Andrew H. Liu, MD is the Training Program Director and an Assistant Professor in Pediatric Allergy & Clinical Immunology at National Jewish Medical and Research Center.
Educational responsibilities and clinical expertise includes:
Clinical research includes:
Liu AH, Jena PK, Wysocki LJ. Tracing the development of single memory-lineage B cells in a highly-defined immune response. J. Exp. Med. (1996) 183:2053-2063.
Liu AH, Gereda JE, Streib JE, Price MR, Thatayatikom A, Klinnert MD, Leung DYM. Immune Predictors for Poor Asthma Control in Young Children. J. Allergy Clin. Immunol. (1999) 103:S230-S231.
Gereda JE, Leung DYM, Price MR, Streib JE, Thatayatikom A, Klinnert MD, Liu AH. Endotoxin Exposure in Infant Wheezers May Protect Against Allergen Sensitization by Driving Th1 Responses. J. Allergy Clin. Immunol. (1999) 103:S206.
Klinnert MD, Liu AH, Price MR, Robinson JA, Hollander JS. Measuring Illness Severity in Asthma-Prone Infants. Am. J. Resp. Crit. Care Med. (1999) 159:A910.
Gereda JE, Leung DYM, Thatayatikom A, Price MR, Streib JE, Klinnert MD, Liu AH. Relation Between House-dust Endotoxin Exposure, Type 1 T-cell development, and Allergen Sensitization in Infants at High Risk of Asthma. (in press, The Lancet).
Andrew H. Liu, M.D.
Immune Pathogenesis and Prevention of Asthma in Young Children
Among infants who suffer from wheezing episodes, a small but substantial subset will go on to have persistent "asthma" in later childhood. Recent reports have indicated that risk factors for the development of asthma include heredity, environmental exposures, and an immune profile typical of allergic inflammation. This atopic immune profile in asthmatic children suggests a T-helper lymphocyte-mediated process through cytokines that support allergen sensitization and eosinophilic inflammation. While studies in adult asthmatic lungs have revealed the importance of these T-helper cells in asthmatic inflammation, the development of T-helper cells during the onset of asthma in young children has been minimally explored. Indeed, studies in animal models and a few studies in humans have raised intriguing questions of the early abnormalities in lymphocyte development that may ultimately lead to mature T-helper cells capable of mediating asthma. As well, measures to reduce asthmatic inflammation in at-risk infants have often been considered, but the effect of such preventive measures on early pro-asthmatic immune development have not been reported.
A recently funded NIH study, entitled the Childhood Asthma Prevention Study ("CAPS"; Principal Investigator - Mary Klinnert, Ph.D.), provides us with an outstanding opportunity to explore these fundamental questions about the development and prevention of asthma. CAPS will enroll 180 toddlers from 9 to 24 months old, with at least 3 previous episodes of wheezing as a high risk factor for asthma. This 5-year, early intervention study will determine the efficacy of a Nurse Home Visitation program in preventing asthma or reducing asthma severity in later childhood. With Co-Investigators Donald Leung, M.D., Ph.D., Mary Klinnert, Ph.D., Lanny Rosenwasser, M.D. and Harold Nelson, M.D., we will also follow CAPS study subjects in order to improve our understanding of the development of asthma in young children. Without altering the impositions on CAPS study subjects, we will be studying: (1) markers of asthma inflammation; (2) allergen sensitization; (3) environmental exposures that may influence the development of asthma (e.g. endotoxin, allergens, cigarette smoke); (4) underlying immune development (i.e. pro-inflammatory cytokines and their immune cellular sources); and (5) the effect of preventive measures on pro-asthmatic immune development. Intriguing preliminary data in the past year by our research group may provide: (1) immune-based, early detection markers that may predict the development of asthma; (2) simple means to follow disease progression or resolution; and (3) new primary prevention strategies for allergy and asthma development.
Stanley J. Szefler, M.D.
Harold S. Nelson, M.D.
Childhood Asthma Management Program
Clinical Research Support Personnel:
Asthma is now recognized as a chronic inflammatory disease of the airways that is characterized by airway obstruction and hyperresponsiveness. Inhaled anti-inflammatory therapy is recognized as the cornerstone of asthma management in older children and adults. Since asthma can occur in early childhood and continuous treatment is needed to maintain control, it is important to understand the relative benefits and risk of continuous anti-inflammatory therapy.
The Childhood Asthma Management Program (CAMP) is a National Heart, Lung and Blood Institute sponsored multicenter trial designed to study the effects of several treatment regimens on lung development. National Jewish is one of eight study sites for CAMP with a Data Coordinating Center at the Johns Hopkins University Center for Clinical Trials. Dr. Stanley Szefler and Dr. Harold Nelson are the directors of the Denver site. This study is the most comprehensive assessment of long-term outcomes of childhood asthma being conducted in the United States.
This important clinical trial is designed to determine the long-term effects of 3 treatments, including two classes of anti-inflammatory agents, budesonide or nedocromil, as compared to placebo. Children, aged 5 to 12 years (one third from ethnic minority groups), were randomized to one of the three treatment groups between 1993 and 1995 and are being followed for a period of time ranging between 4 to 5 1/2 years.
The treatment groups are being compared with respect to lung function (post-bronchodilator FEV1) and bronchial responsiveness (PC20) to methacholine. In addition, comparisons are being made with respect to frequency of self-reported asthma symptoms, days of limited activity, and days lost from school. Physical growth and development (growth rate and bone density), psychological growth and development (neurocognitive functioning and social adjustment), and medication side effects are also being evaluated. This study is unique among previous clinical trials by including a patient education component, a careful analysis of the environment, and also a detailed behavioral assessment. All of this information greatly enhances the quality of the study.
Patient entry began in March 1993 and patients will be followed until a common closing point in 1999. Data analysis for this first part of the study will be completed by December 1999. A wash-out study will be performed to determine whether the medications have long-term effects beyond the treatment period. A long-term follow-up study is also being planned to determine the effect of these treatment strategies on maximal lung and body growth.
The Denver Center has been very active in the overall design and management of the clinical trial, the development of the Patient Education Center, an evaluation of medication adherence and family function, and a study to examine markers of airway inflammation.
Two ancillary studies are currently in place at the National Jewish site. The first study adds more detailed, electronic monitoring of patient adherence with their inhaled medication to better understand factors influencing patterns of asthma medication use. The second study collects more information from the children's families to further our knowledge of how parents can best work with their children to achieve optimal asthma treatment outcome.
Upon completion, the CAMP project will answer some very important clinical questions, such as: Does long-term treatment with anti-inflammatory therapy prevent loss of lung function due to chronic inflammation? Does the long-term use of inhaled steroids affect growth velocity in children? Does the behavior pattern of the child and family affect their ability to follow a long-term management program? Do the benefits of the two anti-asthma medications, budesonide and nedocromil, outweigh the risks for adverse effects? The effect of chronic inflammation on long term lung development and the beneficial and adverse effects of medications on lung and body growth and development have emerged as the most important issues in designing an approach to managing childhood asthma.
Stanley J. Szefler, M.D.
Erwin W. Gelfand, M.D.
Pediatric Clinical Trials Center
Clinical Research Support Personnel:
In 1996, the Department of Pediatrics at National Jewish established the Pediatric Clinical Trials Center (PCTC) under the direction of Drs. Stanley Szefler and Erwin Gelfand to combine clinical research activities in the Department of Pediatrics and to improve our interaction with the pharmaceutical industry and federal government, and also to create opportunities for innovative investigator initiated clinical research. To date, 21 pharmaceutical firms have supported clinical research in the PCTC including Abbott. Aradigm, Ascent, Astra USA, Bayer, Connectics, Forest, Fujisawa USA, Genderm, Genentech, Glaxo Wellcome, Hoechst-Marion Roussel, Estee Lauder, Merck, Novartis, 3M Pharmaceuticals, Rhone Poulenc-Rorer, Schering and Zeneca.
Activities beside asthma include atopic dermatitis, antibody deficiency, sinusitis, rhinitis, bronchitis, medication compliance, home pulmonary function monitoring, and adverse effects of medications. Physician investigators have worked on various projects that include evaluation of medication delivery devices, alternative inhaled propellant devices, medication compliance assessment devices, peak flow meters, inhaled glucocorticoids, systemic glucocorticoids, bronchodilators, novel immunomodulators, antihistamines and antibiotics. Department members have contributed significantly to the design, analysis and publication of these projects. Investigator initiated projects have been developed on inhaled glucocorticoids, leukotriene antagonists, measurements of airway inflammation, and techniques to measure adverse effects of antihistamines.
In 1997, a partnership with Glaxo Wellcome was developed to conduct a multicenter clinical trial on early intervention with inhaled fluticasone propionate, a new high potency inhaled glucocorticoid, in young children with recently diagnosed asthma. A National Jewish study team, centered in the Department of Pediatrics under Drs. Szefler, Iklé, and Gelfand's leadership, serves as the coordinating center for this major multicenter project including responsibility for protocol development, data management and data analysis. This study will address important clinical questions such as: Does early intervention with inhaled glucocorticoids alter the course of chronic asthma? Do the benefits of inhaled glucocorticoids outweigh any risks? Can we develop techniques to predict what patients will go on to have severe asthma?
We are looking forward to continuing work in this area and exploring new opportunities. Our immediate plans include expanding collaborative efforts with the Children's Hospital of Denver and the Department of Medicine at National Jewish to enhance our expertise.