Non-obstructive Chronic Bronchitis (NCB): A Syndrome in Need of Better Definition and Treatment
Chronic bronchitis is an inflammatory disease of the airways of the lungs that affects approximately 6% of the U.S. population. This condition was well defined and classified in a 1965 report to the British Medical Research Council (MRC), which stated, "the essential clinical abnormality common to all persons with chronic bronchitis ... is bronchial hypersecretion which is usually manifest as productive cough" (1). Hypersecretion was considered to be "chronic or recurrent" if expectoration "occurred on most days during at least three consecutive months for more than two successive years". The report further stated that "it is possible to recognize simple, mucopurulent, and obstructive forms of chronic bronchitis separately or in combination with each other" and proposed the term "chronic obstructive bronchitis" to describe those with "chronic bronchitis in which there is persistent, widespread narrowing of the intra-pulmonary airways, at least on expiration, causing increased resistance to airflow".
In the nearly fifty years since the MRC report was published, the definition and classification system for chronic bronchitis (CB) have persisted without substantial modification, but the attention paid to CB has diminished substantially in comparison to other pulmonary conditions. Moreover, clinicians and researchers alike have tended in recent decades to focus on one particular form of CB, namely chronic obstructive bronchitis. That condition is especially serious, since it combines the activity limitations and increased mortality that are characteristic of COPD with the diminished quality of life associated with bronchitic symptoms. Furthermore, the presence of CB enhances the risk of exacerbations among those with COPD.
Unfortunately, research focused on the co-existence of COPD and CB has failed to inform the clinical management of non-obstructive chronic bronchitis (NCB), that is, CB occurring in the absence of or in advance of chronic airflow obstruction sufficient to warrant a proper diagnosis of COPD. An estimated 9 million individuals in the U.S. suffer from non-obstructive chronic bronchitis (NCB) and there is little consensus regarding how the condition should be managed. Some clinicians diagnose Chronic Obstructive Pulmonary Disease (COPD) in those with both chronic bronchitic symptoms and a suggestive history, but without confirming the diagnosis by spirometry, resulting in treatment of NCB patients with drugs whose efficacy has been demonstrated only in subjects with airflow obstruction. Others, assuming that NCB is a benign condition since it is not COPD, have ignored or failed to treat bronchitic symptoms at all. While neither of these approaches is justified, the scientific evidence base for the appropriate management of chronic bronchitis (CB) is admittedly sparse, making it difficult to define what the "correct" management approach should be.
Regardless of precisely how CB should be evaluated and managed, it is important to recognize that it is not a benign condition. All forms of CB, including NCB, appear to be associated with greater rates of chest infections, absence from work, and mortality. Research is needed to better understand NCB and other forms of CB to allow for appropriate methods for prevention, diagnosis, and treatment.
To explore opportunities for research in this area, the National Heart, Lung, and Blood Institute convened a workshop of investigators in Bethesda, Maryland on June 23-24, 2011 to review available studies and to recommend future research leading to new management approaches for all forms of CB. Participants were encouraged to especially consider NCB, since it has received scant attention from the scientific community in recent years. New basic research findings in disease pathogenesis were analyzed for their translational potential. Clinical research findings were assessed for their possible implications regarding pathogenesis, progression, and poly-morbidities. Opportunities for clinical trials of specific drugs were also discussed. The following topics were considered:
- Epidemiological data and relationship of CB with COPD and Asthma
- Assessment of burden of CB in terms of direct and indirect medical costs and impact on quality of life.
- Origin and pathogenetic mechanisms of CB
- Role of basic research and value of existing animal models
- Alterations of microbiome in CB
- Diagnostic tools for CB and their adequacy
- Mechanisms and role of mucus hypersecretion
- Roles of genetic factors, gender, age, geographical location
- Therapeutic options and indications
- Need for clinical trials
- Potential value of updating guidelines for diagnosis and treatment
- Need for discovery and development of new therapeutics and corresponding biomarkers to personalize and monitor these therapeutics
Based on these discussions, the group identified high priority research needs and developed specific research recommendations that could foster rapid advances toward disease preemption and personalized therapy. These are described in detail below.
The MRC definitions continue to describe the clinically relevant types of CB. Among these, NCB deserves special emphasis since it is associated with serious adverse outcomes and receives little research attention at this time. Better sub-typing of this condition is needed to enable investigations of molecular mechanisms that may contribute to the different forms of CB. Quantitative psychometric instruments that take into account variables like frequency of cough and mucus production may also be helpful in measuring NCB onset, severity, and progression. The regulation of mucus production in these patients and its relationship with cigarette smoking and other environmental exposures needs to be better defined, as does the segmental distribution of disease along the respiratory tree. A notable gap in knowledge is the role of the microbiome, including viral, bacterial and fungal organisms, in the origins and development of NCB. Environmental, seasonal, and geographical influences on the microbiome may be highly relevant in the context of NCB. Although some therapies are available, little is known regarding their efficacy, and it is likely that additional, novel therapies will be needed to substantially reduce morbidity and improve patient outcomes in all forms of CB.
- Better define the clinical characteristics of NCB and other forms of CB
- Investigate the molecular, cellular, microbiological, and physiological mechanisms that contribute to NCB and other forms of CB
- Develop better animal models of NCB and other forms of CB, and use these models to investigate pathogenetic mechanisms; better characterize the effects of cigarette smoking and smoking cessation, as well as other environmental factors such as viral and/or bacterial infection; and test novel concepts for prevention or treatment
- Perform clinical trials to test the efficacy of existing and novel management approaches, including smoking cessation, for prevention and treatment of NCB and other forms of CB
- Promote drug discovery and development to deliver new therapeutic approaches for NCB, particularly those aimed at treating overproduction of airway mucus and excessive cough
- Michael J. Holtzman, M.D., Washington University School of Medicine
- Dennis E. Niewoehner, M.D., VA Medical Center
- J. Edwin Blalock, Ph.D., University of Alabama at Birmingham
- Richard Boucher, M.D., University of North Carolina at Chapel Hill
- Homer A. Boushey, M.D., University of California, San Francisco
- Wellington V. Cardoso, M.D., Ph.D., Boston University School of Medicine
- Ronald G. Crystal, M.D., Weill Cornell Medical College
- Burton Dickey, M.D., The University of Texas MD Anderson Cancer Center
- MeiLan K. Han, M.D., M.S., University of Michigan, Ann Arbor
- Monica Kraft, M.D., American Thoracic Society and Duke Asthma Allergy and Airway Center
- David M. Mannino, M.D., University of Kentucky College of Public Health
- Fernando J. Martinez, M.D., M.S., University of Michigan, Ann Arbor
- Stephen P. Peters, M.D., Ph.D., Wake Forest University Health Sciences
- Irina Petrache, M.D., Indiana University
- Stephen I. Rennard, M.D., University of Nebraska
- Rubin M. Tuder, M.D., University of Colorado School of Medicine
- Judith Voynow M.D., Duke University
- John Walsh, Alpha-1 Foundation
- Robert A. Wise, M.D., Bloomberg School of Public Health
- Prescott Woodruff, M.D., University of California, San Francisco
- Antonello Punturieri, M.D., Ph.D., Division of Lung Diseases
- Thomas Croxton, Ph.D., M.D., Division of Lung Diseases
- James P Kiley, Ph.D., Division of Lung Diseases
1) Definition and classification of chronic bronchitis for clinical and epidemiological purposes. A report to the Medical Research Council by their Committee on the Aetiology of Chronic Bronchitis. Lancet. 1965 Apr 10;1(7389):775-9.
Last Updated November 2011