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      Inhaled Nitric Oxide Therapy Fails to Improve Outcome in Experimental Severe Influenza

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          Abstract

          In vitro, nitric oxide (NO) has been shown to have antimicrobial activity against a wide range of viruses, including influenza A virus. Therefore, we hypothesized that inhaled nitric oxide (iNO) would increase survival in vivo by reducing the viral load in C57Bl/6 mice infected with a lethal dose of influenza A/WSN/33 (H1N1; WSN/33) virus. NO was delivered to influenza-infected mice either continuously or intermittently at 80 or 160 ppm, respectively, using both prophylactic and post-infection treatment strategies. Murine survival and weight loss were assessed, and lung viral load was quantified via plaque assay. Here, we report that iNO administered prophylactically or post-influenza infection failed to improve survival of infected mice. No difference in lung viral load was observed between experimental groups. Although NO has antiviral activity against influenza A virus in vitro, iNO therapy provided no apparent benefit when used for treatment of influenza A virus infection in vivo.

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          Oseltamivir resistance during treatment of influenza A (H5N1) infection.

          Menno de Jong, Tran Thanh, Truong Khanh … (2005)
          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. Copyright 2005 Massachusetts Medical Society.
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            Avian flu: isolation of drug-resistant H5N1 virus.

            Q Mai Le, Maki Kiso, Kazuhiko Someya … (2005)
            The persistence of H5N1 avian influenza viruses in many Asian countries and their ability to cause fatal infections in humans have raised serious concerns about a global flu pandemic. Here we report the isolation of an H5N1 virus from a Vietnamese girl that is resistant to the drug oseltamivir, which is an inhibitor of the viral enzyme neuraminidase and is currently used for protection against and treatment of influenza. Further investigation is necessary to determine the prevalence of oseltamivir-resistant H5N1 viruses among patients treated with this drug.
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              Delayed Clearance of Viral Load and Marked Cytokine Activation in Severe Cases of Pandemic H1N1 2009 Influenza Virus Infection

              Kelvin K. W. To, Ivan Hung, Iris W. S. Li … (2010)
              Abstract Background. Infections caused by the pandemic H1N1 2009 influenza virus range from mild upper respiratory tract syndromes to fatal diseases. However, studies comparing virological and immunological profile of different clinical severity are lacking. Methods. We conducted a retrospective cohort study of 74 patients with pandemic H1N1 infection, including 23 patients who either developed acute respiratory distress syndrome (ARDS) or died (ARDS-death group), 14 patients with desaturation requiring oxygen supplementation and who survived without ARDS (survived-without-ARDS group), and 37 patients with mild disease without desaturation (mild-disease group). We compared their pattern of clinical disease, viral load, and immunological profile. Results. Patients with severe disease were older, more likely to be obese or having underlying diseases, and had lower respiratory tract symptoms, especially dyspnea at presentation. The ARDS-death group had a slower decline in nasopharyngeal viral loads, had higher plasma levels of proinflammatory cytokines and chemokines, and were more likely to have bacterial coinfections (30.4%), myocarditis (21.7%), or viremia (13.0%) than patients in the survived-without-ARDS or the mild-disease groups. Reactive hemophagocytosis, thrombotic phenomena, lymphoid atrophy, diffuse alveolar damage, and multiorgan dysfunction similar to fatal avian influenza A H5N1 infection were found at postmortem examinations. Conclusions. The slower control of viral load and immunodysregulation in severe cases mandate the search for more effective antiviral and immunomodulatory regimens to stop the excessive cytokine activation resulting in ARDS and death.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Med Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Medical Sciences
                Publisher: Ivyspring International Publisher (Sydney )
                ISSN (Electronic): 1449-1907
                Publication date Collection: 2012
                Publication date (Electronic): 13 January 2012
                Volume: 9
                Issue: 2
                Pages: 157-162
                Affiliations
                1. Institute of Medical Science, University of Toronto, Toronto, Canada;
                2. Sandra A. Rotman Laboratories, McLaughlin-Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto;
                3. Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, Canada;
                4. Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada.
                Author notes
                ✉ Corresponding author: conrad.liles@ 123456uhn.ca

                CONFLICT OF INTEREST: CM consults and has minority shares in a variety of companies developing unrelated nitric oxide products. ID, KCK, and WCL have declared that no conflict of interest exists.

                Article
                Publisher ID: ijmsv09p0157
                DOI: 10.7150/ijms.3880
                PMC ID: 3258558
                PubMed ID: 22253563
                SO-VID: f3b0f60f-3000-4f36-94eb-5b4fa0c18034
                Copyright © © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                History
                Date received : 29 November 2011
                Date accepted : 6 January 2012
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Medicine
                Keywords: influenza a/wsn/33,severe influenza,nitric oxide
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: influenza a/wsn/33, severe influenza, nitric oxide

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