Abstract
Dr. Langston, to give our readers an historical perspective, how would you describe the medical and research findings, theories, and debates that led to the recognition and characterization of the differences between childhood interstitial lung diseases (chILD) and adult interstitial lung diseases?
My viewpoint is that of a pathologist, somewhat different from those with more clinical-centered concerns. Adult interstitial diseases were first defined in the 1960s and 1970s by a group of pathologists, radiologists, and clinicians who separated interstitial diseases into a number of entities with clear clinical-pathologic distinctions. The names for these entities provided somewhat of an alphabet soup of diseases, including bronchiolitis obliterans-organizing pneumonia (BOOP), lymphoid interstitial pneumonia (LIP), desquamative interstitial pneumonia (DIP), and usual interstitial pneumonia (UIP). As pediatric lung disorders began to be examined, they were initially shunted into these same classifications. Over the past 15 to 20 years, adult physicians, pathologists, pulmonologists, and radiologists have come to understand that these classifications, primarily based on pathology, were limiting and not as useful as they had been initially. And I think this is often the case when you break new ground; there is a tendency to simplify and group conditions together that may eventually be recognized to be more diverse. So these initial characterizations became better defined and more clinically and prognostically relevant. Adult pathologists and radiologists went through a very serious inquiry in which they were basically locked in a room together to define more clearly the features of adult interstitial lung disease. As a result, the classification was revised, and now the pathology results are no longer considered to be the most relevant diagnostic study. Instead, imaging studies are often more important than histology.
While the adult pathologists, radiologists, and clinicians were going through this process, physicians involved in pediatric interstitial lung disease were attempting to use the older adult classifications because they were the only ones available. As more and more pediatric cases were studied, it became clear that this presented a tremendous problem and that pediatric interstitial lung disorders largely cannot be fit into either the old or the new adult characterizations, except for some conditions in older children and adolescents. During this period, there were attempts to sort pediatric interstitial lung diseases into a variety of different classifications—into acute and chronic processes, or known and unknown processes—generally without any organizing principle. Everyone had his or her own kind of laundry list but not a well thought out classification. And I think this was very reasonable, given that our understanding of interstitial lung diseases in children came much later than our understanding in adults. Why should that be? Actually, this delayed understanding of pediatric interstitial lung disease is largely attributable to the lag in the use of lung biopsy for diagnosis in children as opposed to adults. Initial adult classifications were based on histology, and those for children still are, so it was difficult to develop a viable working classification without an understanding of the pathology. People were largely relying on autopsy samples, but we now understand that such samples provide a very skewed view of changes and are particularly poor for understanding the early stages of disease processes.
Open lung biopsies were not performed, even in adults, until after World War II, beginning in the late 1940s. Instead, people relied on resection samples or autopsy material, which also explains why an understanding of adult interstitial lung diseases developed later than many other entities in adult medicine. Children were not biopsied at all until much later, and then biopsy was largely confined to older children. When physicians began doing surgery for repair of congenital cardiac malformations in the late 1950s, lung biopsies were sometimes done concurrently to evaluate the state of the pulmonary vasculature. These were the earliest open lung biopsies done in children. Not many were done, and they were never performed strictly for the purpose of evaluating primary lung disease; in these children, lung disease was only an ancillary issue.
Pediatric lung biopsy did not become a more common procedure—and it is still not common today—until the 1970s and 1980s with the development of effective chemotherapy for childhood cancer. The problems related to opportunistic infections and pulmonary complications of chemotherapy became increasingly important as these children survived for longer periods of time. There was then greater interest in trying to understand what was going on in the lungs and in attempts to facilitate survival through the treatment of opportunistic infections and other problems affecting the lung. The advent of bone marrow and solid organ transplantation led to further experience with lung biopsy in these compromised children. This series of events pretty much spans my career in pediatric pathology. I was involved in a lot of these efforts, and it has been exciting and rewarding to watch the field grow and change!
As people became more experienced with biopsy procedures, they began to apply them in more situations and eventually to use them to diagnose primary lung disorders in children, and then later in the 1990s to address infant lung disorders. This provided experience not just for pathologists and surgeons but also for radiologists and pulmonologists. This increased experience, as well as a variety of technical improvements led to advances in all these areas: imaging improved, functional studies improved, and surgery technique improved with the development of the thoracoscope and its modification for use in infants. Finally, we began to have enough case material and ancillary information to make sense of the different situations in which we see interstitial disease in children.
Initially, pediatric interstitial lung disease was a category based on imaging and functional studies and not on pathology. Historically, we have used evidence of bilateral diffuse infiltrates on imaging studies as a diagnostic benchmark. We then began to categorize the different disease presentations.
I initially became interested in this characterization process because I thought it might be helpful in predicting biopsy results. If we knew that children in certain situations, with a specific set of conditions, were likely to have a certain limited range of diagnoses, perhaps that understanding could facilitate the interpretation of biopsies. I hoped that there would be some predictive power to clinical and imaging investigations that might help narrow the diagnostic category from the more general interstitial lung disease to the more specific. I began looking at the different situations in which diffuse interstitial disease develops in children and defining their underlying status to use this information to guide the pathologic work-up. For example, do children who are immune compromised tend to have a different range of conditions than children who are not? Do babies have a different range of conditions than older children? Making these distinctions became possible once we had enough lung-tissue samples to analyze.
Do you recall any specific events, controversies, or discoveries that illustrate how the unique features of chILD began to be understood?
The evolution of our understanding of chILD has been gradual and has its foundation in the accumulation of information from seemingly disparate areas that have come together to form a more coherent model for pediatric interstitial lung disease. Improvements in the treatment of premature infants and their longer survival led to increasing interest in normal lung development and its corollary, abnormal lung development. The changes in the lungs of surviving premature infants prompted these studies, with bronchopulmonary dysplasia (BPD) being one of the first well-characterized infant lung disorders. It was fairly common and became an important issue to address. Growing out of that was the identification of a number of developmental disorders of the lung, such as alveolar capillary dysplasia with misalignment of pulmonary veins, acinar dysplasia, and the recognition that children with Down's syndrome have characteristic lung changes often with a degree of pulmonary hyperplasia. These initial studies all grew out of autopsy pathology. It was not until the 1990s that we could build on this foundation to understand biopsy samples. At that time, the genetic basis of the surfactant disorders was beginning to be unraveled. The first paper from the group in St. Louis on lung disease related to genetic abnormalities of surfactant B protein, with a fairly specific histological correlate, was published in 1993.
Collections of cases, nothing like the typical adult disorders, were beginning to be reported—conditions such as cellular interstitial pneumonitis or chronic pneumonitis of infancy. There was also a recognition that DIP in children was really nothing like DIP in adults. The recognition of the genetic basis for some infant lung disorders such as those seen with surfactant B protein abnormalities suggested that perhaps other lung disorders in children might represent genetic abnormalities of lung metabolism. These disorders do not appear in adult classification because survival is often limited for affected children and characteristic pathologic features are lost as lung disease becomes end-stage. This understanding marked the initial efforts to look for genetic causes for a number of pediatric lung diseases. We began to be aware that part of what makes pediatric disorders different from those in adults is that developmental, genetic, and growth-related issues are more likely to be operative in pediatric conditions and change their manifestations. These issues are not as important in adult pathology because growth and development are typically complete and not impacted by disease. In contrast, developmental, genetic, and growth abnormalities account for a far greater proportion of disorders in children than in adults. They also impact repair, and the types of changes that occur in an injured developing lung are different from those seen in an injured fully developed lung.
These issues then began to be addressed more systematically. Many physicians were instrumental in these efforts, including Dr. Larry Nogee, whose investigations of surfactant dysfunction mutations and related disorders helped to identify a more mechanistic basis for a proportion of serious lung disease in infants and young children. These understandings have been extended to older children, and there are implications for adult lung disease that were not thought of 20 years ago. Now, to some extent, these new understandings about pediatric interstitial disease impact how we think about adult lung disease. The one-to-one correlation between a genetic abnormality and disease manifestation no longer exists; the manifestations of genetic disorders are influenced by many other factors.
Conditions in which there is severe disease and death are generally those that most easily lead to classification, but they form the tip of the iceberg. For others, different mutations that impact affected pathways in a less severe way might not be recognized until genetic studies become available and mutations are found with less severe disease manifestations and longer survival. For example, mutations in the ATP-binding cassette protein A3 (ABCA3) were initially identified from a group of cases with fatal infant lung disease enriched for familial cases as another genetic disorder of surfactant metabolism. However, with further investigation, it has become clear that there are affected individuals with less severe clinical disease, a different range of pathologic findings, and longer survival.
Dr. Bettina Hilman had a long-term interest in pediatric interstitial lung disease and invested time and energy in multiple attempts to stimulate a better understanding of these disorders. She had pushed for a national registry for pediatric interstitial lung disease and doggedly and virtually single-handedly lobbied for this project. There were two National Heart Lung and Blood Institute (NHLBI)-sponsored workshops that she largely organized to formulate recommendations for investigation into pediatric interstitial lung disease. These occurred in fairly rapid succession as the first recommended a broader approach. Just prior to the second workshop, a group of pathologists who had agreed to participate met at the summer home of J. Thomas Stocker, M.D., then at the Armed Forces Institute of Pathology (AFIP). I was one of the participants in the meeting, which took place on the outskirts of Rocky Mountain National Park, outside Denver. A handful of us spent the weekend at the Stocker's mountain retreat reviewing case material and discussing issues related to the pathology of what was then a rather pathologically undefined entity—interstitial lung disease in children. This took place before the description of some of the diffuse developmental abnormalities and before the genetic underpinnings of the surfactant dysfunction mutations had been described. We each brought with us cases we had been involved in, and we shared them with each other. Dr. Bettina Hilman was the only non-pathologist at this meeting, and this was the first time I met her. She spent the weekend with us. Even though she was not a pathologist, she was deeply involved and listened intently to our fairly wide-ranging discussion. She was trying to develop a registry and had a lot of questions for us about entry criteria: which patients should be included and which should not, how to decide, should there be pathology review, how would that be done and who would do it, and so on. These questions remain relevant for us today. A couple of months after that meeting, the second workshop took place in Washington, DC, and Bettina was there, pushing to get her registry started. Shortly after that, Bettina became quite ill, and without her energy behind it, this registry project fell apart.
What impact did the distinctions and new way of thinking about chILD have on the field of pediatric pulmonology?
I think it has changed our way of thinking in a broader sense. By beginning to understand changes identified in a few of these diseases, we began to wonder whether genetic changes are also associated with some of the other conditions we recognize but do not completely understand. Also, there has been a wider recognition of interstitial lung disease and attempts to standardize its diagnosis and to define appropriate therapy. This has been a slow process and is certainly still very much in its infancy.
With regard to pediatric pulmonology in general, what main challenges does the specialty currently face?
I think the same issues that preoccupied Dr. Hilman in the past are still relevant today: how to get individuals to work together in a field that is considered narrow, in which it is clear that important advances have been made with impact far beyond that specific field. This recognition is driving current studies forward with the recognition that many conceptual advances have come out of areas of study often not thought to be of much importance. An impetus to investigate developmental and genetic bases for these conditions and the recognition of the impact of genetic factors on other disease conditions is a feature of many fields of study and is particularly related to the development of technology that permits these investigations and the example of success stories in these areas. Almost all pediatric disorders are rare; this means that people must work together to advance knowledge for these conditions, and that work must involve multiple institutions. One of the hardest things to do is a multicenter study—to pull together people from different institutions and different disciplines and keep them focused on a goal. They all have other competing interests. To keep such a project moving forward really does require some force of personality! And often the people who can pull this off are not the same people who can get these projects funded, so it requires a collaborative effort between people with different kinds of skills. It not only requires an ability to bring people together but also a lot of good faith and openness.
What led you to pursue a career in medicine and to specialize in pediatric pulmonary diseases in particular?
My father was a physician, and for me and for many women physicians older than me who were the real pioneers—the only women in their classes—this family influence removes some of the mystery and makes a career in medicine seem less of an impossible goal. When I was in college, most women got married, had children, and did not work. Those that did work were generally in traditionally female-oriented occupations, such as nursing or teaching, but that was just beginning to change.
I was not ready to stop, for my education to be done; settling down was not appealing to me. While I did not have a burning ambition for my whole life to be a physician, I certainly found it an appealing prospect, thought I was capable of it, and believed it could be interesting. So I applied to medical school and was accepted. At the time, many medical schools were trying to open up their classes to women, though there were many fewer women applicants. The medical school I attended was an outlier—I was in only the third class to which women had been admitted, and there were still strong feelings between the administration and faculty about whether that had been an appropriate path.
I was young, about two years younger than most of my classmates, and looked even younger. I think that contributed partly to my decision to pursue pathology; it was a bit removed from much of clinical medicine with less patient interaction and more peer interaction. I don't think I thought this through clearly at the time, but I felt more comfortable in that situation as a young physician. Like many life decisions, there was a bit of analysis and a bit of chance to my pathway; I applied to both pediatrics and pathology residency programs, and I matched to a pathology program, so I became a pathologist. I found the pediatric components of my residency interesting and took whatever opportunity I had to focus on them. At that time, there was not a lot of interest in pediatric pathology and not very many pediatric pathologists. There were children's hospitals, but they were smaller and fewer than today, and many major medical centers did not have a children's hospital.
While I found the pediatric aspects of what I did in pathology most interesting, the direction my career took again was largely due to chance, luck, and accident. When I finished my residency, my husband, an internal medicine/infectious disease physician, had finished his fellowship and was looking for a clinical position. We went to Oregon, where he did clinical infectious disease at Kaiser, and I took a position at the medical school in the Department of Pathology, doing general pathology. My husband ended up not enjoying clinical infectious disease, so we only stayed in Oregon a year. He decided that he wanted to be in a more academic environment, where he could do clinical research but not be in a practice-driven setting. He considered several institutions in Canada for reasons that were never clear to me, and we ended up going to Winnipeg, to the University of Manitoba. I looked into a couple of positions there, but the one that appealed the most was at the Children's Hospital. So, basically over the next few years there, I taught myself pediatric pathology and began to be involved in the lung. We were there for five years, during the early 1970s, and at that time, lung disease of prematurity was a huge clinical problem. Surfactant had been described, but the surfactant proteins had not been identified. At Winnipeg, the chairman of the Department of Pediatrics was a pediatrician with an interest in pulmonary physiology. The Dean of the Medical School was also interested in pulmonary physiology, and the pulmonary group on the adult side was advanced and very well led. So there was a lot of interest in lung disease. After I had been there for a couple of years, the chairmanship of the Department of Pathology became vacant, and Dr. William Thurlbeck became chairman. He was a very well-known and experienced lung pathologist and investigator. My early work there was focused on the lung; one of the radiologists and I were working together to develop correlations between pediatric pulmonary pathology and radiology studies. When Dr. Thurlbeck became chairman, our work benefited enormously from his advice and support. He was an important mentor for me, and I miss him still.
—Interview by Vicki Glaser