Matthew J. Memoli

Bacterial Coinfection in Influenza: A Grand Rounds Review

Bacterial coinfection complicated nearly all influenza deaths in the 1918 influenza pandemic and up to 34% of 2009 pandemic influenza A(H1N1) infections managed in intensive care units worldwide. More than 65,000 deaths attributable to influenza and pneumonia occur annually in the United States. Data from 683 critically ill patients with 2009 pandemic influenza A(H1N1) infection admitted to 35 intensive care units in the United States reveal that bacterial coinfection commonly occurs within the first 6 days of influenza infection, presents similarly to influenza infection occurring alone, and is associated with an increased risk of death. Pathogens that colonize the nasopharynx, including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, are most commonly isolated. Complex viral, bacterial, and host factors contribute to the pathogenesis of coinfection. Reductions in morbidity and mortality are dependent on prevention with available vaccines as well as early diagnosis and treatment.

Rapid Selection of Oseltamivir-and Peramivir-Resistant Pandemic H1N1 Virus during Therapy in 2 Immunocompromised Hosts

Pandemic 2009 H1N1 virus isolates containing the neuraminidase inhibitor resistance mutation H275Y have been reported. We describe rapid selection for the H275Y resistance mutation during therapy in 2 immunocompromised individuals at 9 and 14 days of therapy, as well as the first described case of clinically significant resistance to peramivir.

MultiDrug-Resistant 2009 Pandemic Influenza A(H1N1) Viruses Maintain Fitness and Transmissibility in Ferrets

BACKGROUND The 2009 influenza A(H1N1) pandemic called attention to the limited influenza treatment options available, especially in individuals at high risk of severe disease. Neuraminidase inhibitor-resistant seasonal H1N1 viruses have demonstrated the ability to transmit well despite early data indicating that resistance reduces viral fitness. 2009 H1N1 pandemic viruses have sporadically appeared containing resistance to neuraminidase inhibitors and the adamantanes, but the ability of these viruses to replicate, transmit, and cause disease in mammalian hosts has not been fully characterized. METHODS Two pretreatment wild-type viruses and 2 posttreatment multidrug-resistant viruses containing the neuraminidase H275Y mutation collected from immunocompromised patients infected with pandemic influenza H1N1 were tested for viral fitness, pathogenicity, and transmissibility in ferrets. RESULTS The pretreatment wild-type viruses and posttreatment resistant viruses containing the H275Y mutation all demonstrated significant pathogenicity and equivalent viral fitness and transmissibility. CONCLUSIONS The admantane-resistant 2009 pandemic influenza A(H1N1) virus can develop the H275Y change in the neuraminidase gene conferring resistance to both oseltamivir and peramivir without any loss in fitness, transmissibility, or pathogenicity. This suggests that the dissemination of widespread multidrug resistance similar to neuraminidase inhibitor resistance in seasonal H1N1 is a significant threat.

The 1918 influenza pandemic: lessons for 2009 and the future.

The 1918 to 1919 H1N1 influenza pandemic is among the most deadly events in recorded human history, having killed an estimated 50 to 100 million persons. Recent H5N1 avian influenza epizootics associated with sporadic human fatalities have heightened concern that a new influenza pandemic, one at least as lethal as that of 1918, could be developing. In early 2009, a novel pandemic H1N1 influenza virus appeared, but it has not exhibited unusually high pathogenicity. Nevertheless, because this virus spreads globally, some scientists predict that mutations will increase its lethality. Therefore, to accurately predict, plan, and respond to current and future influenza pandemics, we must first better-understand the events and experiences of 1918.Although the entire genome of the 1918 influenza virus has been sequenced, many questions about the pandemic it caused remain unanswered. In this review, we discuss the origin of the 1918 pandemic influenza virus, the pandemics unusual epidemiologic features and the causes and demographic patterns of fatality, and how this information should impact our response to the current 2009 H1N1 pandemic and future pandemics. After 92 yrs of research, fundamental questions about influenza pandemics remain unanswered. Thus, we must remain vigilant and use the knowledge we have gained from 1918 and other influenza pandemics to direct targeted research and pandemic influenza preparedness planning, emphasizing prevention, containment, and treatment.

The Natural History of Influenza Infection in the Severely Immunocompromised vs Nonimmunocompromised Hosts

Severely immunocompromised individuals infected with influenza are different from the influenza infected that are nonimmunocompromised. Issues to consider during medical management include asymptomatic shedding, development of multi-drug resistance during prolonged antiviral therapy, and the potential high risk of pulmonary involvement.

The PB2-E627K Mutation Attenuates Viruses Containing the 2009 H1N1 Influenza Pandemic Polymerase

ABSTRACT The swine-origin H1N1 influenza A virus emerged in early 2009 and caused the first influenza pandemic in 41 years. The virus has spread efficiently to both the Northern and the Southern Hemispheres and has been associated with over 16,000 deaths. Given the virus’s recent zoonotic origin, there is concern that the virus could acquire signature mutations associated with the enhanced pathogenicity of previous pandemic viruses or H5N1 viruses with pandemic potential. We tested the hypothesis that mutations in the polymerase PB2 gene at residues 627 and 701 would enhance virulence but found that influenza viruses containing these mutations in the context of the pandemic virus polymerase complex are attenuated in cell culture and mice. IMPORTANCE Influenza A virus (IAV) evolution is characterized by host-specific lineages, and IAVs derived in whole or in part from animal reservoirs have caused pandemics in humans. Because IAVs are known to acquire host-adaptive genome mutations, and since the PB2 gene of the 2009 H1N1 virus is of recent avian derivation, there exists concern that the pathogenicity of the 2009 H1N1 influenza A pandemic virus could be potentiated by acquisition of the host-adaptive PB2-E627K or -D701N mutations, which have been shown to enhance the virulence of other influenza viruses. We present data from a mouse model of influenza infection showing that such mutations do not increase the virulence of viruses containing the 2009 H1N1 viral polymerase. Influenza A virus (IAV) evolution is characterized by host-specific lineages, and IAVs derived in whole or in part from animal reservoirs have caused pandemics in humans. Because IAVs are known to acquire host-adaptive genome mutations, and since the PB2 gene of the 2009 H1N1 virus is of recent avian derivation, there exists concern that the pathogenicity of the 2009 H1N1 influenza A pandemic virus could be potentiated by acquisition of the host-adaptive PB2-E627K or -D701N mutations, which have been shown to enhance the virulence of other influenza viruses. We present data from a mouse model of influenza infection showing that such mutations do not increase the virulence of viruses containing the 2009 H1N1 viral polymerase.

Evaluation of Antihemagglutinin and Antineuraminidase Antibodies as Correlates of Protection in an Influenza A/H1N1 Virus Healthy Human Challenge Model

ABSTRACT Despite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of ≥1:40 and <1:40. The primary objective was to determine whether participants with HAI titers of ≥1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of ≥1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms. IMPORTANCE This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza. This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza.

IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity

A rare ability to enhance dengue virus disease In some cases, secondary infections of dengue virus can be extremely serious and result in plasma leakage, thrombocytopenia, and hemorrhagic disease. This phenomenon has been attributed to antibody-dependent enhancement. Wang et al. show that a specific subclass of antibody, IgG1, which lacks fucosyl residues on the Fc segment of the heavy chain of the immunoglobulin, is elevated in patients with severe secondary dengue disease. These non-neutralizing antibodies bind activating Fc receptors and appear to cross-react with platelet antigens to cause platelet depletion, contributing to thrombocytopenia. Science, this issue p. 395 Immunoglobulin subclass IgG1, which lacks fucosyl residues, is implicated in severe dengue disease during secondary infections. Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity. We discovered that DHF/DSS patients respond to infection by producing IgGs with enhanced affinity for the activating Fc receptor FcγRIIIA due to afucosylated Fc glycans and IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease.

Glycosylation, Hypogammaglobulinemia, and Resistance to Viral Infections

Genetic defects in MOGS, the gene encoding mannosyl-oligosaccharide glucosidase (the first enzyme in the processing pathway of N-linked oligosaccharide), cause the rare congenital disorder of glycosylation type IIb (CDG-IIb), also known as MOGS-CDG. MOGS is expressed in the endoplasmic reticulum and is involved in the trimming of N-glycans. We evaluated two siblings with CDG-IIb who presented with multiple neurologic complications and a paradoxical immunologic phenotype characterized by severe hypogammaglobulinemia but limited clinical evidence of an infectious diathesis. A shortened immunoglobulin half-life was determined to be the mechanism underlying the hypogammaglobulinemia. Impaired viral replication and cellular entry may explain a decreased susceptibility to infections.

Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus

Please cite this paper as: Kash et al. (2010) Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus. Influenza and Other Respiratory Viruses 4(3), 121–127.