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Background: The sialic acid analogue zanamivir (GG167) is a selective inhibitor of influenza A and B virus neuraminidases. These viral enzymes are essential for the release of virus from infected cells, and they may also reduce the inactivation of virus by respiratory secretions. When administered experimentally directly to the respiratory tract, zanamivir has potent antiviral effects. We assessed the therapeutic activity of zanamivir in adults with acute influenza. Methods: We conducted separate randomized, double-blind studies in 38 centers in North America and 32 centers in Europe during the influenza season of 1994-1995. A total of 417 adults with influenza-like illness of 448 hours duration were randomly assigned to one of three treatments: 6.4 mg of zanamivir by intranasal spray plus 10 mg by inhalation, 10 mg of zanamivir by inhalation plus placebo spray, or placebo by both routes. Treatments were self-administered twice daily for five days. Results: Of 262 patients with confirmed influenza-virus infection (63 percent of all patients), the median length of time to the alleviation of all major symptoms was one day shorter (four days vs. five days) in the 88 patients given inhaled and intranasal zanamivir (P=0.02) and the 85 patients given inhaled zanamivir alone (P=0.05) than in the 89 patients given placebo. Among the infected patients who were febrile at enrollment and among those who began treatment within 30 hours after the onset of symptoms, the median time to the alleviation of major symptoms was four days in both zanamivir groups and seven days in the placebo group (P≤0.01). Viral titers of nasal washings in the group given inhaled and intranasal zanamivir were significantly lower than those in the placebo group. The topically administered zanamivir was well tolerated. Conclusions: In adults with influenza A or B virus infections, direct administration of a selective neuraminidase inhibitor, zanamivir, to the respiratory tract is safe and reduces symptoms if begun early.

Objective:To study compliance with preventive strategies at a university hospital during an outbreak of nosocomial influenza A during the winter of 1988, and the rates of vaccination of healthcare workers and of nosocomial influenza following changes in vaccine practices after the outbreak.Design:Retrospective review of employee health, hospital epidemiology, hospital computing, and clinical microbiology records.Setting:A university hospital.Interventions:Unvaccinated personnel with exposure within the previous 72 hours to an unisolated case of influenza were offered influenza vaccine and 14 days of amantadine hydrochloride prophylaxis. Personnel with exposure more than 72 hours before evaluation were offered vaccine. A mobile cart was introduced for vaccinating personnel after the 1988 outbreak.Results:An outbreak of influenza with 10 nosocomial cases occurred in 1988. Only 4% of exposed employees had been vaccinated previously and 23% of exposed, unvaccinated employees agreed to take vaccine, amantadine, or both. A mobile-cart vaccination program was instituted, and annual vaccination rates steadily increased from 26.3% in 1989 to 1990 to 38% in 1993 to 1994 (PP=.025), but nosocomial influenza rates among patients did not change significantly.Conclusion:A mobile-cart influenza vaccination program was associated with a significant increase in compliance among healthcare workers, but a majority still remained unvaccinated. The rate of nosocomial influenza among patients was not reduced by the modest increase in the vaccination rate, but influenza rates remained acceptably low, perhaps due to respiratory isolation of patients and furlough of employees with influenza.

OBJECTIVE To determine the tolerability and clinical effectiveness of intranasal ipratropium bromide for the treatment of symptoms of common colds. DESIGN Multicenter, double-blind, randomized trial. SETTING 3 university student health services. PATIENTS 411 previously healthy persons 14 to 56 years of age who had cold symptoms that had lasted for no more than 36 hours, rhinorrhea subjectively judged to be of at least moderate severity, and documented nasal discharge of at least 1.5 g over a 1-hour observation period. INTERVENTION Either 1) ipratropium bromide nasal spray 0.06% in buffered salt solution, two 42-micrograms sprays per nostril administered by metered pump spray; 2) control nasal spray, which consisted of buffered salt solution; or 3) no treatment. Treatments were self-administered three or four times daily during waking hours for 4 days. After receiving their morning dose, patients stayed at the study center for 6 hours on study day 1 and 3 hours on study day 2; symptom severity was recorded and nasal mucus discharges were collected and weighed hourly during these periods. RESULTS Ipratropium recipients had 26% less nasal discharge than controls (P = 0.0024) and 34% less nasal discharge than untreated patients (P = 0.0001). Severity of rhinorrhea as judged subjectively was reduced in ipratropium recipients by 31% compared with controls and by 78% compared with untreated patients (P = 0.0001 for both comparisons). In addition to being associated with reductions in daily assessments of the severity of rhinorrhea (P < or = 0.003), ipratropium was associated with reduced sneezing on study days 2 (20% difference; P = 0.03) and 4 (30% difference; P = 0.02) but not with reduced nasal congestion compared with the control spray. Ipratropium was generally well tolerated but was associated with higher rates of blood-tinged mucus (16.8% in the ipratropium group compared with 3.6% in the control group; P = 0.01) and nasal dryness (11.7% in the ipratropium group compared with 3.6% in the control group; P = 0.021) than the control spray. Patient assessments of the overall effectiveness of treatment were more favorable for ipratropium than for the control spray (P < or = 0.026) or for no treatment (P < or = 0.002) on each day of inquiry (study days 1, 2, and 5). CONCLUSIONS Intranasal ipratropium bromide provides specific relief of rhinorrhea and sneezing associated with common colds.

The recovery of human rhinovirus (HRV) from nasal washings and nasal and pharyngeal swabs from volunteers with naturally acquired colds was compared in different cell types. Human embryonic lung fibroblast (HELF) strain WI-38 (sensitivity, 61 to 84%) and HeLa-I, an HRV-susceptible HeLa clone (sensitivity, 86 to 94%), were the most sensitive cell types used. HELF-WI-38 cells showed a cytopathic effect earlier than the other cells used, and the different strains of HRV-susceptible HeLa cells varied in their sensitivities for HRV isolation. HRV was detected in a single cell type in 20 to 35% of the positive samples, suggesting that use of a combination of different HRV-susceptible cell lines is the best approach for the recovery of HRV. Although nasal washings tended to yield more HRV isolates than nasal and pharyngeal swabs, the two sampling methods were not found to be significantly different.

This review will summarize recent developments made in the area of antiviral chemotherapy of rhinovirus and influenza virus infections. It will update previous reviews of this topic1–3 and specifically focus on agents that have been of clinical investigative interest since the previous Symposium three years ago. The only newly approved drug for respiratory viral infections is the anti-influenza agent rimantadine (Flumadine), which has been under study for several decades in the United States. In the USA it was approved in 1993 for prevention of influenza A virus infections in children and adults and for treatment of uncomplicated disease in adults.

A limited number of antiviral drug combinations have been shown to have enhanced activity for important human respiratory viruses. Rimantadine or amantadine combined with ribavirin shows increased antiviral effects in vitro and in experimental animal models. This combination warrants testing in human influenza. Immunoglobulin containing neutralizing anti-RSV antibody combined with ribavirin shows enhanced antiviral effects in experimental animal infections and provides clinical benefit in severe RSV infections of transplant patients. Generally, more effective treatments for acute respiratory viral infections will likely involve combinations of both antivirals and agents that modulate host inflammatory responses to infection.

We conducted a comparative study of the antirhinovirus activities of soluble intercellular adhesion molecule-1 (sICAM-1) and a chimeric ICAM-1/immunoglobulin A (IgA) molecule (ICI-5D/IgA) for nine major receptor group human rhinovirus (HRV) serotypes and for a variant of HRV-39 relatively resistant to inhibition by sICAM-1. ICI-5D/IgA inhibited the infectivity of eight of the nine wild-type HRVs and the resistant HRV-39 variant and was 60 to 170 times more potent than sICAM-1 on a molar basis. In contrast to sICAM-1, ICI-5D/IgA directly neutralized the infectivity of the representative HRVs by approximately 1 log10. These results expand on the antirhinovirus spectrum of ICI-5D/IgA, confirm that dimeric forms of sICAM-1 have a higher antirhinoviral potency than monomeric sICAM-1, and indicate that cross-linking of two adjacent receptor binding sites on the virus capsid by a divalent receptor enhances the direct inactivation of viral infectivity.

Past studies showed that experimental rhinovirus colds in adults resulted in eustachian tube dysfunction and abnormal middle ear pressures. In the present study, the symptoms and pathophysiologic findings accompanying experimental influenza viral infection were documented. A total of 33 healthy adult volunteers were intranasally challenged with an influenza A/Kawasaki/86 (H1N1) virus and cloistered over a 9-day postchallenge period to monitor for evidence of infection, signs and symptoms of illness, and the extent and frequency of pathophysiologic responses of the nose, eustachian tube, and middle ear. Results showed a protective effect of high (≥16) prechallenge specific hemagglutination-inhibition antibody titer on the rate of infection and the magnitude and extent of provoked symptoms and pathophysiologic findings. Infected subjects with low (2O on study days 4 and 5. Five of 21 infected subjects with low prechallenge antibody titers had otoscopic evidence of otitis media with effusion. These results support a causal role for viral upper respiratory tract infection in the pathogenesis of otitis media, possibly mediated by the early development of eustachian tube dysfunction and abnormal middle ear pressure.

Variants of human rhinovirus serotype 39 (HRV-39) relatively resistant to inhibition by soluble intercellular adhesion molecule-1 (sICAM-1) were selected by serial passages in HeLa or WI-38 cells in the presence of sICAM-1. Moderate resistance (four- to fivefold increases in 50% effective inhibitory concentrations [EC50s]) was observed after the second passage in HeLa cells and remained constant during six further passages in the presence of 10 micrograms of sICAM-1 per ml. A 7- to 17-fold increase in EC50s was observed in WI-38 cells during passage with 10 micrograms/ml, and reversion to a nonresistant phenotype was not observed after four passages in the absence of sICAM-1. Resistance of a higher degree was obtained by passing HRV-39 in the presence of 100 micrograms of sICAM-1 per ml in HeLa cells (30-fold EC50 increase). The sICAM-1-resistant phenotype was estimated to constitute 1 in 10(4) to 1 in 10(5) PFU of a nonexposed HRV-39 population. Low to moderate levels of resistance to sICAM-1 inhibition emerge readily during in vitro passage in the presence of sICAM-1 and appear to be phenotypically stable.

Please cite this paper as: Howard et al. (2011) Report of the ‘Mechanisms of lung injury and immunomodulator interventions in influenza’ workshop, 21 March 2010, Ventura, California, USA*. Influenza and Other Respiratory Viruses 5(6), 453–e475. The clinical course of influenza and the extent of lung injury are determined by both viral and host factors, as well as sometimes secondary bacterial infections and exacerbations of underlying conditions. The balance between viral replication and the host immune responses is central to disease pathogenesis, and the extent of lung injury in severe influenza infections may be due in part to overly exuberant or dysregulated innate inflammatory responses or sometimes deficient responses. Acute respiratory distress syndrome (ARDS) is the principal cause of respiratory failure associated with severe influenza. ARDS can be triggered by both direct lung insults (e.g. respiratory pathogens) and systemic insults (e.g. sepsis), and the lung damage is exacerbated by the inflammatory response associated with either infectious or non‐infectious insults. This workshop aimed to review the current understanding of lung injury in acute influenza and describe cellular and molecular mechanisms of lung injury that are common to influenza and infections by other respiratory pathogens. In addition, therapeutic agents that target host response proteins and pathways were identified and investigational agents in development reviewed. A logical strategy would be to combine antiviral treatment with drugs that modify excessive host responses or supplement deficient ones. However, a better understanding of common cell signalling pathways associated with acute lung injury caused by influenza and other pathogens is necessary to understand immunopathologic causes of lung injury. This will help determine which immunomodulatory interventions might be useful, and to predict the appropriate timing and consequences of their use.

Please cite this paper as: Belser et al. (2011) XIth International Symposium on Respiratory Viral Infections. Influenza and Other Respiratory Viruses 5(6), 443–e457.

A PCR assay was developed to detect human rhinovirus (HRV) RNA in nasal washings from individuals experimentally infected with HRV-39 or HRV strain Hanks. Total RNA was purified from samples stored in the presence of vanadyl ribonucleoside complex (VRC) by one of two methods: proteinase K digestion followed by multiple extractions with phenol/chloroform (PK-PC); or denaturation with guanidinium thiocyanate followed by one phenol/chloroform extraction (GTC). The limit of detection of HRV in nasal washings spiked with HRV-39 was lower with the GTC method (1 TCID50) than with the PK-PC method. In a study of 31 nasal washings extracted by the PK-PC method, the sensitivity (93%) and negative predictive value (94%) were sub-optimal in comparison to cell culture. In a study of 60 nasal washings extracted by the GTC method, the number of samples positive by PCR (25) exceeded by two the number positive by isolation in cell culture. A GTC-based method for HRV RNA extraction in nasal washings was superior to a proteinase K-phenol/chloroform-based method in regard to sensitivity, consumption of reagents, material and time.

The anti-influenza virus activity of 2'-deoxy-2'-fluoroguanosine was determined in cell culture and in explants of human respiratory epithelium by yield reduction assay. The concentration causing at least 1.0 log10 reduction in influenza A (H3N2) virus yield (EC90) at 24 h was 2.5 micrograms/ml in primary rhesus monkey kidney and 12 micrograms/ml in Madin-Darby canine kidney (MDCK) cells, compared to 0.5 micrograms/ml and 0.9 micrograms/ml, respectively, for ribavirin. The estimated therapeutic ratios for both compounds were low (< 5 to 25) in these cell types. In contrast, the EC90 values at 48 h for influenza A and influenza B virus were < or = 0.1 micrograms/ml in human respiratory epithelial explants, and concentrations up to 100 micrograms/ml did not inhibit explant outgrowth. Ribavirin was approximately 50-fold less active in this system and inhibited outgrowth at 10 micrograms/ml. 2'-deoxy-2'-fluoroguanosine was also approx. 45-fold more potent than the corresponding adenosine and inosine compounds in explant cultures. Partially resistant variants, with approximate 5-fold increases in EC50 values, could be selected by serial influenza A virus passage in MDCK cells in the presence of 2'-deoxy-2'-fluoroguanosine, which indicated that its antiviral activity is at least partially virus specific. The exceptional activity of 2'-deoxy-2'-fluoroguanosine in human respiratory epithelial cells against both influenza A and B viruses makes this compound an interesting candidate for further investigation.

This study's objective was to determine if the combination of pseudoephedrine hydrochloride and atropine sulfate attenuates the symptomatic and pathophysiologic response of individuals to experimental rhinovirus infection when given after illness begins. Forty-three susceptible adult volunteers were challenged with rhinovirus type 39 and randomly assigned to 1 of 2 treatment groups. Twenty-one subjects were treated with the active medication (0.3 mg atropine sulfate and 60 mg pseudoephedrine) and 22 subjects were treated with inert capsules identical in appearance. Treatments were administered 4 times daily beginning approximately 24 hours after rhinovirus challenge and extending for 5 days. Before challenge and on each of 5 treatment days, all volunteers were asked to rate symptom severity and were evaluated for secretion production (weighed tissues), nasal patency (active posterior rhinomanometry), nasal clearance (dyed saccharin technique), eustachian tube function (9-step test), and middle ear status (tympanometry). Twenty subjects in each group were infected with rhinovirus type 39 and were included in the efficacy analysis. Between-group comparisons showed no significant differences in total symptom scores, combined nasal symptom score, secretion production, or the frequencies of persons with eustachian tube obstruction or abnormal middle ear pressures. However, an objective measure of nasal congestion was significantly lower in the active treatment group. The nasal mucociliary clearance rate was significantly more impaired in that group. Side effects consistent with anticholinergic activity were reported more frequently in the active treatment group.

The immunogenicity and reactogenicity of live and heat-inactivated varicella vaccine were evaluated in 95 healthy seropositive adults (mean age, 32 yrs). Live-attenuated vaccine containing 28,000 pfu, 2800 pfu, or 280 pfu of Oka/Merck strain virus (8.4, 0.84, and 0.08 antigen units, respectively) or heat-inactivated vaccine with comparable antigen content (7.1, 0.71, and 0.07 antigen units) was administered subcutaneously to 15 to 16 adults per group in a randomized, single-blind study. ELISA antibody responses were dose-dependent but independent of whether the vaccine was live or inactivated. Mean titers reached a peak on day 14 and remained elevated through day 42 in recipients of the highest dosages but declined by followup at eleven months. A minority of vaccinees developed a four-fold or greater increase in antibody titer on day 14 (25 to 31 percent in the high-dose groups [greater than or equal to 7.1 antigen units], less than or equal to 7 percent of other groups). The vaccine was generally well tolerated. Localized erythema and swelling occurred at the injection site in 44 to 56 percent of the high- and middle dose recipients [greater than or equal to 0.71 antigen units], compared with 0 to 6 percent of those receiving the lowest dose. Although statistically significant increases in varicella antibody titer were observed after immunization with high doses of live or inactivated vaccine, the duration and clinical significance of this booster effect remains to be determined.

Pirodavir (R77975) is a capsid-binding, antipicornaviral agent with in vitro activity against most rhinovirus (RV) serotypes. We conducted four double-blind, controlled trials to assess the efficacy of intranasal pirodavir in experimentally induced RV infection of susceptible volunteers. Intranasal pirodavir (2 mg per dose) or the hydroxypropyl-beta-cyclodextrin vehicle as a placebo was given by metered pump spray. In three prophylaxis trials, subjects were inoculated with RV within 10 min of the second and third doses. When sprays were given six times per day for a total of 25 doses, infection, detected by either virus shedding or seroconversion, developed in 100% of the 13 placebo-treated subjects and 58% of the 12 pirodavir-treated subjects (P = 0.015). Clinical colds developed in 54% of placebo-treated subjects and 8% of pirodavir-treated subjects during drug administration (efficacy = 85%, P = 0.03), although late-developing colds developed in several subjects in both groups. Significant reductions in morning symptom scores and in the frequency of abnormal middle-ear pressures were also found in the pirodavir group. In contrast, in two prophylaxis studies using three doses daily, no significant antiviral or clinical benefits were observed. When frequent sprays were initiated at 24 h after RV challenge, significant reductions in virus shedding but no clinical benefits were found. Intranasal pirodavir was generally well tolerated but was associated with an excess rate of transient unpleasant taste. The findings indicated that frequent intranasal sprays of pirodavir were effective in preventing experimentally induced RV illness.

The influence of rimantadine-resistance mutations on the virulence of human H3N2 viruses in ferrets was examined. The similarities in virulence of the drug-resistant mutants with single amino acid substitutions at three different locations, 27, 30, and 31, within the M2 sequence and their corresponding sensitive wild-type isolates contrasted with differences in virulence between the three pairs of viruses. These data provide further evidence that rimantadine-resistant viruses that emerge during treatment of patients with the drug are unaltered both in their growth characteristics and virulence.

To facilitate understanding of human rhinovirus (HRV) pathogenesis, methods were developed for detection of HRV infection in vitro using in situ hybridization (ISH). HRV‐14 RNA probes and oligonucleotide probes representing conserved sequences in the 5′‐non‐translated region were labeled with 35S and used to detect infected HeLa or WI‐38 strain human embryonic lung cells in cytological preparations. ISH was shown to be specific for detection of HRV on a single‐cell basis. Subsequently, in human nasal polyps infected in vitro, both oligonucleotide‐ and riboprobes produced a strong signal in association with ciliated epithelial cells. In human adenoids infected in vitro, a signal was observed in nonciliated epithelial cells. This study shows that HRV replicates in ciliated cells in the epithelium of human nasal polyps infected in vitro, and the presence of viral RNA in non‐ciliated cells of the human adenoid infected in vitro suggests that other cell types may also support rhinovirus replication.

ContextA high priority in vaccine research is the development of influenza vaccines that do not use embryonated eggs as the substrate for vaccine production.ObjectiveTo determine the dose-related safety, immunogenicity, and protective efficacy of an experimental trivalent influenza virus hemagglutinin (rHA0) vaccine produced in insect cells using recombinant baculoviruses.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled clinical trial at 3 US academic medical centers during the 2004-2005 influenza season among 460 healthy adults without high-risk indications for influenza vaccine.InterventionsParticipants were randomly assigned to receive a single injection of saline placebo (n = 154); 75 μg of an rHA0 vaccine containing 15 μg of hemagglutinin from influenza A/New Caledonia/20/99(H1N1) and influenza B/Jiangsu/10/03 virus and 45 μg of hemagglutinin from influenza A/Wyoming/3/03(H3N2) virus (n = 153); or 135 μg of rHA0 containing 45 μg of hemagglutinin each from all 3 components (n = 153). Serum samples were taken before and 30 days following immunization.Main Outcome MeasuresPrimary safety end points were the rates and severity of solicited and unsolicited adverse events. Primary immunogenicity end points were the rates of 4-fold or greater increases in serum hemagglutinin inhibition antibody to each of the 3 vaccine strains before and 28 days after inoculation. The prespecified primary efficacy end point was culture-documented influenza illness, defined as development of influenza-like illness associated with influenza virus on a nasopharyngeal swab.ResultsRates of local and systemic adverse effects were low, and the rates of systemic adverse effects were not different in either vaccine group than in the placebo group. Hemagglutinin inhibition antibody responses to the H1 component were seen in 3% of placebo, 51% of 75-μg vaccine, and 67% of 135-μg vaccine recipients, while responses to B were seen in 4% of placebo, 65% of 75-μg vaccine, and 92% of 135-μg vaccine recipients. Responses to the H3 component occurred in 11% of placebo, 81% of 75-μg vaccine, and 77% of 135-μg vaccine recipients. Influenza infections in the study population were due to influenza B and A(H3N2), and influenza A infections were A/California/7/2004–like viruses, an antigenically drifted strain. Seven cases of culture-confirmed CDC-defined influenza-like illness occurred in 153 placebo recipients (4.6%) compared with 2 cases (1.3%) in 150 recipients of 75 μg of vaccine, and 0 cases in recipients of 135 μg of vaccine.ConclusionsIn this study, a trivalent rHA0 vaccine was safe and immunogenic in a healthy adult population. Preliminary evidence of protection against a drifted influenza A(H3N2) virus was obtained, but the sample size was small. Inclusion of a neuraminidase component did not appear to be required for protection.Trial Registrationclinicaltrials.gov Identifier: NCT00328107

Influenza experts have been predicting a pandemic flu for many years. What they fear most is an epidemic like the Spanish flu of 1918 to 1919—the largest outbreak of fatal infectious disease during...

Rationale Because asthma exacerbations are associated with an inflammatory response in the lungs, we analyzed intracellular cytokines in circulating lymphocytes from school age children treated for wheezing in our ED to compare the response in CD4 and CD8 T cells during acute symptoms. Methods Circulating lymphocytes were isolated from actively wheezing children, n=10, children with acute rhinitis, n=10, and controls, n=8 (age range of subjects 4-18 years). Co-expression of cell surface markers CD69, CD3, and CD8, along with the production of intracellular IFN-γ and IL-5, was analyzed by flow cytometry. Nasal washes were assayed for cysteinyl leukotrienes. Total serum IgE and blood eosinophil counts were also assessed. Results Mean IFN-γ/IL-5 ratios from activated CD4 (i.e. CD3+/CD8−) lymphocytes were elevated in rhinitics (122.5) and controls (115.7) compared to wheezing patients (34.4) (p Conclusions Decreased production of IFN-γ relative to IL-5 in circulating lymphocytes from actively wheezing children was more pronounced in CD4 lymphocytes than in CD8 cells.

Rationale This study evaluated safety, tolerability and dose regimen of a new P2Y2 receptor agonist (INS37217) in patients with common cold symptoms. INS37217 is known to regulate mucosal hydration, increase chloride secretion and cilia beat frequency in vitro. Methods In a double-blind, parallel-group tolerability study, 101 subjects with symptoms of common cold received either 10mg/ml or 40mg/ml of INS37217 Nasal Spray or placebo (saline spray) BID or QID for 6 days. Cold symptoms were recorded daily by subjects for 14 days. Mucociliary function was evaluated by an intranasal saccharin-test on Days 0, 2, 6, and 14. Results INS37217 was well tolerated. There were consistent trends toward reduction in symptom scores in all groups of subjects receiving intranasal INS37217 compared to placebo. The INS37217 10mg/ml BID regimen significantly reduced malaise (Days 5, 8, 9, 10 and 11, p≤0.047) and post-nasal drip (Day 10, p≤0.046). At the end of treatment (Day 6), a larger proportion of subjects in the INS37217 10mg/ml group had normal mucociliary clearance (10.9 minutes for 50th percentile) compared to placebo (28.0 minutes for 50th percentile, p=0.070). Conclusion Intranasal treatment with INS37217 for 6 days was well tolerated and appeared to accelerate restoration of mucociliary clearance during colds. Enhancement of mucociliary clearance may have therapeutic value in improving symptoms during colds and possibly in reducing complications. Larger controlled studies of this intervention are warranted.

ContextPrevious studies have shown oseltamivir, a neuraminidase inhibitor, to be effective in preventing influenza and treating experimental influenza.ObjectiveTo evaluate the efficacy and safety of oseltamivir in the treatment of naturally acquired influenza infection.DesignRandomized, placebo-controlled, double-blind study conducted January through March 1998.SettingSixty primary care and university health centers throughout the United States.ParticipantsA total of 629 healthy nonimmunized adults aged 18 to 65 years with febrile respiratory illness of no more than 36 hours' duration with temperature of 38°C or more plus at least 1 respiratory symptom and 1 constitutional symptom.InterventionsIndividuals were randomized to 1 of 3 treatment groups with identical appearing pills: oral oseltamivir phosphate, 75 mg twice daily (n = 211) or 150 mg (n = 209) twice daily, or placebo (n = 209).Main Outcome MeasuresDuration and severity of illness in individuals infected with influenza.ResultsTwo individuals withdrew before receiving medication and were excluded from further analyses. A total of 374 individuals (59.6%) were infected with influenza. Their duration of illness was reduced by more than 30% with both oseltamivir, 75 mg twice daily (median, 71.5 hours; P

ContextAttachment of most rhinovirus subtypes to cells depends on a cellular receptor, the intercellular adhesion molecule 1 (ICAM-1). A recombinant soluble ICAM-1 (tremacamra, formerly BIRR 4) has shown possible efficacy in early studies.ObjectiveTo determine the efficacy and safety of intranasal administration of tremacamra in experimental rhinovirus colds in humans.DesignFour randomized, double-blind, placebo-controlled trials conducted in January to March 1996.Setting and SubjectsVolunteers between the ages of 18 and 60 years who had an antibody titer of 1:4 or less to the challenge virus. Subjects were isolated in a hotel room during study days 0 to 8; symptoms were recorded through day 14. A total of 198 subjects were randomized, of whom 196 received drug or placebo and were included in the safety analysis. A total of 177 subjects were included in the efficacy analysis.InterventionsTremacamra or placebo was given beginning 7 hours before inoculation with rhinovirus type 39 (preinoculation studies) or 12 hours after (postinoculation studies). Tremacamra as an inhaled solution or as a powder (each given preinoculation and postinoculation for a total of 4 studies) and placebo were given in 6 doses at 3-hour intervals daily during days 1 through 7. Recipients of active treatment received 367 µg of tremacamra per nostril per dose for a total of 4.4 mg/d.Main Outcome MeasuresEffect of tremacamra on infection, as determined by virus isolation and seroconversion, and on illness, as determined by symptom scores, clinical colds, and nasal mucus weights. Treatment-by-study interaction was not significant, so results were pooled for the main analysis.ResultsA total of 88 (92%) of the 96 subjects in the placebo groups and 69 (85%) of the 81 subjects in the active treatment groups were infected (P=.19). For placebo vs tremacamra, respectively, the total symptom score (± 95% confidence interval [CI]) was 17.6 (± 2.7) vs 9.6 (± 2.9), the proportion of clinical colds was 64/96 (67% ± 9%) vs 36/81 (44% ± 11%), and the nasal mucus weight was 32.9 (± 8.8) g vs 14.5 (± 9.4) g (P

Objective : To determine the effect of acyclovir and prednisone treatment of herpes zoster on chronic pain and quality-of-life outcomes. Design : Randomized, double-blind, placebo-controlled study with a 2 x 2 factorial design. Setting : 15 university hospitals or affiliated clinics. Patients : 208 immunocompetent patients older than 50 years of age who had localized herpes zoster that developed less than 72 hours before study enrollment. Intervention : Acyclovir or a matched placebo was administered orally, 800 mg five times daily, for 21 days. Prednisone or a matched placebo was administered orally at 60 mg/d for the first 7 days, 30 mg/d for days 8 to 14, and 15 mg/d for days 15 to 21. The four treatments regimens given were acyclovir plus prednisone ; acyclovir plus prednisone placebo ; prednisone plus acyclovir placebo ; and placebos for both acyclovir and prednisone. Measurements : Patients were monitored daily for the first 28 days for lesion healing, resolution of pain, return to usual activity, and return to uninterrupted sleep. Monitoring was then done monthly for 6 months. Patients documented analgesic requirements each day, and adverse events and laboratory abnormalities were recorded at each clinic visit. An intention-to-treat analysis was used. Results : Patients were randomly allocated to receive one of the four regimens. Demographic characteristics were similar for each group. Time to total crusting and healing was accelerated for patients receiving acyclovir plus prednisone compared with patients receiving two placebos ; the risk ratios were 2.27 (95% Cl, 1.46 to 3.55) for total crusting and 2.07 (Cl, 1.26 to 3.38) for healing. Similarly, compared with the placebo group, patients receiving acyclovir plus prednisone had accelerated time to cessation of acute neuritis (risk ratio, 3.02 [CI, 1.42 to 6.41]), time to return to uninterrupted sleep (risk ratio, 2.12 [CI, 1.25 to 3.58]) ; time to return to usual daily activity (risk ratio, 3.22 [CI, 1.92 to 5.40]) ; and time to cessation of analgesic therapy (risk ratio, 3.15 [CI, 1.69 to 5.89]). In the acyclovir plus prednisone group, resolution of pain during the 6 months after disease onset did not statistically differ from that in the other groups. No important clinical or laboratory adverse events occurred in any group. Conclusions : In relatively healthy persons older than 50 years of age who have localized herpes zoster, combined acyclovir and prednisone therapy can improve quality of life.

Objective. —The current study evaluated whether intranasal administration of the sialic acid analog 4-guanidino-Neu5Ac2en (GG167), an inhibitor of influenza virus neuraminidase, was effective and safe in either preventing or treating experimental human influenza. Methods. —Four randomized, double-blind, placebo-controlled trials involving three prophylaxis limbs, two early treatment limbs, and one delayed treatment limb were conducted. Setting. —Isolation in individual rooms. Participants. —Susceptible (serum hemagglutination-inhibition antibody titer ≤1:8) adult volunteers (n=166) were inoculated intranasally with 10 5 TCID 50 influenza A/Texas/91 (H1N1) virus. Intervention. —GG167, 3.6 to 16 mg, was administered intranasally two or six times daily beginning 4 hours before inoculation (prophylaxis) or 1 or 2 days afterward (early or delayed treatment). Main Outcomes. —Virological measures were frequency of infection based on viral shedding and/or seroconversion (prophylaxis) or quantitative viral shedding based on titers and duration of virus recovery (treatment). Clinical measures were the frequency of febrile illness and symptom severity scores. Results. —Intranasal GG167 was well tolerated for both prophylaxis and therapy. For all dose groups combined, GG167 prophylaxis was 82% effective in preventing laboratory evidence of infection and 95% effective in preventing febrile illness ( P P Conclusions. —Direct respiratory administration of the selective neuraminidase inhibitor GG167 appears safe and effective for both prevention and early treatment of experimental influenza. Influenza virus neuraminidase is important for viral replication in humans. ( JAMA . 1996;275:295-299)

Objective To determine whether naproxen, a propionic acid inhibitor of cyclooxygenase, alters the course of experimental rhinovirus colds. Design A randomized, double-blind, controlled trial. Setting Rhinovirus challenge model in volunteers cloistered in individual hotel rooms. Volunteers Eighty-seven healthy young adults with serum neutralizing antibody titers of less than or equal to 1:2 to the challenge virus; 79 were evaluable. Intervention Thirty-nine participants received naproxen (loading dose, 400 mg or 500 mg followed by 200 mg or 500 mg three times daily for 5 days). Forty participants received placebo. Treatment was started 6 hours after viral challenge. Measurements Daily measurement of viral titers, symptoms, nasal mucus production, and nasal tissue use; incidence of infection and illness; and measurement of homotypic serum neutralizing antibody responses. Results Viral titers and serum homotypic antibody responses were similar in the naproxen and placebo groups. Significant reductions in headache, malaise, myalgia, and cough occurred in the naproxen group. A 29% reduction was noted in the total (5-day) symptom score in the naproxen group (95% CI, 16% to 42%). Conclusion Naproxen treatment did not alter virus shedding or serum neutralizing antibody responses in participants with experimental rhinovirus colds, but it had a beneficial effect on the symptoms of headache, malaise, myalgia, and cough. Prostaglandins may be among the inflammatory mediators that play a role in the pathogenesis of rhinovirus colds.

Forty-five university students with proved influenza A/USSR/77 H1N1 infection were randomly treated with either amantadine hydrochloride (14 students), rimantadine hydrochloride (19 students), or placebo (12 students). By 48 hours after initiation of therapy, amantadine and rimantadine recipients had significantly less fever and greater improvement compared with subjects given the placebo. Minor reversible CNS side effects at the end of the five-day course of therapy were observed in one third of the amantadine-treated subjects. However, both amantadine and rimantadine recipients returned to classes earlier and shed smaller amounts of virus than placebo recipients. Thus, both drugs exerted a notable therapeutic effect. Hence, during an influenza outbreak, five days of empirical therapy with amantadine or rimantadine for persons with an influenza-like syndrome should ameliorate clinical symptoms and might decrease spread of virus. ( JAMA 1981;245:1128-1131)

In two placebo-controlled, double-blind studies, the prophylactic efficacy of recombinant DNA-produced interferon alpha 2 (IFN-alpha 2) against induced rhinovirus (RV) type 39 infection in susceptible volunteers was assessed. IFN-alpha 2 was given by intranasal drops in either multiple treatments (11.4 X 10(6) IU four times per day for four days) or one treatment daily (42.8 X 10(6) IU once per day for five days) starting before RV type 39 challenge. The efficacy rates of multiple-dose IFN-alpha 2 for preventing infection, virus shedding, and RV type 39-specific colds were 78%, 78%, and 100%, respectively. The corresponding rates for one daily treatment were 45%, 64%, and 75%, respectively. Both dosage regimens were associated with significant reductions in days of virus shedding and nasal mucus production. In the second study, three IFN-alpha 2 recipients developed transient leukopenia (less than 4,000 leukocytes/mm3). The results suggest that intranasal IFN-alpha 2 may prove to be a safe and effective method of preventing rhinovirus infection and illness.

The therapeutic efficacy of recombinant interferon-alpha 2 (HuIFN-alpha 2) in experimental infection with rhinovirus type 39 was assessed in two randomized, double-blind, placebo-controlled studies. Adult volunteers (serum neutralizing antibody titer, less than or equal to 1:2) were given 9 X 10(6) international units of HuIFN-alpha 2 three times a day for five days by intranasal spray (study 1) or drops (study 2) beginning 28 hr after rhinovirus inoculation. HuIFN-alpha 2 did not prevent rhinovirus infection or colds in either study. Treatment by nasal drops and to a lesser extent by spray was associated with significant reductions in duration and quantity of viral shedding. Treatment by drops was associated with significant but modest effects on nasal symptom scores and trends toward reduced quantities of production of nasal mucus. Despite lower nasal wash concentrations of interferon, HuIFN-alpha 2 drops appeared to have greater antiviral activity and therapeutic efficacy than did HuIFN-alpha 2 spray. These findings suggest that HuIFN-alpha 2 may not be therapeutically useful in treating naturally occurring rhinoviral colds.

In a double-blind, placebo-controlled study, patients with naturally occurring common colds of less than or equal to 48 h duration were randomly assigned to receive nasal sprays of recombinant alfa-2b interferon at 10 or 20 MU/day or placebo four times per day for 5 days. The 10-MU (n = 74), 20-MU (n = 74), and placebo (n = 72) groups had comparable frequencies of documented rhinovirus colds (50 to 65%) and mean durations of pretreatment symptoms (26 to 27 h). The median duration of colds tended to be longer in the 20-MU group (10 days) than the 10-MU group (8 days) or placebo group (8 days) (P = 0.06). In those with proven rhinovirus colds treated within 24 h, the median duration was significantly longer in the 20-MU group (9 days) than in the placebo group (6 days). No differences favoring interferon treatment were found in respiratory symptom scores or resolution of specific symptoms. On days 5 and 7, nasal washings from compliant subjects with proven rhinovirus colds yielded rhinoviruses more often in placebo (47 and 48%, respectively) than in interferon (15 and 16%, respectively) recipients (P less than 0.02), but no differences in new respiratory illness occurrence were observed in household contacts. Interferon recipients had significantly higher frequencies of blood in nasal mucus (16 to 18%) than did placebo recipients (4%) during treatment. Antibiotics for presumed secondary infections were given more often in the 20-MU group (11%) than in the placebo group (0%) (P less than 0.01). Nasal sprays of recombinant alfa-2b interferon were not an effective treatment for natural colds and were associated with toxicity.

Eighty-five immunocompromised patients were entered into a randomized, controlled, crossover study of mucocutaneous herpes simplex virus (HSV) infections. Thirty-nine patients (group A) received vidarabine for seven days followed by placebo for an additional seven days. Forty-six patients (group B) received the reverse regimens. Therapy did not significantly accelerate healing for the total population as assessed by loss of virus from lesions, cessation of lesion formation, and time to crusting. Group A patients demonstrated accelerated loss of pain from lesions (P = 0.0099) and defervescence (P = 0.03). Patients in group A who had HSV type 1 (HSV-1) infections or who were over 40 years of age did clear virus from lesions more rapidly (P = 0.04 and P = 0.03, respectively). No toxicity or significant adverse effects could be attributed to vidarabine administration. Benefit from vidarabine therapy is limited to immunocompromised patients over 40 years of age with HSV-1 infections.

To determine whether rimantadine can protect family members from acquiring influenza A viral illness and to assess the possible selection of drug-resistant strains of virus, we conducted a randomized, double-blind, placebo-controlled study in three communities during two influenza seasons. When influenza A occurred in a family, the members (including the index patient) were given either rimantadine (adult oral dose, 200 mg per day) or placebo for 10 days. The presence of illness was monitored by daily recording of symptoms and temperature measurements; infection was determined by isolation of the virus and by serologic studies. Among households with documented influenza A infections, symptomatic illness occurred in one or more contacts in 10 of 28 families treated with rimantadine and in 10 of 209 families treated with placebo. Asymptomatic secondary influenza A infections were found in five families assigned to receive rimantadine and in four families assigned to receive placebo. Rimantadine-resistant strains of influenza A virus (H3N2 subtype) with mutations consisting of single amino acid changes in the M2 protein (residue 27, 30, or 31) were recovered from eight index patients and five contacts treated with rimantadine. There was apparent transmission of drug-resistant strains of virus in six contacts with secondary illnesses in five families. We conclude that when index patients are treated concurrently, rimantadine is ineffective in protecting household members from influenza A infection. If rimantadine is used for both treatment and postexposure prophylaxis in families, rapid selection and apparent transmission of drug-resistant influenza A viruses can occur.