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Biomedical subjects

Frederick G Hayden

Publications and source records attributed to Frederick G Hayden.

At least 19 recordsLinked to original sources
PubMed2007

WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus.

Recent spread of avian influenza A (H5N1) virus to poultry and wild birds has increased the threat of human infections with H5N1 virus worldwide. Despite international agreement to stockpile antivirals, evidence-based guidelines for their use do not exist. WHO assembled an international multidisciplinary panel to develop rapid advice for the pharmacological management of human H5N1 virus infection in the current pandemic alert period. A transparent methodological guideline process on the basis of the Grading Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to develop evidence-based guidelines. Our development of specific recommendations for treatment and chemoprophylaxis of sporadic H5N1 infection resulted from the benefits, harms, burden, and cost of interventions in several patient and exposure groups. Overall, the quality of the underlying evidence for all recommendations was rated as very low because it was based on small case series of H5N1 patients, on extrapolation from preclinical studies, and high quality studies of seasonal influenza. A strong recommendation to treat H5N1 patients with oseltamivir was made in part because of the severity of the disease. Similarly, strong recommendations were made to use neuraminidase inhibitors as chemoprophylaxis in high-risk exposure populations. Emergence of other novel influenza A viral subtypes with pandemic potential, or changes in the pathogenicity of H5N1 virus strains, will require an update of these guidelines and WHO will be monitoring this closely.

Animals↗
PubMed2006

Antiviral effects on influenza viral transmission and pathogenicity: observations from household-based trials.

Four household-based, randomized clinical trials, two each of zanamivir and oseltamivir, were designed primarily to estimate the effect of postexposure prophylaxis on preventing influenza illness in household contacts. However, the effect of influenza antivirals on infectiousness as well as on the ability of the virus to cause disease--the pathogenicity--have important public health consequences. The authors show how such studies can provide estimates of pathogenicity, antiviral efficacy for pathogenicity, and the antiviral effect on infectiousness. Analysis of the four studies confirmed the high prophylactic efficacy against illness of both zanamivir (75%, 95% confidence interval (CI): 54, 86) and oseltamivir (81%, 95% CI: 35, 94). The effect on reducing infectiousness was 19% (95% CI: -160, 75) for zanamivir and 80% (95% CI: 43, 93) for oseltamivir. Pathogenicity in controls ranged from 44% (95% CI: 33, 55) to 66% (95% CI: 48, 72). Efficacy in reducing pathogenicity for zanamivir was 52% (95% CI: 19, 72) and 56% (95% CI: 14, 77) in the two studies; for oseltamivir, it was 56% (95% CI: 10, 73) and 79% (95% CI: 45, 92). Studies of influenza antivirals in transmission units would be improved if randomization schemes were used that allow estimation of the antiviral effect on infectiousness from individual studies.

Antiviral Agents↗
PubMed2006

Antiviral management of seasonal and pandemic influenza.

The goals of antiviral treatment for influenza are to decrease symptoms and functional disability and, more important, to decrease associated complications, hospitalizations, and mortality. Four drugs have been approved for treatment of and prophylaxis against influenza in the United States, but they are underutilized. The M2 ion channel inhibitors amantadine and rimantadine are effective for prophylaxis, and they decrease the duration of symptoms if they are used for early treatment of influenza A. The rapid emergence of resistance during therapy and, recently, the circulation of resistant H3N2 viruses in the community have decreased the usefulness of these M2 ion channel inhibitors. Early therapy with neuraminidase (NA) inhibitors, either oseltamivir or zanamivir, reduces the duration of symptoms, the duration of disability, and the risk of lower respiratory tract complications. Oseltamivir has been shown to decrease antibiotic use, the number of hospitalizations, and, probably, the risk of death after influenza. NA inhibitors might provide substantial benefits in the treatment of pandemic influenza, with reductions in the numbers of hospitalizations and deaths occurring if such treatment (1) is made available in sufficient time, through rapid distribution, and (2) is available in sufficient quantities as a result of stockpiling. Both of the aforementioned NA inhibitors are highly effective for prophylaxis. Geographically targeted mass chemoprophylaxis might contain the spread of a pandemic virus, but multiple hurdles to successful implementation exist. Resistance to oseltamivir occurs with the H274Y variant in viruses that contain N1; however, to date, such variants have been less fit, have not been transmitted from person to person, and have retained susceptibility to zanamivir. Alternative agents and approaches, including parenteral and combination therapy, for the treatment of influenza are needed in the near and long term.

Amantadine↗
PubMed2006

Seasonal and pandemic influenza: recommendations for preparedness in the United States.

There is a continued need to improve the state of preparedness for a potential influenza pandemic in the United States despite the publication of a pandemic influenza plan by the Department of Health and Human Services. Of particular importance are the sense of urgency for a coordinated response plan, an allocation of adequate funds to deal with this issue, and the need for a national leader to coordinate the development and execution of a national plan, including its relationship to the control of seasonal influenza. In addition, an infrastructure needs to be established in the United States to enable the rapid development and large-scale production of a safe and effective vaccine for new influenza strains; methods to treat influenza pneumonia need to be evaluated; a coordinated public health response needs to be defined; a nationally developed blueprint to deal with logistics of pandemic prevention is required; and there is a need to establish reliable communication systems on a national and local basis, to provide accurate information to the lay public, health care workers, and the agricultural sector.

Antiviral Agents↗
PubMed2006

"Gesundheit!" sneezing, common colds, allergies, and Staphylococcus aureus dispersion.

BACKGROUND: Staphylococcus aureus is among the most important pathogens in today's hospital setting. METHODS: The effects of sneezing on the airborne dispersal of S. aureus and other bacteria were assessed in 11 healthy nasal S. aureus carriers with experimentally induced rhinovirus colds. Airborne dispersal was studied by volumetric air sampling in 2 chamber sessions with and without histamine-induced sneezing. After 2 days of preexposure measurements, volunteers were inoculated with a rhinovirus and monitored for 14 days. Daily quantitative nasal- and skin-culture samples for bacteria and nasal-culture samples for rhinovirus were obtained, cold symptoms were assessed, and volunteer activities were recorded during sessions. RESULTS: All participants developed a cold. Sneezing caused a 4.7-fold increase in the airborne dispersal of S. aureus, a 1.4-fold increase in coagulase-negative staphylococci (CoNS), and a 3.9-fold increase in other bacteria (P < .001). An additional 2.83 colony forming units (cfu) of S. aureus/m3/min, 3.24 cfu of CoNS/m3/min, and 474.61 cfu of other bacteria/m3/min were released per sneeze. Rhinovirus exposure did not change the frequency of sneezing or airborne dispersal. Having respiratory allergies increased the spread of S. aureus by 3.8-fold during sneezing sessions (P < .001). CONCLUSION: Nasal S. aureus carriers disperse a significant amount of S. aureus into the air by sneezing. Experimental colds do not alter bacterial dispersal, but respiratory allergies multiply the effect of dispersing S. aureus.

Adult↗
PubMed2006

Antivirals for influenza: historical perspectives and lessons learned.

The development of the currently available classes of antivirals, the M2 proton channel inhibitors and the neuraminidase inhibitors, provides valuable perspectives relevant to the field of antiviral chemotherapy in general and insights into aspects of viral pathogenesis and antiviral resistance relevant specifically to influenza. The efficacy observed with these antiviral drugs has proven the importance of these antiviral targets, as well as the principle that chemoprophylaxis and early treatment are possible in influenza infections with small molecular weight inhibitors.

Adult↗
PubMed2006

Evaluation of methyl inosine monophosphate (MIMP) and peramivir activities in a murine model of lethal influenza A virus infection.

An inbred murine model (BALB/c) was utilized to assess the protective effect of the immunomodulator methyl inosine 5'-monophosphate (MIMP) against infection with influenza A/PR/8/34 (H1N1) virus. Contrary to the data reported for outbred mice (NMRI) infected with the aerosolized virus (Masihi, Hadden, 2003. J. Int. Immunopharmacol. 3, 1205-1215), there were no improvements in the outcomes of infection in the inbred animals treated with MIMP intranasally 1 day before the challenge and/or orally after the challenge for 5 days (up to 10 mg/kg/day). Nevertheless, complete protection against lethality was afforded by the treatment with the neuraminidase inhibitor peramivir given once daily for 5 days after the challenge (10 mg/kg/day). We speculate that the rapid progression of the disease in inbred mice caused by the intranasal challenge may render the MIMP-treatment ineffective. Our results emphasize the need for careful consideration of murine strains and routes of virus challenge in the design of experiments utilizing lethal influenza virus infection.

Acids, Carbocyclic↗
PubMed2006

Comparative activities of oseltamivir and A-322278 in immunocompetent and immunocompromised murine models of influenza virus infection.

We developed an immunocompromised murine model of influenza virus infection and demonstrated comparable efficacy of oral oseltamivir and A-322278 (both given at dosages of 10 mg/kg/day) in reducing viral replication, decreasing weight loss, and prolonging survival. Once the treatment was discontinued, severe combined immunodeficient (SCID) mice had progressive viral replication and clinical decline. Drug-resistant variants were detected in 4 (29%) of 14 and 2 (13%) of 15 mice (both BALB/c and SCID) treated with oseltamivir or A-322278, respectively; no resistant variants were detected in placebo-treated mice. Amino acid substitutions in the hemagglutinin receptor-binding site at aa 137 or 225 were detected in cloned resistant isolates. A substitution in the neuraminidase (NA) active site (Arg292Lys) was detected in the cloned virus recovered from an oseltamivir-treated mouse. This model would be useful for elucidation of the molecular mechanisms of resistance to NA inhibitors and for testing of anti-influenza therapy options that might prevent the emergence of resistant variants.

Acetamides↗
PubMed2006

Recovery of drug-resistant influenza virus from immunocompromised patients: a case series.

Influenza virus with resistance to antiviral drugs emerges with increased frequency in immunocompromised patients and can limit the benefit of M2 and neuraminidase (NA) inhibitors. We document 3 cases of influenza in severely immunocompromised patients from whom virus variants with molecular markers of resistance to anti-influenza drugs were recovered. Virus variants recovered from 2 patients had mutations in the M2, NA (with a previously recognized Glu119Val NA substitution), and hemagglutinin genes. We describe a novel Asp198Asn NA mutation in an influenza B virus and its decreased susceptibility to both oseltamivir and zanamivir.

Antiviral Agents↗
PubMed2006

Picornavirus infections in children diagnosed by RT-PCR during longitudinal surveillance with weekly sampling: Association with symptomatic illness and effect of season.

RT-PCR is more sensitive for rhinovirus detection than cell culture, but healthy controls are frequently rhinovirus (or picornavirus) positive in cross-sectional studies. Fifteen healthy children were followed over at least three seasons of the year with weekly sampling of nasal/nasopharyngeal secretion for RT-PCR testing for picornavirus and daily recording of respiratory symptoms. One sample positive for picornavirus was diagnosed as an infection; consecutive positive weekly samples constituted a single infection. Picornavirus illness was diagnosed if RNA was detected 7 days prior through 21 days after onset. One hundred fifty-five (21%) of 740 weekly samples were picornavirus positive and associated with illness; 37(5%) positives were not associated with illness (P = 0.001). The 192 positive samples occurred in 121 infections, 74 with a single positive and 47 with "runs" of positives in two or more consecutive samples. Forty five (96%) of the 47 runs comprised 2 or 3 consecutive positives. Ninety six (52%) of 185 reported illnesses during 235 child-months were picornavirus positive (0.4/child-month); 25 infections were asymptomatic (0.11/child-month). The infection rate was highest in fall (0.66/child-month); the winter rate (0.44/child-month) was similar to that in spring (0.5) and summer (0.43). Picornavirus infections in healthy children were common (0.51/child-month), episodic, and usually associated with brief illness; one fifth of infections were asymptomatic. The infection rate was highest in fall; infections in winter occurred at the same rate as in spring and summer.

Carrier State↗
PubMed2006

Respiratory viral threats.

PURPOSE OF REVIEW: To assess new information from peer-reviewed publications in 2005 regarding emerging respiratory viral threats. RECENT FINDINGS: The expanding epizootic of avian A/H5N1 influenza and increasing number of human cases heighten concern regarding the threat of pandemic influenza. Studies of the 1918 pandemic virus have shown the potential for direct interspecies transmission from an avian host. In the absence of an effective vaccine, antiviral agents could provide an important response measure. Inadequate supplies and potential antiviral resistance are limiting factors. Seasonal influenza heavily affects infants and young children, who also serve to foster transmission at the community level, findings that indicate the need for broader immunization strategies in pediatric populations. Like avian influenza, the severe acute respiratory syndrome coronavirus was a zoonotic infection, perhaps derived from related coronaviruses in bats. Molecular diagnostic techniques have led to the recent identification of several new coronaviruses and a respiratory parvovirus. It has also helped to define the impact of previously described ones such as human metapneumovirus and rhinoviruses, which account for the majority of asthma exacerbations and frequent lower respiratory tract illnesses. SUMMARY: Progress has been made in development of possible specific interventions for influenza and possibly severe acute respiratory syndrome coronavirus, but effective antivirals and vaccines for most other respiratory viruses are currently lacking.

Animals↗
PubMed2006

Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use.

Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) develops at a low level following drug treatment, and person-to-person transmission of resistant virus has not been recognized to date. The Neuraminidase Inhibitor Susceptibility Network (NISN) was established to follow susceptibility of isolates and occurrence of NAI resistance at a population level in various parts of the world. Isolates from the WHO influenza collaborating centers were screened for susceptibilities to oseltamivir and zanamivir by a chemiluminescent enzyme inhibition assay, and those considered potentially resistant were analyzed by sequence analysis of the neuraminidase genes. During the first 3 years of NAI use (1999 to 2002), 2,287 isolates were tested. Among them, eight (0.33%) viruses had a >10-fold decrease in susceptibility to oseltamivir, one (0.22%) in 1999 to 2000, three (0.36%) in 2000 to 2001, and four (0.41%) in 2001 to 2002. Six had unique changes in the neuraminidase gene compared to neuraminidases of the same subtype in the influenza sequence database. Although only one of the mutations had previously been recognized in persons receiving NAIs, none were from patients who were known to have received the drugs. During the 3 years preceding NAI use, no resistant variants were detected among 1,054 viruses. Drug use was relatively stable during the period, except for an approximate 10-fold increase in oseltamivir use in Japan during the third year. The frequency of variants with decreased sensitivity to the NAIs did not increase significantly during this period, but continued surveillance is required, especially in regions with higher NAI use.

Antiviral Agents↗
PubMed2006

Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection.

Influenza is a highly infectious disease characterized by recurrent annual epidemics and unpredictable major worldwide pandemics. Rapid spread of the highly pathogenic avian H5N1 strain and escalating human infections by the virus have set off the alarm for a global pandemic. To provide an urgently needed alternative treatment modality for influenza, we have generated a recombinant fusion protein composed of a sialidase catalytic domain derived from Actinomyces viscosus fused with a cell surface-anchoring sequence. The sialidase fusion protein is to be applied topically as an inhalant to remove the influenza viral receptors, sialic acids, from the airway epithelium. We demonstrate that a sialidase fusion construct, DAS181, effectively cleaves sialic acid receptors used by both human and avian influenza viruses. The treatment provides long-lasting effect and is nontoxic to the cells. DAS181 demonstrated potent antiviral and cell protective efficacies against a panel of laboratory strains and clinical isolates of IFV A and IFV B, with virus replication inhibition 50% effective concentrations in the range of 0.04 to 0.9 nM. Mouse and ferret studies confirmed significant in vivo efficacy of the sialidase fusion in both prophylactic and treatment modes.

Amphiregulin↗
PubMed2006

Kinetics of influenza A virus infection in humans.

Currently, little is known about the viral kinetics of influenza A during infection within an individual. We utilize a series of mathematical models of increasing complexity, which incorporate target cell limitation and the innate interferon response, to examine influenza A virus kinetics in the upper respiratory tracts of experimentally infected adults. The models were fit to data from an experimental H1N1 influenza A/Hong Kong/123/77 infection and suggest that it is important to include the eclipse phase of the viral life cycle in viral dynamic models. Doing so, we estimate that after a delay of approximately 6 h, infected cells begin producing influenza virus and continue to do so for approximately 5 h. The average lifetime of infected cells is approximately 11 h, and the half-life of free infectious virus is approximately 3 h. We calculated the basic reproductive number, R(0), which indicated that a single infected cell could produce approximately 22 new productive infections. This suggests that antiviral treatments have a large hurdle to overcome in moderating symptoms and limiting infectiousness and that treatment has to be initiated as early as possible. For about 50% of patients, the curve of viral titer versus time has two peaks. This bimodal behavior can be explained by incorporating the antiviral effects of interferon into the model. Our model also compared well to an additional data set on viral titer after experimental infection and treatment with the neuraminidase inhibitor zanamivir, which suggests that such models may prove useful in estimating the efficacies of different antiviral therapies for influenza A infection.

Administration, Intranasal↗
PubMed2006

Post-exposure influenza prophylaxis with oseltamivir: cost effectiveness and cost utility in families in the UK.

OBJECTIVES: To assess the cost effectiveness and cost utility of preventing post-exposure influenza infection using the neuraminidase inhibitor oseltamivir from a healthcare payer's perspective in the UK. METHODS: A simulation model was developed, based on clinical trial results and published data, to predict morbidity and mortality due to influenza and to compare oseltamivir post-exposure prophylaxis (PEP) with no prophylaxis within families with members aged >or=13 years. Two scenarios were tested:1. Comparison of patients receiving PEP versus patients not receiving PEP and not being treated with oseltamivir should they become infected. 2. Comparison of patients receiving PEP versus patients not receiving PEP but being treated with oseltamivir should they become infected. The model was run with an attack rate in household contacts of 8% for the base case, with higher rates (up to 30%, representing pandemic conditions) tested in sensitivity analyses. A societal perspective and other key parameters were tested in sensitivity analysis. The year of costing was 2002. The time span for the model was up to 1 year (including one influenza season), but loss of life was included in the QALY calculation and based on expected life expectancy. RESULTS: PEP with oseltamivir results in reduced morbidity (i.e. fewer influenza cases) and associated reductions in complications, hospitalisations and mortality due to influenza. When comparing oseltamivir PEP with no prophylaxis for contact attack rates of 8%, 12% and 30%, the mean costs per QALY gained for scenario one were estimated at 29,938 pounds, 18,697 pounds and 5403 pounds, respectively; the mean costs per case avoided were 467 pounds, 293 pounds and 84 pounds, respectively. The corresponding results for scenario two were 52,202 pounds, 31,610 pounds and 9688 pounds per QALY gained. CONCLUSIONS: PEP with oseltamivir is likely to be a cost-effective strategy for family contacts in the UK from a healthcare payer perspective when influenza-like illness contact attack rates are 8% or higher and the only treatment given is 'usual care'.

Acetamides↗
PubMed2006

Influenza, Winter Olympiad, 2002.

Prospective surveillance for influenza was performed during the 2002 Salt Lake City Winter Olympics. Oseltamivir was administered to patients with influenza like illness and confirmed influenza, while their close contacts were given oseltamivir prophylactically. Influenza A/B was diagnosed in 36 of 188 patients, including 13 athletes. Prompt management limited the spread of this outbreak.

Acetamides↗
PubMed2005

Pharmacophore modeling, docking, and principal component analysis based clustering: combined computer-assisted approaches to identify new inhibitors of the human rhinovirus coat protein.

The development and application of a sophisticated virtual screening and selection protocol to identify potential, novel inhibitors of the human rhinovirus coat protein employing various computer-assisted strategies are described. A large commercially available database of compounds was screened using a highly selective, structure-based pharmacophore model generated with the program Catalyst. A docking study and a principal component analysis were carried out within the software package Cerius and served to validate and further refine the obtained results. These combined efforts led to the selection of six candidate structures, for which in vitro anti-rhinoviral activity could be shown in a biological assay.

Antiviral Agents↗