Abstract
BackgroundPatients with influenza virus infection can develop severe pneumonia and acute respiratory distress syndrome (ARDS) which have a high mortality. Influenza virus infection is treated worldwide mainly by neuraminidase inhibitors (NAIs). However, monotherapy with NAIs is insufficient for severe pneumonia secondary to influenza virus infection. We previously demonstrated that mice infected with a lethal dose of influenza virus develop diffuse alveolar damage (DAD) with alveolar collapse similar to that seen in ARDS in humans. Additionally, pulmonary surfactant proteins were gradually increased in mouse serum, suggesting a decrease in pulmonary surfactant in the lung. Therefore, the present study examined whether combination therapy of NAI with exogenous artificial surfactant affects mortality of influenza virus-infected mice.Methodology/Principal FindingsBALB/c mice were inoculated with several viral doses of influenza A/Puerto Rico/8/34 (PR8) virus (H1N1). The mice were additionally administered exogenous artificial surfactant in the presence or absence of a new NAI, laninamivir octanoate. Mouse survival, body weight and general condition were observed for up to 20 days after inoculation. Viral titer and cytokine/chemokine levels in the lungs, lung weight, pathological analysis, and blood O2 and CO2 pressures were evaluated. Infected mice treated with combination therapy of laninamivir octanoate with artificial surfactant showed a significantly higher survival rate compared with those that received laninamivir octanoate monotherapy (p = 0.003). However, virus titer, lung weight and cytokine/chemokine responses were not different between the groups. Histopathological examination, a hydrostatic lung test and blood gas analysis showed positive results in the combination therapy group.Conclusions/SignificanceCombination therapy of laninamivir octanoate with artificial surfactant reduces lethality in mice infected with influenza virus, and eventually suppresses DAD formation and preserves lung function. This combination could be effective for prevention of severe pneumonia secondary to influenza virus infection in humans, which is not improved by NAI monotherapy.
Highlights
Influenza viruses, including highly pathogenic avian influenza (H5N1) and A(H1N1)pdm09 viruses, can induce viral pneumonia in humans [1,2,3,4,5,6,7]
Our previous study demonstrated a gradual increase in SP-A and SP-D, which are originally present in the alveolar lumen, in the serum of mice infected with a middle dose (5 50% mouse lethal dose [MLD50]) of Puerto Rico/8/34 (PR8) virus in association with aggravation of viral pneumonia, suggesting leakage of pulmonary surfactant from the alveolar lumen to capillaries [42]
The present study demonstrated that combination therapy of laninamivir octanoate with artificial surfactant increased survival of mice suffering from influenza virus-induced severe pneumonia, while monotherapy of laninamivir octanoate did not improve survival
Summary
Influenza viruses, including highly pathogenic avian influenza (H5N1) and A(H1N1)pdm viruses, can induce viral pneumonia in humans [1,2,3,4,5,6,7]. Several neuraminidase inhibitors (NAIs) are available and have a therapeutic effect if used within 48 h of the appearance of symptoms. Their effect is thought to be limited for severe pneumonia and ARDS/DAD secondary to influenza virus infection [17,18]. Patients with influenza virus infection can develop severe pneumonia and acute respiratory distress syndrome (ARDS) which have a high mortality. We previously demonstrated that mice infected with a lethal dose of influenza virus develop diffuse alveolar damage (DAD) with alveolar collapse similar to that seen in ARDS in humans. The present study examined whether combination therapy of NAI with exogenous artificial surfactant affects mortality of influenza virus-infected mice
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