Lionel A. Mandell, Richard G. Wunderink, Antonio Anzueto, John G. Bartlett, G. Douglas Campbell, Nathan C. Dean, Scott F. Dowell, Thomas M. File, Jr. Daniel M. Musher, Michael S. Niederman, Antonio Torres, and Cynthia G. Whitney McMaster University Medical School, Hamilton, Ontario, Canada; Northwestern University Feinberg School of Medicine, Chicago, Illinois; University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, and Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas; Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi School of Medicine, Jackson; Division of Pulmonary and Critical Care Medicine, LDS Hospital, and University of Utah, Salt Lake City, Utah; Centers for Disease Control and Prevention, Atlanta, Georgia; Northeastern Ohio Universities College of Medicine, Rootstown, and Summa Health System, Akron, Ohio; State University of New York at Stony Brook, Stony Brook, and Department of Medicine, Winthrop University Hospital, Mineola, New York; and Cap de Servei de Pneumologia i Allergia Respiratoria, Institut Clinic del Torax, Hospital Clinic de Barcelona, Facultat de Medicina, Universitat de Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, CIBER CB06/06/0028, Barcelona, Spain.

/pdf/infectious-diseases-society-of-america-american-thoracic-1cn65eiqga.pdf

Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults

A novel influenza A (H1N1) virus has spread rapidly across the globe. Judging its pandemic potential is difficult with limited data, but nevertheless essential to inform appropriate health responses. By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, we make an early assessment of transmissibility and severity. Our estimates suggest that 23,000 (range 6000 to 32,000) individuals had been infected in Mexico by late April, giving an estimated case fatality ratio (CFR) of 0.4% (range: 0.3 to 1.8%) based on confirmed and suspected deaths reported to that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, giving an upper 95% bound on CFR of 0.6%. Thus, although substantial uncertainty remains, clinical severity appears less than that seen in the 1918 influenza pandemic but comparable with that seen in the 1957 pandemic. Clinical attack rates in children in La Gloria were twice that in adults ( /=15 years: 29%). Three different epidemiological analyses gave basic reproduction number (R0) estimates in the range of 1.4 to 1.6, whereas a genetic analysis gave a central estimate of 1.2. This range of values is consistent with 14 to 73 generations of human-to-human transmission having occurred in Mexico to late April. Transmissibility is therefore substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics.

/pdf/pandemic-potential-of-a-strain-of-influenza-a-h1n1-early-2igit7d602.pdf

Pandemic Potential of a Strain of Influenza A (H1N1) : Early Findings

Avian influenza A (H5N1) viruses cause severe disease in humans, but the basis for their virulence remains unclear. In vitro and animal studies indicate that high and disseminated viral replication is important for disease pathogenesis. Laboratory experiments suggest that virus-induced cytokine dysregulation may contribute to disease severity. To assess the relevance of these findings for human disease, we performed virological and immunological studies in 18 individuals with H5N1 and 8 individuals infected with human influenza virus subtypes. Influenza H5N1 infection in humans is characterized by high pharyngeal virus loads and frequent detection of viral RNA in rectum and blood. Viral RNA in blood was present only in fatal H5N1 cases and was associated with higher pharyngeal viral loads. We observed low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in H5N1-infected individuals, particularly in those who died, and these correlated with pharyngeal viral loads. Genetic characterization of H5N1 viruses revealed mutations in the viral polymerase complex associated with mammalian adaptation and virulence. Our observations indicate that high viral load, and the resulting intense inflammatory responses, are central to influenza H5N1 pathogenesis. The focus of clinical management should be on preventing this intense cytokine response, by early diagnosis and effective antiviral treatment.

/pdf/fatal-outcome-of-human-influenza-a-h5n1-is-associated-with-2li6tz2o9n.pdf

Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia

Influenza viruses cause annual epidemics and occasional pandemics that have claimed the lives of millions. The emergence of new strains will continue to pose challenges to public health and the scientific communities. A prime example is the recent emergence of swine-origin H1N1 viruses that have transmitted to and spread among humans, resulting in outbreaks internationally. Efforts to control these outbreaks and real-time monitoring of the evolution of this virus should provide us with invaluable information to direct infectious disease control programmes and to improve understanding of the factors that determine viral pathogenicity and/or transmissibility.

/pdf/emergence-and-pandemic-potential-of-swine-origin-h1n1-3dy3x98p24.pdf

Emergence and pandemic potential of swine-origin H1N1 influenza virus.

Influenza virus remains a serious health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Here we used a human non-immune antibody phage-display library and the H5 hemagglutinin ectodomain to select ten neutralizing antibodies (nAbs) that were effective against all group 1 influenza viruses tested, including H5N1 ‘bird flu’ and the H1N1 ‘Spanish flu’. The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion. Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism. Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

/pdf/structural-and-functional-bases-for-broad-spectrum-38r6t4y8np.pdf

Structural and Functional Bases for Broad-Spectrum Neutralization of Avian and Human Influenza A Viruses

Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents.

/pdf/oseltamivir-resistance-during-treatment-of-influenza-a-h5n1-5g8p3ihyjp.pdf

Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection

A novel avian-origin influenza A/H7N9 virus infecting humans was first identified in March 2013 and, as of 30 May 2013, has caused 132 human infections leading to 33 deaths. Phylogenetic studies suggest that this virus is a reassortant, with the surface hemagglutinin (HA) and neuraminidase (NA) genes being derived from duck and wild-bird viruses, respectively, while the six “internal gene segments” were derived from poultry H9N2 viruses. Here we determine the pathogenicity of a human A/Shanghai/2/2013 (Sh2/H7N9) virus in healthy adult mice in comparison with that of A/chicken/Hong Kong/HH8/2010 (ck/H9N2) virus, highly pathogenic avian influenza (HPAI) A/Hong Kong/483/1997 (483/H5N1) virus, and a duck influenza A H7N9 virus of different genetic derivation, A/duck/Jiangxi/3286/2009 (dk/H7N9). Intranasal infection of mice with Sh2/H7N9 virus doses of 10 3 , 10 4 , and 10 5  PFU led to significant weight loss without fatality. This virus was more pathogenic than dk/H7N9 and ck/H9N2 virus, which has six internal gene segments that are genetically similar to Sh2/H7N9. Sh2/H7N9 replicated well in the nasal cavity and lung, but there was no evidence of virus dissemination beyond the respiratory tract. Mice infected with Sh2/H7N9 produced higher levels of proinflammatory cytokines in the lung and serum than did ck/H9N2 and dk/H7N9 but lower levels than 483/H5N1. Cytokine induction was positively correlated with virus load in the lung at early stages of infection. Our results suggest that Sh2/H7N9 virus is able to replicate and cause disease in mice without prior adaptation but is less pathogenic than 483/H5N1 virus. IMPORTANCE An H7N9 virus isolate causing fatal human disease was found to be more pathogenic for mice than other avian H9N2 or H7N9 viruses but less pathogenic than the highly pathogenic avian influenza virus (HPAI) H5N1. Similarly, the ability of Sh2/H7N9 to elicit proinflammatory cytokines in the lung and serum of mice was intermediate to ck/H9N2 and dk/H7N9 on the one hand and HPAI H5N1 on the other. These findings accord with the observed epidemiology in humans, in whom, as with seasonal influenza viruses, H7N9 viruses cause severe disease predominantly in older persons while HPAI H5N1 can cause severe respiratory disease and death in children and young adults.

Pathogenicity of the Novel A/H7N9 Influenza Virus in Mice

In February 2013, a patient hospitalized with pneumonia and acute respiratory distress syndrome (ARDS) was confirmed to be infected with a rare subtype of H7N9 avian influenza A virus (A/Shanghai/1/2013) [1]. Since then, a total of 132 laboratory-confirmed human H7N9 infections have been reported in eastern China and Taiwan, resulting in a 28% mortality rate (as of 30 May 2013) [2, 3]. No human H7N9 cases have been reported in other countries. The virus did not spread efficiently among humans, but limited, nonsustained human-to-human transmission could not be excluded in a few family clusters [4]. Viruses of the H7N9 subtype had not been previously isolated from humans, and infections with low-pathogenic avian influenza viruses have not been associated with severe infection or death. This is important because current seasonal influenza vaccines contain only H1N1 and H3N2 influenza A antigens, and all population groups are immunologically naive to both H7 and N9 surface antigens. The presence of H7 surface antigen is also troubling as highly pathogenic viruses of this HA subtype were shown to infect humans and 1 fatal case was reported [5].

Although vaccines are the most effective option for controlling influenza infections, none are available for prevention of H7N9 infections [6]. Human influenza H7N9 viruses are resistant to adamantanes as they harbor an S31N amino acid substitution in the M2; thus, neuraminidase (NA) inhibitors (NAIs) are the only option for control of H7N9 influenza infections [1]. The NAI oseltamivir is recommended for treatment of human H7N9 infections [4, 7]. Challenges in H7N9 antiviral treatment include the development of ARDS as a common complication in patients hospitalized with pneumonia [1, 8] as well as limited clinical experience and knowledge about the effectiveness of oseltamivir on human H7N9 infections. Moreover, human H7N9 viruses with NAI resistance-associated mutations (R152K and R292K, N2 numbering) were reported during treatment, emphasizing that the emergence of drug-resistant viruses should be monitored [1, 9].

Mouse models are well established for evaluating viral pathogenesis and the efficacy of antiviral drugs, as mice and humans develop similar changes in the respiratory tract, with the predominant involvement of the lower airway in mice [10]. Whereas pathological changes caused by human H7N9 viruses in mice have been reported recently [11–13], ARDS was not described, and therapeutic strategies have not been fully explored.

Here we evaluate the susceptibility of a panel of N9 influenza viruses to NAIs in vitro, establish the pathogenicity of A/Anhui/1/2013 (H7N9) in BALB/c mice, and examine the efficacy of oseltamivir treatment against lethal H7N9 virus challenge.

The Neuraminidase Inhibitor Oseltamivir is Effective against A/Anhui/1/2013 (H7N9) Influenza Virus in a Mouse Model of Acute Respiratory Distress Syndrome

/pdf/continuing-evolution-of-h9n2-influenza-viruses-endemic-in-2qponf277e.pdf

Joseph Malik Sriyal Peiris

Papers

Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection

Pathogenicity of the Novel A/H7N9 Influenza Virus in Mice

The Neuraminidase Inhibitor Oseltamivir is Effective against A/Anhui/1/2013 (H7N9) Influenza Virus in a Mouse Model of Acute Respiratory Distress Syndrome

Continuing evolution of H9N2 influenza viruses endemic in poultry in southern China.