it was these same small airways that offered the major site of airflow resistance in the patients with Chronic Obstructive Pulmonary Disease (COPD).

In the conclusion section of his thesis he wrote: “In adults with chronic bronchitis and emphysema the peripheral airways may be severely obstructed and go unrecognized because they normally contribute little to resistance and in severe emphysema the increase which occurs in resistance is due almost entirely to a marked elevation in small airway resistance.”

Jim used morphometric techniques to study the normal and COPD lungs and concluded that, “….the most important mechanism of this obstruction is mucus plugging of the airway lumen with inflammatory narrowing and in some cases obliteration of the small airways.” In their NEJM paper, Hogg, Macklem and Thurlbeck suggested that this process be called “small airways disease.” This started a growth industry; a PubMed search of “small airway disease” now yields more than 74,000 citations!

The discovery that the small conducting airways are a silent zone within the lungs where disease can progress over many years without affecting routinely used tests of lung function suggested that early detection would be beneficial. This ushered in the development of a variety of specialized tests of “small airway disease” designed to detect early abnormalities at a hopefully reversible stage. Closing Volume, Closing Capacity, the slope of Phase 3 of the single breath nitrogen washout, the volume of isoflow (VisoV) on flow volume curves done while breathing air and a mixture of 80% Helium and 20% oxygen (Heliox), frequency dependence of compliance and maximal mid-expiratory flow were all proposed as more sensitive tests of small airway disease.¹² Although the tests proved sensitive, they were not found to be accurate in predicting that minority of smokers who later develop COPD and, therefore, the search has continued.¹³ More recently proposed tests include measures derived from the forced oscillation technique (FOT) and the multiple inert gas washout maneuver.^14,15

Study of the pathological mechanism of small airway disease proceeded in parallel with the investigation of the functional effects; in fact, Jim has spent his career since the publication of the 1968 paper trying to figure out WHY! He has asked; what are the cellular and molecular mechanisms for the increase in small airway résistance? And, how can it be prevented or reversed?

The next major publication that his thesis inspired was another NEJM paper.¹⁶ Cosio made qualitative estimates of 7 pathological changes seen on histological sections of diseased small airways and developed a small airway disease score that was then compared to tests of lung function done on the same subjects prior to the resection of their lung tissue. They scored airway occlusion, goblet and squamous cell metaplasia, epithelial ulceration, inflammatory cell infiltration, fibrosis, pigment deposition and smooth muscle hyperplasia/hypertrophy. The average score correlated well with the slope of phase III of the single breath washout test and with the VisoV on flow volume curves done breathing air and Heliox.

Jim has continued to ask the same questions about the small airways but has used progressively more sophisticated and accurate techniques to get answers. By the turn of the last century, morphometric techniques and immunohistochemistry had progressed sufficiently to allow him to make a much more precise examination of peripheral airway pathology in COPD. In 2004, Jim published another NEJM paper titled, “The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease.”¹⁷ The small airways were assessed in surgically resected lung tissue from 159 patients with a range of airway obstruction based on the GOLD classification scheme. He found that the severity of airflow obstruction was strongly associated with increased thickness of the airway walls and the accumulation of an inflammatory mucous exudate in the lumen and walls of the small airways. Jim was able to characterize the distribution of the inflammatory cell type in the airways and made the novel observation that advanced COPD was associated with accumulation of lymphoid aggregates in the airway walls indicating the development of an adaptive immune response. These observations have had a fundamental effect on how we think of peripheral airway inflammation in COPD and have stimulated the search for the antigen(s) against which the adaptive immune response is directed.

Most recently, Jim has used new techniques to address a question he posed in his thesis: is the increase in small airway resistance in COPD due to loss or narrowing of the peripheral airways? To answer this Jim and his student John McDonough made use of the recent development of micro computed tomography (CT). Micro CT cannot be performed on a living subject or even a whole excised lung but can be applied to small samples of lung where it can provide 3 dimensional images with a resolution that approaches microscopic examination. Jim and John used this method to count the total number of airways in the lungs of patients who were having lung transplantation for COPD…published in yet another NEJM paper¹⁸! To their surprise, they found a 90% loss of peripheral airways in addition to thickening and narrowing of the remaining airways. They also found that this obliteration of the peripheral airways occurred even in areas of the lung not affected by emphysema suggesting that the loss of airways preceded the development of emphysema.

This is another game changer. If complete obliteration and loss of peripheral small airways occurs at an early stage of disease the impetus to detect small airways’ dysfunction early is even more critical to its prevention than previously thought. To address the natural history of small airway obliteration Jim and his colleagues made use of a unique tissue bank of lungs that he has collected from donors over the last 4 decades. Koo et al.¹⁹ performed microCT imaging on paraffin imbedded lung tissue from smokers who had a range of disease severity (GOLD stage). They found that the number of terminal bronchioles was reduced to 60% of normal in subjects with mild COPD (GOLD stage 1). This result indicates that early intervention will be required for disease modification in smokers.

The study of the small airways of the lung has been a life-long quest for Jim and it continues to this day. He still goes into the lab most days, inspiring and encouraging younger colleagues and trainees to study the small airways. He continues to make important contributions to the study of lung structure and function. The world has benefitted greatly from his disappointment at not making the Flin Flon Bombers!