The role of viruses in contributing to the exacerbation of pulmonary symptoms and progression of lung disease in CF has been the subject of numerous studies during the past three decades (1
). Most of these studies have relied on viral detection in clinical specimens by using standard tissue culture, immunofluorescence, or serological assays, and, not surprisingly, most found a positive correlation between the presence of respiratory viruses and worsening of symptoms. In general, typical respiratory viruses have been identified in these studies, although their relative frequencies vary widely among studies, most likely due to differences in detection methods, patient ages, and seasons. Respiratory syncytial virus (RSV) has typically been the most common virus identified, followed by influenza A and B viruses (328
). Parainfluenza virus and adenovirus have usually been found at lower frequencies, and older studies did not include assays for the detection of coronavirus or human metapneumovirus. Several studies have shown that although the frequency of infection, seasonal occurrence, and distribution of viruses involved do not differ significantly between CF patients and non-CF controls, infections of CF patients are often more severe and have a longer duration (132
More recently, nucleic acid-based detection methods, including virus-specific PCR and microarray-based assays, have been used to investigate the epidemiology of viral respiratory infection in CF patients. Punch and colleagues (241
) used a multiplex reverse transcriptase PCR assay capable of detecting influenza A and B viruses; parainfluenza viruses 1, 2, and 3; RSV; and adenovirus to investigate 52 sputum samples from 38 Australian adults with CF who were hospitalized with exacerbations of respiratory symptoms. Overall, 12 (23%) of the samples were PCR positive: 4 samples were positive for influenza B virus, 3 each were positive for parainfluenza and influenza A viruses, and 2 were positive for RSV. A study by Olesen and colleagues (225
) employed PCR assays for the same viruses as well as for human rhinovirus and human metapneumovirus in a prospective study of 75 Danish children (median age, 8 years) whose sputum samples were tested monthly during a 12-month period in 2002 and 2003. A total of 96 specimens from 45 patients were virus PCR positive, with rhinovirus accounting for the great majority of virus isolates (87%). Parainfluenza virus accounted for 6% of the positive specimens, influenza A virus accounted for 3% of the positive specimens, and adenovirus and RSV each accounted for 2% of positive tests; no specimens were PCR positive for influenza B virus or metapneumovirus. In contrast, Garcia and colleagues (104
) used serological assays to detect metapneumovirus infection in 20 of 42 (48%) children aged 7 to 18 years with acute respiratory illness studied prospectively at a Texas CF care center during a 7-month period in the winter of 1998 and 1999.
Another recent prospective study by Wat and colleagues (341
) assessed the incidence of respiratory viruses in 71 Welsh children (median age, 9 years) with CF during a 17-month period between 2002 and 2004. Nasal swabs were obtained whenever subjects had an exacerbation of respiratory symptoms and/or when subjects were asymptomatic during bimonthly clinic visits. Specimens were examined for the presence of respiratory viruses, including influenza A and B viruses, RSV, parainfluenza virus types 1 to 4, rhinovirus, and coronavirus by using real-time nucleic acid sequence-based amplification. Among the 138 specimens obtained during episodes of respiratory exacerbation, 63 (46%) were positive for one of the viruses included in the test panel. In contrast, 23 of 136 (17%) specimens from asymptomatic patients were positive. Rhinovirus was the most common virus detected for both groups, and significantly more influenza viruses were detected in children with exacerbations than in those without exacerbations.
The observation made by several older studies that respiratory viral infections are no more frequent in individuals with CF than in non-CF controls was again demonstrated recently in a prospective study from the Netherlands (327
). Twenty young children with CF (mean age, 3.5 years) and 18 age-matched, healthy, non-CF control subjects were contacted twice weekly during a 6-month winter period. Nasal swabs were collected when children had respiratory symptoms or at least every 2 weeks and examined by using PCR assays to detect rhinovirus, enterovirus, coronavirus, adenovirus, metapneumovirus, RSV, and influenza A and B viruses. No differences between the CF patients and controls in either the frequency of respiratory viral infection or the distribution of the viruses involved were found. Rhinovirus was detected in all of the study subjects; coronavirus and enterovirus were the next most common viruses detected. Metapneumovirus and influenza viruses were found in only seven and three children, respectively.
Although it seems clear that the epidemiology of respiratory virus infection among persons with CF does not differ significantly from that of the general population, the impact that such infections have on the progression of pulmonary disease in CF remains an active area of investigation. Evidence from both in vitro
and in vivo
models strongly suggests that synergy between viruses and bacteria plays an important role in promoting bacterial colonization of the respiratory epithelium and possibly in decreasing bacterial clearance from lungs (142
). Recent studies also suggest that respiratory viruses interact with CF epithelial cells to potentiate the proinflammatory effects of bacterial infection, possibly through facilitating the dispersal of bacteria from biofilms within the airway lumen (267