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Detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease.

Common colds are associated with exacerbations of chronic obstructive pulmonary disease (COPD). However, the role of the common cold virus (human rhinovirus) in the production of symptoms and lower airway inflammation at COPD exacerbation is unknown. Thirty three patients with moderate-to-severe COPD were seen at baseline, when the number of chest infections in the previous year was noted, and acutely at COPD exacerbation. Within 48 h after the onset of the exacerbation and at baseline, nasal aspirates and induced sputum were taken for rhinovirus reverse transcriptase polymerase chain reaction (RT-PCR) analysis and determination of cytokine levels. Symptoms, recorded on diary cards, were noted and forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured. At exacerbation, mean FEV1 and FVC fell significantly from baseline (p<0.001). Ten of 43 exacerbations were associated with rhinovirus infection, detected in induced sputum. In four of these, nasopharyngeal samples contained no detectable rhinovirus. All baseline samples were negative for rhinovirus. The simultaneous presence of increased nasal discharge/nasal congestion (in 26 of the 43 exacerbations) and increased sputum (29 exacerbations) was strongly associated with the presence of rhinovirus (odds ratio 6.15; p=0.036). Total symptom scores were greater for rhinovirus as compared to nonrhinovirus exacerbations (p=0.039). Median baseline sputum interleukin-6 levels rose from 90.2 to 140.3 pg x mL(-1) at exacerbation (p=0.005); the change was greater in the presence of rhinovirus infection (p=0.008). Rhinovirus infection can be detected at chronic obstructive pulmonary disease exacerbation. This is associated with elevation of lower airway interleukin-6 levels, which may mediate lower airway symptom expression during chronic obstructive pulmonary disease exacerbations.

Aged↗

Rhinovirus infection induces expression of its own receptor intercellular adhesion molecule 1 (ICAM-1) via increased NF-kappaB-mediated transcription.

Virus infections, the majority of which are rhinovirus infections, are the major cause of asthma exacerbations. Treatment is unsatisfactory, and the pathogenesis unclear. Lower airway lymphocyte and eosinophil recruitment and activation are strongly implicated, but the mechanisms regulating these processes are unknown. Intercellular adhesion molecule-1 (ICAM-1) has a central role in inflammatory cell recruitment to the airways in asthma and is the cellular receptor for 90% of rhinoviruses. We hypothesized that rhinovirus infection of lower airway epithelium might induce ICAM-1 expression, promoting both inflammatory cell infiltration and rhinovirus infection. We therefore investigated the effect of rhinovirus infection on respiratory epithelial cell ICAM-1 expression and regulation to identify new targets for treatment of virus-induced asthma exacerbations. We observed that rhinovirus infection of primary bronchial epithelial cells and the A549 respiratory epithelial cell line increased ICAM-1 cell surface expression over 12- and 3-fold, respectively. We then investigated the mechanisms of this induction in A549 cells and observed rhinovirus-induction of ICAM-1 promoter activity and ICAM-1 mRNA transcription. Rhinovirus induction of ICAM-1 promoter activity was critically dependent upon up-regulation of NF-kappaB proteins binding to the -187/-178 NF-kappaB binding site on the ICAM-1 promoter. The principal components of the rhinovirus-induced binding proteins were NF-kappaB p65 homo- or heterodimers. These studies identify ICAM-1 and NF-kappaB as new targets for the development of therapeutic interventions for virus-induced asthma exacerbations.

Asthma↗

Rhinovirus infection associated with serious lower respiratory illness in patients with bronchopulmonary dysplasia.

OBJECTIVE: To determine the characteristics of rhinovirus infection in patients with bronchopulmonary dysplasia. SUBJECTS AND METHODS: Between July 1, 1993, and July 1, 1995, 40 patients with bronchopulmonary dysplasia were identified. Viral cultures were obtained in ambulatory patients presenting with an acute respiratory illness requiring hospitalization or in hospitalized patients with a respiratory deterioration. When rhinovirus was isolated epidemiologic data were collected, and the characteristics of the illness, its severity and outcome were noted. Key features of rhinovirus and respiratory syncytial virus (RSV) bronchiolitis were compared. RESULTS: There were 8 cases of lower respiratory tract illness associated with rhinovirus infection in 6 infants (mean age, 7.1 +/- 4.1 months) and 1 child (age, 40 months), an incidence of 0.15 infection/patient year. The mean gestational age and birth weight of these patients were 27.3 (+/- 2.75) weeks and 853 (+/-341) g, respectively. There were 5 males. Four patients needed intensive care unit admission and 1 required mechanical ventilation. By comparison there were 13 cases of RSV bronchiolitis, an incidence of 0.25 infection/patient year. The 2 groups were similar epidemiologically and an equal proportion of patients with rhinovirus and RSV needed intensive care unit admission. A greater percentage of patients with RSV required mechanical ventilation (50% vs. 14%), but this difference was not statistically significant. Three cases of rhinovirus were nosocomial, and 1 infant had a second infection. Four patients required 5 hospitalizations caused by rhinovirus infection, and the mean duration of hospital stay was 11 days. All children had sustained worsening in their respiratory status after rhinoviral illness requiring additional therapy. CONCLUSIONS: Rhinovirus is a common and potentially serious lower respiratory pathogen in bronchopulmonary dysplasia patients. Rhinovirus infection has lasting pulmonary sequelae in these children.

Acute Disease↗

Natural and experimental rhinovirus infections of the lower respiratory tract.

Rhinoviruses are the cause of the majority of common colds, but their role in lower respiratory disorders is less clear. Recent studies using the polymerase chain reaction to detect rhinoviruses have established respiratory viral infections as major factors in the induction of acute exacerbations of asthma in both adults and children, both in mild exacerbations and in more severe exacerbations leading to hospital admission. Rhinoviruses were the major virus type detected in these studies, accounting for two-thirds of viruses detected. It is not known whether rhinoviruses produce their effects by directly invading the lower airway or by indirect means. Previous clinical studies provide some evidence that rhinoviruses are capable of infecting the lower airway. However, the immunologic response, both in the upper and lower airways, remains poorly defined. Recent studies have provided evidence of increased cellular activation in peripheral blood and in bronchial biopsies in atopic subjects compared with normal subjects during experimental rhinovirus infections. The reasons for these different cellular responses are unclear. Rhinoviruses as well as other respiratory viruses have been shown to increase levels of a variety of cytokines from respiratory epithelium, monocytes, or macrophages. Prominent among these cytokines is interleukin (IL)-8. We have detected increased levels of IL-8 in nasal secretions from subjects with wild-type rhinovirus infections. We studied the mechanisms of rhinovirus-induced IL-8 production and and found protein release from both pulmonary epithelial and peripheral blood mononuclear cells. This protein production was accompanied by increased mRNA expression and evidence of infection of both pulmonary epithelial and monocyte cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Infection of a human respiratory epithelial cell line with rhinovirus. Induction of cytokine release and modulation of susceptibility to infection by cytokine exposure.

Rhinovirus infections cause over one third of all colds and are a contributing factor to exacerbations of asthma. To gain insights into the early biochemical events that occur in infected epithelial cells, we develop, for the first time, a model in which a pure respiratory epithelial cell population can be routinely infected by rhinovirus. Viral infection was confirmed by demonstrating that viral titers of supernatants and lysates from infected cell increased with time and by PCR. Infection by rhinovirus 14 was inhibited by homotypic antiserum and by antibodies to intercellular adhesion molecule-1 (ICAM-1), the receptor for this virus. Susceptibility of epithelial cells to infection by rhinovirus 14 (but not rhinovirus 2, an ICAM-1 independent strain) can be increased by preexposure of cells to TNF alpha, whereas IFN gamma reduces susceptibility to infection by both rhinovirus strains. Rhinovirus infection per se does not markedly alter ICAM-1 expression on epithelial cells. Finally, we demonstrate that rhinovirus infection induced increased production of IL-8, IL-6, and GM-CSF from epithelial cells. Production of IL-8 correlated with viral replication during the first 24 h after infection. This model should provide useful insights into the pathogenesis of rhinovirus infections.

Base Sequence↗

Airborne rhinovirus detection and effect of ultraviolet irradiation on detection by a semi-nested RT-PCR assay.

BACKGROUND: Rhinovirus, the most common cause of upper respiratory tract infections, has been implicated in asthma exacerbations and possibly asthma deaths. Although the method of transmission of rhinoviruses is disputed, several studies have demonstrated that aerosol transmission is a likely method of transmission among adults. As a first step in studies of possible airborne rhinovirus transmission, we developed methods to detect aerosolized rhinovirus by extending existing technology for detecting infectious agents in nasal specimens. METHODS: We aerosolized rhinovirus in a small aerosol chamber. Experiments were conducted with decreasing concentrations of rhinovirus. To determine the effect of UV irradiation on detection of rhinoviral aerosols, we also conducted experiments in which we exposed aerosols to a UV dose of 684 mJ/m2. Aerosols were collected on Teflon filters and rhinovirus recovered in Qiagen AVL buffer using the Qiagen QIAamp Viral RNA Kit (Qiagen Corp., Valencia, California) followed by semi-nested RT-PCR and detection by gel electrophoresis. RESULTS: We obtained positive results from filter samples that had collected at least 1.3 TCID50 of aerosolized rhinovirus. Ultraviolet irradiation of airborne virus at doses much greater than those used in upper-room UV germicidal irradiation applications did not inhibit subsequent detection with the RT-PCR assay. CONCLUSION: The air sampling and extraction methodology developed in this study should be applicable to the detection of rhinovirus and other airborne viruses in the indoor air of offices and schools. This method, however, cannot distinguish UV inactivated virus from infectious viral particles.

Air Microbiology↗

Duration of protection of calves against rhinovirus challenge exposure by infectious bovine rhinotracheitis virus-induced interferon in nasal secretions.

Six calves inoculated intranasally with a vaccinal strain of infectious bovine rhinotracheitis (IBR) virus and 6 control calves were given a placebo. All calves were subsequently challenge exposed (by aerosol) with rhinovirus--3 of the calves from each group at 2 days after they were inoculated with IBR virus or with placebo and the remaining calves at 6 days. Nasal excretion of viruses, interferon (IFN) concentrations in nasal secretions (NS), and neutralizing antibody in sera and NS were determined. All calves given the vaccinal IBR virus subsequently had IFN in their NS. Interferon was detected as early as 1 day, reached maximal titers at 2 to 4 days, and persisted in individual calves for 5 to 10 days after inoculation. Rhinovirus shedding was not detected from IBR virus-inoculated calves whose NS contained both rhinovirus antibody and IFN at the time of challenge exposure; such calves were protected at either 2 or 6 days after IBR virus inoculation. The outcome of rhinovirus challenge exposure of calves whose NS contained IFN, but not rhinovirus antibody, varied with the day of challenge exposure. Rhinovirus excretion was detected from 2 of these calves challenge exposed 2 days after IBR virus inoculation, but was not detected from a calf challenge exposed 6 days after inoculation. However, while IFN was present in NS from the former 2 calves, rhinovirus shedding was markedly reduced as compared with that from control calves without IFN or NS antibody at the time of challenge exposure. Consistent relationship was not observed between the rhinovirus neutralizing antibody titer of calves' sera and NS. The antibody titer of NS more closely correlated with protective immunity to rhinovirus infection than did the serum antibody titer.

Animals↗

Virological and serological analysis of rhinovirus infections during the first two years of life in a cohort of children.

The occurrence of rhinovirus infections in a cohort of 329 children during the first 2 years of life was determined by virus detection and serological methods. Rhinovirus detection on nasopharyngeal aspirates and middle ear fluids comprised a combination of virus isolation in HeLa Ohio cells and a reverse transcription-polymerase chain reaction (RT-PCR)-hybridization assay on the inoculated cell cultures. Nasopharyngeal aspirates were collected when the child was referred to the study clinic because of respiratory symptoms. Nasopharyngeal aspirates and middle ear fluids were collected after clinical diagnosis of an acute otitis media. Complement-fixing antibodies to rhinovirus were determined from scheduled serum specimens collected at 6, 12, 18, and 24 months of age and from paired sera taken in the cases of acute otitis media. Rhinovirus infections were shown to be common in infants, 24% of the children had complement-fixing antibodies at the age of 6 months and 22% had had at least one rhinovirus episode indicated by virus detection. At the age of 2 years, 91.3% of the children had rhinovirus-specific antibodies, while 79% of the children had experienced rhinovirus infection as judged by the virus detection tests. However, the complement-fixation assay was poor as a diagnostic test. Of 458 acute otitis media episodes studied, 41% were shown to be associated with a rhinovirus by RT-PCR-hybridization, while significant fourfold rise in rhinoviral antibodies was detected only in 7% of the cases.

Acute Disease↗

Translation and replication properties of the human rhinovirus genome in vivo and in vitro.

The poor translation efficiency of genome-length human rhinovirus RNA in vitro using HeLa cell extract-supplemented rabbit reticulocyte lysate has hampered the study of rhinovirus IRES-mediated translation and polyprotein synthesis in a cell-free system. In contrast, the efficient in vitro translation characteristics of poliovirus RNAs have ultimately allowed the programming of cell-free coupled translation/replication extracts which are able to produce infectious poliovirus particles in vitro. A possible explanation for the decreased burst size observed during the course of a rhinovirus infection, compared to poliovirus infection, is reduced levels of polyprotein synthesis in vivo. In order to test this hypothesis and extend in vitro translation/replication technology to the study of human rhinoviruses, a chimeric cDNA construct was engineered which allowed the in vitro synthesis of T7 transcripts containing the intact poliovirus type 1 (PV1) 5' noncoding region (5' NCR) and initiation codon upstream of the human rhinovirus 14 (HRV14) polyprotein-coding region and 3'-terminal sequences. These chimeric RNAs translated efficiently in vitro and were used successfully to program a cell-free replication extract. Unexpectedly, parental HRV14 RNAs also translated efficiently in the HeLa cell-free translation/replication extract but replicated less efficiently than the chimera in vitro. The chimeric HRV14/PV1 RNAs were infectious and gave rise to a virus with a growth phenotype similar to that of parental HRV14. Preliminary characterization of this chimeric virus suggests that the biological properties characteristic of rhinovirus in vivo are determined primarily by the rhinovirus gene products. Although the translation efficiency of the HRV14 5' NCR may be a limitation in rabbit reticulocyte lysate-based in vitro translation extracts, it does not appear to be a major limiting determinant for growth of rhinovirus in vivo or replication in the HeLa cell-free extract.

Animals↗

Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study.

BACKGROUND: Rhinovirus infections cause exacerbations of asthma. We postulated that people with asthma are more susceptible to rhinovirus infection than people without the disease and compared the susceptibility of these groups. METHODS: We recruited 76 cohabiting couples. One person in every couple had atopic asthma and one was healthy. Participants completed daily diary cards of upper-respiratory-tract (URT) and lower-respiratory-tract (LRT) symptoms and measured peak expiratory flow twice daily. Every 2 weeks nasal aspirates were taken and examined for rhinovirus. Mixed models were used to compare risks of infection between groups. We also compared the severity and duration of infections. FINDINGS: We analysed 753 samples. Rhinovirus was detected in 10.1% (38/378) of samples from participants with asthma and 8.5% (32/375) of samples from healthy participants. After adjustment for confounding factors, asthma did not significantly increase risk of infection (odds ratio 1.15, 95% CI 0.71-1.87). Groups did not differ in frequency, severity, or duration of URT infections or symptoms associated with rhinovirus infection. First rhinovirus infection was associated more frequently with LRT infection in participants with asthma than in healthy individuals (12 of 28 infections vs four of 23, respectively, p=0.051). Symptoms of LRT associated with rhinovirus infection were significantly more severe (p=0.001) and longer-lasting in participants with asthma than in healthy participants (p=0.005). INTERPRETATION: People with atopic asthma are not at greater risk of rhinovirus infection than healthy individuals but suffer from more frequent LRT infections and have more severe and longer-lasting LRT symptoms.

Adult↗

Development and application of a new method for amplification and detection of human rhinovirus RNA.

A method based on nucleic acid sequence based amplification (NASBA) was developed for detection of rhinovirus RNA. Appropriate collection and storage conditions for maintenance of rhinovirus RNA integrity in clinical samples was determined. Two silica-based extraction methods were evaluated for preparation of RNA from virus isolates and clinical samples. Primers and probes were selected from the non-translated region at the 5' end and from VP4 of sequenced rhinoviruses. Amplified products were detected by 'in-solution' hybridization, with analysis by polyacrylamide gel electrophoresis (enzyme linked gel assay or ELGA), and by a microtitre-based plate hybridization assay. Using propagated picornavirus isolates in vitro the rhinovirus NASBA, with detection of amplified sequences by ELGA or plate hybridization, was confirmed as sensitive and specific for detection of rhinovirus RNA. The method was applied successfully to analysis of rhinovirus sequences in clinical samples from individuals with respiratory-tract symptoms. Rhinovirus NASBA will be useful for studies of the molecular epidemiology of respiratory infections and monitoring of response to anti-rhinovirus therapy.

Common Cold↗

[Rhinovirus and acute respiratory infections in hospitalized children. Retrospective study 1998-2000].

OBJECTIVES: Rhinoviruses are the most common aetiological agents of colds, but the frequency and the severity of other locations of the infection are not well known. This study describes the clinical aspects and the severity of rhinovirus infections in hospitalised children. METHODS: Isolation in culture and a RT-PCR were performed for the detection of rhinovirus in nasal aspirates from hospitalised children from September 1998 to October 2000. A group of 211 children found to be positive for rhinovirus was studied. RESULTS: Rhinovirus-infected children suffered from the following clinical syndromes: 60 (28.4%) upper airway infections, 81 (38.4%) bronchiolitis, 25 (11.9%) pneumonias and 12 (4.7%) acute attacks of asthma. Clinical symptoms were wheezing (32%), ronchi (37%) and 29% of children presented with acute distress respiratory syndrome; 40% of the available chest X-Ray were abnormal. Eight children were hospitalised in the intensive care unit and two children died. Twenty-five children (10.9%) had a nosocomial infection; a dual infection was observed in 19 cases (9%) with the following viruses: RSV (3), influenza (2) parainfluenza (8), adenovirus (2), enterovirus (4); 19 (9%) children had a secondary bacterial infection. Rhinoviruses were detected in nasal aspirates in 112 cases (53%) according to the culture and in the rhinovirus culture-negative samples in 99 cases (47%) according to the RT-PCR assay. CONCLUSION: After eliminating cases of bacterial or viral dual infections, the clinical aspects of rhinovirus infections in children are the following: upper respiratory tract infections (25.6%), bronchiolitis ou bronchitis (25.6%), pneumonia (6.2%), acute attack of asthma (5.7%). The virological diagnosis according to culture is mainly improved by molecular techniques.

Adolescent↗

Human rhinovirus 3 at 3.0 A resolution.

BACKGROUND: The over 100 serotypes of human rhinoviruses (HRV) are major causative agents of the common cold in humans. These HRVs can be roughly divided into a major and minor group according to their cellular receptors. They can also be divided into two antiviral groups, A and B, based on their sensitivity to different capsid-binding antiviral compounds. The crystal structures of HRV14 and HRV16, major-receptor group rhinoviruses, as well as HRV1A, a minor-receptor group rhinovirus, were determined previously. Sequence comparisons had shown that HRV14 seemed to be an outlier among rhinoviruses. Furthermore, HRV14 was the only virus with no cellular 'pocket factor' in a hydrophobic pocket which is targeted by many capsid-binding antiviral compounds and is thought to regulate viral stability. HRV3, another major-receptor group virus, was chosen for study because it is one of a subset of serotypes that best represents the drug sensitivity of most rhinovirus serotypes. Both HRV3 and HRV14 belong to antiviral group A, while HRV16 and HRV1A belong to antiviral group B. RESULTS: HRV3 was found to be very similar to HRV14 in sequence and structure. Like HRV14, crystallized HRV3 also has no bound pocket factor. The structure of HRV3 complexed with an antiviral compound, WIN56291, was also determined and found to be similar to the same antiviral compound complexed with HRV14. CONCLUSIONS: The amino-acid sequence and structural similarity between HRV3 and HRV14 suggests that rhinoviruses in the same antiviral group have similar amino-acid sequences and structures. The similar amino-acid composition in the pocket region and the viral protein VP1 N termini in all known group B HRV sequences suggests that these viruses may all contain pocket factors and ordered N-terminal amphipathic helices in VP1. Both of these factors contribute to viral stability, which is consistent with the observations that group B rhinoviruses have a higher chance of successful transmission from one host to another and is a possible explanation for the observed higher pathogenicity of these rhinoviruses.

Antigens, Viral↗

Rhinoviruses in Seattle families, 1975-1979.

Rhinovirus infections in Seattle families with schoolchildren (1975-1979) and in selected outpatients were revealed by virus shedding or antibody rise. These observations extend those in the Seattle Virus Watch (1965-1969). Analysis of rhinovirus serotype prevalence again revealed certain "common" persisting serotypes but provided no further evidence that new serotypes are continuing to emerge. Two seasonal peaks, spring higher than fall, were again evident. Infection rates, again inversely related to age, were lower overall than in the Virus Watch (0.42 vs. 0.64 per person-year), probably because there were fewer young children. Frequencies of antibody response by virus shedders again varied widely by serotype but differed greatly from those in the Virus Watch in rank order of response rate, suggesting that immunogenicity is not a stable serotype characteristic. The frequency and magnitude of antibody response of virus shedders increased with age. Antibody-related protection against infection was evident only in persons age greater than or equal to 10 years. Observations in 7 families during successive homotypic infection episodes indicate that postinfection immunity to natural challenge requires persistence of antibody. Of all reported respiratory illness, 11.9% (0.31 per person-year) were due to rhinoviruses and 6.9% to influenza viruses. Of viruses recovered from family members, rhinoviruses, herpes simplex, and influenza comprised 56%, 12.6%, and 12.4%, respectively. Although households often experienced greater than or equal to 2 concurrent or closely consecutive episodes of infection with different viruses, only 29 individuals were shown to shed 2 viruses at the same time. Most of the second viruses, include 3 rhinoviruses and 18 other nonhemadsorbing viruses, appeared when 582 rhinovirus-positive specimens were retested after treatment with homotypic antibody. These results suggest that rhinoviruses interfere with nonhemadsorbing viruses in cell culture but mostly with other rhinoviruses in humans.

Adolescent↗

Two groups of rhinoviruses revealed by a panel of antiviral compounds present sequence divergence and differential pathogenicity.

A variety of chemically different compounds inhibit the replication of several serotypes of rhinoviruses (common-cold viruses). We noticed that one of these antiviral compounds, WIN 51711, had an antiviral spectrum clearly distinctive from a consensus spectrum or other capsid-binding compounds, although all of them were shown to share the same binding site. A systematic evaluation of all known rhinovirus capsid-binding compounds against all serotyped rhinoviruses was therefore initiated. Multivariate analysis of the results revealed the existence of two groups of rhinoviruses, which we will call antiviral groups A and B. The differential sensitivity of members of these groups to antiviral compounds suggests the existence of a dimorphic binding site. The antiviral groups turned out to be a reflection of a divergence of rhinovirus serotypes on a much broader level. Similarities in antiviral spectra were highly correlated with sequence similarities, not only of amino acids lining the antiviral compound-binding-site, but also of amino acids of the whole VP1 protein. Furthermore, analysis of epidemiological data indicated that group B rhinoviruses produced more than twice as many clinical infections per serotype than group A rhinoviruses did. Rhinoviruses belonging to the minor receptor group were without exception all computed to lie in the same region of antiviral group B.

Amino Acid Sequence↗

Exacerbations of asthma in adults during experimental rhinovirus infection.

To determine the incidence of wheezing in adult asthmatics with rhinovirus infection, we exposed 21 asthmatic volunteers to 1 of 2 rhinovirus serotypes. Symptoms, spirometry, and histamine inhalation challenge were assessed prior to, daily during, and 3 wk after the rhinovirus infection. Four volunteers had fiberoptic bronchoscopy performed on the fourth study day. Nineteen volunteers became infected with rhinovirus; 17 of 19 had typical coryzal symptoms. Volunteers did not have significant changes in spirometry or histamine sensitivity during rhinovirus infection when taken as a group or when categorized by severity of asthma or severity of the clinical illness. A subgroup of 4 volunteers was identified that had a 10% or greater decrease in FEV1 and a parallel increase in histamine sensitivity during rhinovirus infection; these 4 volunteers were not otherwise distinguishable from the group as a whole. Rhinovirus was recovered from bronchoscopy specimens of 1 of the 4 infected volunteers bronchoscoped. Thus, exacerbations of wheezing occurred in the minority of experimental rhinovirus infections in adult asthmatics, suggesting that other viral pathogens may play a more important role in precipitating asthma attacks.

Adult↗

Recent advances in rhinovirus therapeutics.

Human rhinoviruses are the major causative agents of the common cold. Because there are greater than 100 viral serotypes, little immunological protection is afforded to humans by prior rhinovirus exposure, which accounts for the high incidence of infection. In most cases, rhinovirus leads to a short self-limiting illness. However, for asthmatics, the elderly and immunocompromised patients, rhinovirus infection can lead to life-threatening complications. This has spurred a consistent effort over recent decades to identify effective treatments and preventions for rhinovirus infection. While some work has focused on alleviating the symptoms induced as a result of inflammatory pathways stimulated by rhinoviruses, the majority of the research has been focused on limiting or preventing viral infection altogether. Various approaches have been taken to halt rhinovirus infection. Prevention of virus-cell interaction has been the aim of research on viral capsid binders and cell receptor blockers. Interference with correct viral protein processing is the goal of the design and testing of protease inhibitors. Current work is attempting to interfere with viral RNA replication by testing silencing RNA molecules. In this review, we will discuss recent advances in the development and testing of human rhinovirus therapeutics.

Antiviral Agents↗

An update on the pathophysiology of rhinovirus upper respiratory tract infections.

Upper respiratory tract infections are one of the most common infectious diseases in man and are characterized by relatively mild symptoms. However, complications of bacterial super-infection or asthma exacerbations are not seldomly seen. Most upper respiratory tract infections are caused by rhinoviruses. The rhinovirus is a non-enveloped 30 nm RNA-virus with over 100 serotypes that belongs to the Picornaviridae family and only replicates in primates. It is characterized by a single positive stranded genome acting not only as a template for RNA synthesis, but also encoding for a single polypeptide necessary for viral replication. The viral capsid has an icosahedral symmetry and demonstrates deep canyons, with a receptor-binding domain. Rhinoviruses are transmitted mainly via direct- or indirect contact with infected secretions and invade their host by binding to the ICAM-1 receptor on the nasal epithelium. Typical for rhinovirus upper respiratory tract infections are isolated scattered foci of infected epithelium, not showing any striking damage or cytopathic alterations, between large areas of normal epithelium. Today there is still little detailed knowledge on the pathophysiology of common cold, especially on the aspect of cellular migration and defense. A better understanding in mechanisms underlying this cellular response would not only have therapeutical consequences, but may also explain the relationship between viral infectious rhinitis and asthma or atopy. During a rhinovirus infection, a selective neutrophil and monocyte recruitment is observed. In vitro and in vivo data have demonstrated a time-limited, rhinovirus-induced increase in bradykinin, cytokine, chemokine and sICAM-1 concentrations. Epithelial derived proinflammatory cytokines initiate an adhesion cascade and activate T lymphocytes that create a TH1-type cytokine environment within the infected tissue, necessary to eradicate the virus infection. The selective recruitment of neutrophils seems linked to increased concentrations of the chemokine IL-8 and common cold symptoms. It is doubtful that the cytokine-regulated-production of specific neutralising immunoglobulins is necessary for recovery from viral illnesses and presumably only contributes to a late and temporary protection against rhinovirus reinfection. These observations confirm the crucial role that cytokines and mediators play in the pathogenesis of a rhinovirus infection by mediating chemotaxis, transmigration and activation of inflammatory- and immunocompetent cells.

Animals↗