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

Memoli, Matthew J.; Athota, Rani; Reed, Susan; Czajkowski, Lindsay; Bristol, Tyler; Proudfoot, Kathleen; Hagey, Rachel J.; Voell, Jocelyn; Fiorentino, Charles; Ademposi, Angela; Shoham, Shmuel; Taubenberger, Jeffery K.

doi:10.1093/cid/cit725

Cited by 227 publications

(233 citation statements)

References 29 publications

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“…The findings reinforce the need for rapid point-of-care diagnostics and mobilization of drug stockpiles quickly during pandemics. It is important to note that these results are based on otherwise healthy adults with influenza virus infection and may not extrapolate to all treatment populations, including, for example, hospitalized patients with severe influenza or immunocompromised patients, who may exhibit prolonged viral shedding and hence the potential for a larger therapeutic window (21,22).…”

Section: Discussionmentioning

confidence: 99%

A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

Kamal

Gieschke

Lemenuel‐Diot

et al. 2015

Antimicrob Agents Chemother

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A population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate ␤, free virus produced at rate p and cleared at rate c, and infected cells cleared at rate ␦, was implemented in NONMEM with an inhibitory Hill function on virus production (p), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75-mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (␤) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (c) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation. O seltamivir is an orally active antiviral which inhibits the neuraminidase enzyme necessary for the release of newly replicated influenza virus from infected cells. Oseltamivir has a wide spectrum of activity, acting against a range of influenza A and B subtypes. The Centers for Disease Control and Prevention reported that 99.6% of the 2009 H1N1 viral strains tested were susceptible to oseltamivir (see http://www.cdc.gov/H1N1flu /recommendations.htm). The standard regimen of 75 mg twice a day (b.i.d.) for 5 days is used for treatment of seasonal influenza as previous studies in adult subjects showed that this regimen results in plasma levels sufficient to inhibit neuraminidase enzyme activity from all the tested seasonal influenza virus strains (1, 2). The same treatment regimen was applied in the most recent H1N1 pandemic in 2009-2010 without a prospective dose optimization trial, due to the impracticality of performing such a study on an emergent viral strain during a pandemic. The World Health Organization has recommended use of higher doses (150-mg regimen) for treatment of highly virulent strains such as H5N1 (3). In addition, there were reported concerns regarding the ability of oseltamivir manufacturing capacity to fully meet global stockpiling demands if a rapid pandemic ensues (4, 5). This factor, in addition to opportunities for enh...

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Section: Discussionmentioning

confidence: 99%

A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

Kamal

Gieschke

Lemenuel‐Diot

et al. 2015

Antimicrob Agents Chemother

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“…The present patient had several risk factors attributable to prolonged viral shedding, such as an advanced age, carrying malignant lymphoma, receiving anti-lymphoma therapies, lymphopenia and the administration of PSL, all of which might have led to an immunocompromised state that could hinder viral clearance (3)(4)(5)(6)(7)(8)(9). Furthermore, prolonged viral shedding and the long-term administration of anti-viral drugs may have provided a conductive growth environment for the drug-resistant viral strains (14)(15)(16).…”

Section: Discussionmentioning

confidence: 86%

“…In the healthy adult population, the average duration of viral shedding is reported to be 4.8 days (1). Prolonged shedding, defined as seven days or more (2), can sometimes occur in childhood, elderly people and immunocompromised hosts, including patients with hematologic malignancy (3)(4)(5)(6)(7)(8)(9). Systemic glucocorticoid administration, diabetes or chronic lung disease can also impede viral clearance (4).…”

Section: Introductionmentioning

confidence: 99%

Persistent Infection of Drug-resistant Influenza A Virus during Chemotherapy for Malignant Lymphoma

et al. 2016

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We herein report the case of an 80-year-old man with malignant lymphoma who became persistently infected with influenza A virus. Although he was repeatedly treated with NA inhibitors, such as oseltamivir or peramivir, nasal cavity swab tests for influenza A antigen continued to be positive for more than 2 months. Virological analyses revealed that he was infected with the NA inhibitor-resistant A (H3N2) virus possessing an R292K substitution in the NA protein. These findings suggest that a drug-resistant influenza virus strain might selectively survive antiviral therapy in elderly patients with refractory malignant lymphoma undergoing multiple chemotherapies.

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“…1,2 These highly immunosuppressed patients present with fewer clinical symptoms, have prolonged viral shedding, are at increased risk for nosocomial transmission, are more apt to develop antiviral resistance and are more likely to progress to lower-tract disease. 1 Although vaccination has been shown to be the most important intervention for influenza prevention, many of these patients mount attenuated or inadequate protective responses to influenza vaccine. 2,3 In healthcare settings with large numbers of cancer, transplant and immunosuppressed patients, vaccination of healthcare personnel (HCP) is a critical component for influenza prevention.…”

Section: Introductionmentioning

confidence: 99%

Employee influenza vaccination in a large cancer center with high baseline compliance rates: Comparison of carrot versus stick approaches

Podczervinski

Stednick

Helbert

et al. 2015

American Journal of Infection Control

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Background Influenza is a major complication in cancer and hematopoietic cell transplant (HCT) recipients. We set out to maximize influenza vaccination rates in healthcare personnel at our large ambulatory cancer center with high baseline compliance and to assess alternatives to mandatory policies. Methods Baseline influenza vaccine compliance rates at our center were over 85%. In 2011 an incentive-based “carrot” campaign was implemented, and in 2012 a penalty-based “stick” approach to declining staff was required. Yearly approaches were compared using Kaplan-Meier survival estimates. Results Both the incentive and penalty approaches significantly improved upon the baseline rates of vaccination (2010 vs. 2011 [p=0.0001]; 2010 vs. 2012 [p<0.0001), but 2012 significantly improved over 2011 (p<0.0001). Staff with direct patient contact had significantly higher rates of vaccination when compared to those with indirect and minimal contact in every campaign year, except in the penalty-driven campaign from 2012 (p<0.001, <0.001, 0.24, and p<0.001, <0.001, 0.17, respectively). Conclusion A multifaceted staff vaccination program that included education, training and active declination was more effective than one offering incentives. Improvements in vaccination rates in the penalty-driven campaign were driven by staff without direct care responsibilities. High compliance with system-wide influenza vaccination was achieved without requiring mandatory vaccination.

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

Abstract: ClinicalTrials.gov identifier NCT00533182.

Cited by 227 publications

References 29 publications

A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression

Persistent Infection of Drug-resistant Influenza A Virus during Chemotherapy for Malignant Lymphoma

Employee influenza vaccination in a large cancer center with high baseline compliance rates: Comparison of carrot versus stick approaches

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