With the appearance of the novel influenza A (H1N1) virus 2009 strain we have recently experienced a new influenza pandemic [1
]. The clinical spectrum of pandemic influenza A (H1N1) virus infection was broad, ranging from mild upper respiratory tract illness with or without fever and occasional gastrointestinal symptoms such as vomiting or diarrhea and exacerbation of underlying conditions, to severe complications such as pneumonia resulting in respiratory failure, acute respiratory distress syndrome, multi-organ failure and even death [3
]. Many patients died from severe complications associated with the pandemic influenza A (H1N1) virus infection despite receiving intensive care [3
], and as of the 25th
of July 2010, 18,398 laboratory-confirmed fatal cases of pandemic influenza A (H1N1) have been reported to the World Health Organization [5
]. The influenza A (H1N1) virus human infections event has now moved into a post-pandemic period, with a pattern that has been transitioning towards that of seasonal influenza [6
]. Beside the influenza A (H1N1) pandemic the global burden of seasonal influenza epidemics is believed to be some 3-5 million cases of severe illness and 300,000–500,000 deaths every year [7
]. Additionally, we still face the threat of infection with the highly pathogenic avian influenza A (H5N1) virus.
Three classes of anti-influenza drugs have been used for chemoprophylaxis and treatment of influenza virus infections [8
] (Figure 1
): amantadine (1
) and rimantadine (2
) which inhibit viral membrane protein (M2) of the proton channel that is necessary for uncoating; oseltamivir (3
), zanamivir (4
), peramivir (5
) and laninamivir octanoate (6
) which inhibit viral neuraminidase (NA) that is necessary for virion release and ribavirin (7
) that inhibits enzyme activity essential for viral replication. Initial diagnostic testing found that the pandemic influenza A (H1N1) virus was susceptible to NA inhibitors, but resistant to M2 inhibitors [9
], therefore, oseltamivir has been used widely for treatment and chemoprophylaxis of pandemic influenza A (H1N1) [2
]. Sporadic cases of oseltamivir-resistant pandemic influenza A (H1N1) virus have been reported worldwide [10
]. This oseltamivir resistance was caused by the NA mutation H275Y [10
]. Person-to-person transmission of oseltamivir-resistant viruses in healthy adults has been confirmed [11
]. In cases of development of oseltamivir-resistance, treatment options are limited because zanamivir is not licensed for treatment of children under 7 years old and is contraindicated in persons with underlying airway disease. Recently, it has been reported that a single inhalation of laninamivir octanoate was an effective and well-tolerated drug for the treatment of children with oseltamivir-resistant influenza A (H1N1) virus infection [12
]. Additionally, intravenous drip infusion of peramivir has offered a new treatment option for children and infants suffering from influenza virus infections and patients where oral administration was difficult or not possible [13
]. It was also effective for severe influenza-associated complications, such as acute respiratory failure [14
]. Nonetheless, NA inhibitor-resistant viruses with H275Y mutation emerged early and replicated in patients, who have received hematopoietic cell transplant, under treatment with immunosuppressive drugs after intravenous drip infusion of peramivir [15
]. A young adult with pandemic influenza A (H1N1) virus infection was treated with intravenous peramivir, but died from severe viral pneumonia [16
]. These results suggest the need for development of new anti-influenza drugs utilizing alternative antiviral mechanisms and consideration of using anti-influenza drug combinations. Some such approaches have been explored, whereby a triple combination of amantadine, ribavirin and oseltamivir was highly active and synergistic against drug resistant influenza virus strains in vitro
In cases of severe influenza-associated complications, the pathological manifestations are the result of complex biological phenomena, such as apoptosis induction, macrophage activation, oxidative tissue damage and higher contents of pro-inflammatory cytokines [18
]. The pathogenesis of severe influenza-associated complications involves not only apoptotic cell death mediated through virus replication in the infected cells, but also the injury of non-infected cells by superoxide anion derived from activated phagocytes (i.e.
, macrophages and neutrophils) infiltrated into the virus-infected organs [19
]. As illustrated in Figure 2
], host cells secrete cysteine-cysteine (C-C) chemokines that primarily target monocytes [e.g., monocyte chemoattractant protein (MCP)-1, regulated on activation, normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein (MIP)-1α/β) and monocyte differentiation-inducing (MDI) factor (i.e.
, interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon (IFN)-β] in response to influenza virus replication prior to undergoing apoptotic cell degradation. The C-C chemokines act on immature monocytes circulating in the bloodstream, recruiting them to the site of infection. The MDI factor acts on the recruited monocytes, resulting in differentiation into well-matured macrophages capable of phagocytosing and producing superoxide anion. The activated macrophages move to the virus- infected host cell and phagocytose apoptotic cell debris resulting from the viral infection. An abrupt increase in superoxide anion production occurs during phagocytosis. This superoxide anion induces injuries in non-infected cells. These superoxide anion-mediated pathways represent a part of the mechanisms of extensive tissue injury observed during severe influenza-associated complications [20
], therefore, it has been suggested that an agent with antiviral and antioxidant activities could be a drug of choice for the treatment of patients with such severe complications [21
]. This review article updates knowledge of antioxidant therapy as a potential approach to these severe influenza-associated complications.
Scavenging of superoxide is an important tool in the development of new strategies for the prevention of organ failure during severe influenza-associated complications. Since the most important aspect in viral disease treatment is to inhibit virus replication, an agent with antiviral and antioxidant activities should be a drug of choice for the treatment of patients with severe influenza-associated complications. Selected compounds, such as PDTC, NAC, glutathione, NDGA, thujaplicin, resveratrol, (+)-vitisin A, ambroxol, ascorbic acid, F36, EGCG, ECG, Q3R, isoquercetin and oligonol, possess both antiviral and antioxidant activities. Consequently, they are potential drugs of interest for severe influenza-associated complications. In theory, combination of these antioxidants with current anti-influenza drugs could improve conventional chemotherapy for severe influenza-associated complications.