Avian influenza A (H5N1) infection in humans.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
Frederick G Hayden
Publications and source records attributed to Frederick G Hayden.
Influenza A (H5N1): will it be the next pandemic influenza? Are we ready?
Explore the source record for details and available documents.
Disease Outbreaks↗
Protection afforded by intranasal immunization with the neuraminidase-lacking mutant of influenza A virus in a ferret model.
Protective efficacy of the intranasal immunization with the neuraminidase (NA)-deficient mutant of the influenza A virus was investigated in ferrets. Despite the highly attenuated replication in vivo, the mutant completely protected the animals against the wild type virus challenge. When challenge was done with antigenic drift variants, significant reductions in the viral titers, inflammatory cell counts, and protein concentrations were observed in the nasal washes of the immunized animals. The genetically engineered NA-deficient mutant also protected animals against the challenge and induced humoral immune response against the foreign protein that replaced the NA. We conclude that the NA as antigen is dispensable in the live attenuated influenza virus vaccine and that the NA-lacking mutant can be used as a virus vector.
Administration, Intranasal↗
Cardiac findings during uncomplicated acute influenza in ambulatory adults.
BACKGROUND: Previous studies have reported abnormal cardiac findings in up to 43% of ambulatory adults with influenza. This study was conducted to determine the frequency, magnitude, and duration of myocardial dysfunction in such persons. METHODS: We enrolled 30 previously healthy young adults without known cardiovascular disease who presented to the clinic <or=72 h after onset of influenza symptoms and had a positive influenza antigen test. Most patients received antiviral therapy, and all underwent serial electrocardiography and had blood specimens collected on days 1, 4, 11, and 28 after presentation for measurement of total creatine kinase (CK) level, CK isoenzyme MB (CK-MB) level, troponin I level, and selected cytokine levels. Echocardiography was performed on days 4, 11, and 28. RESULTS: None of the patients had an elevated CK-MB index or troponin I level. Abnormal electrocardiogram findings were noted in 53%, 33%, 27%, and 23% of patients on days 1, 4, 11, and 28, respectively, but none of the findings were considered to be clinically significant. No patient had significant changes in the ejection fraction or abnormal wall motions. CONCLUSIONS: Most ambulatory young adults with acute influenza have clinically insignificant abnormal electrocardiogram findings early during the illness. These abnormalities resolve promptly and are not associated with changes in cardiac markers or echocardiogram findings.
Adolescent↗
Influenza treatment with neuraminidase inhibitors: cost-effectiveness and cost-utility in healthy adults in the United Kingdom.
We assessed the cost-effectiveness and cost-utility of treating influenza with neuraminidase inhibitors (oseltamivir and zanamivir) from a health care payer's and societal perspective in the United Kingdom. A simulation model was developed to predict morbidity and mortality due to influenza and its specified complications, comparing neuraminidase inhibitors with usual care in an otherwise healthy adult population. Robustness of the results was tested by one-way and multiway as well as probabilistic sensitivity analyses. Treatment with either neuraminidase inhibitor results in reduced morbidity and faster return to normal activities. However, oseltamivir dominates zanamivir in cost-utility analysis due to its lower costs. Comparing oseltamivir with usual care, the costs are pound14.36 per day of normal activity gained and pound5,600 per quality-adjusted life-year gained from the healthcare payer perspective. Oseltamivir dominates usual care from the societal perspective. Treatment with oseltamivir is a cost-effective strategy for otherwise healthy adults in the UK from both the healthcare payer and societal perspective.
Acetamides↗
Weekly point prevalence of Streptococcus pneumoniae, Hemophilus influenzae and Moraxella catarrhalis in the upper airways of normal young children: effect of respiratory illness and season.
The aim was to determine the effect of respiratory illness and season on carriage rates in the upper airways of Streptococcus pneumoniae, Hemophilus influenzae and Moraxella catarrhalis in normal children. Sixteen healthy children, 1-10 years old, amenable to weekly sampling were followed longitudinally for at least three seasons of the year. Respiratory symptoms were recorded daily; weekly nasal aspirate/wash samples were cultured on selective agars. Urea concentration in samples was used to define dilution of secretion. 68% of 950 samples were culture positive; 44% of positives had two or all three species. Each species was detected in about one third of samples. Bacteria were detected in 76% of samples during illness vs. 65% during wellness (p=0.004). Seasonal carriage rates varied from 56% in summer and fall to 85% in winter. There was a strong inverse correlation between dilution of secretion and bacterial detection rate in illness and wellness aspirate samples during the four seasons (r=-0.82, p=0.01). Detection of bacteria varied with the amount of secretion in the sample. This variation accounts for the apparent differences in bacterial carriage during illness vs. wellness and during different seasons.
Carrier State↗
Relationship of pleconaril susceptibility and clinical outcomes in treatment of common colds caused by rhinoviruses.
Pleconaril, a specific inhibitor of human picornaviruses, showed therapeutic efficacy against community-acquired colds caused by rhinoviruses in two placebo-controlled trials. Virological assessments were conducted during these trails, including virus culture and drug susceptibility testing. Nasal mucus samples collected from the enrolled patients were tested for the presence of picornavirus by reverse transcriptase PCR and culture. In total, 827 baseline nasal mucus samples were positive by virus culture (420 in the placebo group and 407 in the pleconaril group). Pleconaril treatment was associated with a more rapid loss of culturable virus. By study day 3, the number of samples positive by culture fell to 282 for the placebo-treated subjects and 202 for the pleconaril-treated subjects (P < 0.0001); and by day 6, the number of samples in the two groups positive by culture fell to 196 and 165, respectively (P = 0.07). The clinical benefit correlated strongly with the pleconaril susceptibility of the baseline virus isolate. Pleconaril-treated subjects infected with the more highly susceptible viruses (50% effective concentration < or = 0.38 microg/ml) experienced a median 1.9- to 3.9-day reduction in symptom duration compared with that for the placebo-treated subjects. By contrast, subjects whose baseline virus isolate susceptibility was >0.38 microg/ml did not benefit from pleconaril treatment. These results indicate that the magnitude of symptomatic improvement in pleconaril-treated subjects with community-acquired colds is related to the drug susceptibility of the infecting virus, clearly linking the antiviral effects of the drug to clinical efficacy. Post-baseline virus isolates with reduced susceptibility or full resistance to pleconaril were recovered from 10.7% and 2.7% of drug-treated subjects, respectively. These patients shed low levels of virus and had no unusual clinical outcomes. Nevertheless, studies on the biologic properties and transmissibility of these variant viruses are warranted.
Antiviral Agents↗
Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors.
The susceptibilities of five zanamivir-resistant and six oseltamivir-resistant influenza viruses were assessed against four neuraminidase (NA) inhibitors, including peramivir and A-315675, by a fluorometric NA activity inhibition assay. The enzyme activity of a majority of the variants was effectively inhibited by either A-315675 or both peramivir and A-315675 (50% inhibitory concentration, <10 nM). A novel oseltamivir-resistant influenza virus B variant carrying substitution at residue 198 (Asp-->Asn) (N2 numbering) retained susceptibility to peramivir and A-315675. In vivo, the Asn198 variant showed no apparent fitness impairment as judged by its recovery on day 5 from the nasal washes of ferrets coinfected with equal doses of the wild-type virus and the Asn198 variant. Based on the sequence analysis of the virus in the nasal washes, oseltamivir treatment (5 mg/kg twice daily for 5 days) did not provide growth advantage to the Asn198 variant. Nevertheless, treatment with A-315675 (prodrug A-322278) reduced the number of the animals (two of seven) shedding the Asn198 variant. These studies indicate that different patterns of susceptibility and cross-resistance between NA inhibitors may prove important if antiviral resistance to zanamivir and oseltamivir were to emerge.
Animals↗
Effect of hemagglutinin glycosylation on influenza virus susceptibility to neuraminidase inhibitors.
Inhibition of neuraminidase (NA) activity prevents release of progeny virions from influenza-infected cells and removal of neuraminic (sialic) acid moieties from glycans attached to hemagglutinin (HA). Neuraminic acid moieties situated near the HA receptor-binding site can reduce the efficiency of virus binding and decrease viral dependence on NA activity for replication. With the use of reverse genetics technique, we investigated the effect of glycans attached at Asn 94a, 129, and 163 on the virus susceptibility to NA inhibitors in MDCK cells and demonstrated that the glycan attached at Asn 163 plays a dominant role in compensation for the loss of NA activity.
Acetamides↗
Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment.
OBJECTIVE: Oseltamivir is the only oral neuraminidase inhibitor currently available; we determined the tolerability and antiviral efficacy of oral peramivir for treatment and prophylaxis of experimental human influenza A and B. PARTICIPANTS: 288 susceptible, healthy volunteers (ages 18-45) were inoculated intranasally with A/Texas/36/ 91/H1N1 or B/Yamagata/16/88 virus in four randomized, double-blind, placebo-controlled trials. INTERVENTIONS: For treatment dosing was initiated at 24 h after inoculation with peramivir doses ranging from 100-800 mg/day for 5 days. For prophylaxis dosing was initiated 24 h before inoculation and continued for 4 days with peramivir doses ranging from 50-800 mg/day. OUTCOMES: The primary outcome measure for treatment was quantitative viral detection defined by the area under the curve (AUC) for nasal wash viral titres. For prophylaxis the primary outcome measure was the incidence of virus recovery. RESULTS: In influenza A treatment, peramivir 400 mg q24h and 200mg q12h, but not lower doses, resulted in significant reductions in viral titre AUC. In influenza B treatment, both 400 and 800/400 mg once daily dose groups reduced AUC values. In influenza A prophylaxis, the percentage of individuals with nasal viral shedding did not differ significantly in the placebo (58%), 50 mg (61%), 200 mg (37%) and 400 mg (31%) dose groups. In influenza B prophylaxis, shedding frequencies were similar in placebo (55%), 200 mg (41%), 400 mg (35%) and 800 mg (47%) dose groups. The drug was well tolerated in all four studies, with nausea and headache being the most common side effects. No drug-resistant variants were detected. CONCLUSION: Early treatment with peramivir was associated with significant antiviral effects in experimentally induced influenza in humans. Prophylaxis did not significantly reduce viral shedding. The relatively low blood peramivir concentrations observed may explain the lack of more robust antiviral effects, and parenteral dosing should be studied.
Acids, Carbocyclic↗
Clinical issues and research in respiratory failure from severe acute respiratory syndrome.
The National Heart, Lung, and Blood Institute, along with the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases, convened a panel to develop recommendations for treatment, prevention, and research for respiratory failure from severe acute respiratory syndrome (SARS) and other newly emerging infections. The clinical and pathological features of acute lung injury (ALI) from SARS appear indistinguishable from ALI from other causes. The mainstay of treatments for ALI remains supportive. Patients with ALI from SARS who require mechanical ventilation should receive a lung protective, low tidal volume strategy. Adjuvant treatments recommended include prevention of venous thromboembolism, stress ulcer prophylaxis, and semirecumbent positioning during ventilation. Based on previous experience in Canada, infection control resources and protocols were recommended. Leadership structure, communication, training, and morale are an essential aspect of SARS management. A multicenter, placebo-controlled trial of corticosteroids for late SARS is justified because of widespread clinical use and uncertainties about relative risks and benefits. Studies of combined pathophysiologic endpoints were recommended, with mortality as a secondary endpoint. The group recommended preparation for studies, including protocols, ethical considerations, Web-based registries, and data entry systems.
Adrenal Cortex Hormones↗
Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
We determined the efficacy of postexposure prophylaxis (PEP) and treatment of ill index cases with oseltamivir, in an attempt to prevent influenza transmission in households, in a study conducted in 277 households with 298 index cases (62% with laboratory-confirmed influenza) and 812 contacts aged > or =1 year. Contacts were randomized by household to receive treatment (5 days; n=402), if illness developed, or PEP for 10 days (n=410), and the number of households with at least 1 contact developing laboratory-confirmed influenza was measured. PEP provided a protective efficacy of 58.5% (95% confidence interval [CI], 15.6%-79.6%; P=.0114) for households against proven influenza and 68.0% (95% CI, 34.9%-84.2%; P=.0017) for individual contacts, compared with treatment of index cases alone. No oseltamivir-resistant variants were detected in treated index cases or contacts. PEP of household contacts of those with influenza reduces the secondary spread of influenza in families when the initial household case is treated.
Acetamides↗
Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing.
BACKGROUND: Viral respiratory tract infections and atopy are associated with attacks of wheezing during childhood. However, information about the relationship between viral infections and atopy among children whose attacks of wheezing lead to hospitalization is unclear. OBJECTIVE: To evaluate the prevalence of viral respiratory tract pathogens among infants and children hospitalized for wheezing and to analyze the results in relation to the patient's age, atopic characteristics, and season of admission. METHODS: This was a case-control study of children (age 2 months to 18 years) admitted for wheezing to the University of Virginia Medical Center over a period of 12 months. Children without wheezing were enrolled as controls. Nasal secretions were evaluated for viral pathogens by using cultures, PCR tests, and antigen detection. Total IgE and specific IgE antibody to common aeroallergens was measured in serum. RESULTS: Seventy percent of children hospitalized for wheezing before age 3 years (n=79) were admitted between December and March, whereas 46% of children age 3 to 18 years (n=54) were hospitalized between September and November. Among children younger than 3 years, viral pathogens were detected in 84% (66/79) of wheezing children and 55% (42/77) of controls (P <.001). Respiratory syncytial virus was the dominant pathogen during the winter months, but rhinovirus was more common during other months. Total serum IgE levels were generally low, and values from wheezing and control subjects overlapped considerably. Among children 3 years and older, 61% (33/54) of subjects admitted for wheezing tested positive for virus (predominantly rhinovirus), compared with 21% (12/56) of controls (P <.001). The total serum IgE values among wheezing children (geometric mean, 386 IU/mL; 95% CI, 259-573) were substantially elevated compared with those of controls (geometric mean, 38 IU/mL; 95% CI, 26-56; P <.001). A significantly higher percentage of wheezing children compared with controls was sensitized to at least 1 of the inhaled allergens tested: 84% (36/43) compared with 33% (15/45; P <.001). The atopic characteristics of wheezing children who tested positive or negative for virus were similar. CONCLUSIONS: Viral infections were the dominant risk factor for wheezing among children hospitalized before 3 years of age. By comparison, a large majority of the wheezing children age 3 to 18 years had striking atopic characteristics that may be critical as a risk factor for hospitalization and an adverse response to viral infections, especially infections caused by rhinovirus.
Adolescent↗
Preventing nosocomial influenza by improving the vaccine acceptance rate of clinicians.
OBJECTIVES: To assess the effects of interventions to prevent transmission of influenza and to increase employee compliance with influenza vaccination. DESIGN: The change in the proportion of hospitalized patients with laboratory-confirmed nosocomial influenza was observed over time and assessed using chi-square for trend analysis. The association between nosocomial influenza in patients and healthcare worker (HCW) compliance with vaccine was assessed by logistic regression. SETTING: A 600-bed, tertiary-care academic hospital. METHODS: After an outbreak of influenza A at this hospital in 1988, a mobile cart program was instituted with increased efforts to motivate employees to be vaccinated and furloughed when ill as well as new measures to prevent nosocomial spread. RESULTS: HCW vaccination rates increased from 4% in 1987-1988 to 67% in 1999-2000 (P < .0001). Proportions of nosocomially acquired influenza cases among employees or patients both declined significantly (P < .0001). Logistic regression analysis revealed a significant inverse association between HCW compliance with vaccination and the rate of nosocomial influenza among patients (P < .001). CONCLUSION: A mobile cart vaccination program and an increased emphasis on HCWs to receive the vaccine were associated with a significant increase in vaccine acceptance and a significant decrease in the rate of nosocomial influenza among patients.
Adult↗
Pandemic influenza: is an antiviral response realistic?
BACKGROUND: Antiviral agents could play a significant role in the response to a future influenza pandemic, especially if an effective vaccine is unavailable. There is, however, a limited availability of antiviral drugs, as was the case during the A/Fujian(H3N2) epidemic in the 2003-2004 season. There are major differences among the available antiviral agents in terms of clinical pharmacology, adverse effects and resistance profiles, all of which must be considered when selecting agents for pandemic use and stockpiling. The logistic issues involved in delivering the drug to large populations must also be considered. The M2 ion channel inhibitors amantadine and rimantadine are partially effective for chemoprophylaxis of pandemic influenza, and when used for early treatment they provide some symptom relief. Interpandemic studies demonstrate that the neuraminidase inhibitors would be effective for both prevention and treatment of influenza. CONCLUSION: Given the limited supply and the previously demonstrated inability of the manufacturing sector to meet surging needs, an effective antiviral response could not currently be launched in the United States. Antiviral agents could be important in managing and treating pandemic influenza and reduce lower respiratory complications and hospitalizations.
Amantadine↗
Multiple sclerosis attacks are associated with picornavirus infections.
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system, which often follows a relapsing-remitting (RR) course with discrete attacks. MS attacks have been associated with upper respiratory infections (URIs), but the specific viruses responsible have not been identified. We studied a cohort of 16 RRMS patients experiencing URI and followed them for clinically identifiable attacks. The viral causes of 21 separate URIs were investigated using culture and polymerase chain reaction (PCR) of nasal swab specimens, and by serology. Sibleys 'at-risk' period for MS attacks, beginning two weeks before and continuing for five weeks after a URI, was used for the analysis. Seven of the nine (78%) URIs due to picornaviruses were associated with an MS attack during the at-risk period. By contrast, only two of 12 (17%) picornavirus-negative URIs were associated with an MS attack (P = 0.01). The possible role of picornaviruses in the pathogenesis of MS deserves further study.
Adult↗
Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: results of 2 double-blind, randomized, placebo-controlled trials.
The novel capsid-binding antiviral pleconaril inhibits in vitro replication of most rhinoviruses and enteroviruses. Oral pleconaril treatment was studied in 2 parallel randomized, double-blind, placebo-controlled trials. Among 1363 picornavirus-infected participants (65%) in the studies combined, the median time to alleviation of illness was 1 day shorter for pleconaril recipients than for placebo recipients (P<.001). Cold symptom scores and frequency of picornavirus cultured from nasal mucus specimens were lower among pleconaril recipients by day 2 of treatment. No treatment effects were seen in those without picornavirus infection. Pleconaril was associated with a higher incidence of nausea (6% vs. 4%) and diarrhea (9% vs. 7%) and with small increases in mean serum cholesterol levels and platelet counts, compared with baseline measurements. A subsequent 6-week prophylaxis study found that pleconaril induces cytochrome P-450 3A enzymes, which metabolize a variety of drugs, including ethinyl estradiol. Early pleconaril treatment was well tolerated and significantly reduced the duration and severity of colds due to picornaviruses in adults.
Administration, Oral↗
Rhinovirus infections in hematopoietic stem cell transplant recipients with pneumonia.
Little is known about the impact of human rhinovirus (HRV) and coronavirus infections in hematopoietic stem cell transplant (HSCT) recipients. We tested bronchoalveolar lavage (BAL) samples obtained from HSCT recipients with acute pulmonary infiltrates for HRV (n=122) and coronavirus (n=46) by reverse-transcriptase polymerase chain reaction. HRV RNA was detected in 6 (8%) of 77 patients, and coronavirus RNA was detected in 0 of 46 of BAL samples from HSCT recipients. The fatality rate in HRV-infected patients was high (83%), but all patients had significant coinfections, and the overall mortality rate was not different from that of patients who were negative for HRV in BAL samples. These results suggest that HRV may be a cause of lower respiratory tract infections in HSCT recipients and that its detection in BAL samples is associated with frequent copathogens. Whether the poor prognosis is due to HRV or the copathogen is not clear.
Adolescent↗