Human Rhinovirus Infection Research Articles

Impaired type I and III interferon response to rhinovirus infection during pregnancy and asthma

BackgroundAcute respiratory tract infections are common ailments to all individuals and the human rhinoviruses (HRVs) cause most of these infections. Pregnant women have increased susceptibility and disease severity to viral...

Clinical Spectrum of Human Rhinovirus Infections in Hospitalized Hong Kong Children

Human rhinovirus (HRV) is classified into A, B, and C genogroups. HRVs cause mild upper respiratory infections, but HRV-C was recently found to be a major cause of asthma exacerbation in whites. This study elucidated disease spectrum of HRV infections among Hong Kong children hospitalized with respiratory illnesses. This retrospective study recruited 128 children with asthma exacerbations and 192 inpatient controls without allergy and hospitalized for respiratory illnesses within the same week. Their clinical information was retrieved from case records. HRVs in nasopharyngeal aspirates were detected by molecular assays using primers targeting consensus VP4/VP2 coding regions, and their genogroups identified by sequencing. The mean (standard deviation) age of cases and controls was 5.6 (3.6) years and 5.4 (3.8) years, respectively (P = 0.601). HRV was detected in 107 (84.9%) cases and 63 (33.0%) controls (P < 0.0001), and HRV-C in 69.8% and 18.8% of these groups, respectively (P < 0.0001). Detection of HRV-A and -B was similar between these groups (P > 0.15). More subjects with HRV-C needed oxygen supplementation (11.1% vs. 2.6%; P = 0.043). Among controls, HRV infection was associated with acute bronchiolitis (P < 0.001) and bronchitis (P = 0.04), which paralleled those of HRV-C. HRV-A was associated with acute bronchiolitis (P = 0.005). Phylogenetic analysis revealed a diverse group of HRV serotypes (21 for HRV-A, 2 for HRV-B, and 32 for HRV-C). HRV-C is associated with asthma exacerbation, whereas the presence of all HRVs, or either HRV-A or HRV-C alone, is associated with wheezing respiratory infections in nonasthmatic children. HRV is an important respiratory virus responsible for childhood wheezing illnesses.

Development of a Quantitative Real-Time Nucleic Acid Sequence-Based Amplification Assay with an Internal Control Using Molecular Beacon Probes for Selective and Sensitive Detection of Human Rhinovirus Serotypes

Evidence demonstrating that human rhinovirus (HRV) disease is not exclusively limited to the upper airways and may cause lower respiratory complications, together with the frequency of HRV infections and the increasing number of immunocompromised patients underline the need for rapid and accurate diagnosis of HRV infections. In this study, we developed the first quantitative real-time nucleic acid sequence-based amplification assay with an internal control using molecular beacon probes for selective and sensitive detection of human rhinovirus serotypes. We described a simple method to accurately quantify RNA target by computing the time to positivity (TTP) values for HRV RNA. Quantification capacity was assessed by plotting these TTP values against the starting number of target molecules. By using this simple method, we have significantly increased the diagnostic accuracy, precision, and trueness of real-time NASBA assay. Specificity of the method was verified in both in silico and experimental studies. Moreover, for assessment of clinical reactivity of the assay, NASBA has been validated on bronchoalveolar lavage (BAL) specimens. Our quantitative NASBA assay was found to be very specific, accurate, and precise with high repeatability and reproducibility.

Rhinoviruses, allergic inflammation, and asthma.

Summary: Viral infections affect wheezing and asthma in children and adults of all ages. In infancy, wheezing illnesses are usually viral in origin, and children with more severe wheezing episodes are more likely to develop recurrent episodes of asthma and to develop asthma later in childhood. Children who develop allergen‐specific immunoglobulin E (allergic sensitization) and those who wheeze with human rhinoviruses (HRV) are at especially high risk for asthma. In older children and adults, HRV infections generally cause relatively mild respiratory illnesses and yet contribute to acute and potentially severe exacerbations in patients with asthma. These findings underline the importance of understanding the synergistic nature of allergic sensitization and infections with HRV in infants relative to the onset of asthma and in children and adults with respect to exacerbations of asthma. This review discusses clinical and experimental evidence of virus–allergen interactions and evaluates theories which relate immunologic responses to respiratory viruses and allergens to the pathogenesis and disease activity of asthma. Greater understanding of the relationship between viral respiratory infections, allergic inflammation, and asthma is likely to suggest new strategies for the prevention and treatment of asthma.

Detection of human rhinoviruses in the lower respiratory tract of lung transplant recipients

The occurrence of human rhinoviruses (HRV) and its relationship to clinical and histopathological findings were investigated in 127 bronchoalveolar lavage specimens from 36 lung transplant recipients by real-time RT-PCR. In addition, 286 samples from 235 other immunocompromised and immunocompetent patients were also studied. HRV was detected in 41.7% of lung transplant recipients vs 14.5% of other patients (p < 0.0001), and no differences in viral load were observed. Acute respiratory insufficiency was found in 15 cases, three of which were HRV positive (viral load, 6.3x106 RNA copies/ml in one patient with chronic graft dysfunction). A diagnosis of pneumonia was made in 10 out of 127 cases, two of which were HRV positive (viral load, 103-104 in cases of co-infection). Acute rejection was diagnosed in 12 cases, three of which were HRV positive (viral load, 103 in two cases of co-infection and 105 in a single infection). HRV infection may involve the lower respiratory tract, particularly in the presence of an impaired pulmonary background, such as a transplanted lung. Clinical evaluation should take into account the viral load, with a load of >105 possibly being associated with clinical symptoms, although lower loads can be detected in both symptomatic and asymptomatic patients.

Decreased innate interferon production in type 2 polarized macrophages upon human rhinovirus infection (110.1)

Abstract The role of M1 and M2 macrophages (derived in a type 1, respectively in a type 2 cytokine milieu) in human rhinovirus (HRV) infections is not known. M2 macrophage numbers are believed to be increased in asthma and could play a role in the increased susceptibility to HRV-infections. We hypothesized that upon HRV infection M2 produce less innate interferons (IFN-α/β/λ) as compared to M1 macrophages. Methods. Monocyte-derived macrophages (MDM) obtained from PBMC were polarized to M2 (by treatment with IL-4) and to M1 (by treatment with IFN-γ&amp;TNF-α) and infected with HRV16. IFN-α/β/λ gene expression was measured by RT-PCR and protein levels by ELISA. Supernatants of HRV16-infected M1&amp; M2 and MDM were titrated on Hela-Ohio cells to ascertain their 50% tissue culture infective dose TCID50/ml. Results. Upon HRV16 infection we found increased IFN-α1, -β and -λ1 gene expression at 8h and IFN-α1 and -λ1 gene expression at 24 h in M1 as compared to M2 macrophages and MDM. Increased production of IFN-β and -λ1 at 8h and for IFN-α, -β and -λ1 at 24 h, 48 h and 72 h was observed in HRV16-infected M1 as compared to M2 macrophages and MDM. Rhinovirus titer was decreased in M1 macrophages. In conclusion, M1 macrophages produce high levels of antiviral IFN-α/β/λ1 and consequently are less susceptible to virus infection. In contrast M2 macrophages produce low levels of IFN-α/β/λ and this could play a role in virus-induced exacerbations of asthma.

Human Rhinovirus Infections in Rural Thailand: Epidemiological Evidence for Rhinovirus as Both Pathogen and Bystander

BackgroundWe describe human rhinovirus (HRV) detections in SaKaeo province, Thailand.MethodsFrom September 1, 2003–August 31, 2005, we tested hospitalized patients with acute lower respiratory illness and outpatient controls without fever or respiratory symptoms for HRVs with polymerase chain reaction and molecularly-typed select HRVs. We compared HRV detection among hospitalized patients and controls and estimated enrollment adjusted incidence.ResultsHRVs were detected in 315 (16%) of 1919 hospitalized patients and 27 (9.6%) of 280 controls. Children had the highest frequency of HRV detections (hospitalized: <1 year: 29%, 1–4 year: 29%, ≥65 years: 9%; controls: <1 year: 24%, 1–4 year: 14%, ≥65 years: 2.8%). Enrollment adjusted hospitalized HRV detection rates were highest among persons aged <1 year (1038/100,000 persons/year), 1–4 years (457), and ≥65 years (71). All three HRV species were identified, HRV-A was the most common species in most age groups including children aged <1 year (61%) and all adult age groups. HRV-C was the most common species in the 1–4 year (51%) and 5–19 year age groups (54%). Compared to controls, hospitalized adults (≥19 years) and children were more likely to have HRV detections (odds ratio [OR]: 4.8, 95% confidence interval [CI]: 1.5, 15.8; OR: 2.0, CI: 1.2, 3.3, respectively) and hospitalized children were more likely to have HRV-A (OR 1.7, CI: 0.8, 3.5) or HVR-C (OR 2.7, CI: 1.2, 5.9) detection.ConclusionsHRV rates were high among hospitalized children and the elderly but asymptomatic children also had substantial HRV detection. HRV (all species), and HRV-A and HRV-C detections were epidemiologically-associated with hospitalized illness. Treatment or prevention modalities effective against HRV could reduce hospitalizations due to HRV in Thailand.

ChemInform Abstract: The Human Rhinovirus: Human‐Pathological Impact, Mechanisms of Antirhinoviral Agents, and Strategies for Their Discovery

AbstractReview: 359 refs.

Human rhinovirus infection in young African children with acute wheezing

BackgroundInfections caused by human rhinoviruses (HRVs) are important triggers of wheezing in young children. Wheezy illness has increasingly been recognised as an important cause of morbidity in African children, but there is little information on the contribution of HRV to this. The aim of this study was to determine the role of HRV as a cause of acute wheezing in South African children.MethodsTwo hundred and twenty children presenting consecutively at a tertiary children's hospital with a wheezing illness from May 2004 to November 2005 were prospectively enrolled. A nasal swab was taken and reverse transcription PCR used to screen the samples for HRV. The presence of human metapneumovirus, human bocavirus and human coronavirus-NL63 was assessed in all samples using PCR-based assays. A general shell vial culture using a pool of monoclonal antibodies was used to detect other common respiratory viruses on 26% of samples. Phylogenetic analysis to determine circulating HRV species was performed on a portion of HRV-positive samples. Categorical characteristics were analysed using Fisher's Exact test.ResultsHRV was detected in 128 (58.2%) of children, most (72%) of whom were under 2 years of age. Presenting symptoms between the HRV-positive and negative groups were similar. Most illness was managed with ambulatory therapy, but 45 (35%) were hospitalized for treatment and 3 (2%) were admitted to intensive care. There were no in-hospital deaths. All 3 species of HRV were detected with HRV-C being the most common (52%) followed by HRV-A (37%) and HRV-B (11%). Infection with other respiratory viruses occurred in 20/128 (16%) of HRV-positive children and in 26/92 (28%) of HRV-negative samples.ConclusionHRV may be the commonest viral infection in young South African children with acute wheezing. Infection is associated with mild or moderate clinical disease.

Modulation of Epithelial Biology by Rhinovirus Infection: Role in Inflammatory Airway Diseases

The human airway epithelial cell is the primary site of human rhinovirus (HRV) infection in both the upper and lower airways, but HRV infection does not cause overt epithelial cytotoxicity at either location. Therefore, it is thought that HRV infections induce symptoms of the common cold or exacerbate lower airway diseases, such as asthma and chronic obstructive pulmonary disease, by altering epithelial cell biology. This premise has led to intense investigation of the interactions of HRV with epithelial cells. This article reviews current knowledge regarding how HRV induces epithelial induction of proinflammatory cytokines and chemokines. In addition, the contributions of epithelial cells to host antiviral responses will be reviewed along with evidence that HRV-infected epithelial cells may contribute to the airway remodeling that is a characteristic feature of asthma.

Innate Inflammatory Responses of Pediatric Cystic Fibrosis Airway Epithelial Cells

There is controversy regarding whether cystic fibrosis (CF) airway epithelial cells (AECs) are intrinsically proinflammatory. The objective of the current study was to characterize the inflammatory profiles of AECs from children with CF compared with cells from healthy control subjects. We obtained AECs from healthy children (12) and children with CF (27). Biochemical and functional characteristics were assessed by stimulating cells with IFNγ, LPS, a cocktail referred to as cytomix, which consists of IFNγ, IL-1β, TNF-α, and LPS, or with human rhinovirus (HRV). Cytokine production was assessed using ELISA. Apoptotic responses to HRV infection were measured via production of single-stranded DNA. Our results indicated that CF and healthy cells exhibited similar morphology in monolayer culture. CF cells constitutively produced greater amounts of IL-6, IL-1β, and prostaglandin E(2), but similar levels of IL-8 and soluble intracellular adhesion molecule-1 compared with healthy cells, and this profile was maintained through repeated passage. Stimulation with LPS or cytomix elicited similar levels of IL-8 in CF and non-CF cells. In contrast, exposure to HRV1b resulted in a marked increase in IL-8 production from CF compared with non-CF cells. CF cells also exhibited reduced apoptosis and increased viral replication compared with non-CF cells after exposure to HRV1b. We conclude that CF and healthy AECs have similar basal and stimulated expression of IL-8 in response to proinflammatory stimuli, but elevated IL-8 release in response to HRV infection. The elevated IL-8, together with dampened apoptotic responses by CF cells to HRV, could contribute to augmented airway inflammation in the setting of recurrent viral infections early in life.

Higher Rhinovirus-Induced Production of TSLP in Nasal Epithelial Cells from Asthmatic than Healthy Subjects

RATIONALE: Airway epithelial cells secrete thymic stromal lymphopoietin (TSLP), which induces dendritic cells to promote development of Th2 responses. TSLP also increases natural killer cell cytotoxicity. We investigated whether human rhinovirus (HRV) infection induces airway epithelial production of TSLP in asthmatic subjects.

Usefulness of Published PCR Primers in Detecting Human Rhinovirus Infection

We conducted a preliminary comparison of the relative sensitivity of a cross-section of published human rhinovirus (HRV)–specific PCR primer pairs, varying the oligonucleotides and annealing temperature. None of the pairs could detect all HRVs in 2 panels of genotyped clinical specimens; >1 PCR is required for accurate description of HRV epidemiology.

Viral etiology among the elderly presenting acute respiratory infection during the influenza season

Acute respiratory tract infections are the most common illness in all individuals. Rhinoviruses have been reported as the etiology of more than 50% of respiratory tract infections worldwide. The study prospectively evaluated 47 elderly individuals from a group of 384 randomly assigned for acute respiratory viral infections (cold or flu) and assessed the occurrence of human rhinovirus (HRV), influenza A and B, respiratory syncytial virus and metapneumovirus (hMPV) in Botucatu, State of São Paulo, Brazil. Forty-nine nasal swabs collected from 47 elderly individuals following inclusion visits from 2002 to 2003 were tested by GenScan RT-PCR. HRV-positive samples were sequenced for phylogenetic analysis. No sample was positive for influenza A/B or RSV. HRV was detected in 28.6% (14/47) and hMPV in 2% (1/47). Of 14 positive samples, 9 isolates were successfully sequenced, showing the follow group distribution: 6 group A, 1 group B and 2 group C HRVs. The high incidence of HRV during the months of the influenza season requires further study regarding HRV infection impact on respiratory complications among this population. Infection caused by HRV is very frequent and may contribute to increasing the already high demand for healthcare during the influenza season.

Host and viral factors associated with severity of human rhinovirus–associated infant respiratory tract illness

BackgroundRisk factors for severe human rhinovirus (HRV)–associated infant illness are unknown.ObjectivesWe sought to examine the role of HRV infection in infant respiratory tract illness and assess viral and host risk factors for HRV-associated disease severity.MethodsWe used a prospective cohort of term, previously healthy infants enrolled during an inpatient or outpatient visit for acute upper or lower respiratory tract illness during the fall-spring months of 2004-2008. Illness severity was determined by using an ordinal bronchiolitis severity score, with higher scores indicating more severe disease. HRV was identified by means of real-time RT-PCR. The VP4/VP2 region from HRV-positive specimens was sequenced to determine species.ResultsOf 630 infants with bronchiolitis or upper respiratory tract illnesses (URIs), 162 (26%) had HRV infection; HRV infection was associated with 18% of cases of bronchiolitis and 47% of cases of URI. Among infants with HRV infection, 104 (64%) had HRV infection alone. Host factors associated with more severe HRV-associated illness included a maternal and family history of atopy (median score of 3.5 [interquartile range [IQR], 1.0-7.8] vs 2.0 [IQR, 1.0-5.2] and 3.5 [IQR, 1.0-7.5] vs 2.0 [IQR, 0-4.0]). In adjusted analyses maternal history of atopy conferred an increase in the risk for more severe HRV-associated bronchiolitis (odds ratio, 2.39; 95% CI, 1.14-4.99; P = .02). In a similar model maternal asthma was also associated with greater HRV-associated bronchiolitis severity (odds ratio, 2.49, 95% CI, 1.10-5.67; P = .03). Among patients with HRV infection, 35% had HRVA, 6% had HRVB, and 30% had HRVC.ConclusionHRV infection was a frequent cause of bronchiolitis and URIs among previously healthy term infants requiring hospitalization or unscheduled outpatient visits. Substantial viral genetic diversity was seen among the patients with HRV infection, and predominant groups varied by season and year. Host factors, including maternal atopy, were associated with more severe infant HRV-associated illness.

Host Response Cytokine Signatures in Viral and Nonviral Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Viruses are strongly associated with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Interferon-inducible protein-10 has been recently described as a biomarker of human rhinovirus infection, but there are no reports on the role of other immune mediators in AECOPD of viral origin. As an attempt to evaluate the differences in the systemic immune mediators profiles between AECOPD patients with presence/absence of viral infection, we measured 27 cytokines, chemokines, and cellular growth factors in the plasma of 40 patients with AECOPD needing of hospitalization by using a Luminex-based assay. These patients were screened for the presence of 16 different respiratory viruses in pharyngeal swabs. Ten healthy controls were recruited for comparison purposes. Both the group of patients with an associated viral infection (n = 11) and those with no viral infection (n = 29) showed high levels of vascular endothelial growth factor, interleukin-13 (IL-13), and IL-2. On the other hand, viral infection in AECOPD induced a coordinated response of innate immunity chemokines (eotaxin, interferon-inducible protein-10, IL-8), Th1 cytokines (IL-12p70, IL-15), and the immunomodulatory IL-10. This profile corresponds to a typical antiviral response signature previously documented for other viral infections. The identification of early cytokine signatures associated with viral infection in AECOPD could contribute to design better treatment strategies for this disease.

The Effect of a Low Concentration of Hypochlorous Acid on Rhinovirus Infection of Nasal Epithelial Cells

Low concentrations of hypochlorous acid (HOCl) have been shown to exhibit both antibacterial and anti-influenza virus activity, but HOCl still has not been used to kill human rhinovirus (HRV). To model the antiviral effect of nasal irrigation with low-level HOCl in patients with the common cold, we tested the effects of a low concentration of HOCl on HRV infection of primary human nasal epithelial cells (HNEC). Cells were infected with HRV for 24 hours and treated with HOCl three times, for 5 minutes each time, at 12 hour intervals. The effects of HOCl on rhinovirus-induced secretion of IL-6 and IL-8 were assessed by ELISA and HRV replication was determined by viral titration. HOCl treatment significantly inhibited HRV-induced secretion of IL-6 and IL-8 and significantly reduced viral titer. The effects of HOCl peaked at 1 minute after HOCl generation and decreased thereafter. These in vitro findings indicate that nasal irrigation with low-level HOCl solution may improve clinical symptoms in patients with the common cold.

The human rhinovirus: human‐pathological impact, mechanisms of antirhinoviral agents, and strategies for their discovery

As the major etiological agent of the common cold, human rhinoviruses (HRV) cause millions of lost working and school days annually. Moreover, clinical studies proved an association between harmless upper respiratory tract infections and more severe diseases e.g. sinusitis, asthma, and chronic obstructive pulmonary disease. Both the medicinal and socio‐economic impact of HRV infections and the lack of antiviral drugs substantiate the need for intensive antiviral research. A common structural feature of the approximately 100 HRV serotypes is the icosahedrally shaped capsid formed by 60 identical copies of viral capsid proteins VP1‐4. The capsid protects the single‐stranded, positive sense RNA genome of about 7,400 bases in length. Both structural as well as nonstructural proteins produced during the viral life cycle have been identified as potential targets for blocking viral replication at the step of attachment, entry, uncoating, RNA and protein synthesis by synthetic or natural compounds. Moreover, interferon and phytoceuticals were shown to protect host cells. Most of the known inhibitors of HRV replication were discovered as a result of empirical or semi‐empirical screening in cell culture. Structure–activity relationship studies are used for hit optimization and lead structure discovery. The increasing structural insight and molecular understanding of viral proteins on the one hand and the advent of innovative computer‐assisted technologies on the other hand have facilitated a rationalized access for the discovery of small chemical entities with antirhinoviral (anti‐HRV) activity. This review will (i) summarize existing structural knowledge about HRV, (ii) focus on mechanisms of anti‐HRV agents from synthetic and natural origin, and (iii) demonstrate strategies for efficient lead structure discovery. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 1, 42–92, 2010

Rhinovirus infection and acute exacerbation of asthma in children

Human rhinovirus (HRV) infection is an important predisposing factor of acute asthma attacks and exacerbations, but the pathogenic mechanism is extremely complex. Inflammatory responses can be caused by the direct effect of rhinovirus and the release of inflammatory mediators and inflammatory cell infiltration. HRV infection stimulates the body's abnormal immune response, especially Thl / Th2 immune imbalance and dysfunction of regulatory T cells has attracted extensive attention. In-depth study in the pathogenic mechanism of acute asthma exacerbation induced by HRV infection in children is essential to elucidate the pathogenesis of asthma and to explore immunotherapy of asthma. Key words: Rhinovirus; Asthma; Acute exacerbation

Rhinovirus species and their clinical presentation among different risk groups of non‐hospitalized patients

Infections caused by Human Rhinoviruses (HRVs) account for 25-50% of respiratory illnesses among individuals presenting influenza-like illness (ILI). HRVs could be classified in at least three species: HRV-A, HRV-B, and HRV-C. The HRV-C species has frequently been described among children and has led to severe illness resulting in hospitalization; however, the occurrence among adults is unknown. The aim of this study was to assess the clinical presentation and species distribution of HRV infections in different populations during 2001-2008. A total of 770 samples were collected. Subjects consisted of 136 adults from the general community and 207 health-care workers (2001-2003), 232 renal-transplanted outpatients (2002-2004), 70 children with congenital heart disease (2005) and 125 children from a day-care center (2008). Amplification of HRV genes was performed by reverse transcriptase-polymerase chain reaction (RT-PCR) and followed by sequencing and phylogenetic analysis. HRV was detected in 27.4% of samples (211/770), with 72 children (36.9%) and 139 adults infected (24.2%). A total of 89.61% (138/154) unknown HRV strains were sequenced, and 79.22% (122/138) were analyzed. We identified 74 isolates (60.7%) of the HRV A species, 21 (17.2%) of the HRV B species and 27 isolates (22.1%) of the HRV C species. HRV species A and B caused ILI among adult patients, whereas HRV-C did not. The dynamics of infection among different species deserve further analysis.