Review Article

Current Concepts

Update on Avian Influenza A (H5N1) Virus Infection in Humans

Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus

N Engl J Med 2008; 358:261-273January 17, 2008

Article

The unprecedented epizootic of avian influenza A (H5N1) viruses among birds continues to cause human disease with high mortality and to pose the threat of a pandemic. This review updates a 2005 report1 and incorporates information recently published or presented at the Second World Health Organization (WHO) Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus.2

Viral Ecology

Highly pathogenic avian influenza A (H5N1) viruses are entrenched among poultry in parts of Asia, Africa, and perhaps the Middle East. The highly pathogenic avian influenza H5 hemagglutinin has evolved into many phylogenetically distinct clades and subclades (Figure 1Figure 1Evolution of the Hemagglutinin and Other Key Mutations Associated with Virulence or Drug Resistance in Avian Influenza A (H5N1) Virus.)4,5 that generally correlate with antigenic differences that must be considered in the selection of candidates for H5N1 vaccines.6,7 These diverse lineages have been largely separate geographically since 2005 (Figure 1),5 although clade 2.3 viruses from China have recently circulated in other Southeast Asian countries.8

The influenza A (H5N1) viruses that have infected humans have been entirely avian in origin, and they reflect strains circulating locally among poultry and wild birds. Avian influenza viruses can be maintained, amplified, and disseminated in live-poultry markets. Migratory birds may spread A (H5N1) viruses to new geographic regions, but their importance as an ecologic reservoir is uncertain. The spread of influenza A (H5N1) viruses appears to be principally related to the movement of poultry and poultry products,9,10 although recent outbreaks of clade 2.2 virus infection in sub-Saharan Africa,11 Egypt, and Europe may indicate introduction of the virus by wild birds. The risk of the introduction of influenza A (H5N1) viruses into North America by birds migrating through Alaska appears to be low.12

Epidemiology of Human Infections

Incidence and Demographic Characteristics

Despite widespread exposures to poultry infected with avian influenza A (H5N1) viruses,13,14 influenza A (H5N1) disease in humans remains very rare. Since May 2005, the numbers of both affected countries13 and confirmed cases of influenza A (H5N1) virus infection (340 cases as of December 14, 2007) have increased, in part because of the spread of clade 2.2 viruses across Eurasia and to Africa5,15 (Fig. 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org).

The median age of patients with influenza A (H5N1) virus infection is approximately 18 years, with 90% of patients 40 years of age or younger and older adults underrepresented.16 The overall case fatality proportion is 61%; it is highest among persons 10 to 19 years of age and lowest among persons 50 years of age or older. 16 Whether preexisting immunity, differences in exposure, or other factors might contribute to the apparently lower frequency of infection and lethal illness among older adults is uncertain. Most patients with influenza A (H5N1) virus infection were previously healthy. Of six affected pregnant women, four have died, and the two survivors had a spontaneous abortion.17

Increases in human cases of influenza A (H5N1) have been observed during cooler months in association with increases in outbreaks among poultry (see Fig. 1 of the Supplementary Appendix).18 However, because cases have occurred year-round, clinicians must be alert to possible human infection at any time, especially in countries with outbreaks of influenza A (H5N1) among birds. To date, no cases of influenza A (H5N1) illness have been identified among short-term travelers visiting countries affected by outbreaks among poultry or wild birds,19 although clinicians in unaffected countries should consider this possibility in travelers with exposures to poultry.

Surveillance for cases of influenza A (H5N1) has focused on patients with severe illness, but milder illnesses in children, which are not pneumonic,20,21 occur. Limited seroepidemiologic studies conducted since 2003 involving villagers living with backyard poultry, workers in live-poultry markets, and health care workers suggest that asymptomatic or mild human influenza A (H5N1) virus infection is rare (Table 1 of the Supplementary Appendix).14

Transmission

Direct avian-to-human H5N1 virus transmission is the predominant means of human infection, although the exact mode and sites of influenza A (H5N1) virus acquisition in the respiratory tract are incompletely understood. Handling of sick or dead poultry during the week before the onset of illness is the most commonly recognized risk factor.22,23 Most patients have acquired A (H5N1) infection from poultry raised inside or outside their houses. Slaughtering, defeathering, or preparing sick poultry for cooking; playing with or holding diseased or dead poultry; handling fighting cocks or ducks that appear to be well; and consuming raw or undercooked poultry or poultry products have all been implicated as potential risk factors.21-24 The defeathering of dead wild swans was implicated in one case cluster.25

The influenza A (H5N1) virus can also infect multiple mammalian hosts,26,27 including domestic cats28 and dogs.29 None have been implicated in influenza A (H5N1) virus transmission to humans yet, but any animal infected with the virus theoretically poses a risk of transmission and of being a host for viral adaptation to mammals.26

Clusters of human influenza A (H5N1) illness with at least two epidemiologically linked cases have been identified in 10 countries and have accounted for approximately one quarter of cases.20,21,24,30-32 Most clusters have involved two or three persons; the largest affected eight. More than 90% of case clusters have occurred among blood-related family members, suggesting possible genetic susceptibility, although one statistical model indicated that these clusters might have occurred because of chance alone.33 Most persons in case clusters probably acquired infection from common-source exposures to poultry, but limited, nonsustained human-to-human transmission has probably occurred during very close, unprotected contact with a severely ill patient.20,30,32 In the largest cluster, transmission probably occurred from the index case to six blood-related family members and subsequently to another family member.32 Respiratory secretions and all bodily fluids, including feces, should be considered potentially infectious.

In one quarter or more of patients with influenza A (H5N1) virus infection, the source of exposure is unclear, and environment-to-human transmission remains possible.20,24 For some patients, the only identified risk factor was visiting a live-poultry market.34,35 Plausible transmission routes include contact with virus-contaminated fomites or with fertilizer containing poultry feces, followed by self-inoculation of the respiratory tract or inhalation of aerosolized infectious excreta. It is unknown whether influenza A (H5N1) virus infection can begin in the human gastrointestinal tract. In several patients, diarrheal disease preceded respiratory symptoms,36 and virus has been detected in feces.3,37 Acquisition of influenza A (H5N1) virus infection in the gastrointestinal tract has been implicated in other mammals.26 Drinking potable water and eating properly cooked foods are not considered to be risk factors, but ingestion of virus-contaminated products or swimming or bathing in virus-contaminated water might pose a risk.

Incubation Period

After exposure to infected poultry, the incubation period generally appears to be 7 days or less, and in many cases this period is 2 to 5 days. In clusters in which limited, human-to-human transmission has probably occurred, the incubation period appears to be approximately 3 to 5 days, although in one cluster it was estimated to be 8 to 9 days.20,30

Pathogenesis

Viral Factors

The viral and host factors that determine host-restriction and disease manifestations are incompletely understood.38 Preferential binding of the influenza A (H5N1) virus to α2,3-linked sialic acid receptors on avian cells39 is thought to be key in preventing influenza A (H5N1) and other avian influenza viruses from readily infecting humans. Some influenza A (H5N1) viruses isolated from humans have acquired mutations that permit binding to both α2,3-linked sialic acid receptors and α2,6-linked sialic acid receptors,40 but these mutations appear to be insufficient for efficient human-to-human transmission. To date, influenza A (H5N1) viruses have shown no transmissibility or poor transmissibility between ferrets and between swine, and reassortment between an influenza A (H5N1) virus and an influenza A (H3N2) virus did not confer transmissibility in ferrets.41 Changes in multiple viral genes are probably required to generate a potentially pandemic influenza A (H5N1) virus.

All recent influenza A (H5N1) viruses retain a polybasic amino acid motif at the HA1–HA2 connecting peptide that is characteristic of highly pathogenic avian influenza viruses. Geographic variations in this motif have not been associated with obvious changes in the virulence of infection in humans. Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and replication at temperatures present in the upper respiratory tract (Figure 1).42 However, these mutations do not correlate with obvious differences in mortality among humans with this viral infection.3,21

Viral Replication

The primary pathologic process that causes death is fulminant viral pneumonia. The target cells for replication of the influenza A (H5N1) virus include type 2 alveolar pneumocytes and macrophages.17,43,44 Bronchiolar and alveolar cells, but not epithelia from the trachea or upper respiratory tract, express detectable α2,3-linked sialic acid receptors.43-45 However, influenza A (H5N1) viruses replicate in ex vivo organ cultures of the upper respiratory tract,44 postmortem studies show virus in tracheal epithelia,17,46 and high titers of virus are detectable in specimens of throat and tracheal aspirates from humans infected with influenza A (H5N1) virus.3 These findings suggest that the initial infection may occur in either the upper or lower respiratory tract, although the latter may support more efficient replication.

Limited data show that patients with influenza A (H5N1) disease may have detectable viral RNA in the respiratory tract for up to 3 weeks, presumably because of negligible preexisting immunity and possibly viral evasion of immune responses.3 One patient with fatal infection treated with both antiviral agents and corticosteroids had viral antigen and RNA in tracheal samples on day 27 after the onset of illness.17 Viral loads in the pharynx are higher and plasma viral RNA is detected more often in patients with fatal disease than in those with nonfatal disease, indicating that levels of viral replication influence the outcome.3 The reported presence of infectious virus in the blood, cerebrospinal fluid, or viscera of several patients with fatal disease indicates that, as in birds and several mammalian species, disseminated infection occurs in some humans.3,17,36,37,46 A fatal influenza A (H5N1) infection in one pregnant woman who received corticosteroids for treatment of the disease was associated with virus infection of the brain, placenta, and fetus.17 Infectious virus and viral RNA have been detected in feces and intestines, suggesting that the virus sometimes replicates in the gastrointestinal tract.1,3,36,37,46

Pathological Findings

The few reported autopsies of patients with influenza A (H5N1) virus infection have shown diffuse alveolar damage with hyaline membrane formation, patchy interstitial lymphoplasmacytic infiltrates, bronchiolitis with squamous metaplasia, and pulmonary congestion with varying degrees of hemorrhage.17,46,47 Acute exudative, diffuse alveolar damage with macrophages, neutrophils, and activated lymphocytes has been detected in patients who died within 2 weeks after the onset of illness. Apoptosis in alveolar cells and infiltrating leukocytes are prominent findings.46 Lymphocyte depletion occurs in the spleen, lymph nodes, and tonsils; histiocytic hyperplasia and reactive hemophagocytosis presumably result from host cytokine responses and viral infection. Edema and degeneration of myocytes in the heart and extensive acute tubular necrosis in the kidney have been observed.

Host Responses

Higher plasma levels of macrophage and neutrophil-attractant chemokines and both proinflammatory and antiinflammatory cytokines (interleukin-6, interleukin-10, and interferon-γ) have been observed in patients with influenza A (H5N1) virus infection — particularly in patients with fatal infection — than in patients with conventional influenza.3 Plasma levels of cytokines and chemokines correlate positively with pharyngeal viral loads,3 suggesting that these responses are driven by high-level viral replication. In vitro experiments involving primary human macrophages and lung pneumocytes show differential up-regulation of multiple cytokines by influenza A (H5N1) virus as compared with human influenza viruses,48 indicating that viral hyperinduction probably contributes to hypercytokinemia.

In mouse models of influenza A (H5N1) virus infection, mice with deficient induction of interleukin-6, macrophage inflammatory protein 1α, or tumor necrosis factor α or its receptors49,50 and mice treated with glucocorticoids,50 had similar mortality as compared with wild-type animals; mice without interleukin-1 receptors had increased mortality.49 Tissue damage in human influenza A (H5N1) disease probably results from the combined effects of unrestrained viral infection and inflammatory responses induced by influenza A (H5N1) infection. Knowledge of the mechanisms of hypercytokinemia is insufficient to guide safe, rational immunomodulatory treatment at present.

Clinical Features

Currently, illness due to influenza A (H5N1) viruses typically manifests as severe pneumonia that often progresses rapidly to the acute respiratory distress syndrome. The time from the onset of illness to presentation (median, 4 days) or to death (median, 9 to 10 days) has remained unchanged from 2003 through 2006 (Table 1Table 1Case Fatality Proportion According to Clade or Subclade and Median Time from Onset of Illness to Hospitalization or Death in Patients with Confirmed Influenza A (H5N1) Illness.).16 Observed differences in mortality among patients with presumed clade 1 and clade 2 virus infections (Table 1 and Table 2Table 2Clinical and Common Laboratory Features of Influenza A (H5N1) Disease at Hospital Admission.)1,21,24,35,51 are difficult to interpret because of variations in medical practices and the time from the onset of illness to treatment among affected countries.

Febrile upper respiratory illnesses without pneumonia in children have been reported more frequently since 2005.20,21 Early consultation and antiviral therapy may have altered the clinical course of these illnesses. Less frequent gastrointestinal symptoms have been reported since 2005 (Table 2), suggesting that some manifestations of clade 1 and 2 virus infections may differ from each other. Leukopenia, lymphopenia, mild-to-moderate thrombocytopenia, and elevated levels of aminotransferases are common but not universal (Table 2). Lymphopenia and increased levels of lactate dehydrogenase at presentation have been associated with a poor prognosis.1,3,21,37 Other reported abnormalities include elevated levels of creatine phosphokinase, hypoalbuminemia, and increased d-dimer levels and changes indicative of disseminated intravascular coagulopathy.20,21

The nonspecific clinical presentation of influenza A (H5N1) disease has often resulted in misdiagnosis of subsequently confirmed cases (Table 3Table 3Initial Diagnosis in Patients with Confirmed Influenza A (H5N1) Virus Infection.); influenza A (H5N1) virus infection has been suspected in only a small number of patients. Health care staff should include influenza A (H5N1) virus infection in the differential diagnosis for patients who present with epidemiologic risk factors and unusual courses of illness, especially rapidly progressing pneumonia (see Fig. 2 of the Supplementary Appendix).

Laboratory Diagnosis

Detection of viral RNA by means of conventional or real-time reverse-transcriptase polymerase chain reaction remains the best method for the initial diagnosis of influenza A (H5N1). 52 These assays can provide results within 4 to 6 hours and can be performed under biosafety level 2 conditions. The genetic variability of influenza A (H5N1) viruses7,8 calls for frequent updating of primers and probes. Consequently, access to sequences from recent influenza A (H5N1) viral isolates is essential. To detect other influenza A virus infections and reduce false negative results due to mutations in the H5 hemagglutinin gene, a conserved influenza A gene (e.g., matrix or nucleoprotein) should also be targeted.

Diagnostic yields are higher with throat specimens than with nasal swabs because of higher viral loads of influenza A (H5N1) in the throat.1,3 However, nasal swabs are useful for detecting human influenza viruses, so collection of both specimens is recommended. If they are available, tracheal aspirates have higher viral titers and yields than specimens from the upper respiratory tract.3 Negative results in single respiratory specimens do not rule out influenza A (H5N1) virus infection,21 and repeated collection of multiple specimen types is recommended.52 Previous antiviral treatment may reduce the diagnostic yield. Detection of influenza A (H5N1) viral RNA in feces or blood may provide prognostic information,3 but it has lower diagnostic sensitivity than influenza A (H5N1) viral RNA in respiratory specimens.

Commercially available rapid assays for influenza-antigen detection have poor clinical sensitivity for the detection of influenza A (H5N1) virus (Table 2 of the Supplementary Appendix),1,20,21 and they do not differentiate between human and avian subtypes of influenza A viruses. Although rapid antigen tests have similar analytic sensitivity for detecting human and avian influenza A (H5N1) viruses, they require 1000 times higher levels of virus than viral cultures to be positive.53

The detection of anti-H5 antibodies is essential for epidemiologic investigations and may provide retrospective diagnostic confirmation in patients. Seroconversion generally occurs 2 to 3 weeks after infection. Microneutralization assays are the most reliable methods for detecting antibodies to avian viruses, but they are labor-intensive and require biosafety level 3 facilities and appropriate strains of influenza A (H5N1) viruses. As compared with initial samples, elevations of four times or more or single titers of 1:80 or more in convalescent-phase samples are considered to be diagnostic.52 Modified nonpathogenic influenza A (H5N1) virus generated by reverse genetics or lentivirus pseudotyped with H5 hemagglutinin54 may provide alternatives for performing neutralization tests in biosafety level 2 facilities. Hemagglutination-inhibition assays with the use of horse erythrocytes show promising results but require further validation.

Treatment

Antiviral Agents

Susceptibility to current antiviral agents varies among circulating strains of influenza A (H5N1) viruses. Clade 1 viruses and most clade 2 viruses from Indonesia are fully resistant to M2 inhibitors, whereas clade 2 viruses from the lineages in other parts of Eurasia and Africa are usually susceptible (Klimov A: personal communication). As compared with influenza A (H5N1) viruses from 1997 or influenza A (H1N1) viruses in vitro,55 clade 1 viruses generally show enhanced susceptibility to oseltamivir carboxylate, but the high-level replication of some oseltamivir-susceptible strains requires higher doses or more prolonged administration, or both, in animal models.55,56 Clade 1 viruses appear to be 15 to 30 times more sensitive to oseltamivir than clade 2 isolates from Indonesia and Turkey,56,57 although the possible clinical relevance of such differences in oseltamivir susceptibility remains to be determined. During oseltamivir therapy, the emergence of highly resistant variants with an H274Y neuraminidase mutation may be associated with a fatal outcome.58 Infection by influenza A (H5N1) viruses containing an N294S mutation that causes a reduction in oseltamivir susceptibility by a factor of 12 to 15 times was reported to be present in two Egyptian patients with fatal disease before therapy,59 and avian influenza A (H5N1) viruses with reduced susceptibility to neuraminidase inhibitors are occasionally detected.60

Early treatment with oseltamivir is recommended,61,62, and data from uncontrolled clinical trials suggest that it improves survival (Table 4Table 4Effects of Treatment and Time to Treatment with Oseltamivir on Survival among Patients with Influenza A (H5N1) Infection.), although the optimal dose and duration of therapy are uncertain. Mortality remains high despite administration of oseltamivir; late initiation of therapy appears to be a major factor. Uncontrolled viral replication, as reflected in the detection of persistent pharyngeal RNA after completion of standard therapy, is associated with a poor prognosis.58 Higher levels of viral replication and slower clearance of infection probably occur in the lower respiratory tract.3 The oral bioavailability of oseltamivir in patients with severe diarrhea or gastrointestinal dysfunction related to influenza A (H5N1) virus infection or those in whom the drug has been administered extemporaneously (e.g., by means of a nasogastric tube) is uncertain.

A higher dose of oseltamivir (e.g., 150 mg twice daily in adults) and an increased duration of therapy, for a total of 10 days, may be reasonable, given the high levels of replication of the influenza A (H5N1) virus, observations of progressive disease despite early administration of standard-dose oseltamivir (75 mg twice daily for 5 days in adults) within 1 to 3 days after the onset of the illness, and the proven safety of higher doses in adults with seasonal influenza, especially if there is pneumonic disease at presentation or evidence of clinical progression.62 In mouse models of amantadine-sensitive influenza A (H5N1) virus infection, as compared with monotherapy, the combination of oseltamivir and amantadine significantly increased survival rates and inhibited viral replication in the internal organs.64 No adverse pharmacologic interactions have been shown in humans.65 In areas where influenza A (H5N1) viruses are likely to be susceptible to amantadine, combination treatment with oseltamivir would be reasonable, especially in seriously ill patients.

Although zanamivir is active against oseltamivir-resistant variants with N1 neuraminidase mutations at H274Y66 or N294S, the value of inhaled zanamivir has not been studied in human influenza A (H5N1) disease. Suboptimal delivery to sites of infection in patients with pneumonic or extrapulmonary disease is a concern. Parenteral delivery of zanamivir or the neuraminidase inhibitor peramivir results in antiviral activity in animal models of influenza A (H5N1) virus infection; these agents and others are under clinical development (Table 3 of the Supplementary Appendix).

Other Treatments

Supportive care with correction of hypoxemia and treatment of nosocomial complications remains fundamental in the management of influenza A (H5N1) disease.2,62 Corticosteroids should not be used routinely.62 Corticosteroid therapy has thus far not been shown to be effective in patients with influenza A (H5N1) virus infection, 1 and prolonged or high-dose corticosteroid therapy can result in serious adverse events, including opportunistic infections such as central nervous system toxoplasmosis (Soeroso S: unpublished data). In northern Vietnam, mortality was 59% among 29 recipients of corticosteroids, as compared with 24% among 38 persons who did not receive corticosteroids (P=0.004) (Cao T, Thanh Liem N: personal communication). The possible value of other immunomodulators remains to be determined.

Prevention

Avian influenza A viruses are readily inactivated by a variety of chemical agents and physical conditions, including soaps, detergents, alcohols, and chlorination.67,68 Guidelines for the prevention of infection with influenza A (H5N1) virus in various risk groups, including poultry workers, travelers, and health care workers, are available from the U.S. Centers for Disease Control and Prevention and the WHO.

Antiviral Chemoprophylaxis

WHO guidelines for the use of antiviral agents for prophylaxis in persons who have been exposed to influenza A (H5N1) viruses in the current pandemic-alert period have been published.61 Mathematical models of an emerging outbreak of influenza A (H5N1) in rural Asia predict that a strategy of mass, targeted antiviral chemoprophylaxis and social-distancing measures might extinguish or delay pandemic spread of the virus. The WHO has a stockpile of oseltamivir for this purpose and is working with partners for implementation of its distribution in the event of an outbreak.69

Immunization

Safe and immunogenic inactivated H5 vaccines have been developed.6 Reverse genetics permits the rapid generation of seed viruses with attenuated virulence, but the changing antigenicity of circulating strains of influenza A (H5N1) viruses calls for new candidate vaccines from different lineages6 and the development of vaccines that elicit cross-clade immunogenicity. H5 hemagglutinin appears to be a weak human immunogen. For subvirion vaccines without adjuvants, persons who have not received a priming dose require two doses with a high hemagglutinin antigen content (Table 4 of the Supplementary Appendix). As compared with conventional subunit vaccines, certain oil-in-water adjuvant agents6,70,71 or the use of whole-virus H5N1 vaccines6,72,73 can substantially reduce the amount of vaccine antigen required to induce immune responses in persons who have not received a priming dose, and they can induce immune responses to antigenically drifted viruses. However, the specific adjuvant, formulation, dose, stability, and ratio with the antigen are important variables that require clinical testing for each candidate vaccine. Alum adjuvants have not consistently improved the responses to H5 vaccines,6,73,74 whereas certain proprietary adjuvants (e.g., MF59 and AS03) appear to be highly effective and allow for considerable antigen-sparing and cross-reactive antibody responses.6,70,71 These adjuvants have also been associated with increased rates of local and sometimes systemic reactogenicity.

The antibody levels required for protection against human influenza A (H5N1) illness are unclear. The durability of antibody responses is limited, but boosting with a homologous vaccine70 or virus vaccine with viral antigen from another clade75 appears to be effective in persons who have received two priming doses. Prepriming might allow single doses of a homologous vaccine to be sufficient for an antigenically drifted pandemic virus. However, decisions regarding the use of vaccine before a pandemic and stockpiling require complex risk–benefit and cost–benefit analyses that include effects on the seasonal capacity of vaccine production, because the timing and cause of the next influenza pandemic are unknown, and it is unclear whether immunization of large populations could have adverse consequences.

Initial studies in children and elderly persons suggest that antibody responses to subvirion vaccines at high doses (45 or 90 μg) are similar to those in young adults. Approximately 15 to 20% of older adults have some baseline neutralizing antibodies to H5N1 virus and may have a response to a single dose.6 The mechanisms leading to these antibodies are uncertain. Other studies to date have shown that intradermal H5 vaccines at low doses are poorly immunogenic and may be associated with injection-site reactions.6 Intranasal live attenuated H5 vaccines are highly effective in animal models,76 but they show a variable ability to replicate in humans and to induce immune responses. Various investigational approaches, including conserved antigen vaccines, vectored H5 vaccines, and other adjuvants, are being explored.

Two authors (Drs. Hayden and Shindo) are staff members of the WHO. The authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions or the stated policy of the WHO. The views expressed in this article do not necessarily reflect those of the other organizations whose staff participated in the WHO consultation.

© World Health Organization 2008. All rights reserved. Published with permission from the World Health Organization.

Dr. Chotpitayasunondh reports receiving grant support from Sanofi Pasteur and lecture fees from Sanofi Pasteur, GlaxoSmithKline, and Merck; and Dr. Peiris, consulting fees from GlaxoSmithKline and Novartis and travel expenses and lecture fees from Novartis, Roche, and Sanofi Pasteur. No other potential conflict of interest relevant to this article was reported.

We thank Drs. Christoph Steffen and Kaat Vandermaele of the WHO for their help with access to data and development of the management algorithm, Diane Ramm of the University of Virginia for her assistance in the preparation of an earlier version of the manuscript, and our colleagues in countries affected by A (H5N1) virus for their willingness to share unpublished clinical data for this article.

Source Information

The members of the writing committee (Abdel-Nasser Abdel-Ghafar, M.D., Tawee Chotpitayasunondh, M.D., Zhancheng Gao, M.D., Ph.D., Frederick G. Hayden, M.D., Nguyen Duc Hien, M.D., Ph.D., Menno D. de Jong, M.D., Ph.D., Azim Naghdaliyev, M.D., J.S. Malik Peiris, M.D., Nahoko Shindo, M.D., Santoso Soeroso, M.D., and Timothy M. Uyeki, M.D.) assume responsibility for the overall content and integrity of the article.

Address reprint requests to Dr. Hayden at the Global Influenza Program, Department of Epidemic and Pandemic Alert and Response, World Health Organization, 20 Ave. Appia, Ch-1211, Geneva 27, Switzerland, or at haydenf@who.int.

Affiliations of the writing committee are listed in the Appendix. The participants in the meeting of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus, Antalya, Turkey, March 19–21, 2007, are listed in the Supplementary Appendix, which is available with the full text of this article at www.nejm.org.

Appendix

The writing committee's affiliations are as follows: the Ministry of Health and Population, Cairo (A.-N.A.-G.); the Queen Sirikit National Institute of Child Health, Bangkok, Thailand (T.C.); the Peking University People's Hospital, Beijing (Z.G.); the Global Influenza Program, World Health Organization, Geneva (F.G.H., N.S.); the University of Virginia, Charlottesville (F.G.H.); the National Institute for Infectious and Tropical Diseases, Hanoi (N.D.H.); the Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam (M.D.J.); the Abulfaz Karayev Children's Hospital No. 2, Baku, Azerbaijan (A.N.); the University of Hong Kong, Hong Kong (J.S.M.P.); the National Infectious Diseases Hospital, Jakarta, Indonesia (S.S.); and the Centers for Disease Control and Prevention, Atlanta (T.M.U.).

References

References

1. 1

   The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005;353:1374-1385[Erratum, N Engl J Med 2006;354:884.]
   Full Text | Web of Science | Medline

2. 2

   World Health Organization. Summary of the second WHO consultation on clinical aspects of human infection with avian influenza A (H5N1) virus. (Accessed December 20, 2007, at http://www.who.int/csr/disease/avian_influenza/meeting19_03_2007/en/index.html.)
   

3. 3

   de Jong M, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006;12:1203-1207
   CrossRef | Web of Science | Medline

4. 4

   Chen H, Smith GJD, Li KS, et al. Establishment of multiple sublineages of H5N1 influenza virus in Asia: implications for pandemic control. Proc Natl Acad Sci U S A 2006;103:2845-2850
   CrossRef | Web of Science | Medline

5. 5

   Webster RG, Govorkova EA. H5N1 Influenza -- continuing evolution and spread. N Engl J Med 2006;355:2174-2177
   Full Text | Web of Science | Medline

6. 6

   World Health Organization. Third WHO meeting on evaluation of pandemic influenza prototype vaccines in clinical trials, Geneva, 15-16 February 2007. (Accessed December 20, 2007, at http://www.who.int/vaccine_research/diseases/influenza/meeting_150207/en/.)
   

7. 7

   Idem. Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as pre-pandemic vaccines. March 2007. (Accessed December 20, 2007, at http://www.who.int/csr/disease/avian_influenza/guidelines/h5n1virus/en/index.html.)
   

8. 8

   Smith GJD, Fan XH, Wang J, et al. Emergence and predominance of an H5N1 influenza variant in China. Proc Natl Acad Sci U S A 2006;103:16936-16941
   CrossRef | Web of Science | Medline

9. 9

   Gauthier-Clerc M, Lebarbenchon C, Thomas F. Recent expansion of highly pathogenic avian influenza H5N1: a critical review. Ibis 2007;149:202-214
   CrossRef | Web of Science

10. 10

    Kilpatrick AM, Chmura AA, Gibbons DW, Fleischer RC, Marra PP, Daszak P. Predicting the global spread of H5N1 avian influenza. Proc Natl Acad Sci U S A 2006;103:19368-19373
    CrossRef | Web of Science | Medline

11. 11

    Ducatez MF, Olinger CM, Owoade AA, et al. Avian flu: multiple introductions of H5N1 in Nigeria. Nature 2006;442:37-37
    CrossRef | Web of Science | Medline

12. 12

    Winker K, McCracken KG, Gibson D, et al. Movements of birds and avian influenza from Asia into Alaska. Emerg Infect Dis 2007;13:547-552
    CrossRef | Web of Science | Medline

13. 13

    Fielding R, Bich TH, Quang LN, et al. Live poultry exposures, Hong Kong and Hanoi, 2006. Emerg Infect Dis 2007;13:1065-1067
    Web of Science | Medline

14. 14

    Vong S, Coghlan B, Mardy S, et al. Low frequency of poultry-to-human H5N1 virus transmission, Southern Cambodia, 2005. Emerg Infect Dis 2006;12:1542-1547
    CrossRef | Web of Science | Medline

15. 15

    World Health Organization. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. (Accessed December 20, 2007, at http://www.who.int/csr/disease/avian_influenza/country/cases_table_2007_12_14/en/index.html.)
    

16. 16

    Update: WHO-confirmed human cases of avian influenza A(H5N1) infection, 25 November 2003-24 November 2006. Wkly Epidemiol Rec 2007;82:41-48http://www.who.int/wer/2007/wer8206.pdf
    

17. 17

    Gu J, Xie Z, Gao Z, et al. H5N1 infection of the respiratory tract and beyond: a molecular pathology study. Lancet 2007;370:1137-1145
    CrossRef | Web of Science | Medline

18. 18

    Park AW, Glass K. Dynamic patterns of avian and human influenza in east and southeast Asia. Lancet Infect Dis 2007;7:543-548
    CrossRef | Web of Science | Medline

19. 19

    Ortiz JR, Wallis TR, Katz MA, et al. No evidence of avian influenza A (H5N1) among returning US travelers. Emerg Infect Dis 2007;13:294-297
    CrossRef | Web of Science | Medline

20. 20

    Kandun IN, Wibisono H, Sedyaningsih ER, et al. Three Indonesian clusters of H5N1 virus infection in 2005. N Engl J Med 2006;355:2186-2194
    Full Text | Web of Science | Medline

21. 21

    Oner AF, Bay A, Arslan S, et al. Avian influenza A (H5N1) infection in eastern Turkey in 2006. N Engl J Med 2006;355:2179-2185
    Full Text | Web of Science | Medline

22. 22

    Dinh PN, Long HT, Tien NTK, et al. Risk factors for human infection with avian influenza A H5N1, Vietnam, 2004. Emerg Infect Dis 2006;12:1841-1847
    CrossRef | Web of Science | Medline

23. 23

    Areechokchai D, Jiraphongsa C, Laosiritaworn Y, Hanshaoworakul W, O'Reilly M. Investigation of avian influenza (H5N1) outbreak in humans -- Thailand, 2004. MMWR Morb Mortal Wkly Rep 2006;55:Suppl 1:3-6
    Medline

24. 24

    Sedyaningsih ER, Isfandari S, Setiawaty V, et al. Epidemiology of cases of H5N1 virus infection in Indonesia, July 2005-June 2006. J Infect Dis 2007;196:522-527
    CrossRef | Web of Science | Medline

25. 25

    Human avian influenza in Azerbaijan, February-March 2006. Wkly Epidemiol Rec 2007;81:183-188http://www.who.int/wer/2006/wer8118.pdf
    

26. 26

    Thiry E, Zicola A, Addie D, et al. Highly pathogenic avian influenza H5N1 virus in cats and other carnivores. Vet Microbiol 2007;122:25-31
    CrossRef | Web of Science | Medline

27. 27

    Mumford E, Bishop J, Hendrickx S, Embarek PB, Perdue M. Avian influenza H5N1: Risks at the human-animal interface. Food Nutr Bull 2007;28:Suppl:S357-S363
    Web of Science | Medline

28. 28

    Leschnik M, Weikel J, Mostl K, et al. Subclinical infection with avian influenza A (H5N1) virus in cats. Emerg Infect Dis 2007;13:243-247
    CrossRef | Web of Science | Medline

29. 29

    Songserm T, Amonsin A, Jam-on R, et al. Fatal avian influenza A H5N1 in a dog. Emerg Infect Dis 2006;12:1744-1747
    CrossRef | Web of Science | Medline

30. 30

    Ungchusak K, Auewarakul P, Dowell SF, et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med 2005;352:333-340
    Full Text | Web of Science | Medline

31. 31

    Olsen SJ, Ungchusak K, Sovann L, et al. Family clustering of avian influenza A (H5N1). Emerg Infect Dis 2005;11:1799-1801
    Web of Science | Medline

32. 32

    World Health Organization. Avian influenza — situation in Indonesia — update 16. 2006. (Accessed December 20, 2007, at http://www.who.int/csr/don/2006_05_31/en/print.html.)
    

33. 33

    Pitzer VE, Olsen SJ, Bergstrom CT, Dowell SF, Lipsitch M. Little evidence for genetic susceptibility to influenza A (H5N1) from family clustering data. Emerg Infect Dis 2007;13:1074-1076
    Web of Science | Medline

34. 34

    Wang M, Di B, Zhou D-H, et al. Food markets with live birds as source of avian influenza. Emerg Infect Dis 2006;12:1773-1775
    CrossRef | Web of Science | Medline

35. 35

    Yu H, Feng Z, Zhang X, et al. Human influenza A (H5N1) cases, urban areas of People's Republic of China, 2005-2006. Emerg Infect Dis 2007;13:1061-1061
    Web of Science | Medline

36. 36

    de Jong MD, Cam BV, Qui PT, et al. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. N Engl J Med 2005;352:686-691
    Full Text | Web of Science | Medline

37. 37

    Buchy P, Mardy S, Vong S, et al. Influenza A/H5N1 virus infection in humans in Cambodia. J Clin Virol 2007;39:164-168
    CrossRef | Web of Science | Medline

38. 38

    Peiris JSM, de Jong MD, Guan Y. Avian influenza virus (H5N1): a threat to human health. Clin Microbiol Rev 2007;20:243-267
    CrossRef | Web of Science | Medline

39. 39

    Stevens J, Blixt O, Tumpey TM, Taubenberger JK, Paulson JC, Wilson IA. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 2006;312:404-410
    CrossRef | Web of Science | Medline

40. 40

    Yamada S, Suzuki Y, Suzuki T, et al. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature 2006;444:378-382
    CrossRef | Web of Science | Medline

41. 41

    Maines TR, Chen LM, Matsuoka Y, et al. Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. Proc Natl Acad Sci U S A 2006;103:12121-12126
    CrossRef | Web of Science | Medline

42. 42

    Hatta M, Hatta Y, Kim JH, et al. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PloS Pathog 2007;3:1374-1379
    CrossRef | Web of Science | Medline

43. 43

    van Riel D, Munster VJ, de Wit E, et al. H5N1 virus attachment to lower respiratory tract. Science 2006;312:399-399
    CrossRef | Web of Science | Medline

44. 44

    Nicholls JM, Chan MCW, Chan WY, et al. Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract. Nat Med 2007;13:147-149
    CrossRef | Web of Science | Medline

45. 45

    Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006;440:435-436
    CrossRef | Web of Science | Medline

46. 46

    Uiprasertkul M, Kitphati TC, Pathavathana P, et al. Apoptosis and pathogenesis of avian influenza A (H5N1) virus in humans. Emerg Infect Dis 2007;13:708-712
    Web of Science | Medline

47. 47

    Ng WF, To KF, Lam WWL, Ng TK, Lee KC. The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1 -- a review. Hum Pathol 2006;37:381-390
    CrossRef | Web of Science | Medline

48. 48

    Chan MC, Cheung CY, Chui WH, et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 2005;6:135-135
    CrossRef | Web of Science | Medline

49. 49

    Szretter KJ, Gangappa S, Lu X, et al. Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J Virol 2007;81:2736-2744
    CrossRef | Web of Science | Medline

50. 50

    Salomon R, Hoffmann E, Webster RG. Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A 2007;104:12479-12481
    CrossRef | Web of Science | Medline

51. 51

    Yu H, Shu Y, Hu S, et al. The first confirmed human case of avian influenza A (H5N1) in Mainland China. Lancet 2006;367:84-84
    CrossRef | Web of Science | Medline

52. 52

    World Health Organization. Collecting, preserving and shipping specimens for the diagnosis of avian influenza A (H5N1) virus infection: guide for field operations. (Accessed December 20, 2007, at http://www.who.int/csr/resources/publications/surveillance/whocdscsredc2004.pdf.)
    

53. 53

    Chan KH, Lam SY, Puthavathana P, et al. Comparative analytical sensitivities of six rapid influenza A antigen detection test kits for detection of influenza A subtypes H1N1, H3N2 and H5N1. J Clin Virol 2007;38:169-171
    CrossRef | Web of Science | Medline

54. 54

    Nefkens I, Garcia JM, Ling CS, et al. Hemagglutinin pseudotyped lentiviral particles: characterization of a new method for avian H5N1 influenza sero-diagnosis. J Clin Virol 2007;39:27-33
    CrossRef | Web of Science | Medline

55. 55

    Yen HL, Monto AS, Webster RG, Govorkova EA. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 (H5N1) influenza virus in mice. J Infect Dis 2005;192:665-672
    CrossRef | Web of Science | Medline

56. 56

    Govorkova EA, Ilyushina NA, Boltz DA, Douglas A, Yilmaz N, Webster RG. Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus. Antimicrob Agents Chemother 2007;51:1414-1424
    CrossRef | Web of Science | Medline

57. 57

    McKimm-Breschkin J, Selleck P, Usman TB, Johnson M. Reduced sensitivity of influenza A (H5N1) to oseltamivir. Emerg Infect Dis 2007;13:1354-1357
    Web of Science | Medline

58. 58

    de Jong MD, Thanh TT, Khanh TH, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005;353:2667-2672
    Full Text | Web of Science | Medline

59. 59

    Saad MD, Boynton BR, Earhart KC, et al. Detection of oseltamivir resistance mutation N294S in humans with influenza A H5N1. In: Program and abstracts of the Options for the Control of Influenza Conference, Toronto, June 17–23, 2007:228. abstract.
    

60. 60

    Hurt AC, Selleck P, Komadina N, Shaw R, Brown L, Barr IG. Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes. Antiviral Res 2007;73:228-231
    CrossRef | Web of Science | Medline

61. 61

    World Health Organization. WHO rapid advice guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus. 2006. (Accessed December 20, 2007, at http://www.who.int/medicines/publications/WHO_PSM_PAR_2006.6.pdf.)
    

62. 62

    Idem. Clinical management of human infection with avian influenza A (H5N1) virus. 2007. (Accessed December 20, 2007, at http://www.who.int/csr/disease/avian_influenza/guidelines/ClinicalManagement07.pdf.)
    

63. 63

    Sedyaningsih ER, Isfandari S, Setyaway V, et al. Clinical features of avian influenza A (H5N1) infection in Indonesia, July 2005–April 2007. In: Abstract book for the Options for the Control of Influenza VI Conference, Toronto, June 17–23, 2007:329.
    

64. 64

    Ilyushina NA, Hoffmann E, Solomon R, Webster RG, Govorkova EA. Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice. Antivir Ther 2007;12:363-370
    Web of Science | Medline

65. 65

    Morrison D, Roy S, Rayner C, et al. A randomized, crossover study to evaluate the pharmacokinetics of amantadine and oseltamivir administered alone and in combination. PLoS Clin Trials (in press).
    

66. 66

    Le QM, Kiso M, Someya K, et al. Avian flu: isolation of drug-resistant H5N1 virus. Nature 2005;437:1108-1108[Erratum, Nature 2005;438:754.]
    CrossRef | Web of Science | Medline

67. 67

    De Benedictis P, Beato MS, Capua I. Inactivation of avian influenza viruses by chemical agents and physical conditions: a review. Zoonoses Public Health 2007;54:51-68
    CrossRef | Web of Science | Medline

68. 68

    Rice EW, Adcock NJ, Sivaganesan M, Brown JD, Stallknecht DE, Swayne D. Chlorine inactivation of highly pathogenic avian influenza virus (H5N1). Emerg Infect Dis 2007;13:1568-1570
    Web of Science | Medline

69. 69

    World Health Organization. WHO interim protocol: rapid operations to contain the initial emergence of pandemic influenza. Updated October 2007. (Accessed December 20, 2007, at http://www.who.int/csr/disease/avian_influenza/guidelines/draftprotocol/en/index.html.)
    

70. 70

    Stephenson I, Bugarini R, Nicholson KG, et al. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 2005;191:1210-1215
    CrossRef | Web of Science | Medline

71. 71

    Leroux-Roels I, Borkowski A, Vanwolleghem T, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007;370:580-589
    CrossRef | Web of Science | Medline

72. 72

    Lin J, Zhang J, Dong X, et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 2006;368:991-997
    CrossRef | Web of Science | Medline

73. 73

    Barrett N. Safety and immunogenicity of a cell culture (vero) derived whole virus H5N1 vaccine: a Phase I/II dose escalation study. In: Program of the IX International Symposium on Respiratory Viral Infections, Hong Kong, March 3–6, 2007.
    

74. 74

    Bresson JL, Perronne C, Launay O, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 2006;367:1657-1664
    CrossRef | Web of Science | Medline

75. 75

    Goji N, Nolan C, Hill H, Wolff M, Rowe T, Treanor J. Immune responses of healthy subjects to a single dose of intramuscular inactivated influenza A/Vietnam/1203/2004 (H5N1) vaccine after priming with an antigenic variant. In: Final program and abstracts of the 44th Annual Meeting of IDSA, Toronto, October 12–15, 2006:64.
    

76. 76

    Lu X, Edwards LE, Desheva JA, et al. Cross-protective immunity in mice induced by live-attenuated or inactivated vaccines against highly pathogenic influenza A (H5N1) viruses. Vaccine 2006;24:6588-6593
    CrossRef | Web of Science | Medline

Citing Articles (155)

Citing Articles

1. 1

   2012. Avian Influenza (A/H5N1). , 187-199.
   CrossRef

2. 2

   T. R. Maines, J. A. Belser, K. M. Gustin, N. van Hoeven, H. Zeng, N. Svitek, V. von Messling, J. M. Katz, T. M. Tumpey. (2012) Local Innate Immune Responses and Influenza Virus Transmission and Virulence in Ferrets. Journal of Infectious Diseases 205:3, 474-485
   CrossRef

3. 3

   P. Yang, W. Shi, S. Cui, Y. Zhang, X. Liu, Q. Wang. (2012) Infection With Multiple Avian Influenza Viruses in a Man Without Poultry-Handling Practices Suggesting an Increased Probability of Emergent Pandemic Influenza Virus in General Population. Clinical Infectious Diseases 54:2, 307-307
   CrossRef

4. 4

   Paul A. Tambyah, Annelies Wilder-Smith, Borislava G. Pavlova, P. Noel Barrett, Helen M.L. Oh, David S. Hui, Kwok-yung Yuen, Sandor Fritsch, Gerald Aichinger, Alexandra Loew-Baselli, Maikel van der Velden, Friedrich Maritsch, Otfried Kistner, Hartmut J. Ehrlich. (2012) Safety and immunogenicity of two different doses of a Vero cell-derived, whole virus clade 2 H5N1 (A/Indonesia/05/2005) influenza vaccine. Vaccine 30:2, 329-335
   CrossRef

5. 5

   Libo Dong, Feng Liu, Jeffery Fairman, David K. Hong, David B. Lewis, Thomas Monath, John F. Warner, Jessica A. Belser, Jenish Patel, Kathy Hancock, Jacqueline M. Katz, Xiuhua Lu. (2012) Cationic liposome–DNA complexes (CLDC) adjuvant enhances the immunogenicity and cross-protective efficacy of a pre-pandemic influenza A H5N1 vaccine in mice. Vaccine 30:2, 254-264
   CrossRef

6. 6

   Joseph J. Jablonski, Dipwanita Basu, Daniel A. Engel, H. Mario Geysen. (2012) Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1. Bioorganic & Medicinal Chemistry 20:1, 487-497
   CrossRef

7. 7

   Junjie Zhang, Ting Liu, Xiaomei Tong, Gang Li, Jinghua Yan, Xin Ye. (2012) Identification of novel virus inhibitors by influenza A virus specific reporter cell based screening. Antiviral Research 93:1, 48-54
   CrossRef

8. 8

   Charles-Édouard Luyt, Alain Combes, Jean-Louis Trouillet, Ania Nieszkowska, Jean Chastre. (2011) Virus-induced acute respiratory distress syndrome: Epidemiology, management and outcome. La Presse Médicale 40:12, e561-e568
   CrossRef

9. 9

   Zhongpeng Zhao, Fang Yan, Zhongwei Chen, Deyan Luo, Yueqiang Duan, Penghui Yang, Zhong Li, Daxin Peng, Xiufan Liu, Xiliang Wang. (2011) Cross clade prophylactic and therapeutic efficacy of polyvalent equine immunoglobulin F(ab′)2 against highly pathogenic avian influenza H5N1 in mice. International Immunopharmacology 11:12, 2000-2006
   CrossRef

10. 10

    Qunfeng Wu, Shaobo Xiao, Huiying Fan, Yang Li, Jinfang Xu, Zhen Li, Wei Lu, Xiaoyue Su, Wei Zou, Meilin Jin, Huanchun Chen, Liurong Fang. (2011) Protective immunity elicited by a pseudotyped baculovirus-mediated bivalent H5N1 influenza vaccine. Antiviral Research 92:3, 493-496
    CrossRef

11. 11

    Shu-Chang An, Li-Li Xu, Feng-Di Li, Lin-Lin Bao, Chuan Qin, Zhan-Cheng Gao. (2011) Triple combinations of neuraminidase inhibitors, statins and fibrates benefit the survival of patients with lethal avian influenza pandemic. Medical Hypotheses 77:6, 1054-1057
    CrossRef

12. 12

    Eric M. Vela, Mathew A. Buccellato, Kevin Tordoff, Greg Stark, John E. Bigger. (2011) Efficacy of a heterologous vaccine and adjuvant in ferrets challenged with influenza virus H5N1. Influenza and Other Respiratory Virusesno-no
    CrossRef

13. 13

    Michael G Ison. (2011) Antivirals and resistance: influenza virus. Current Opinion in Virology 1:6, 563-573
    CrossRef

14. 14

    K. M. Gustin, T. R. Maines, J. A. Belser, N. van Hoeven, X. Lu, L. Dong, I. Isakova-Sivak, L.-M. Chen, J. T. M. Voeten, J. G. M. Heldens, H. van den Bosch, N. J. Cox, T. M. Tumpey, A. I. Klimov, L. Rudenko, R. O. Donis, J. M. Katz. (2011) Comparative Immunogenicity and Cross-Clade Protective Efficacy of Mammalian Cell-Grown Inactivated and Live Attenuated H5N1 Reassortant Vaccines in Ferrets. Journal of Infectious Diseases 204:10, 1491-1499
    CrossRef

15. 15

    James R. Smith, Craig R. Rayner, Barbara Donner, Martina Wollenhaupt, Klaus Klumpp, Regina Dutkowski. (2011) Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience. Advances in Therapy 28:11, 927-959
    CrossRef

16. 16

    Wendy A. Howard, Malik Peiris, Frederick G. Hayden. (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
    CrossRef

17. 17

    Vanessa Escuret, Olivier Ferraris, Bruno Lina. (2011) The antiviral resistance of influenza virus. Therapy 8:6, 741-762
    CrossRef

18. 18

    Mingli Fang, Min Wan, Sheng Guo, Ran Sun, Ming Yang, TieSuo Zhao, Youyou Yan, Yongsheng Zhang, Wenhui Huang, Xiuli Wu, Yongli Yu, Liying Wang, Shucheng Hua. (2011) An oligodeoxynucleotide capable of lessening acute lung inflammatory injury in mice infected by influenza virus. Biochemical and Biophysical Research Communications 415:2, 342-347
    CrossRef

19. 19

    Jessica A. Belser, Cynthia B. Snider, Nancy J. Cox, Frederick G. Hayden. (2011) XIth International Symposium on Respiratory Viral Infections. Influenza and Other Respiratory Viruses 5:6, 443-e457
    CrossRef

20. 20

    Rogier Bodewes, Joost H.C.M. Kreijtz, Geert van Amerongen, Ron A.M. Fouchier, Albert D.M.E. Osterhaus, Guus F. Rimmelzwaan, Thijs Kuiken. (2011) Pathogenesis of Influenza A/H5N1 Virus Infection in Ferrets Differs between Intranasal and Intratracheal Routes of Inoculation. The American Journal of Pathology 179:1, 30-36
    CrossRef

21. 21

    Ilyse Darwish, Samira Mubareka, W Conrad Liles. (2011) Immunomodulatory therapy for severe influenza. Expert Review of Anti-infective Therapy 9:7, 807-822
    CrossRef

22. 22

    Andrés Antón, Tomás Pumarola. (2011) Influenza in immunocompromised patients: considerations for therapy. Future Virology 6:7, 855-868
    CrossRef

23. 23

    John Doukas, Jane Morrow, Dawn Bellinger, Thomas Hilgert, Terrie Martin, Doug Jones, Rohit Mahajan, Denis Rusalov, Sean Sullivan, Alain Rolland. (2011) Nonclinical biodistribution, integration, and toxicology evaluations of an H5N1 pandemic influenza plasmid DNA vaccine formulated with Vaxfectin®. Vaccine 29:33, 5443-5452
    CrossRef

24. 24

    Raquel Almansa, Raúl Ortiz de Lejarazu, M.a Ángeles Jiménez-Sousa, Lucia Rico, Encarnación Largo, Verónica Iglesias, Eva Golvano, Jesús F. Bermejo-Martin. (2011) H5 influenza haemagglutinin and cytokine profiles in cultured PBMCs from adults and children. Inmunología 30:3, 79-84
    CrossRef

25. 25

    CH Rasul, MA Bakar, AA Mamun, MS Siraz, RU Zaman. (2011) Burden and outcome of human influenza in a tertiary care hospital of Bangladesh. Asian Pacific Journal of Tropical Medicine 4:6, 478-481
    CrossRef

26. 26

    S. Sakabe, K. Iwatsuki-Horimoto, R. Takano, C. A. Nidom, M. t. Q. Le, T. Nagamura-Inoue, T. Horimoto, N. Yamashita, Y. Kawaoka. (2011) Cytokine production by primary human macrophages infected with highly pathogenic H5N1 or pandemic H1N1 2009 influenza viruses. Journal of General Virology 92:6, 1428-1434
    CrossRef

27. 27

    Ni Luh Putu Indi Dharmayant, Fera Ibrahim, . Darminto, Amin Soebandrio. (2011) Influenza H5N1 Virus of Birds Surrounding H5N1 Human Cases Have Specific Characteristics on the Matrix Protein. HAYATI Journal of Biosciences 18:2, 82-90
    CrossRef

28. 28

    K. M. Gustin, J. A. Belser, D. A. Wadford, M. B. Pearce, J. M. Katz, T. M. Tumpey, T. R. Maines. (2011) Influenza virus aerosol exposure and analytical system for ferrets. Proceedings of the National Academy of Sciences 108:20, 8432-8437
    CrossRef

29. 29

    Willard Lew, Michael Z. Wang, Xiaowu Chen, James F. Rooney, Choung Kim. 2011. Neuraminidase Inhibitors as Anti-Influenza Agents. , 351-376.
    CrossRef

30. 30

    Chang-Zheng DONG. (2011) Advances on genomic evolution of influenza virus. Hereditas (Beijing) 33:3, 189-197
    CrossRef

31. 31

    Azher M. Merchant, Evie G. Marcolini, Michael E. Winters. (2011) Treating Critical Illness Caused by the 2009 H1N1 Influenza A Virus. The Journal of Emergency Medicine 40:5, 522-527
    CrossRef

32. 32

    Lei You, Eun Jeong Cho, John Leavitt, Li-Chung Ma, Gaetano T. Montelione, Eric V. Anslyn, Robert M. Krug, Andrew Ellington, Jon D. Robertus. (2011) Synthesis and evaluation of quinoxaline derivatives as potential influenza NS1A protein inhibitors. Bioorganic & Medicinal Chemistry Letters 21:10, 3007-3011
    CrossRef

33. 33

    D. Viasus, J. R. Paño-Pardo, J. Pachón, A. Campins, F. López-Medrano, A. Villoslada, M. C. Fariñas, A. Moreno, J. Rodríguez-Baño, J. A. Oteo, J. Martínez-Montauti, J. Torre-Cisneros, F. Segura, F. Gudiol, J. Carratalà, . (2011) Factors associated with severe disease in hospitalized adults with pandemic (H1N1) 2009 in Spain. Clinical Microbiology and Infection 17:5, 738-746
    CrossRef

34. 34

    Amy J. Behrman. 2011. Health Hazards and Emergency Care for Health Care Workers. , 175-198.
    CrossRef

35. 35

    J. Scott Weese, Martha B. Fulford. 2011. Viral Diseases. , 241-274.
    CrossRef

36. 36

    Donna M. Tscherne, Adolfo García-Sastre. (2011) Virulence determinants of pandemic influenza viruses. Journal of Clinical Investigation 121:1, 6-13
    CrossRef

37. 37

    Erik De Clercq. (2011) The next ten stories on antiviral drug discovery (part E): advents, advances, and adventures. Medicinal Research Reviews 31:1, 118-160
    CrossRef

38. 38

    Yumiko Imai. (2011) Pathogenesis and therapeutic targets for severe respiratory failure mediated by emerging respiratory virus infection. Folia Pharmacologica Japonica 138:4, 141-145
    CrossRef

39. 39

    Ji-Won Ha, Kevin M. Downard. (2011) Evolution of H5N1 influenza virus through proteotyping of hemagglutinin with high resolution mass spectrometry. The Analyst 136:16, 3259
    CrossRef

40. 40

    J. A. Belser, H. Zeng, J. M. Katz, T. M. Tumpey. (2011) Infection With Highly Pathogenic H7 Influenza Viruses Results in an Attenuated Proinflammatory Cytokine and Chemokine Response Early After Infection. Journal of Infectious Diseases 203:1, 40-48
    CrossRef

41. 41

    Catherine J. Sanders, Peter C. Doherty, Paul G. Thomas. (2011) Respiratory epithelial cells in innate immunity to influenza virus infection. Cell and Tissue Research 343:1, 13-21
    CrossRef

42. 42

    Hiroyuki Furuya, Shoji Kawachi, Mika Shigematsu, Kazuo Suzuki, Tetsu Watanabe. (2011) Clinical factors associated with severity in hospitalized children infected with avian influenza (H5N1). Environmental Health and Preventive Medicine 16:1, 64-68
    CrossRef

43. 43

    Eun Young Choi, Jin Won Huh, Chae-Man Lim, Younsuck Koh, Sung-Han Kim, Sang-Ho Choi, Won Young Kim, Won Kim, Mi-Na Kim, Sang-Bum Hong. (2011) Critically Ill Patients with Pandemic Influenza A/H1N1 2009 at a Medical Center in Korea. Tuberculosis and Respiratory Diseases 70:1, 28
    CrossRef

44. 44

    Philip R. Dormitzer, Grazia Galli, Flora Castellino, Hana Golding, Surender Khurana, Giuseppe Del Giudice, Rino Rappuoli. (2011) Influenza vaccine immunology. Immunological Reviews 239:1, 167-177
    CrossRef

45. 45

    Jessica A. Belser, Taronna R. Maines, Terrence M. Tumpey, Jacqueline M. Katz. (2010) Influenza A virus transmission: contributing factors and clinical implications. Expert Reviews in Molecular Medicine 12,
    CrossRef

46. 46

    P. HORBY, H. SUDOYO, V. VIPRAKASIT, A. FOX, P. Q. THAI, H. YU, S. DAVILA, M. HIBBERD, S. J. DUNSTAN, Y. MONTEERARAT, J. J. FARRAR, S. MARZUKI, N. T. HIEN. (2010) What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1?. Epidemiology and Infection 138:11, 1550-1558
    CrossRef

47. 47

    Grigoris Zoidis, Nicolas Kolocouris, John M. Kelly, S. Radhika Prathalingam, Lieve Naesens, Erik De Clercq. (2010) Design and synthesis of bioactive adamantanaminoalcohols and adamantanamines. European Journal of Medicinal Chemistry 45:11, 5022-5030
    CrossRef

48. 48

    F. Daneschwar, S. Tschudin Sutter, A.F. Widmer, M. Battegay. (2010) 42-jähriger, adipöser Patient mit beatmungspflichtiger H1N1-Infektion. Der Internist 51:10, 1308-1312
    CrossRef

49. 49

    Xian-Chun Tang, Hai-Rong Lu, Ted M. Ross. (2010) Hemagglutinin Displayed Baculovirus Protects Against Highly Pathogenic Influenza. Vaccine 28:42, 6821-6831
    CrossRef

50. 50

    Kum Thong Wong. (2010) Emerging epidemic viral encephalitides with a special focus on henipaviruses. Acta Neuropathologica 120:3, 317-325
    CrossRef

51. 51

    Aeron C. Hurt, Sue Lowther, Deborah Middleton, Ian G. Barr. (2010) Assessing the development of oseltamivir and zanamivir resistance in A(H5N1) influenza viruses using a ferret model. Antiviral Research 87:3, 361-366
    CrossRef

52. 52

    M. CEYHAN, I. YILDIRIM, O. FERRARIS, M. BOUSCAMBERT-DUCHAMP, E. FROBERT, N. UYAR, H. TEZER, A. F. ONER, T. BUZGAN, M. A. TORUNOGLU, B. OZKAN, R. YILMAZ, M. G. KURTOGLU, Y. LALELI, S. BADUR, B. LINA. (2010) Serosurveillance study on transmission of H5N1 virus during a 2006 avian influenza epidemic. Epidemiology and Infection 138:09, 1274-1280
    CrossRef

53. 53

    Ying Chen, Gongxun Zhong, Guojun Wang, Guohua Deng, Yanbing Li, Jianzhong Shi, Zhuo Zhang, Yuntao Guan, Yongping Jiang, Zhigao Bu, Yoshihiro Kawaoka, Hualan Chen. (2010) Dogs are highly susceptible to H5N1 avian influenza virus. Virology 405:1, 15-19
    CrossRef

54. 54

    Christine Korteweg, Jiang Gu. (2010) Pandemic influenza A (H1N1) virus infection and avian influenza A (H5N1) virus infection: a comparative analysisThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process.. Biochemistry and Cell Biology 88:4, 575-587
    CrossRef

55. 55

    Yuwarat Monteerarat, Saori Sakabe, Somying Ngamurulert, Sirawat Srichatraphimuk, Wasana Jiamtom, Kridsada Chaichuen, Arunee Thitithanyanont, Parichart Permpikul, Taweesak Songserm, Pilaipan Puthavathana, Chairul A. Nidom, Le Quynh Mai, Kiyoko Iwatsuki-Horimoto, Yoshihiro Kawaoka, Prasert Auewarakul. (2010) Induction of TNF-α in human macrophages by avian and human influenza viruses. Archives of Virology 155:8, 1273-1279
    CrossRef

56. 56

    Bo Wah Leung, Hualan Chen, George G. Brownlee. (2010) Correlation between polymerase activity and pathogenicity in two duck H5N1 influenza viruses suggests that the polymerase contributes to pathogenicity. Virology 401:1, 96-106
    CrossRef

57. 57

    Kurt J. Vandegrift, Susanne H. Sokolow, Peter Daszak, A. Marm Kilpatrick. (2010) Ecology of avian influenza viruses in a changing world. Annals of the New York Academy of Sciences 1195:1, 113-128
    CrossRef

58. 58

    R. Dutkowski, J.R. Smith, B.E. Davies. (2010) Safety and pharmacokinetics of oseltamivir at standard and high dosages. International Journal of Antimicrobial Agents 35:5, 461-467
    CrossRef

59. 59

    James R. Smith, Robert E. Ariano, Stephen Toovey. (2010) The use of antiviral agents for the management of severe influenza. Critical Care Medicine 38, e43-e51
    CrossRef

60. 60

    Wook Jin Choi, Won Young Kim, Sung-Han Kim, Bum Jin Oh, Won Kim, Kyung Su Lim, Sang-Bum Hong, Chae-Man Lim, Yoinsuck Koh. (2010) Clinical characteristics of pneumonia in hospitalized patients with novel influenza A (H1N1) in Korea. Scandinavian Journal of Infectious Diseases 42:4, 311-314
    CrossRef

61. 61

    J. R. Smith. (2010) Oseltamivir in human avian influenza infection. Journal of Antimicrobial Chemotherapy 65:Supplement 2, ii25-ii33
    CrossRef

62. 62

    Lena M. Napolitano, Pauline K. Park, Krishnan Raghavendran, Robert H. Bartlett. (2010) Nonventilatory strategies for patients with life-threatening 2009 H1N1 influenza and severe respiratory failure. Critical Care Medicine 38, e74-e90
    CrossRef

63. 63

    Elizabeth A. Driskell, Cheryl A. Jones, David E. Stallknecht, Elizabeth W. Howerth, S. Mark Tompkins. (2010) Avian influenza virus isolates from wild birds replicate and cause disease in a mouse model of infection. Virology 399:2, 280-289
    CrossRef

64. 64

    N. R. London, W. Zhu, F. A. Bozza, M. C. P. Smith, D. M. Greif, L. K. Sorensen, L. Chen, Y. Kaminoh, A. C. Chan, S. F. Passi, C. W. Day, D. L. Barnard, G. A. Zimmerman, M. A. Krasnow, D. Y. Li. (2010) Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza. Science Translational Medicine 2:23, 23ra19-23ra19
    CrossRef

65. 65

    R. D. Smith, M. Petticrew. (2010) Public health evaluation in the twenty-first century: time to see the wood as well as the trees. Journal of Public Health 32:1, 2-7
    CrossRef

66. 66

    Michael J. Loeffelholz. (2010) Avian Influenza A H5N1 Virus. Clinics in Laboratory Medicine 30:1, 1-20
    CrossRef

67. 67

    Larry R. Smith, Mary K. Wloch, Ming Ye, Luane R. Reyes, Souphaphone Boutsaboualoy, Casey E. Dunne, Jennifer A. Chaplin, Denis Rusalov, Alain P. Rolland, Cindy L. Fisher, Mohamed S. Al-Ibrahim, Martin L. Kabongo, Roy Steigbigel, Robert B. Belshe, Ernest R. Kitt, Alice H. Chu, Ronald B. Moss. (2010) Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin. Vaccine 28:13, 2565-2572
    CrossRef

68. 68

    Bradley P. Fuhrman. (2010) Pandemic planning—Preparing for the expected*. Pediatric Critical Care Medicine 11:2, 299-300
    CrossRef

69. 69

    Burke A. Cunha. (2010) Swine Influenza (H1N1) Pneumonia: Clinical Considerations. Infectious Disease Clinics of North America 24:1, 203-228
    CrossRef

70. 70

    Guobin Tian, Xianying Zeng, Yanbing Li, Jianzhong Shi, Hualan Chen. (2010) Protective Efficacy of the H5 Inactivated Vaccine Against Different Highly Pathogenic H5N1 Avian Influenza Viruses Isolated in China and Vietnam. Avian Diseases 54:s1, 287-289
    CrossRef

71. 71

    Raoul E. Nap, Maarten P. H. M. Andriessen, Nico E. L. Meessen, Marcel J. I. J. Albers, Tjip S. van der Werf. (2010) Pandemic influenza and pediatric intensive care*. Pediatric Critical Care Medicine 11:2, 185-198
    CrossRef

72. 72

    H. Yoon, O. K. Moon, S. J. More, C. K. Park, J. Y. Park, Y. J. Lee, S. D. Lee, J. K. Ha, S. K. Jeong, J. W. Jeong, S. J. Lee. (2010) An Outbreak of Highly Pathogenic Avian Influenza at a Public Animal Exhibit in Seoul, Korea, During 2008. Zoonoses and Public Health 57:2, 142-145
    CrossRef

73. 73

    C. Casper, J. Englund, M. Boeckh. (2010) How I treat influenza in patients with hematologic malignancies. Blood 115:7, 1331-1342
    CrossRef

74. 74

    Nurettin Erben, Elif Doyuk Kartal, Saygin Nayman Alpat, Ilhan Ozgunes, Gaye Usluer. (2010) A case of pneumonia following human infection with avian influenza a (H5N1). Central European Journal of Medicine 5:1, 59-61
    CrossRef

75. 75

    Suryaprakash Sambhara, Gregory A. Poland. (2010) H5N1 Avian Influenza: Preventive and Therapeutic Strategies Against a Pandemic. Annual Review of Medicine 61:1, 187-198
    CrossRef

76. 76

    M.A. Bürkle, L. Frey, B. Zwißler. (2010) Neue Influenza-A/H1N1-2009-Virus-Pandemie. Der Anaesthesist 59:1, 11-22
    CrossRef

77. 77

    Burke A. Cunha, Uzma Syed, Nardeen Mickail, Stephanie Strollo. (2010) Rapid clinical diagnosis in fatal swine influenza (H1N1) pneumonia in an adult with negative rapid influenza diagnostic tests (RIDTs): Diagnostic swine influenza triad. Heart & Lung: The Journal of Acute and Critical Care 39:1, 78-86
    CrossRef

78. 78

    Hu Ge, Yi-Fei Wang, Jun Xu, Qiong Gu, Hai-Bo Liu, Pei-Gen Xiao, Jiaju Zhou, Yanhuai Liu, Zirong Yang, Hua Su. (2010) Anti-influenza agents from Traditional Chinese Medicine. Natural Product Reports 27:12, 1758
    CrossRef

79. 79

    Maricela Montalvo-Corral, Jesús Hernández. (2010) Genetic analysis of avian influenza virus from migratory waterfowl in Mexico. Archives of Virology 155:1, 97-101
    CrossRef

80. 80

    Alejandro Rodríguez, Thiago Lisboa, Jordi Rello. (2010) Gripe A (H1N1)v pandémica en UCI: ¿qué hemos aprendido?. Archivos de Bronconeumología 46, 24-31
    CrossRef

81. 81

    W.R.J. Taylor, E. Burhan, H. Wertheim, P.Z. Soepandi, P. Horby, A. Fox, R. Benamore, L. de Simone, T.T. Hien, F. Chappuis. (2010) Avian influenza – A review for doctors in travel medicine. Travel Medicine and Infectious Disease 8:1, 1-12
    CrossRef

82. 82

    Jane Baer, Felix Santiago, Hongmei Yang, Hulin Wu, Jeanne Holden-Wiltse, John Treanor, David J. Topham. (2010) B cell responses to H5 influenza HA in human subjects vaccinated with a drifted variant. Vaccine 28:4, 907-915
    CrossRef

83. 83

    Isabel Leroux-Roels, François Roman, Sheron Forgus, Cathy Maes, Fien De Boever, Mamadou Dramé, Paul Gillard, Robbert van der Most, Marcelle Van Mechelen, Emmanuel Hanon, Geert Leroux-Roels. (2010) Priming with AS03A-adjuvanted H5N1 influenza vaccine improves the kinetics, magnitude and durability of the immune response after a heterologous booster vaccination: An open non-randomised extension of a double-blind randomised primary study. Vaccine 28:3, 849-857
    CrossRef

84. 84

    Nicolas Sabarth, M. Keith Howard, Helga Savidis-Dacho, André van Maurik, P. Noel Barrett, Otfried Kistner. (2010) Comparison of single, homologous prime-boost and heterologous prime-boost immunization strategies against H5N1 influenza virus in a mouse challenge model. Vaccine 28:3, 650-656
    CrossRef

85. 85

    Kelvin K.W. To, Kwok-Hung Chan, Iris W.S. Li, Tak-Yin Tsang, Herman Tse, Jasper F.W. Chan, Ivan F.N. Hung, Sik-To Lai, Chi-Wai Leung, Yat-Wah Kwan, Yu-Lung Lau, Tak-Keung Ng, Vincent C.C. Cheng, Joseph S.M. Peiris, Kwok-Yung Yuen. (2010) Viral load in patients infected with pandemic H1N1 2009 influenza A virus. Journal of Medical Virology 82:1, 1-7
    CrossRef

86. 86

    Aeron C. Hurt, Jessica K. Holien, Michael W. Parker, Ian G. Barr. (2009) Oseltamivir Resistance and the H274Y Neuraminidase Mutation in Seasonal, Pandemic and Highly Pathogenic Influenza Viruses. Drugs 69:18, 2523-2531
    CrossRef

87. 87

    Jianjun Chen, Fang Fang, Zhongdong Yang, Xueying Liu, Hongbo Zhang, Zhiping Zhang, Xianen Zhang, Ze Chen. (2009) Characterization of highly pathogenic H5N1 avian influenza viruses isolated from poultry markets in central China. Virus Research 146:1-2, 19-28
    CrossRef

88. 88

    Na Ding, Nana Wu, Qinggang Xu, Keping Chen, Chiyu Zhang. (2009) Molecular evolution of novel swine-origin A/H1N1 influenza viruses among and before human. Virus Genes 39:3, 293-300
    CrossRef

89. 89

    Joseph Sriyal Malik Peiris, Chung Yan Cheung, Connie Yin Hung Leung, John Malcolm Nicholls. (2009) Innate immune responses to influenza A H5N1: friend or foe?. Trends in Immunology 30:12, 574-584
    CrossRef

90. 90

    Cheguo Tsai, Catherine Caillet, Hongxing Hu, Fan Zhou, Heng Ding, Guoliang Zhang, Boping Zhou, Shixia Wang, Shan Lu, Philippe Buchy, Vincent Deubel, Frederick R. Vogel, Paul Zhou. (2009) Measurement of neutralizing antibody responses against H5N1 clades in immunized mice and ferrets using pseudotypes expressing influenza hemagglutinin and neuraminidase. Vaccine 27:48, 6777-6790
    CrossRef

91. 91

    Piyarat Suntarattiwong, Richard G. Jarman, Jens Levy, Henry C. Baggett, Robert V. Gibbons, Tawee Chotpitayasunondh, James M. Simmerman. (2009) Clinical Performance of a Rapid Influenza Test and Comparison of Nasal Versus Throat Swabs to Detect 2009 Pandemic Influenza A (H1N1) Infection in Thai Children. The Pediatric Infectious Disease Journal1
    CrossRef

92. 92

    J. S. Malik Peiris, Wen-wei Tu, Hui-ling Yen. (2009) A novel H1N1 virus causes the first pandemic of the 21 ^st century. European Journal of Immunology 39:11, 2946-2954
    CrossRef

93. 93

    Stephen P. Jackson, Jiri Bartek. (2009) The DNA-damage response in human biology and disease. Nature 461:7267, 1071-1078
    CrossRef

94. 94

    Ruth M. Farrell, Richard H. Beigi. (2009) Pandemic Influenza and Pregnancy: An Opportunity to Reassess Maternal Bioethics. American Journal of Public Health 99:S2, S231-S235
    CrossRef

95. 95

    Tino F. Schwarz, Thomas Horacek, Markus Knuf, Hanns-Gerd Damman, François Roman, Mamadou Dramé, Paul Gillard, Wolfgang Jilg. (2009) Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine 27:45, 6284-6290
    CrossRef

96. 96

    Scott Santibañez, Anthony E. Fiore, Toby L. Merlin, Stephen Redd. (2009) A Primer on Strategies for Prevention and Control of Seasonal and Pandemic Influenza. American Journal of Public Health 99:S2, S216-S224
    CrossRef

97. 97

    Charlotte D'Souza, Meena Kanyalkar, Mamata Joshi, Evans Coutinho, Sudha Srivastava. (2009) Search for novel neuraminidase inhibitors: Design, synthesis and interaction of oseltamivir derivatives with model membrane using docking, NMR and DSC methods. Biochimica et Biophysica Acta (BBA) - Biomembranes 1788:9, 1740-1751
    CrossRef

98. 98

    Punam Mangtani, Tippi K Mak, Dina Pfeifer. (2009) Pandemic H1N1 infection in pregnant women in the USA. The Lancet 374:9688, 429-430
    CrossRef

99. 99

    Jing-Jiao Zhou, Dan-Yun Fang, Jie Fu, Jiang Tian, Jun-Mei Zhou, Hui-Jun Yan, Yu Liang, Li-Fang Jiang. (2009) Infection and replication of avian influenza H5N1 virus in an infected human. Virus Genes 39:1, 76-80
    CrossRef

100. 100

     Mark Phillippe. (2009) Pandemic Influenza. Obstetrics & Gynecology 114:2, Part 1, 206-208
     CrossRef

101. 101

     John C. Kash. (2009) Applications of high-throughput genomics to antiviral research: Evasion of antiviral responses and activation of inflammation during fulminant RNA virus infection. Antiviral Research 83:1, 10-20
     CrossRef

102. 102

     Naoto Keicho, Satoru Itoyama, Koichi Kashiwase, Nguyen Chi Phi, Hoang Thuy Long, Le Dang Ha, Vo Van Ban, Bach Khanh Hoa, Nguyen Thi Le Hang, Minako Hijikata, Shinsaku Sakurada, Masahiro Satake, Katsushi Tokunaga, Takehiko Sasazuki, Tran Quy. (2009) Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population. Human Immunology 70:7, 527-531
     CrossRef

103. 103

     Aeron C. Hurt, Chantal Baas, Yi-Mo Deng, Sally Roberts, Anne Kelso, Ian G. Barr. (2009) Performance of influenza rapid point-of-care tests in the detection of swine lineage A(H1N1) influenza viruses. Influenza and Other Respiratory Viruses 3:4, 171-176
     CrossRef

104. 104

     K.H. Chan, S.T. Lai, L.L.M. Poon, Y. Guan, K.Y. Yuen, J.S.M. Peiris. (2009) Analytical sensitivity of rapid influenza antigen detection tests for swine-origin influenza virus (H1N1). Journal of Clinical Virology 45:3, 205-207
     CrossRef

105. 105

     Mathias Dreger, Bo Wah Leung, George G. Brownlee, Tao Deng. (2009) A quantitative strategy to detect changes in accessibility of protein regions to chemical modification on heterodimerization. Protein Science 18:7, 1448-1458
     CrossRef

106. 106

     David S. Fedson. (2009) Confronting the next influenza pandemic with anti-inflammatory and immunomodulatory agents: why they are needed and how they might work. Influenza and Other Respiratory Viruses 3:4, 129-142
     CrossRef

107. 107

     Yousuke Furuta, Kazumi Takahashi, Kimiyasu Shiraki, Kenichi Sakamoto, Donald F. Smee, Dale L. Barnard, Brian B. Gowen, Justin G. Julander, John D. Morrey. (2009) T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Research 82:3, 95-102
     CrossRef

108. 108

     Prasert Auewarakul, Sunisa Chatsurachai, Alita Kongchanagul, Pumaree Kanrai, Sikarin Upala, Prapat Suriyaphol, Pilaipan Puthavathana. (2009) Codon volatility of hemagglutinin genes of H5N1 avian influenza viruses from different clades. Virus Genes 38:3, 404-407
     CrossRef

109. 109

     E. GUERNE BLEICH, P. PAGANI, N. HONHOLD. (2009) Progress towards practical options for improving biosecurity of small-scale poultry producers. World's Poultry Science Journal 65:02, 211
     CrossRef

110. 110

     Holly Brodzinski, Richard M. Ruddy. (2009) Review of New and Newly Discovered Respiratory Tract Viruses in Children. Pediatric Emergency Care 25:5, 352-360
     CrossRef

111. 111

     HongLiang Wang, ChengYu Jiang. (2009) Avian influenza H5N1: an update on molecular pathogenesis. Science in China Series C: Life Sciences 52:5, 459-463
     CrossRef

112. 112

     CuiLin Xu, LiBo Dong, Li Xin, Yu Lan, YongKun Chen, LiMei Yang, YueLong Shu. (2009) Human avian influenza A (H5N1) virus infection in China. Science in China Series C: Life Sciences 52:5, 407-411
     CrossRef

113. 113

     Sheng-Fan Wang, Kuan-Hsuan Chen, Arunee Thitithanyanont, Ling Yao, Yuan-Ming Lee, Yu-Jiun Chan, Shih-Jen Liu, Pele Chong, Wu-Tse Liu, Jason C. Huang, Yi-Ming Arthur Chen. (2009) Generating and characterizing monoclonal and polyclonal antibodies against avian H5N1 hemagglutinin protein. Biochemical and Biophysical Research Communications 382:4, 691-696
     CrossRef

114. 114

     SA Hamilton, IJ East, J-A Toribio, MG Garner. (2009) Are the Australian poultry industries vulnerable to large outbreaks of highly pathogenic avian influenza?. Australian Veterinary Journal 87:5, 165-174
     CrossRef

115. 115

     Jesus F Bermejo-Martin, Alberto Tenorio-Abreu, Tomas Vega, Jose M Eiros, Javier Castrodeza, Raul Ortiz de Lejarazu. (2009) Prepandemic influenza vaccines. The Lancet Infectious Diseases 9:4, 206-207
     CrossRef

116. 116

     Michael Schotsaert, Marina De Filette, Walter Fiers, Xavier Saelens. (2009) Universal M2 ectodomain-based influenza A vaccines: preclinical and clinical developments. Expert Review of Vaccines 8:4, 499-508
     CrossRef

117. 117

     G. Galli, D. Medini, E. Borgogni, L. Zedda, M. Bardelli, C. Malzone, S. Nuti, S. Tavarini, C. Sammicheli, A. K. Hilbert, V. Brauer, A. Banzhoff, R. Rappuoli, G. Del Giudice, F. Castellino. (2009) From the Cover: Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels. Proceedings of the National Academy of Sciences 106:10, 3877-3882
     CrossRef

118. 118

     C. R. Baskin, H. Bielefeldt-Ohmann, T. M. Tumpey, P. J. Sabourin, J. P. Long, A. Garcia-Sastre, A.-E. Tolnay, R. Albrecht, J. A. Pyles, P. H. Olson, L. D. Aicher, E. R. Rosenzweig, K. Murali-Krishna, E. A. Clark, M. S. Kotur, J. L. Fornek, S. Proll, R. E. Palermo, C. L. Sabourin, M. G. Katze. (2009) Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proceedings of the National Academy of Sciences 106:9, 3455-3460
     CrossRef

119. 119

     Na Jia, Sake J. de Vlas, Yun-Xi Liu, Jiu-Song Zhang, Lin Zhan, Rong-Li Dang, Yong-Hong Ma, Xian-Jun Wang, Ti Liu, Guo-Ping Yang, Qing-Li Wen, Jan H. Richardus, Shan Lu, Wu-Chun Cao. (2009) Serological reports of human infections of H7 and H9 avian influenza viruses in northern China. Journal of Clinical Virology 44:3, 225-229
     CrossRef

120. 120

     Prasert Auewarakul. (2009) Pathogenesis of the H5N1 avian influenza virus in humans and mammalian models. Future Virology 4:2, 177-184
     CrossRef

121. 121

     S. Yongkiettrakul, K. Boonyapakron, A. Jongkaewwattana, A. Wanitchang, U. Leartsakulpanich, P. Chitnumsub, L. Eurwilaichitr, Y. Yuthavong. (2009) Avian influenza A/H5N1 neuraminidase expressed in yeast with a functional head domain. Journal of Virological Methods 156:1-2, 44-51
     CrossRef

122. 122

     Irina A. Leneva, Rupert J. Russell, Yury S. Boriskin, Alan J. Hay. (2009) Characteristics of arbidol-resistant mutants of influenza virus: Implications for the mechanism of anti-influenza action of arbidol. Antiviral Research 81:2, 132-140
     CrossRef

123. 123

     H.-L. Yen, J. R. Aldridge, A. C. M. Boon, N. A. Ilyushina, R. Salomon, D. J. Hulse-Post, H. Marjuki, J. Franks, D. A. Boltz, D. Bush, A. S. Lipatov, R. J. Webby, J. E. Rehg, R. G. Webster. (2009) Changes in H5N1 influenza virus hemagglutinin receptor binding domain affect systemic spread. Proceedings of the National Academy of Sciences 106:1, 286-291
     CrossRef

124. 124

     Frederick Hayden. (2009) Developing New Antiviral Agents for Influenza Treatment: What Does the Future Hold?. Clinical Infectious Diseases 48:S1, S3-S13
     CrossRef

125. 125

     Yixin Chen, Kun Qin, Wai Lan Wu, Guoqiang Li, Jun Zhang, Hailian Du, Mun Hon Ng, J. Wai‐Kuo Shih, J. S. Malik Peiris, Yi Guan, Honglin Chen, Ningshao Xia. (2009) Broad Cross‐Protection against H5N1 Avian Influenza Virus Infection by Means of Monoclonal Antibodies that Map to Conserved Viral Epitopes. The Journal of Infectious Diseases 199:1, 49-58
     CrossRef

126. 126

     K. Mattison, S. Bidawid, J. Farber. 2009. Hepatitis viruses and emerging viruses. , 891-929.
     CrossRef

127. 127

     Alexey Khalenkov, Shimon Perk, Alexander Panshin, Natalia Golender, Robert G. Webster. (2009) Modulation of the severity of highly pathogenic H5N1 influenza in chickens previously inoculated with Israeli H9N2 influenza viruses. Virology 383:1, 32-38
     CrossRef

128. 128

     Jung Hyun Kim, Soon Hyo Kwon, Eun Jung Lee, Eun Jung Kim, Tae Hyong Kim, Jin Seok Jeon, Hyunjin Noh, Dong Cheol Han. (2009) Two Cases of Respiratory Distress Syndrome Caused by Hospital-Acquired Pandemic Influenza (H1N1 2009) in Kidney Transplant Recipients. Infection and Chemotherapy 42:2, 117
     CrossRef

129. 129

     Sung-Han Kim. (2009) Treatment of Severe Pandemic Influenza A/H1N1 Infection. Infection and Chemotherapy 41:5, 265
     CrossRef

130. 130

     Zachary A. Bornholdt, B. V. Venkataram Prasad. (2008) X-ray structure of NS1 from a highly pathogenic H5N1 influenza virus. Nature 456:7224, 985-988
     CrossRef

131. 131

     Angie Lackenby, Catherine I Thompson, Jane Democratis. (2008) The potential impact of neuraminidase inhibitor resistant influenza. Current Opinion in Infectious Diseases 21:6, 626-638
     CrossRef

132. 132

     Regan N. Theiler, Sonja A. Rasmussen, Tracee A. Treadwell, Denise J. Jamieson. (2008) Emerging and Zoonotic Infections in Women. Infectious Disease Clinics of North America 22:4, 755-772
     CrossRef

133. 133

     Antonios Kolocouris, Philip Spearpoint, Stephen R. Martin, Alan J. Hay, Marta López-Querol, Francesc X. Sureda, Elizaveta Padalko, Johan Neyts, Erik De Clercq. (2008) Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues. Bioorganic & Medicinal Chemistry Letters 18:23, 6156-6160
     CrossRef

134. 134

     Ruth Harvey, Jun X. Wheeler, Chantal L. Wallis, James S. Robertson, Othmar G. Engelhardt. (2008) Quantitation of haemagglutinin in H5N1 influenza viruses reveals low haemagglutinin content of vaccine virus NIBRG-14 (H5N1). Vaccine 26:51, 6550-6554
     CrossRef

135. 135

     Benoit Baras, Nancy Bouveret, Jeanne-Marie Devaster, Louis Fries, Paul Gillard, Roland Sänger, Emmanuel Hanon. (2008) A vaccine manufacturer’s approach to address medical needs related to seasonal and pandemic influenza viruses. Influenza and Other Respiratory Viruses 2:6, 251-260
     CrossRef

136. 136

     M. Khanna, P. Kumar, K. Choudhary, B. Kumar, V. K. Vijayan. (2008) Emerging influenza virus: A global threat. Journal of Biosciences 33:4, 475-482
     CrossRef

137. 137

     Mary Elizabeth Wilson. (2008) Preface. Medical Clinics of North America 92:6, xiii-xviii
     CrossRef

138. 138

     Melanie Saville, Grenville Marsh, Agnes Hoffenbach. (2008) Improving seasonal and pandemic influenza vaccines. Influenza and Other Respiratory Viruses 2:6, 229-235
     CrossRef

139. 139

     David M. Morens, Jeffery K. Taubenberger, Anthony S. Fauci. (2008) Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness. The Journal of Infectious Diseases 198:7, 962-970
     CrossRef

140. 140

     Gerardo Rojo Marcos, Juan Cuadros González, Alberto Arranz Caso. (2008) Enfermedades infecciosas importadas en España. Medicina Clínica 131:14, 540-550
     CrossRef

141. 141

     Jonathan A. McCullers. (2008) Planning for an Influenza Pandemic: Thinking beyond the Virus. The Journal of Infectious Diseases 198:7, 945-947
     CrossRef

142. 142

     Laurel Yong-Hwa Lee, Do Lien Anh Ha, Cameron Simmons, Menno D. de Jong, Nguyen Van Vinh Chau, Reto Schumacher, Yan Chun Peng, Andrew J. McMichael, Jeremy J. Farrar, Geoffrey L. Smith, Alain R.M. Townsend, Brigitte A. Askonas, Sarah Rowland-Jones, Tao Dong. (2008) Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. Journal of Clinical Investigation
     CrossRef

143. 143

     Marc Girard, Laszlo Palkonyay, Marie Paule Kieny. (2008) Report of the 4th meeting on the “Evaluation of pandemic influenza prototype vaccines in clinical trials”. Vaccine 26:39, 4975-4977
     CrossRef

144. 144

     Urban Kumlin, Sigvard Olofsson, Ken Dimock, Niklas Arnberg. (2008) Sialic acid tissue distribution and influenza virus tropism. Influenza and Other Respiratory Viruses 2:5, 147-154
     CrossRef

145. 145

     Thijs Kuiken, Jeffery K. Taubenberger. (2008) Pathology of human influenza revisited. Vaccine 26, D59-D66
     CrossRef

146. 146

     Maria D. Van Kerkhove, Sowath Ly, Davun Holl, Javier Guitian, Punam Mangtani, Azra C. Ghani, Sirenda Vong. (2008) Frequency and patterns of contact with domestic poultry and potential risk of H5N1 transmission to humans living in rural Cambodia. Influenza and Other Respiratory Viruses 2:5, 155-163
     CrossRef

147. 147

     Mitchell R White, Mona Doss, Patrick Boland, Tesfaldet Tecle, Kevan L Hartshorn. (2008) Innate immunity to influenza virus: implications for future therapy. Expert Review of Clinical Immunology 4:4, 497-514
     CrossRef

148. 148

     Matthew J. Memoli, David M. Morens, Jeffery K. Taubenberger. (2008) Pandemic and seasonal influenza: therapeutic challenges. Drug Discovery Today 13:13-14, 590-595
     CrossRef

149. 149

     Catherine WM Ong, Paul Ananth Tambyah. (2008) Update on antivirals and vaccines for seasonal and potential pandemic use. Expert Review of Respiratory Medicine 2:3, 391-402
     CrossRef

150. 150

     Prasert Auewarakul, Arunee Thitithanyanont, Anucha Apisarnthanarak, Pokrath Hansasuta, Porntippa Lekcharoensuk, Pilaipan Puthvathana. (2008) Bangkok International Conference on Avian Influenza 2008. Expert Review of Vaccines 7:3, 293-298
     CrossRef

151. 151

     Hua Wang, Zijian Feng, Yuelong Shu, Hongjie Yu, Lei Zhou, Rongqiang Zu, Yang Huai, Jie Dong, Changjun Bao, Leying Wen, Hong Wang, Peng Yang, Wei Zhao, Libo Dong, Minghao Zhou, Qiaohong Liao, Haitao Yang, Min Wang, Xiaojun Lu, Zhiyang Shi, Wei Wang, Ling Gu, Fengcai Zhu, Qun Li, Weidong Yin, Weizhong Yang, Dexin Li, Timothy M Uyeki, Yu Wang. (2008) Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China. The Lancet 371:9622, 1427-1434
     CrossRef

152. 152

     Timothy M. UYEKI. (2008) Global epidemiology of human infections with highly pathogenic avian influenza A (H5N1) viruses. Respirology 13:s1, S2-S9
     CrossRef

153. 153

     Mee Soo Chang, Jun Hee Woo. (2008) Clinical Use of Tamiflu (Oseltamivir). Journal of the Korean Medical Association 51:8, 757
     CrossRef

154. 154

     Steven E. Weinberger, Barbara A. Cockrill, Jess Mandel. 2008. Pneumonia. , 289-305.
     CrossRef

155. 155

     Tran Tan Thanh, H. Rogier van Doorn, Menno D. de Jong. (2008) Human H5N1 influenza: Current insight into pathogenesis. The International Journal of Biochemistry & Cell Biology 40:12, 2671-2674
     CrossRef