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How to approach and treat viral infections in ICU patients

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Abstract

Patients with severe viral infections are often hospitalized in intensive care units (ICUs) and recent studies underline the frequency of viral detection in ICU patients. Viral infections in the ICU often involve the respiratory or the central nervous system and can cause significant morbidity and mortality especially in immunocompromised patients. The mainstay of therapy of viral infections is supportive care and antiviral therapy when available. Increased understanding of the molecular mechanisms of viral infection has provided great potential for the discovery of new antiviral agents that target viral proteins or host proteins that regulate immunity and are involved in the viral life cycle. These novel treatments need to be further validated in animal and human randomized controlled studies.

Introduction

The prevalence of viral diseases has increased due to the availability of modern diagnostic tests that allow rapid detection of viruses [1]. Viral diseases may additionally be associated with significant morbidity and mortality as is the case with some emerging viral diseases, such as the Middle East Respiratory Syndrome coronavirus or avian influenza [2, 3]. Patients with severe viral infections are often hospitalized in intensive care units (ICUs); on the other hand recent studies have underlined the frequency of virus detection in ICU patients [46]. The majority of viral infections that require ICU care involve the respiratory tract or the central nervous system. However, other organ systems, such as the gastrointestinal tract, may be severely affected by viruses and require support or close monitoring. The reported incidence of viral infections reported in the ICU varies widely across studies and geographic regions and has changed over the recent years based on the epidemiology of emerging viral infections such as human metapneumovirus and adenovirus infections [7, 8]. Improved molecular detections methods have also significantly changed the epidemiology of viral infections in the ICU over the last years [7]. Multi-institutional databases and time-series models may be useful tools to characterize and forecast the burden of severe viral infections at the local and institutional levels [9, 10]. Clinical signs and symptoms are rarely sufficient to make a specific diagnosis of a viral infection. Often a combination of the appropriate clinical syndrome together with epidemiologic clues but more importantly specific laboratory tests is used to reach the diagnosis [11]. Viral infections can cause severe morbidity and mortality in certain hosts such as immunocompromised patients (Table 1) [1252]. Herein, we review the literature on the role of viruses in ICU in adults [excluding Human Immunodeficiency Virus (HIV)] with a focus on treatment of these infections.

Table 1 Etiologies and treatment of viral syndromes in the ICU

Review

Respiratory infections

In recent years, viruses have been identified as an increasingly frequent cause of community-acquired pneumonia (CAP) [53], because of the availability of new diagnostic tools, such as Polymerase Chain Reaction (PCR). On the other hand the emergence of the pandemic influenza virus in 2009 as well as the emergence of viruses with pandemic potential such as the avian influenza viruses or new coronaviruses has emphasized the role of viruses in severe community acquired pneumonia in places where these viruses are endemic [54]. Viral nosocomial pneumonia [hospital-acquired, healthcare-associated pneumonia (HCAP) or ventilator-associated pneumonia (VAP)] have been described but the pathogenicity and the roles of viruses recovered from the lower respiratory tract in patients with pneumonia remains controversial. Severe viral infections such as influenza, severe acute respiratory syndrome (SARS) may cause respiratory failure which may rapidly progress to acute respiratory distress syndrome (ARDS) and multi-organ failure [5558]. Except for pneumonia, acute respiratory failure can occur in patients with chronic obstructive pulmonary disease (COPD) and lead to hospitalization and the need for mechanical ventilation [5558]. In addition, viruses can cause ARDS and neurogenic respiratory failure (for example through development of Guillain-Barré Syndrome) [5558].

Causes of viral pneumonia

Respiratory viruses are the most common cause of viral CAP

Although severe community-acquired pneumonia is usually caused by bacteria, viruses account for approximately 3-10% of cases in large series [5965]. The most common cause of viral pneumonia in adults is influenza virus type A and B [32, 53, 6573]. Immunocompromised patients are more likely to have viral pneumonias caused by respiratory syncytial virus (RSV), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), adenovirus and rarely measles (21-35). Recent molecular diagnostic methods have significantly changed the epidemiology of viral pneumonias in the ICU over the last years with the increasing detection of viruses such as human metapneumovirus and adenovirus infections [7, 8]. Radiographic findings are variable and not virus specific; an “atypical” pneumonia presentation is often seen in otherwise healthy individuals while on the other hand severe lobar or bilateral pneumonia can be seen in immunocompromised hosts. All the reported respiratory viruses can cause severe pneumonia with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation, but the frequency of this complication is not known [5558].

Respiratory viruses may be the cause of HCAP

Viral pneumonias may be nosocomially acquired, especially during peak respiratory periods and in immunocompromised patients [7476]. In a recent retrospective study, 34% of the 134 HCAP patients had at least one respiratory virus recovered either in the lower respiratory tract or the nasopharyngeal swab [77], with the most frequent being rhinovirus, parainfluenza virus, human Metapneumovirus and influenza. Patients with viral HCAP or bacterial VAP had the same mortality rate [77].

Mostly latent viruses, particularly Herpesviridae, are identified in patients with VAP

Although data on viral nosocomial pneumonia are scarce, the role of respiratory viruses as a cause of nosocomial pneumonia is probably limited. In two studies in ICU patients, <5.5% of mechanically ventilated patients with VAP had a respiratory sample positive for respiratory viruses [6, 72, 78] and in many of these cases the mechanical ventilation duration before virus detection may have indicated carriage before ICU admission. Latent viruses such as Herpesviridae including herpes simplex virus (HSV) and cytomegalovirus (CMV) are known to be a cause of pneumonia or systemic disease in immunocompromised patients [79] but are often reactivated in non-immunocompromised ICU patients. ICU patients are known to experience immunoparalysis since an initial proinflammatory is followed by an anti-inflammatory response; this immunological state is responsible for nosocomial infections and latent virus reactivation [80, 81]. In most patients, viral detection reflects viral reactivation without lung parenchymal involvement. However, viral lung disease may develop, usually in patients with prolonged mechanical ventilation [6, 82, 83]. Mimivirus, an emergent virus, has also been described as a possible cause for nosocomial VAP [8488]. Although patients with high HSV and CMV viremia often have worse prognosis, the exact significance of detection of HSV, CMV or mimivirus in the lower respiratory tract of ventilated non-immunocompromised ICU patients is unclear [46, 72, 82, 83, 89]. Further clinical research work is needed to elucidate the role of these viruses in the pathogenesis of nosocomial viral pneumonia.

Treatment of viral respiratory infections

Treatment of viral CAP remains largely supportive

Influenza is the only virus for which Food and Drug Administration (FDA)-approved therapeutic agents are available for adults. The most effective measure against influenza remains vaccination, particularly for the elderly or high-risk individuals [90]. Antivirals for the treatment of influenza include the M2 channel inhibitors and the neuraminidase inhibitors [91]. Although treatment with neuraminidase inhibitors (oseltamivir or zanamivir) is recommended in all patients with suspected or confirmed influenza requiring hospitalization [92] their use in non-severe influenza could be more harmful than beneficial because of the possibility of selection of resistant mutants [93]. Thus, it would be appropriate to use them only for patients with severe disease presentation, for example, severe pneumonia, requiring mechanical ventilation or patients at high risk for influenza associated complications e.g immunocompromised individuals. Alternatively it can be used in all suspect cases in areas endemic for a strain with high mortality e.g. an avian influenza strain. Higher dosing regimens such as 150 mg twice daily may be safe and well tolerated [9498], have been used to treat seriously ill patients [58, 99, 100] and may have a benefit for treatment of Influenza B [101], some influenza A strains with reduced susceptibility [12, 102106] as well as infection sites with limited drug penetration (eg, central nervous system, as in some H5N1 cases) [96, 98, 107, 108]. However, overall supportive evidence is lacking [91, 94, 95, 99, 101, 102, 109111] and antiviral resistance may emerge even with higher doses of oseltamivir [112].

Novel antivirals can be considered for treatment of respiratory viral infections

Two new neuraminidase inhibitors have recently been described: peramivir and laninamivir octanoate. Peramivir, which can be given as a single intravenous dose, was authorized for a short period by the US Food and Drug Administration (FDA) for emergent intravenous use in hospitalized patients with the 2009 H1N1 pandemic influenza virus [113]. Laninamivir is given as a single inhaled dose for the treatment of seasonal influenza in adults and may also treat oseltamivir-resistant virus [113]. In addition, new therapeutics for the treatment of influenza A virus infections are under development [1315, 18, 28, 39, 50, 114195]. In this regard, the drug, favipiravir (T-705) has been shown to inhibit a variety of influenza viruses, including highly pathogenic avian influenza H5N1 viruses. Finally, numerous antivirals such as entry inhibitors, nucleoside analogues such as cidofovir, viral enzyme inhibitors (such as terminase and helicase enzyme inhibitors), and translation inhibitors may be utilized in an off-label indication for treatment of viral infections [13, 113].

Combination antiviral therapy can be used for treatment of resistant influenza

Except for HIV, hepatitis C and hepatitis B, combination drug therapies are not established for other viruses, such as HSV and influenza. Triple and dual drug combinations may be synergistic in their antiviral action [196]. The efficacy of oseltamivir-zanamivir combinations for seasonal influenza was established in a randomized controlled clinical study [188]. However, clinical antagonism between oseltamivir and zanamivir was suggested in another study [188, 193].

Other therapies for treatment of influenza

Low-dose systemic corticosteroids may be used for septic shock related to severe influenza [58] since evidence from RCTs suggests that corticosteroids may be associated with delayed clearance of viruses [2123] and invasive fungal infections [197]. Case control studies and a RCT suggested that plasma and hyperimmune globulin have demonstrated favorable responses in patients with severe avian influenza A (H5N1) and H1N1pdm09 infection compared with controls [27, 28, 198]. Further evaluation of novel treatments with RCTs is needed.

Viral infections of the nervous system in the ICU

Several viruses may infect the central nervous system (CNS) and cause inflammation of the meninges and brain parenchyma causing meningitis, encephalitis, seizures, coma and respiratory failure, secondary to aspiration, neuromuscular weakness and increasing atelectasis [32].

The etiology of meningoencephalitis is often not identified

Several viruses may cause infectious and postinfectious complications in the nervous system (Table 1). Despite advances in molecular techniques a specific cause is found in less than half of the cases [32].

Modern ICU care has significantly improved prognosis of viral nervous system infections

Acyclovir has significantly improved the prognosis of HSV encephalitis. Although without treatment, the mortality was more than 70% and has now decreased to <20% [32], many of the survivors have persisting neurological deficits. The prognosis of other viral encephalitides is generally comparable to that of HSV encephalitis [32].

Treatment of viral infections of the nervous system

Supportive therapy is the mainstay of treatment of viral nervous system infections

Neurologic and systemic complications may exacerbate brain damage and should be identified and treated early with supportive therapy to optimize neurologic recovery (Table 1). Evidence from RCTs is lacking and thus corticosteroids should not be used routinely; they may be used in selected cases with significant edema, in postinfectious encephalitis and in VZV encephalitis [32].

Early administration of antivirals is key for treatment of herpetic viral infections

The drug of choice for the treatment of HSV encephalitis is high-dose intravenous acyclovir which should be administered as early as possible for 14 to 21 days. A clinical trial is currently assessing longer courses of therapy using oral valacyclovir [32]. There are no clinical trials regarding the use of antivirals for VZV encephalitis [32] but acyclovir for up to 3 weeks is recommended for severe infections like encephalitis. A longer course of therapy may be considered for immunocompromised patients. Foscarnet is the preferred agent against HHV-6 whereas combination therapy with foscarnet and ganciclovir is recommended as initial treatment of CMV encephalitis (Table 1).

The use of antivirals is limited in non-herpetic viral nervous system infections

Antivirals have not been proven effective for enterovirus encephalitis. The drug pleconaril is an inhibitor of viral replication and may be an option for patients with severe Enterovirus infections [32]. Use of oseltamivir is appropriate for severe influenza. There is also no specific treatment for most causes of encephalitis although experimental therapies may be considered [13, 113].

Viral causes of shock in the ICU

Viral myocarditis can cause cardiogenic shock

Numerous viruses can cause viral myocarditis, including Coxsackie viruses group A and B (Table 1) [41]. Most patients recover, but persistent cardiac dysfunction is associated with 20% one-year mortality [199]. The majority of patients with acute myocarditis have evidence of heart failure. In severe cases mechanical ventricular assist device support is necessary until resolution or cardiac transplantation is available [199]. Although immunosuppressive medicines including corticosteroids were applied in many studies with viral myocarditis, meta-analyses have shown that their effects remain controversial since they do not reduce mortality [37]. In a systematic review, the use of intravenous immunoglobulins (IVIGs) in viral myocarditis was not recommended [38]. Experimental strategies for treatment of viral myocarditis have been developed [13, 113, 200].

Viral Hemorrhagic Fevers (VHF) can cause distributive shock

Viral hemorrhagic fevers (VHF) are caused by RNA viruses. The main vectors involved in transmission are and rodents or arthropods (Table 1). The clinical syndrome of hemorrhagic fever is secondary to capillary leakage due to increased vascular permeability. Other clinical manifestations depend on the virus involved and include, hepatitis, encephalitis, and/or nephropathy as well as multiorgan failure. Disseminated intravascular coagulopathy (DIC) is one of the common characteristic findings to many but not all of these viruses. There is a wide range of case-fatality rates that may vary from 1% to 90% [113]. Immediate isolation is critical for effective infection control and prevention of transmission in suspect cases. Close collaboration with local and national public health authorities is necessary to alert the community of a possible outbreak [113]. Since there are no effective therapeutic interventions for most of the viruses the care is largely supportive. No corticosteroids should be used. There are no antiviral drugs available for the treatment of hemorrhagic fever viruses, and there is only one vaccine widely available, i.e. the yellow fever 17D vaccine. Ribavirin has been reported to be an effective therapy for Lassa fever [49], but not against other hemorrhagic fever virus infections in humans [113]. Specific immune human plasma has been successful in treating certain hemorrhagic fevers such as the Argentinian hemorrhagic fever [42]. Emerging therapies with activity against VHF including Ebola have been described and are under development [13, 113, 201, 202].

Other important considerations regarding treatment of viral infections in the ICU

Infection control measures have a major role in the management of viral infections in the ICU

The primary factor responsible for transmission of viral infections in the ICU seems to be inadequate training in or compliance with infection control procedures [203, 204]. The use of nebulizers, open suctioning of respiratory secretions, the use of Bi-PAP, endotracheal intubation, outdated ventilation systems may also lead to spread of viral infections in the ICU setting [203, 204]. Infection control measures should include airborne, droplet and contact precautions. Disinfectants are highly active against many viruses [203, 204].

Vaccines are not adequate in preventing the spread of many viral infections in the ICU

Vaccination is possible to prevent infections with some viruses: influenza A and B viruses, HBV, varicella-zoster virus, Yellow fever virus and poliovirus. However vaccines are not available for major viral infections such as herpes simplex virus (HSV) and antiviral therapy is needed to control viral infections that cannot be prevented by vaccination.

Numerous antiviral drugs are undergoing clinical trials

The emergence of resistant viruses underlines the need to find novel antiviral. A few novel strategies have been introduced for antiviral research but further research is needed before they can be used for treatment of drug-resistant viral infections [13, 113].

Targeting latency may lead to complete treatment of chronic latent infections

Despite effective antiviral therapy for certain chronic viral infection (e.g. Hepatitis B), the virus can integrate its genome into the host cell and become latent. Therefore, new therapies that can completely remove viral components integrated in host cells are needed [13, 113].

Conclusion

Patients with severe viral infections are often hospitalized in intensive care units (ICUs). Viral infections can cause severe morbidity and mortality in certain hosts (Table 1) [46]. The mainstay of therapy of viral infections is supportive care. Antiviral therapy is available for a limited number of infections including influenza and herpetic infections. Novel antiviral treatments that target viral proteins (mostly involved in enzymatic activities or in the viral replication machinery) or host proteins that regulate immunity or other cellular processes in host cells and are involved in the viral life cycle need to be further validated in animal and human randomized controlled studies.

References

  1. 1.

    Luyt CE: Virus diseases in ICU patients: a long time underestimated; but be aware of overestimation. Intensive Care Med. 2006, 32: 968-970. 10.1007/s00134-006-0203-9.

  2. 2.

    Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY: Avian influenza A (H5N1) infection in humans. N Engl J Med. 2005, 353: 1374-1385.

  3. 3.

    Peiris JS, Yuen KY, Osterhaus AD, Stohr K: The severe acute respiratory syndrome. N Engl J Med. 2003, 349: 2431-2441. 10.1056/NEJMra032498.

  4. 4.

    Bruynseels P, Jorens PG, Demey HE, Goossens H, Pattyn SR, Elseviers MM, Weyler J, Bossaert LL, Mentens Y, Ieven M: Herpes simplex virus in the respiratory tract of critical care patients: a prospective study. Lancet. 2003, 362: 1536-1541. 10.1016/S0140-6736(03)14740-X.

  5. 5.

    Ong GM, Lowry K, Mahajan S, Wyatt DE, Simpson C, O'Neill HJ, McCaughey C, Coyle PV: Herpes simplex type 1 shedding is associated with reduced hospital survival in patients receiving assisted ventilation in a tertiary referral intensive care unit. J Med Virol. 2004, 72: 121-125. 10.1002/jmv.10524.

  6. 6.

    Luyt CE, Combes A, Deback C, Aubriot-Lorton MH, Nieszkowska A, Trouillet JL, Capron F, Agut H, Gibert C, Chastre J: Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med. 2007, 175: 935-942. 10.1164/rccm.200609-1322OC.

  7. 7.

    Spaeder MC, Custer JW, Bembea MM, Aganga DO, Song X, Scafidi S: A multicenter outcomes analysis of children with severe viral respiratory infection due to human metapneumovirus. Pediatr Crit Care Med. 2013, 14: 268-272. 10.1097/PCC.0b013e3182720fc7.

  8. 8.

    Spaeder MC: Severe adenoviral respiratory infection in children. Intensive Care Med. 2013, 39: 1157-1158. 10.1007/s00134-013-2893-0.

  9. 9.

    Spaeder MC, Fackler JC: Time series model to predict burden of viral respiratory illness on a pediatric intensive care unit. Med Decis Making. 2011, 31: 494-499. 10.1177/0272989X10388042.

  10. 10.

    Ghelani SJ, Spaeder MC, Pastor W, Spurney CF, Klugman D: Demographics, trends, and outcomes in pediatric acute myocarditis in the United States, 2006 to 2011. Circ Cardiovasc Qual Outcomes. 2012, 5: 622-627. 10.1161/CIRCOUTCOMES.112.965749.

  11. 11.

    Greenberg SB: Infections in the immunocompromised rheumatologic patient. Crit Care Clin. 2002, 18: 931-956. 10.1016/S0749-0704(02)00022-2.

  12. 12.

    Hayden F: Developing new antiviral agents for influenza treatment: what does the future hold?. Clin Infect Dis. 2009, 48 (Suppl 1): S3-S13.

  13. 13.

    De Clercq E: A Cutting-Edge View on the Current State of Antiviral Drug Development. Med Res Rev. 2013, [in press]

  14. 14.

    Furuta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, Gowen BB, Julander JG, Morrey JD: T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Res. 2009, 82: 95-102. 10.1016/j.antiviral.2009.02.198.

  15. 15.

    Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL: Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013, 100: 446-454. 10.1016/j.antiviral.2013.09.015.

  16. 16.

    Taber LH, Knight V, Gilbert BE, McClung HW, Wilson SZ, Norton HJ, Thurson JM, Gordon WH, Atmar RL, Schlaudt WR: Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics. 1983, 72: 613-618.

  17. 17.

    De Clercq E: Another ten stories in antiviral drug discovery (part C): "Old" and "new" antivirals, strategies, and perspectives. Med Res Rev. 2009, 29: 611-645. 10.1002/med.20153.

  18. 18.

    De Clercq E: The next ten stories on antiviral drug discovery (part E): advents, advances, and adventures. Med Res Rev. 2011, 31: 118-160. 10.1002/med.20179.

  19. 19.

    Esmonde TF, Herdman G, Anderson G: Chickenpox pneumonia: an association with pregnancy. Thorax. 1989, 44: 812-815. 10.1136/thx.44.10.812.

  20. 20.

    Hecht DW, Snydman DR, Crumpacker CS, Werner BG, Heinze-Lacey B: Ganciclovir for treatment of renal transplant-associated primary cytomegalovirus pneumonia. J Infect Dis. 1988, 157: 187-190. 10.1093/infdis/157.1.187.

  21. 21.

    Buckingham SC, Jafri HS, Bush AJ, Carubelli CM, Sheeran P, Hardy RD, Ottolini MG, Ramilo O, DeVincenzo JP: A randomized, double-blind, placebo-controlled trial of dexamethasone in severe respiratory syncytial virus (RSV) infection: effects on RSV quantity and clinical outcome. J Infect Dis. 2002, 185: 1222-1228. 10.1086/340024.

  22. 22.

    Gustafson LM, Proud D, Hendley JO, Hayden FG, Gwaltney JM: Oral prednisone therapy in experimental rhinovirus infections. J Allergy Clin Immunol. 1996, 97: 1009-1014. 10.1016/S0091-6749(96)80077-7.

  23. 23.

    Puhakka T, Makela MJ, Malmstrom K, Uhari M, Savolainen J, Terho EO, Pulkkinen M, Ruuskanen O: The common cold: effects of intranasal fluticasone propionate treatment. J Allergy Clin Immunol. 1998, 101: 726-731. 10.1016/S0091-6749(98)70301-X.

  24. 24.

    Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS: Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?. Lancet. 2002, 360: 1831-1837. 10.1016/S0140-6736(02)11772-7.

  25. 25.

    So LK, Lau AC, Yam LY, Cheung TM, Poon E, Yung RW, Yuen KY: Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet. 2003, 361: 1615-1617. 10.1016/S0140-6736(03)13265-5.

  26. 26.

    Mer M, Richards GA: Corticosteroids in life-threatening varicella pneumonia. Chest. 1998, 114: 426-431. 10.1378/chest.114.2.426.

  27. 27.

    Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, Liu R, Watt CL, Chan WM, Lai KY, Koo CK, Buckley T, Chow FL, Wong KK, Chan HS, Ching CK, Tang BS, Lau CC, Li IW, Liu SH, Chan KH, Lin CK, Yuen KY: Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011, 52: 447-456. 10.1093/cid/ciq106.

  28. 28.

    Hung IF, To KK, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CC, Liu SH, Chan KH, Lin CK, Yuen KY: Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013, 144: 464-473. 10.1378/chest.12-2907.

  29. 29.

    Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD: Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med. 1988, 109: 783-788. 10.7326/0003-4819-109-10-783.

  30. 30.

    Schmidt GM, Kovacs A, Zaia JA, Horak DA, Blume KG, Nademanee AP, O'Donnell MR, Snyder DS, Forman SJ: Ganciclovir/immunoglobulin combination therapy for the treatment of human cytomegalovirus-associated interstitial pneumonia in bone marrow allograft recipients. Transplantation. 1988, 46: 905-907. 10.1097/00007890-198812000-00022.

  31. 31.

    Hussey GD, Klein M: A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med. 1990, 323: 160-164. 10.1056/NEJM199007193230304.

  32. 32.

    Kramer AH: Viral encephalitis in the ICU. Crit Care Clin. 2013, 29: 621-649. 10.1016/j.ccc.2013.03.011.

  33. 33.

    Pyrgos V, Younus F: High-dose steroids in the management of acute flaccid paralysis due to West Nile virus infection. Scand J Infect Dis. 2004, 36: 509-512. 10.1080/00365540410020659.

  34. 34.

    Walid MS, Mahmoud FA: Successful treatment with intravenous immunoglobulin of acute flaccid paralysis caused by west nile virus. Perm J. 2009, 13: 43-46.

  35. 35.

    Braun LE, Tsuchida T, Spiegel H: Meningoencephalitis in a child complicated by myocarditis, quadriparesis and respiratory failure. Pediatr Infect Dis J. 2006, 25: 853-10.1097/01.inf.0000234058.31683.70. 855-856

  36. 36.

    Hruska JF, Bernstein JM, Douglas RG, Hall CB: Effects of ribavirin on respiratory syncytial virus in vitro. Antimicrob Agents Chemother. 1980, 17: 770-775. 10.1128/AAC.17.5.770.

  37. 37.

    Chen HS, Wang W, Wu SN, Liu JP: Corticosteroids for viral myocarditis. Cochrane Database Syst Rev. 2013, 10: CD004471-

  38. 38.

    Robinson JL, Hartling L, Crumley E, Vandermeer B, Klassen TP: A systematic review of intravenous gamma globulin for therapy of acute myocarditis. BMC Cardiovasc Disord. 2005, 5: 12-10.1186/1471-2261-5-12.

  39. 39.

    Dennert R, Velthuis S, Schalla S, Eurlings L, van Suylen RJ, van Paassen P, Tervaert JW, Wolffs P, Goossens VJ, Bruggeman C, Waltenberger J, Crijns HJ, Heymans S: Intravenous immunoglobulin therapy for patients with idiopathic cardiomyopathy and endomyocardial biopsy-proven high PVB19 viral load. Antivir Ther. 2010, 15: 193-201. 10.3851/IMP1516.

  40. 40.

    Wildenbeest JG, Wolthers KC, Straver B, Pajkrt D: Successful IVIG treatment of human parechovirus-associated dilated cardiomyopathy in an infant. Pediatrics. 2013, 132: e243-e247. 10.1542/peds.2012-1136.

  41. 41.

    Liu ZL, Liu ZJ, Liu JP, Kwong JS: Herbal medicines for viral myocarditis. Cochrane Database Syst Rev. 2013, 8: CD003711-

  42. 42.

    Enria DA, Maiztegui JI: Antiviral treatment of Argentine hemorrhagic fever. Antiviral Res. 1994, 23: 23-31. 10.1016/0166-3542(94)90030-2.

  43. 43.

    Jahrling PB, Frame JD, Rhoderick JB, Monson MH: Endemic Lassa fever in Liberia. IV. Selection of optimally effective plasma for treatment by passive immunization. Trans R Soc Trop Med Hyg. 1985, 79: 380-384. 10.1016/0035-9203(85)90388-8.

  44. 44.

    Huggins JW, Hsiang CM, Cosgriff TM, Guang MY, Smith JI, Wu ZO, LeDuc JW, Zheng ZM, Meegan JM, Wang QN: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis. 1991, 164: 1119-1127. 10.1093/infdis/164.6.1119.

  45. 45.

    Sautto G, Mancini N, Gorini G, Clementi M, Burioni R: Possible future monoclonal antibody (mAb)-based therapy against arbovirus infections. Biomed Res Int. 2013, 2013: 838491-

  46. 46.

    Gould EA, Buckley A, Barrett AD, Cammack N: Neutralizing (54 K) and non-neutralizing (54 K and 48 K) monoclonal antibodies against structural and non-structural yellow fever virus proteins confer immunity in mice. J Gen Virol. 1986, 67 (Pt 3): 591-595.

  47. 47.

    Ray D, Shi PY: Recent advances in flavivirus antiviral drug discovery and vaccine development. Recent Pat Antiinfect Drug Discov. 2006, 1: 45-55. 10.2174/157489106775244055.

  48. 48.

    Fisher-Hoch SP, Khan JA, Rehman S, Mirza S, Khurshid M, McCormick JB: Crimean Congo-haemorrhagic fever treated with oral ribavirin. Lancet. 1995, 346: 472-475. 10.1016/S0140-6736(95)91323-8.

  49. 49.

    McCormick JB, King IJ, Webb PA, Scribner CL, Craven RB, Johnson KM, Elliott LH, Belmont-Williams R: Lassa fever. Effective therapy with ribavirin. N Engl J Med. 1986, 314: 20-26. 10.1056/NEJM198601023140104.

  50. 50.

    De Clercq E: Yet another ten stories on antiviral drug discovery (part D): paradigms, paradoxes, and paraductions. Med Res Rev. 2010, 30: 667-707.

  51. 51.

    Moleta DB, Kakitani FT, Lima AS, Franca JC, Raboni SM: Acute pancreatitis associated with acute viral hepatitis: case report and review of literature. Rev Inst Med Trop Sao Paulo. 2009, 51: 349-351.

  52. 52.

    Alevritis EM, Sarubbi FA, Jordan RM, Peiris AN: Infectious causes of adrenal insufficiency. South Med J. 2003, 96: 888-890. 10.1097/01.SMJ.0000073269.49575.DF.

  53. 53.

    Ruuskanen O, Lahti E, Jennings LC, Murdoch DR: Viral pneumonia. Lancet. 2011, 377: 1264-1275. 10.1016/S0140-6736(10)61459-6.

  54. 54.

    Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, Cummings DA, Alabdullatif ZN, Assad M, Almulhim A, Makhdoom H, Madani H, Alhakeem R, Al-Tawfiq JA, Cotten M, Watson SJ, Kellam P, Zumla AI, Memish ZA: Hospital outbreak of Middle East respiratory syndrome corona virus. N Engl J Med. 2013, 369: 407-416. 10.1056/NEJMoa1306742.

  55. 55.

    Chan PK, Chan MC, Cheung JL, Lee N, Leung TF, Yeung AC, Wong MC, Ngai KL, Nelson EA, Hui DS: Influenza B lineage circulation and hospitalization rates in a subtropical city, Hong Kong, 2000-2010. Clin Infect Dis. 2013, 56: 677-684. 10.1093/cid/cis885.

  56. 56.

    Peiris JS, Yu WC, Leung CW, Cheung CY, Ng WF, Nicholls JM, Ng TK, Chan KH, Lai ST, Lim WL, Yuen KY, Guan Y: Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet. 2004, 363: 617-619. 10.1016/S0140-6736(04)15595-5.

  57. 57.

    Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, Ahuja A, Yung MY, Leung CB, To KF, Lui SF, Szeto CC, Chung S, Sung JJ: A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003, 348: 1986-1994. 10.1056/NEJMoa030685.

  58. 58.

    Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, Uyeki TM, Zaki SR, Hayden FG, Hui DS, Kettner JD, Kumar A, Lim M, Shindo N, Penn C, Nicholson KG: Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med. 2010, 362: 1708-1719.

  59. 59.

    Greenberg SB: Viral pneumonia. Infect Dis Clin North Am. 1991, 5: 603-621.

  60. 60.

    Rello J, Diaz E: Pneumonia in the intensive care unit. Crit Care Med. 2003, 31: 2544-2551. 10.1097/01.CCM.0000089928.84326.D2.

  61. 61.

    Moine P, Vercken JB, Chevret S, Chastang C, Gajdos P: Severe community-acquired pneumonia. Etiology, epidemiology, and prognosis factors. French Study Group for Community-Acquired Pneumonia in the Intensive Care Unit. Chest. 1994, 105: 1487-1495. 10.1378/chest.105.5.1487.

  62. 62.

    de Roux A, Marcos MA, Garcia E, Mensa J, Ewig S, Lode H, Torres A: Viral community-acquired pneumonia in nonimmunocompromised adults. Chest. 2004, 125: 1343-1351. 10.1378/chest.125.4.1343.

  63. 63.

    Diaz A, Barria P, Niederman M, Restrepo MI, Dreyse J, Fuentes G, Couble B, Saldias F: Etiology of community-acquired pneumonia in hospitalized patients in chile: the increasing prevalence of respiratory viruses among classic pathogens. Chest. 2007, 131: 779-787. 10.1378/chest.06-1800.

  64. 64.

    Woodhead M: Community-acquired pneumonia in Europe: causative pathogens and resistance patterns. Eur Respir J Suppl. 2002, 36: 20s-27s.

  65. 65.

    Jennings LC, Anderson TP, Beynon KA, Chua A, Laing RT, Werno AM, Young SA, Chambers ST, Murdoch DR: Incidence and characteristics of viral community-acquired pneumonia in adults. Thorax. 2008, 63: 42-48. 10.1136/thx.2006.075077.

  66. 66.

    Doyle JS, Buising KL, Thursky KA, Worth LJ, Richards MJ: Epidemiology of infections acquired in intensive care units. Semin Respir Crit Care Med. 2011, 32: 115-138. 10.1055/s-0031-1275525.

  67. 67.

    Chiche L, Forel JM, Papazian L: The role of viruses in nosocomial pneumonia. Curr Opin Infect Dis. 2011, 24: 152-156. 10.1097/QCO.0b013e328343b6e4.

  68. 68.

    Ramsey CD, Kumar A: Influenza and endemic viral pneumonia. Crit Care Clin. 2013, 29: 1069-1086. 10.1016/j.ccc.2013.06.003.

  69. 69.

    Ramsey C, Kumar A: H1N1: viral pneumonia as a cause of acute respiratory distress syndrome. Curr Opin Crit Care. 2011, 17: 64-71. 10.1097/MCC.0b013e3283427259.

  70. 70.

    Sprung CL, Zimmerman JL, Christian MD, Joynt GM, Hick JL, Taylor B, Richards GA, Sandrock C, Cohen R, Adini B: Recommendations for intensive care unit and hospital preparations for an influenza epidemic or mass disaster: summary report of the European Society of Intensive Care Medicine’s Task Force for intensive care unit triage during an influenza epidemic or mass disaster. Intensive Care Med. 2010, 36: 428-443. 10.1007/s00134-010-1759-y.

  71. 71.

    Osawa R, Singh N: Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care. 2009, 13: R68-10.1186/cc7875.

  72. 72.

    Luyt CE, Combes A, Nieszkowska A, Trouillet JL, Chastre J: Viral infections in the ICU. Curr Opin Crit Care. 2008, 14: 605-608. 10.1097/MCC.0b013e32830f1e12.

  73. 73.

    Johnstone J, Majumdar SR, Fox JD, Marrie TJ: Human metapneumovirus pneumonia in adults: results of a prospective study. Clin Infect Dis. 2008, 46: 571-574. 10.1086/526776.

  74. 74.

    Hall CB, Douglas RG, Geiman JM, Messner MK: Nosocomial respiratory syncytial virus infections. N Engl J Med. 1975, 293: 1343-1346. 10.1056/NEJM197512252932604.

  75. 75.

    Aitken C, Jeffries DJ: Nosocomial spread of viral disease. Clin Microbiol Rev. 2001, 14: 528-546. 10.1128/CMR.14.3.528-546.2001.

  76. 76.

    Horcajada JP, Pumarola T, Martinez JA, Tapias G, Bayas JM, de la Prada M, Garcia F, Codina C, Gatell JM, Jimenez de Anta MT: A nosocomial outbreak of influenza during a period without influenza epidemic activity. Eur Respir J. 2003, 21: 303-307. 10.1183/09031936.03.00040503.

  77. 77.

    Choi SH, Hong SB, Ko GB, Lee Y, Park HJ, Park SY, Moon SM, Cho OH, Park KH, Chong YP, Kim SH, Huh JW, Sung H, Do KH, Lee SO, Kim MN, Jeong JY, Lim CM, Kim YS, Woo JH, Koh Y: Viral infection in patients with severe pneumonia requiring intensive care unit admission. Am J Respir Crit Care Med. 2012, 186: 325-332. 10.1164/rccm.201112-2240OC.

  78. 78.

    Daubin C, Vincent S, Vabret A, du Cheyron D, Parienti JJ, Ramakers M, Freymuth F, Charbonneau P: Nosocomial viral ventilator-associated pneumonia in the intensive care unit: a prospective cohort study. Intensive Care Med. 2005, 31: 1116-1122. 10.1007/s00134-005-2706-1.

  79. 79.

    Anderson LJ: Major trends in nosocomial viral infections. Am J Med. 1991, 91: 107S-111S.

  80. 80.

    Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA: The sepsis seesaw: tilting toward immunosuppression. Nat Med. 2009, 15: 496-497. 10.1038/nm0509-496.

  81. 81.

    Hotchkiss RS, Monneret G, Payen D: Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013, 13: 260-268. 10.1016/S1473-3099(13)70001-X.

  82. 82.

    Papazian L, Fraisse A, Garbe L, Zandotti C, Thomas P, Saux P, Pierrin G, Gouin F: Cytomegalovirus. An unexpected cause of ventilator-associated pneumonia. Anesthesiology. 1996, 84: 280-287. 10.1097/00000542-199602000-00005.

  83. 83.

    Papazian L, Doddoli C, Chetaille B, Gernez Y, Thirion X, Roch A, Donati Y, Bonnety M, Zandotti C, Thomas P: A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients. Crit Care Med. 2007, 35: 755-762. 10.1097/01.CCM.0000257325.88144.30.

  84. 84.

    Raoult D, Audic S, Robert C, Abergel C, Renesto P, Ogata H, La SB, Suzan M, Claverie JM: The 1.2-megabase genome sequence of Mimivirus. Science. 2004, 306: 1344-1350. 10.1126/science.1101485.

  85. 85.

    Dare RK, Chittaganpitch M, Erdman DD: Screening pneumonia patients for mimivirus. Emerg Infect Dis. 2008, 14: 465-467. 10.3201/eid1403.071027.

  86. 86.

    Berger P, Papazian L, Drancourt M, La SB, Auffray JP, Raoult D: Ameba-associated microorganisms and diagnosis of nosocomial pneumonia. Emerg Infect Dis. 2006, 12: 248-255. 10.3201/eid1202.050434.

  87. 87.

    La SB, Marrie TJ, Auffray JP, Raoult D: Mimivirus in pneumonia patients. Emerg Infect Dis. 2005, 11: 449-452. 10.3201/eid1103.040538.

  88. 88.

    Raoult D, Renesto P, Brouqui P: Laboratory infection of a technician by mimivirus. Ann Intern Med. 2006, 144: 702-703. 10.7326/0003-4819-144-9-200605020-00023.

  89. 89.

    Oud L: Comment on: “Nosocomial viral ventilator-associated pneumonia in the intensive care unit” by Daubin et al. Intensive Care Med. 2006, 32: 613-615. 10.1007/s00134-005-0034-0.

  90. 90.

    Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E: Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med. 2007, 357: 1373-1381. 10.1056/NEJMoa070844.

  91. 91.

    Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM: Antiviral agents for the treatment and chemoprophylaxis of influenza –- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011, 60: 1-24.

  92. 92.

    Centers for Disease Control and Prevention: Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season. 2014, http://www.cdc.gov/H1N1flu/antiviral.htm. Accessed January 2014. Ref Type: Online Source

  93. 93.

    Aoki FY, Boivin G, Roberts N: Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther. 2007, 12: 603-616.

  94. 94.

    Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, Rode A, Kinnersley N, Ward P: Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000, 355: 1845-1850. 10.1016/S0140-6736(00)02288-1.

  95. 95.

    Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG: Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000, 283: 1016-1024. 10.1001/jama.283.8.1016.

  96. 96.

    Widmer N, Meylan P, Ivanyuk A, Aouri M, Decosterd LA, Buclin T: Oseltamivir in seasonal, avian H5N1 and pandemic A/H1N1 influenza: pharmacokinetic and pharmacodynamic characteristics. Clin Pharmacokinet. 2009, 2010 (49): 741-765.

  97. 97.

    Davies BE: Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J Antimicrob Chemother. 2010, 65 (Suppl 2): ii5-ii10.

  98. 98.

    Dutkowski R, Smith JR, Davies BE: Safety and pharmacokinetics of oseltamivir at standard and high dosages. Int J Antimicrob Agents. 2010, 35: 461-467. 10.1016/j.ijantimicag.2009.12.023.

  99. 99.

    Lee N, Ison MG: Diagnosis, management and outcomes of adults hospitalized with influenza. Antivir Ther. 2012, 17: 143-157. 10.3851/IMP2059.

  100. 100.

    Schunemann HJ, Hill SR, Kakad M, Bellamy R, Uyeki TM, Hayden FG, Yazdanpanah Y, Beigel J, Chotpitayasunondh T, Del Mar C, Farrar J, Tran TH, Ozbay B, Sugaya N, Fukuda K, Shindo N, Stockman L, Vist GE, Croisier A, Nagjdaliyev A, Roth C, Thomson G, Zucker H, Oxman AD: WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus. Lancet Infect Dis. 2007, 7: 21-31. 10.1016/S1473-3099(06)70684-3.

  101. 101.

    Lee N, Hui DS, Zuo Z, Ngai KL, Lui GC, Wo SK, Tam WW, Chan MC, Wong BC, Wong RY, Choi KW, Sin WW, Lee EL, Tomlinson B, Hayden FG, Chan PK: A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and B infections. Clin Infect Dis. 2013, 57: 1511-1519. 10.1093/cid/cit597.

  102. 102.

    Taylor WR, Thinh BN, Anh GT, Horby P, Wertheim H, Lindegardh N, de Jong MD, Stepniewska K, Hanh TT, Hien ND, Bien NM, Chau NQ, Fox A, Ngoc NM, Crusat M, Farrar JJ, White NJ, Ha NH, Lien TT, Trung NV, Day N, Binh NG: Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 influenza. PLoS One. 2008, 3: e3410-10.1371/journal.pone.0003410.

  103. 103.

    Nguyen HT, Fry AM, Gubareva LV: Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods. Antivir Ther. 2012, 17: 159-173. 10.3851/IMP2067.

  104. 104.

    McSharry JJ, Weng Q, Brown A, Kulawy R, Drusano GL: Prediction of the pharmacodynamically linked variable of oseltamivir carboxylate for influenza A virus using an in vitro hollow-fiber infection model system. Antimicrob Agents Chemother. 2009, 53: 2375-2381. 10.1128/AAC.00167-09.

  105. 105.

    Wang D, Sleeman K, Huang W, Nguyen HT, Levine M, Cheng Y, Li X, Tan M, Xing X, Xu X, Klimov AI, Gubareva LV, Shu Y: Neuraminidase inhibitor susceptibility testing of influenza type B viruses in China during 2010 and 2011 identifies viruses with reduced susceptibility to oseltamivir and zanamivir. Antiviral Res. 2013, 97: 240-244. 10.1016/j.antiviral.2012.12.013.

  106. 106.

    Garg S, Moore Z, Lee N, McKenna J, Bishop A, Fleischauer A, Springs CB, Nguyen HT, Sheu TG, Sleeman K, Finelli L, Gubareva L, Fry AM: A cluster of patients infected with I221V influenza b virus variants with reduced oseltamivir susceptibility--North Carolina and South Carolina, 2010-2011. J Infect Dis. 2013, 207: 966-973. 10.1093/infdis/jis776.

  107. 107.

    Lee N, Wong CK, Chan PK, Lindegardh N, White NJ, Hayden FG, Wong EH, Wong KS, Cockram CS, Sung JJ, Hui DS: Acute encephalopathy associated with influenza A infection in adults. Emerg Infect Dis. 2010, 16: 139-142. 10.3201/eid1601.090007.

  108. 108.

    Jhee SS, Yen M, Ereshefsky L, Leibowitz M, Schulte M, Kaeser B, Boak L, Patel A, Hoffmann G, Prinssen EP, Rayner CR: Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers. Antimicrob Agents Chemother. 2008, 52: 3687-3693. 10.1128/AAC.00327-08.

  109. 109.

    South East Asia Infectious Disease Clinical Research Network: Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ. 2013, 346: f3039-

  110. 110.

    Lee N, Chan PK, Wong CK, Wong KT, Choi KW, Joynt GM, Lam P, Chan MC, Wong BC, Lui GC, Sin WW, Wong RY, Lam WY, Yeung AC, Leung TF, So HY, Yu AW, Sung JJ, Hui DS: Viral clearance and inflammatory response patterns in adults hospitalized for pandemic 2009 influenza A(H1N1) virus pneumonia. Antivir Ther. 2011, 16: 237-247. 10.3851/IMP1722.

  111. 111.

    Centers for Disease Control and Prevention (CDC): Update: Recommendations for Middle East respiratory syndrome coronavirus (MERS-CoV). MMWR Morb Mortal Wkly Rep. 2013, 62: 557-

  112. 112.

    Centers for Disease Control and Prevention (CDC): Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients - Seattle, Washington, 2009. MMWR Morb Mortal Wkly Rep. 2009, 58: 893-896.

  113. 113.

    De Clercq E: Antivirals: past, present and future. Biochem Pharmacol. 2013, 85: 727-744. 10.1016/j.bcp.2012.12.011.

  114. 114.

    Malakhov MP, Aschenbrenner LM, Smee DF, Wandersee MK, Sidwell RW, Gubareva LV, Mishin VP, Hayden FG, Kim DH, Ing A, Campbell ER, Yu M, Fang F: Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection. Antimicrob Agents Chemother. 2006, 50: 1470-1479. 10.1128/AAC.50.4.1470-1479.2006.

  115. 115.

    Smee DF, Hurst BL, Wong MH: Effects of TheraMax on influenza virus infections in cell culture and in mice. Antivir Chem Chemother. 2011, 21: 231-237. 10.3851/IMP1744.

  116. 116.

    Smee DF, Bailey KW, Wong MH, O'Keefe BR, Gustafson KR, Mishin VP, Gubareva LV: Treatment of influenza A (H1N1) virus infections in mice and ferrets with cyanovirin-N. Antiviral Res. 2008, 80: 266-271. 10.1016/j.antiviral.2008.06.003.

  117. 117.

    Selvam P, Murugesh N, Chandramohan M, Sidwell RW, Wandersee MK, Smee DF: Anti-influenza virus activities of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)amino]-N-(4,6-dimethyl-2-pyrimidin-2-yl) benzenesulphonamide and its derivatives. Antivir Chem Chemother. 2006, 17: 269-274.

  118. 118.

    Ubillas R, Jolad SD, Bruening RC, Kernan MR, King SR, Sesin DF, Barrett M, Stoddart CA, Flaster T, Kuo J, Ayala F, Meza E, Castanel M, McMeekin D, Rozhon E, Tempesta MS, Barnard D, Huffman J, Smee D, Sidwell R, Soike K, Brazier A, Safrin S, Orlando R, Kenny PT, Berova N, Nakanishi K: SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de Drago). Phytomedicine. 1994, 1: 77-106. 10.1016/S0944-7113(11)80026-7.

  119. 119.

    Shigeta S, Mori S, Kodama E, Kodama J, Takahashi K, Yamase T: Broad spectrum anti-RNA virus activities of titanium and vanadium substituted polyoxotungstates. Antiviral Res. 2003, 58: 265-271. 10.1016/S0166-3542(03)00009-3.

  120. 120.

    Shigeta S, Mori S, Yamase T, Yamamoto N, Yamamoto N: Anti-RNA virus activity of polyoxometalates. Biomed Pharmacother. 2006, 60: 211-219. 10.1016/j.biopha.2006.03.009.

  121. 121.

    Ono L, Wollinger W, Rocco IM, Coimbra TL, Gorin PA, Sierakowski MR: In vitro and in vivo antiviral properties of sulfated galactomannans against yellow fever virus (BeH111 strain) and dengue 1 virus (Hawaii strain). Antiviral Res. 2003, 60: 201-208. 10.1016/S0166-3542(03)00175-X.

  122. 122.

    Krajczyk A, Kulinska K, Kulinski T, Hurst BL, Day CW, Smee DF, Ostrowski T, Januszczyk P, Zeidler J: Antivirally active ribavirin analogues - 4,5-disubstituted 1,2,3-triazole nucleosides: biological evaluation against certain respiratory viruses and computational modelling. Antivir Chem Chemother. 2014, 23: 161-171.

  123. 123.

    Sidwell RW, Bailey KW, Wong MH, Barnard DL, Smee DF: In vitro and in vivo influenza virus-inhibitory effects of viramidine. Antiviral Res. 2005, 68: 10-17. 10.1016/j.antiviral.2005.06.003.

  124. 124.

    Smee DF, Wandersee MK, Wong MH, Bailey KW, Sidwell RW: Treatment of mannan-enhanced influenza B virus infections in mice with oseltamivir, ribavirin and viramidine. Antivir Chem Chemother. 2004, 15: 261-268.

  125. 125.

    Gilbert BE, Wilson SZ, Knight V, Couch RB, Quarles JM, Dure L, Hayes N, Willis G: Ribavirin small-particle aerosol treatment of infections caused by influenza virus strains A/Victoria/7/83 (H1N1) and B/Texas/1/84. Antimicrob Agents Chemother. 1985, 27: 309-313. 10.1128/AAC.27.3.309.

  126. 126.

    Huggins J, Zhang ZX, Bray M: Antiviral drug therapy of filovirus infections: S-adenosylhomocysteine hydrolase inhibitors inhibit Ebola virus in vitro and in a lethal mouse model. J Infect Dis. 1999, 179 (Suppl 1): S240-S247.

  127. 127.

    Tam RC, Lau JY, Hong Z: Mechanisms of action of ribavirin in antiviral therapies. Antivir Chem Chemother. 2001, 12: 261-272.

  128. 128.

    Sookoian S, Castano G, Flichman D, Cello J: Effects of ribavirin on cytokine production of recall antigens and phytohemaglutinin-stimulated peripheral blood mononuclear cells. (Inhibitory effects of ribavirin on cytokine production). Ann Hepatol. 2004, 3: 104-107.

  129. 129.

    Kumaki Y, Day CW, Smee DF, Morrey JD, Barnard DL: In vitro and in vivo efficacy of fluorodeoxycytidine analogs against highly pathogenic avian influenza H5N1, seasonal, and pandemic H1N1 virus infections. Antiviral Res. 2011, 92: 329-340. 10.1016/j.antiviral.2011.09.001.

  130. 130.

    Smee DF, Hurst BL, Day CW: D282, a non-nucleoside inhibitor of influenza virus infection that interferes with de novo pyrimidine biosynthesis. Antivir Chem Chemother. 2012, 22: 263-272. 10.3851/IMP2105.

  131. 131.

    Wunderlich K, Juozapaitis M, Ranadheera C, Kessler U, Martin A, Eisel J, Beutling U, Frank R, Schwemmle M: Identification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase. Antimicrob Agents Chemother. 2011, 55: 696-702. 10.1128/AAC.01419-10.

  132. 132.

    Manz B, Gotz V, Wunderlich K, Eisel J, Kirchmair J, Stech J, Chase G, Frank R, Schwemmle M: Disruption of the viral polymerase complex assembly as a novel approach to attenuate influenza A virus. J Biol Chem. 2011, 286: 8414-8424. 10.1074/jbc.M110.205534.

  133. 133.

    Gerritz SW, Cianci C, Kim S, Pearce BC, Deminie C, Discotto L, McAuliffe B, Minassian BF, Shi S, Zhu S, Zhai W, Pendri A, Li G, Poss MA, Edavettal S, McDonnell PA, Lewis HA, Maskos K, Mortl M, Kiefersauer R, Steinbacher S, Baldwin ET, Metzler W, Bryson J, Healy MD, Philip T, Zoeckler M, Schartman R, Sinz M, Leyva-Grado VH, et al: Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers. Proc Natl Acad Sci U S A. 2011, 108: 15366-15371. 10.1073/pnas.1107906108.

  134. 134.

    Kao RY, Yang D, Lau LS, Tsui WH, Hu L, Dai J, Chan MP, Chan CM, Wang P, Zheng BJ, Sun J, Huang JD, Madar J, Chen G, Chen H, Guan Y, Yuen KY: Identification of influenza A nucleoprotein as an antiviral target. Nat Biotechnol. 2010, 28: 600-605. 10.1038/nbt.1638.

  135. 135.

    McCown M, Diamond MS, Pekosz A: The utility of siRNA transcripts produced by RNA polymerase i in down regulating viral gene expression and replication of negative- and positive-strand RNA viruses. Virology. 2003, 313: 514-524. 10.1016/S0042-6822(03)00341-6.

  136. 136.

    Barik S: siRNA for Influenza Therapy. Viruses. 2010, 2: 1448-1457. 10.3390/v2071448.

  137. 137.

    Truong NP, Gu W, Prasadam I, Jia Z, Crawford R, Xiao Y, Monteiro MJ: An influenza virus-inspired polymer system for the timed release of siRNA. Nat Commun. 2013, 4: 1902-

  138. 138.

    Mollaie HR, Monavari SH, Arabzadeh SA, Shamsi-Shahrabadi M, Fazlalipour M, Afshar RM: RNAi and miRNA in Viral Infections and Cancers. Asian Pac J Cancer Prev. 2013, 14: 7045-7056. 10.7314/APJCP.2013.14.12.7045.

  139. 139.

    Rossignol JF, La FS, Chiappa L, Ciucci A, Santoro MG: Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem. 2009, 284: 29798-29808. 10.1074/jbc.M109.029470.

  140. 140.

    Maddry JA, Chen X, Jonsson CB, Ananthan S, Hobrath J, Smee DF, Noah JW, Noah D, Xu X, Jia F, Maddox C, Sosa MI, White EL, Severson WE: Discovery of novel benzoquinazolinones and thiazoloimidazoles, inhibitors of influenza H5N1 and H1N1 viruses, from a cell-based high-throughput screen. J Biomol Screen. 2011, 16: 73-81. 10.1177/1087057110384613.

  141. 141.

    Rao JR, Jha AK, Rawal RK, Sharon A, Day CW, Barnard DL, Smee DF, Chu CK: (-)-Carbodine: enantiomeric synthesis and in vitro antiviral activity against various strains of influenza virus including H5N1 (avian influenza) and novel 2009 H1N1 (swine flu). Bioorg Med Chem Lett. 2009, 2010 (20): 2601-2604.

  142. 142.

    Selvam P, Chandramohan M, Hurst BL, Smee DF: Activity of isatine-sulfadimidine derivatives against 2009 pandemic H1N1 influenza virus in cell culture. Antivir Chem Chemother. 2010, 20: 143-146. 10.3851/IMP1471.

  143. 143.

    Selvam P, Vijayalakshimi P, Smee DF, Gowen BB, Julander JG, Day CW, Barnard DL: Novel 3-sulphonamido-quinazolin-4(3H)-one derivatives: microwave-assisted synthesis and evaluation of antiviral activities against respiratory and biodefense viruses. Antivir Chem Chemother. 2007, 18: 301-305.

  144. 144.

    Smee DF, McKernan PA, Nord LD, Willis RC, Petrie CR, Riley TM, Revankar GR, Robins RK, Smith RA: Novel pyrazolo[3,4-d]pyrimidine nucleoside analog with broad-spectrum antiviral activity. Antimicrob Agents Chemother. 1987, 31: 1535-1541. 10.1128/AAC.31.10.1535.

  145. 145.

    Lai KY, Ng WY, Osburga Chan PK, Wong KF, Cheng F: High-dose N-acetylcysteine therapy for novel H1N1 influenza pneumonia. Ann Intern Med. 2010, 152: 687-688. 10.7326/0003-4819-152-10-201005180-00017.

  146. 146.

    Garozzo A, Tempera G, Ungheri D, Timpanaro R, Castro A: N-acetylcysteine synergizes with oseltamivir in protecting mice from lethal influenza infection. Int J Immunopathol Pharmacol. 2007, 20: 349-354.

  147. 147.

    Mata M, Morcillo E, Gimeno C, Cortijo J: N-acetyl-L-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV). Biochem Pharmacol. 2011, 82: 548-555. 10.1016/j.bcp.2011.05.014.

  148. 148.

    Geiler J, Michaelis M, Naczk P, Leutz A, Langer K, Doerr HW, Cinatl J: N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem Pharmacol. 2010, 79: 413-420. 10.1016/j.bcp.2009.08.025.

  149. 149.

    Murray JL, McDonald NJ, Sheng J, Shaw MW, Hodge TW, Rubin DH, O’Brien WA, Smee DF: Inhibition of influenza A virus replication by antagonism of a PI3K-AKT-mTOR pathway member identified by gene-trap insertional mutagenesis. Antivir Chem Chemother. 2012, 22: 205-215. 10.3851/IMP2080.

  150. 150.

    Takeda S, Munakata R, Abe S, Mii S, Suzuki M, Kashiwada T, Azuma A, Yamamoto T, Gemma A, Tanaka K: Hypercytokinemia with 2009 pandemic H1N1 (pH1N1) influenza successfully treated with polymyxin B-immobilized fiber column hemoperfusion. Intensive Care Med. 2010, 36: 906-907. 10.1007/s00134-010-1830-8.

  151. 151.

    Patel P, Nandwani V, Vanchiere J, Conrad SA, Scott LK: Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 influenza A--an associated respiratory failure and hemodynamic shock. Pediatr Crit Care Med. 2011, 12: e87-e89. 10.1097/PCC.0b013e3181e2a569.

  152. 152.

    Chong JL, Sapari S, Kuan YC: A case of acute respiratory distress syndrome associated with novel H1N1 treated with intravenous immunoglobulin G. J Microbiol Immunol Infect. 2011, 44: 319-322. 10.1016/j.jmii.2010.07.001.

  153. 153.

    Kubota-Koketsu R, Yunoki M, Okuno Y, Ikuta K: Significant neutralizing activities against H2N2 influenza A viruses in human intravenous immunoglobulin lots manufactured from 1993 to 2010. Biologics. 2012, 6: 245-247.

  154. 154.

    Nath A, Tyler KL: Novel approaches and challenges to treatment of central nervous system viral infections. Ann Neurol. 2013, 74: 412-422.

  155. 155.

    Yasuda S, Huffman JH, Smee DF, Sidwell RW, Miyata K: Spectrum of virus inhibition by consensus interferon YM643. Antivir Chem Chemother. 2000, 11: 337-341.

  156. 156.

    Morales DJ, Lenschow DJ: The antiviral activities of ISG15. J Mol Biol. 2013, 425: 4995-5008. 10.1016/j.jmb.2013.09.041.

  157. 157.

    Radigan KA, Urich D, Misharin AV, Chiarella SE, Soberanes S, Gonzalez A, Perlman H, Wunderink RG, Budinger GR, Mutlu GM: The effect of rosuvastatin in a murine model of influenza A infection. PLoS One. 2012, 7: e35788-10.1371/journal.pone.0035788.

  158. 158.

    Kumaki Y, Morrey JD, Barnard DL: Effect of statin treatments on highly pathogenic avian influenza H5N1, seasonal and H1N1pdm09 virus infections in BALB/c mice. Future Virol. 2012, 7: 801-818. 10.2217/fvl.12.71.

  159. 159.

    Kwong JC, Li P, Redelmeier DA: Influenza morbidity and mortality in elderly patients receiving statins: a cohort study. PLoS One. 2009, 4: e8087-10.1371/journal.pone.0008087.

  160. 160.

    Makris D, Manoulakas E, Komnos A, Papakrivou E, Tzovaras N, Hovas A, Zintzaras E, Zakynthinos E: Effect of pravastatin on the frequency of ventilator-associated pneumonia and on intensive care unit mortality: open-label, randomized study. Crit Care Med. 2011, 39: 2440-2446. 10.1097/CCM.0b013e318225742c.

  161. 161.

    Yamaya M, Shinya K, Hatachi Y, Kubo H, Asada M, Yasuda H, Nishimura H, Nagatomi R: Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells. J Pharmacol Exp Ther. 2010, 333: 81-90. 10.1124/jpet.109.162149.

  162. 162.

    Viasus D, Pano-Pardo JR, Cordero E, Campins A, Lopez-Medrano F, Villoslada A, Farinas MC, Moreno A, Rodriguez-Bano J, Oteo JA, Martinez-Montauti J, Torre-Cisneros J, Segura F, Carratala J: Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia. J Infect. 2011, 62: 193-199. 10.1016/j.jinf.2011.01.014.

  163. 163.

    Martin-Loeches I, Bermejo-Martin JF, Valles J, Granada R, Vidaur L, Vergara-Serrano JC, Martin M, Figueira JC, Sirvent JM, Blanquer J, Suarez D, Artigas A, Torres A, Diaz E, Rodriguez A: Macrolide-based regimens in absence of bacterial co-infection in critically ill H1N1 patients with primary viral pneumonia. Intensive Care Med. 2013, 39: 693-702. 10.1007/s00134-013-2829-8.

  164. 164.

    Ishii H, Komiya K, Yamagata E, Yatera K, Chojin Y, Yamamoto H, Mukae H, Kadota J: Clarithromycin has limited effects in non-elderly, non-severe patients with seasonal influenza virus A infection. J Infect. 2012, 64: 343-345. 10.1016/j.jinf.2011.12.002.

  165. 165.

    Budd A, Alleva L, Alsharifi M, Koskinen A, Smythe V, Mullbacher A, Wood J, Clark I: Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrob Agents Chemother. 2007, 51: 2965-2968. 10.1128/AAC.00219-07.

  166. 166.

    Bauer CM, Zavitz CC, Botelho FM, Lambert KN, Brown EG, Mossman KL, Taylor JD, Stampfli MR: Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. PLoS One. 2010, 5: e13251-10.1371/journal.pone.0013251.

  167. 167.

    Aldridge JR, Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, Brown SA, Doherty PC, Webster RG, Thomas PG: TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci U S A. 2009, 106: 5306-5311. 10.1073/pnas.0900655106.

  168. 168.

    Pitocco D, Giubilato S, Zaccardi F, Di SE, Buffon A, Biasucci LM, Liuzzo G, Crea F, Ghirlanda G: Pioglitazone reduces monocyte activation in type 2 diabetes. Acta Diabetol. 2009, 46: 75-77. 10.1007/s00592-008-0058-3.

  169. 169.

    Moseley CE, Webster RG, Aldridge JR: Peroxisome proliferator-activated receptor and AMP-activated protein kinase agonists protect against lethal influenza virus challenge in mice. Influenza Other Respir Vir. 2010, 4: 307-311. 10.1111/j.1750-2659.2010.00155.x.

  170. 170.

    Carey MA, Bradbury JA, Seubert JM, Langenbach R, Zeldin DC, Germolec DR: Contrasting effects of cyclooxygenase-1 (COX-1) and COX-2 deficiency on the host response to influenza A viral infection. J Immunol. 2005, 175: 6878-6884. 10.4049/jimmunol.175.10.6878.

  171. 171.

    Carey MA, Bradbury JA, Rebolloso YD, Graves JP, Zeldin DC, Germolec DR: Pharmacologic inhibition of COX-1 and COX-2 in influenza A viral infection in mice. PLoS One. 2010, 5: e11610-10.1371/journal.pone.0011610.

  172. 172.

    Lee SM, Gai WW, Cheung TK, Peiris JS: Antiviral effect of a selective COX-2 inhibitor on H5N1 infection in vitro. Antiviral Res. 2011, 91: 330-334. 10.1016/j.antiviral.2011.07.011.

  173. 173.

    Lee SM, Gai WW, Cheung TK, Peiris JS: Antiviral activity of a selective COX-2 inhibitor NS-398 on avian influenza H5N1 infection. Influenza Other Respir Vir. 2011, 5 (Suppl 1): 230-232.

  174. 174.

    Zheng BJ, Chan KW, Lin YP, Zhao GY, Chan C, Zhang HJ, Chen HL, Wong SS, Lau SK, Woo PC, Chan KH, Jin DY, Yuen KY: Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci U S A. 2008, 105: 8091-8096. 10.1073/pnas.0711942105.

  175. 175.

    Aspord C, Laurin D, Richard MJ, Vie H, Chaperot L, Plumas J: Induction of antiviral cytotoxic T cells by plasmacytoid dendritic cells for adoptive immunotherapy of posttransplant diseases. Am J Transplant. 2011, 11: 2613-2626. 10.1111/j.1600-6143.2011.03722.x.

  176. 176.

    Wu CC, Hayashi T, Takabayashi K, Sabet M, Smee DF, Guiney DD, Cottam HB, Carson DA: Immunotherapeutic activity of a conjugate of a Toll-like receptor 7 ligand. Proc Natl Acad Sci U S A. 2007, 104: 3990-3995. 10.1073/pnas.0611624104.

  177. 177.

    Sidwell RW, Smee DF, Huffman JH, Bailey KW, Warren RP, Burger RA, Penney CL: Antiviral activity of an immunomodulatory lipophilic desmuramyl dipeptide analog. Antiviral Res. 1995, 26: 145-159. 10.1016/0166-3542(94)00072-G.

  178. 178.

    Hayden FG, Douglas RG, Simons R: Enhancement of activity against influenza viruses by combinations of antiviral agents. Antimicrob Agents Chemother. 1980, 18: 536-541. 10.1128/AAC.18.4.536.

  179. 179.

    Wilson SZ, Knight V, Wyde PR, Drake S, Couch RB: Amantadine and ribavirin aerosol treatment of influenza A and B infection in mice. Antimicrob Agents Chemother. 1980, 17: 642-648. 10.1128/AAC.17.4.642.

  180. 180.

    Galegov GA, Pushkarskaya NL, Obrosova-Serova NP, Zhdanov VM: Combined action of ribovirin and rimantadine in experimental myxovirus infection. Experientia. 1977, 33: 905-906. 10.1007/BF01951273.

  181. 181.

    Bantia S, Kellogg D, Parker CD, Babu YS: Combination of peramivir and rimantadine demonstrate synergistic antiviral effects in sub-lethal influenza A (H3N2) virus mouse model. Antiviral Res. 2010, 88: 276-280. 10.1016/j.antiviral.2010.09.020.

  182. 182.

    Govorkova EA, Fang HB, Tan M, Webster RG: Neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in MDCK cells. Antimicrob Agents Chemother. 2004, 48: 4855-4863. 10.1128/AAC.48.12.4855-4863.2004.

  183. 183.

    Ilyushina NA, Hoffmann E, Salomon R, Webster RG, Govorkova EA: Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice. Antivir Ther. 2007, 12: 363-370.

  184. 184.

    Smee DF, Wong MH, Bailey KW, Sidwell RW: Activities of oseltamivir and ribavirin used alone and in combination against infections in mice with recent isolates of influenza A (H1N1) and B viruses. Antivir Chem Chemother. 2006, 17: 185-192.

  185. 185.

    Ilyushina NA, Hay A, Yilmaz N, Boon AC, Webster RG, Govorkova EA: Oseltamivir-ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice. Antimicrob Agents Chemother. 2008, 52: 3889-3897. 10.1128/AAC.01579-07.

  186. 186.

    Smee DF, Bailey KW, Morrison AC, Sidwell RW: Combination treatment of influenza A virus infections in cell culture and in mice with the cyclopentane neuraminidase inhibitor RWJ-270201 and ribavirin. Chemotherapy. 2002, 48: 88-93. 10.1159/000057668.

  187. 187.

    Smee DF, Hurst BL, Wong MH, Tarbet EB, Babu YS, Klumpp K, Morrey JD: Combinations of oseltamivir and peramivir for the treatment of influenza A (H1N1) virus infections in cell culture and in mice. Antiviral Res. 2010, 88: 38-44. 10.1016/j.antiviral.2010.07.003.

  188. 188.

    Duval X, van der Werf S, Blanchon T, Mosnier A, Bouscambert-Duchamp M, Tibi A, Enouf V, Charlois-Ou C, Vincent C, Andreoletti L, Tubach F, Lina B, Mentre F, Leport C: Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS Med. 2010, 7: e1000362-10.1371/journal.pmed.1000362.

  189. 189.

    Hoopes JD, Driebe EM, Kelley E, Engelthaler DM, Keim PS, Perelson AS, Rong L, Went GT, Nguyen JT: Triple combination antiviral drug (TCAD) composed of amantadine, oseltamivir, and ribavirin impedes the selection of drug-resistant influenza A virus. PLoS One. 2011, 6: e29778-10.1371/journal.pone.0029778.

  190. 190.

    Nguyen JT, Smee DF, Barnard DL, Julander JG, Gross M, de Jong MD, Went GT: Efficacy of combined therapy with amantadine, oseltamivir, and ribavirin in vivo against susceptible and amantadine-resistant influenza A viruses. PLoS One. 2012, 7: e31006-10.1371/journal.pone.0031006.

  191. 191.

    Nguyen JT, Hoopes JD, Le MH, Smee DF, Patick AK, Faix DJ, Blair PJ, de Jong MD, Prichard MN, Went GT: Triple combination of amantadine, ribavirin, and oseltamivir is highly active and synergistic against drug resistant influenza virus strains in vitro. PLoS One. 2010, 5: e9332-10.1371/journal.pone.0009332.

  192. 192.

    Nguyen JT, Hoopes JD, Smee DF, Prichard MN, Driebe EM, Engelthaler DM, Le MH, Keim PS, Spence RP, Went GT: Triple combination of oseltamivir, amantadine, and ribavirin displays synergistic activity against multiple influenza virus strains in vitro. Antimicrob Agents Chemother. 2009, 53: 4115-4126. 10.1128/AAC.00476-09.

  193. 193.

    Tarbet EB, Vollmer AH, Hurst BL, Barnard DL, Furuta Y, Smee DF: In vitro activity of favipiravir and neuraminidase inhibitor combinations against oseltamivir-sensitive and oseltamivir-resistant pandemic influenza A (H1N1) virus. Arch Virol. 2014, 159 (6): 1279-1291. 10.1007/s00705-013-1922-1.

  194. 194.

    Tarbet EB, Maekawa M, Furuta Y, Babu YS, Morrey JD, Smee DF: Combinations of favipiravir and peramivir for the treatment of pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Antiviral Res. 2012, 94: 103-110. 10.1016/j.antiviral.2012.03.001.

  195. 195.

    Smee DF, Hurst BL, Wong MH, Bailey KW, Tarbet EB, Morrey JD, Furuta Y: Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice. Antimicrob Agents Chemother. 2010, 54: 126-133. 10.1128/AAC.00933-09.

  196. 196.

    Smee DF, von Itzstein M, Bhatt B, Tarbet EB: Exacerbation of influenza virus infections in mice by intranasal treatments and implications for evaluation of antiviral drugs. Antimicrob Agents Chemother. 2012, 56: 6328-6333. 10.1128/AAC.01664-12.

  197. 197.

    Lat A, Bhadelia N, Miko B, Furuya EY, Thompson GR: Invasive aspergillosis after pandemic (H1N1) 2009. Emerg Infect Dis. 2010, 16: 971-973. 10.3201/eid1606.100165.

  198. 198.

    Zhou B, Zhong N, Guan Y: Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med. 2007, 357: 1450-1451. 10.1056/NEJMc070359.

  199. 199.

    Liu P, Martino T, Opavsky MA, Penninger J: Viral myocarditis: balance between viral infection and immune response. Can J Cardiol. 1996, 12: 935-943.

  200. 200.

    De Clercq E: Antiviral drug discovery: ten more compounds, and ten more stories (part B). Med Res Rev. 2009, 29: 571-610. 10.1002/med.20149.

  201. 201.

    Warren TK, Warfield KL, Wells J, Enterlein S, Smith M, Ruthel G, Yunus AS, Kinch MS, Goldblatt M, Aman MJ, Bavari S: Antiviral activity of a small-molecule inhibitor of filovirus infection. Antimicrob Agents Chemother. 2010, 54: 2152-2159. 10.1128/AAC.01315-09.

  202. 202.

    Cote M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J: Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011, 477: 344-348. 10.1038/nature10380.

  203. 203.

    Tomlinson B, Cockram C: SARS: experience at Prince of Wales Hospital, Hong Kong. Lancet. 2003, 361: 1486-1487. 10.1016/S0140-6736(03)13218-7.

  204. 204.

    Seto WH, Tsang D, Yung RW, Ching TY, Ng TK, Ho M, Ho LM, Peiris JS: Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS). Lancet. 2003, 361: 1519-1520. 10.1016/S0140-6736(03)13168-6.

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Correspondence to Sotirios Tsiodras.

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Competing interests

The authors report no competing interests. ST is a principal investigator in a multinational, multicenter clinical study evaluating zanamivir vs oseltamivir, sponsored by GSK.

Authors’ contributions

TK and ST conceived and designed the paper and wrote the first draft. TK, IM, AM and ST reviewed the available literature and summarized the data in table formats. All authors have read, critically revised the different versions and approved the final submitted version of the manuscript.

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Keywords

  • Influenza
  • Herpes Simplex Virus
  • Avian Influenza
  • Oseltamivir
  • Zanamivir