Viral Infection and Exacerbations of Chronic Obstructive Pulmonary Disease

James C. Hogg, Ph.D.

University of British Columbia, McDonald Research Laboratory,/iCAPTURE Centre, St. Paul's Hospital, Vancouver, Canada

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Population-based studies have established that persons with chronic lung disease experience more acute lower respiratory symptoms in association with an upper respiratory tract infection than healthy control subjects (1, 2). Smith and coworkers (2) were able to show greater numbers of viral isolates in association with an acute exacerbation of chronic obstructive pulmonary disease (COPD) compared with periods when no acute illness was present. Before the invention of the polymerase chain reaction (PCR), these types of data established a statistically significant relationship between an acute respiratory illness in patients with COPD and laboratory evidence of rhinovirus, influenza virus, parainfluenza virus, and coronavirus infection.

Seemungal and coworkers (3) return to this problem in this issue of the Journal (pp. 1618-1623) with a report based on a study of 137 patients with stable COPD recruited from the outpatient department of a London teaching hospital. These patients kept diary cards to record peak expiratory flow rate, any increase over their chronic stable symptoms of dyspnea, sputum volume and purulence (i.e., major symptoms), and/or evidence of nasal congestion, discharge, wheeze, sore throat, or cough (i.e., minor symptoms). An exacerbation was defined as an increase in two major symptoms or one major and one minor symptom on two consecutive days, where the first day was considered the day of onset. Laboratory investigation was initiated on the patients who reported to the clinic with an exacerbation whereas an exacerbation reported after the event was not investigated. Using these criteria, 321 exacerbations were reported by 83 of the 137 patients in the study and laboratory investigation was carried out in 168 of these 321. The 168 studied in the laboratory provided 67 positive PCR results, 4 positive cultures, and 10 patients with positive serology for an infectious agent. Rhinovirus accounted for 39 of 67 positive PCR results, respiratory syncytial virus (RSV) for 17, with the remainder being scattered over coronavirus (7 of 67), influenza B (2 of 67), parainfluenza (1 of 67), and Chlamydia pneumoniae (1 of 67). The four positive cultures included two for rhinovirus, and one each for influenza A and adenovirus, and neither of these were positive by PCR. The 10 cases with positive serology included 5 cases of influenza A, 3 of influenza B, and 2 of RSV. This heavy reliance on PCR to establish a diagnosis of viral infection requires comment.

The techniques available to study viral infection include culture to prove replication of complete viral particles, hybridization techniques performed with or without PCR to detect viral nucleic acids, immunohistochemistry to detect viral proteins, electron microscopy to demonstrate a fully assembled virus, and measurements of a specific host immune response to the virus in either serum or cells or tissue. These techniques test for different things, have different sensitivities and specificities, and the predictive power of a positive result is highly variable. Most are impractical for routine use because they are expensive to perform, require expert interpretation, and are not widely available outside specialized centers. PCR is an attractive method because it provides the greatest sensitivity, and a single specimen can be screened for several types of virus, using the newer multiplex methods. The downside of PCR is that it may be too sensitive in that it can detect small amounts of residual viral nucleic acid when there is no other laboratory or clinical evidence that a viral infection is present (4). As viral infections come and go, often in a subclinical fashion, they might leave small amounts of their nucleic acid behind to be demonstrated during an exacerbation of COPD caused by something else. The earlier studies by Smith and coworkers (2) used far less sensitive methods, but reduced the risk of a false-positive result by studying patients twice: once when they were having an exacerbation and on another occasion when they were well. They attributed only those cases with a positive test during the exacerbation and a negative test when the patient was well. This approach helps to rule out individuals who are simply carriers of the virus. A similar approach might have resulted in a more conservative interpretation of the present study.

In spite of this technical caveat, the authors' conclusion that a substantial proportion of COPD exacerbations are due to viral infection is compelling. An exacerbation associated with a virus produced more symptoms, more laboratory evidence of an acute-phase response, and a prolonged recovery phase. The predominance of rhinovirus infection is of interest in that its receptor (intercellular adhesion molecule 1, ICAM-1) is upregulated in the airway epithelium of smokers (5, 6) and this might assist the virus in establishing an infection in the lower airways (7). The observation that the symptoms of a cold could be present up to 18 days before the onset of an exacerbation is also relevant to the fact that acute viral infections predispose to bacterial infection and might initiate an exacerbation that requires antibiotic therapy (8).

Fabbri and coworkers (9) have pointed out that acute episodic disease is used to define asthma, whereas exacerbations are not included in the definition of COPDeven though this type of acute illness may be the most common reason that a patient with COPD seeks medical attention. The data of Seemungal and coworkers suggest that viral infection may initiate many of these acute events in patients with COPD and that rhinovirus is the most common etiologic agent. As ICAM-1 is known to be the receptor for the rhinovirus, this molecule might be an attractive target for therapy in this frequently disabling and expensive clinical problem.

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