© 2006 American Thoracic Society doi: 10.1164/rccm.200609-1387ED
Rhinovirus InfectionsMore Than a Common ColdUniversity of Michigan, Ann Arbor, Michigan
National Heart and Lung Institute, Imperial College London, London, United Kingdom Rhinoviruses, single-stranded RNA viruses from the Picornaviridae family, are responsible for the majority of common colds. Perhaps more importantly, viral infections trigger the great majority of asthma exacerbations, and rhinoviruses account for two-thirds of these (1). A recent study detected rhinoviruses in 82% of children admitted to an emergency room for acute asthma (2). Rhinovirus infection has also been associated with nearly half of all chronic obstructive pulmonary disease (COPD) exacerbations (3). In addition, evidence has emerged that rhinoviruses are the most common cause of wheezing illness in the first year of life, and rhinovirus-induced wheezing illness in the first year of life is the strongest predictor of subsequent third-year wheezing (4). The precise mechanism by which rhinoviruses induce exacerbations of airway disease is unknown. Because rhinovirus replication is optimal at 33°–35°C, infections were once thought to be restricted to upper airway tissues. Until recently, rhinoviruses had not been reliably cultured from lower airway secretions. However, rhinoviruses can replicate in lower airway cells even at core temperature, although greater viral yields are obtained at cooler temperatures (5). Also, temperatures of the large airways are 33°–35°C during resting breathing at room temperature (6). Thus, conditions in the lower airways may be permissive for rhinovirus replication. After experimental infection, rhinovirus RNA has been detected in lower airway secretions and epithelial cells (7, 8), and rhinovirus capsid protein has been found in airway epithelial cells, albeit sporadically (9). Together these findings suggest that rhinoviruses can grow in the lower airways, although the extent of rhinovirus replication in these locations is unknown. It is conceivable that certain individuals are more susceptible to rhinovirus infection and its complications. Compared with normal volunteers, adults with asthma have increased susceptibility to rhinovirus infection both in vitro (10, 11) and in vivo (12). The mechanisms of this increased susceptibility are just beginning to be understood and relate to impaired innate immune responses (10, 11). A recent study examining the persistence of rhinovirus RNA after asthma exacerbation in children showed that RNA was detectable in 44% of patients 6 weeks after infection, and exacerbations with persistent virus were more severe (2). These data suggest that individuals with asthma possess increased susceptibility to rhinovirus infections. The possibility that host factors contribute to rhinovirus susceptibility merits investigation. In this issue of the Journal (pp. 1392–1399), Kaiser and colleagues (13) describe an immunosuppressed lung transplant recipient who was chronically infected for 13 months with a single rhinovirus strain. Despite retransplantation, 5 of 12 subsequent bronchoalveolar lavage specimens were positive for rhinovirus by cell culture, and the patient died of progressive respiratory failure. Rhinovirus-positive cells were detected in the lung parenchyma by immunohistochemistry. Sequencing of the viral protein 1 capsid glycoprotein and a portion of the 5' noncoding region confirmed persistence of the same rhinovirus strain, which was serologically closely related to serotypes 64 and 94. An additional prospective study of 68 lung transplant recipients showed persistent rhinovirus infection for many months in two additional patients, one of whom also died of respiratory failure; the other appeared to clear the virus after 8 months, and this was accompanied by resolution of clinical illness. Why is this report important? This article has obvious ramifications for the growing number of patients undergoing bone marrow and solid organ transplant patients, in whom opportunistic infection with viruses, bacteria, fungi, and parasites is common. Although Kaiser and coworkers (13) did not identify gross histologic modification of the lung parenchyma, the persistence of single strains of rhinovirus accompanied by persistent clinical symptoms, combined with progressive respiratory failure in two of three patients, suggests that rhinoviruses can cause clinically significant, chronic lower respiratory tract infections in immunosuppressed patients. Respiratory syncytial virus, influenza viruses, and parainfluenza viruses have all been reported to cause serious lower respiratory tract infections in immunocompromised hosts, and human metapneumovirus has recently been added to this list (14). Specific antiviral therapies are available for influenza viruses and are in development for each of the others; thus, early diagnosis will be essential for optimal management of these serious infections. In appropriate situations, diagnostic tests for rhinoviruses are therefore clearly warranted and efforts to hasten development of antiviral agents are urgently needed. The report by Kaiser and colleagues (13) ends once and for all the argument that rhinoviruses cannot infect the lower airways. Although interesting new data suggest that rhinoviruses may induce proinflammatory responses in lung cells independent of viral replication (15), replication is almost certainly required for a maximal response. However, until the present report, which includes positive bronchoalveolar cultures and lung immunohistochemistry, incontrovertible evidence of rhinoviral replication in the lung in the setting of spontaneous infection has been lacking. This report informs our understanding of the mechanisms underlying rhinovirus-induced exacerbations of asthma and COPD.
Although transplant patients are clearly different from most patients with chronic airway disease, the data presented by Kaiser and colleagues (13) are consistent with the notion that immune defects predispose patients to rhinovirus infection. Indeed, it has been shown that peripheral blood monocytes from patients with asthma have a deficient type II interferon- FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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