Q J Med 2001; 94: 1-3
© 2001 Association of Physicians
Editorial |
The rhinovirus—not such an innocent?
Allergy and Clinical Immunology Unit, 2nd Department of Paediatrics, University of Athens, Greece National Heart and Lung Institute at St Mary's, Imperial College School of Medicine, London, UK
Human rhinoviruses (RVs) are probably the commonest pathogens afflicting mankind.1 They were isolated some four decades ago from common cold sufferers, and several epidemiological studies have confirmed that they are by far the commonest common cold viruses after the first years of life.2 However, in all these years, the general consensus was that the common cold, and consequently RVs, represented a mild nuisance, rather than a true disease, and not much attention has been paid to them. Evidence suggesting that RV infections can also produce serious complications came early,3 but since they involved immunocompromised patients, they were still considered exceptional. Nevertheless, data supporting the view that RV infection can result in considerable morbidity and even mortality has steadily increased, becoming compelling during recent years. Several factors have attributed to this change of view. Most certainly, our understanding of the epidemiology and complications of RV infections is now much clearer, partly due to advances in detection methodology.4 In addition, the prevalence of respiratory diseases related to RV infections, most notably asthma, has increased dramatically during the last decades, probably a result of environmental and/or lifestyle changes.5 Finally, an increasing awareness of economic aspects of health eventually revealed that direct and indirect costs of RV infections are substantial.6
The details of social and ecological alterations and economical implications are out of the scope of this editorial. In contrast, the medical consequences of RV infections are undoubtedly a daily experience for most physicians—not infrequently a personal one!
RV colds per se will keep an average person in bed for about a whole year of their lives.1 However, this is not necessarily a big concern—there are even suggestions that this may be part of our immune system's regular training.7 In contrast, the complications of RV infection are unquestionably significant diseases with appreciable morbidity and mortality. RV infections are the commonest trigger of asthma exacerbations, are very frequently implicated in other respiratory diseases such as otitis media and sinusitis, and evidence suggesting their involvement in pneumonia and exacerbations of COPD and cystic fibrosis is increasing.
There is no doubt that the advent of the polymerase chain reaction (PCR) and the development of sensitive PCR protocols for the detection of RVs has contributed enormously to the evaluation of RV involvement in respiratory diseases.8 RVs are difficult to culture, and due to the large number of serotypes, serological diagnosis is not feasible. PCR methods developed in research labs have been shown to be between 3–5 times more successful in identifying rhinoviruses than the best available standard (culture) methods. For this reason, any serious attempt to diagnose RV infections must use PCR. Indeed PCR methods are now being adopted by increasing numbers of clinical diagnostic laboratories (Vivienne James, Public Health Laboratory Service UK, personal communication). Furthermore, viral shedding decreases in parallel to cold symptoms, i.e. earlier than the development of complications that would lead a patient to visit their physician or the hospital. Therefore, prospective studies using PCR are more likely to be able to evaluate the involvement of RVs in airway disease.
In such studies, it was shown that asthma exacerbations are associated with virally confirmed colds in over 80% of exacerbations in children9 and 60% in adults (Corne & Johnston, manuscript in preparation), RVs accounting for more than half these colds. Additionally, the seasonal distribution of hospital admissions for asthma parallels the identification rates of respiratory viruses in the community and, most interestingly, peaks soon after the start of school terms.10 This pattern of segregation-dependent disease is a characteristic of RV colds, in contrast to other respiratory viruses such as influenza and RSV that occur in well-defined epidemics each winter. Time-trend analysis has also suggested that asthma mortality can be partly attributed to virus-induced episodes, particularly in the young and in the elderly.11
Asthma is an increasing public health problem, currently costing more on a global scale than tuberculosis and HIV/AIDS combined.12 In addition to days lost from work or school, hospitalizations and the fortunately infrequent mortality, asthma patients feel in many cases socially stigmatized by their chronic disease, adding an important psychological and quality-of-life parameter to the problem. The role of RVs, which as mentioned are responsible for around half of asthma exacerbations, cannot be overlooked.
Further correlations of RVs with respiratory diseases have been known for some time, but are frequently underestimated. In prospective studies even before the advent of PCR, it was shown that at least 45% of episodes of acute otitis media are preceded by a common cold.13 RVs and RSV were the agents most frequently isolated from the middle ear effusion. In more detailed studies of RV infection in humans, a dysfunction of the tympanic membrane has been shown to exist in 80% of colds.14
Similar are the findings in regard to acute sinusitis. In a recent study using high-resolution CT scans, sinus inflammation was present in the majority of colds. As in the case of otitis, RVs have been isolated from the sinuses.15 Furthermore, fluticasone propionate treatment tended to prevent paranasal sinusitis, especially in RV-positive subjects.16 In both otitis and sinusitis, the microbiological, virological and clinical data indicate that RVs can be the unique cause, as well as predisposing to bacterial complications.
In regard to pneumonia, there is little doubt that in young children respiratory viruses are the main agents implicated.17 In contrast, the aetiology of community-acquired pneumonia in older children and adults is still debated.18 This is partly due to the fact that the presence of any agent (bacterial or viral) does not necessarily indicate a causative role, especially for organisms for which the clinical significance and/or duration of a carrier state has not been established. It should be emphasized that a study investigating the role of viral infections in community acquired pneumonia using methods of adequate spectrum and sensitivity has yet to be carried out.
Although circumstantial evidence has suggested that RVs may be implicated in community-acquired pneumonia, there has been a considerable skepticism regarding the ability of RVs to directly cause the disease. This was based on the belief that RVs could not replicate in the lower airway where the temperature is 37°C, preferring cooler temperatures that occur in the nose.19 However, we showed that differences in RV replication between 33°C and 37°C are minimal, and there may even be strains that prefer the higher temperature, suggesting that temperature itself is not an important factor in relation to upper and lower airway infections with RV.20 More importantly, we proceeded to show that following an experimental RV cold in human volunteers, the virus can be detected and is replicating in the bronchial epithelium.21 Furthermore, the finding that the detection frequency in the lower airway was the same as that observed in the upper respiratory airway suggested that lower-airway infection with RV is likely to be the norm rather than the exception.
The finding that RVs can directly infect the lung supports suggestions for these agents as the sole cause of pneumonia, without excluding the possibility of a role for bacterial superinfection in addition. Indeed, in a study of immunocompromised children with a RV respiratory infection, 32% developed fatal pneumonia, and in most of them no other agents could be isolated either before death from bronchoalveolar lavage fluid, or from autopsy specimens.22
Furthermore, there is increasing evidence that direct RV infection of the lungs may result in pulmonary function abnormalities and disease progression observed in children with cystic fibrosis and bronchopulmonary dysplasia.23,24 The RV-related morbidity and mortality in the immunocompromised should not be overlooked. More than a decade ago, it was shown that 66% of hospitalized children from whom RV was isolated had a severe underlying disease.25 Most of these children were admitted for acute respiratory disease, and focal infiltrates were present in their X-rays.
Finally, in addition to their association with a significant burden of disease in the young, the epidemiological burden of RV infections is also heavy in the elderly. It is widely accepted that colds may result in lower respiratory or systemic involvement in the aged, leading to hospitalizations and even death. RVs were around 50% of identified viruses in respiratory episodes in this age group.26 In comparison to normal adults, elderly subjects have double the duration of illness, and complications in 62% of RV infections, in contrast to 5–34% reported in the control group.26 While mortality is generally not high in the overall population, it can be considerable in long-term care facilities, where RV outbreaks may occur due to segregation. In one study such an outbreak resulted in 3% mortality.27
In conclusion, there is little doubt that RVs, which for many years have been regarded as relatively benign pathogens, can in fact cause considerable morbidity, cost a lot of money, and kill, particularly if the host is weak. Several pharmaceutical companies are now developing antiviral agents against RVs. These agents clearly require further development, but they must also be matched with parallel development in rapid diagnosis if they are to be effectively targeted. It will be interesting to see how these agents impact on the increasingly evident clinical burden of disease if they reach the clinic.
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