Efficacy and safety of aerosol inhalation of recombinant human interferon α1b (IFNα1b) injection for noninfluenza viral pneumonia, a multicenter, randomized, double-blind, placebo-controlled trial

Pneumonia is the leading cause of death in children in developing countries and the elderly in developed countries. Among the pathogens which cause community-acquired pneumonia (CAP), viral pneumonia is attracting increasing attention. It occurs in approximately 200 million people each year worldwide, while adults and children each accounting for 50% of cases [1]. In recent years, with the development of molecular assays, respiratory viruses have become the leading CAP pathogens [2]. CAP is the most common infectious disease in the United States and the eighth cause of death [3]. It is reported that the economic burden of CAP in the United States alone was estimated to exceed $17 billion per year [4]. A CAP study in the United States found that the three most common adult pneumonia pathogens were rhinovirus, influenza virus, and Streptococcus pneumoniae. Other pathogens include human metapneumovirus, respiratory syncytial virus, parainfluenza virus, coronavirus, and adenovirus [2]. Common viruses include influenza virus (8%), rhinovirus (5.7%), respiratory syncytial virus (2.2%), and coronavirus (3.3%) [5]. In recent years, the mortality of newly developed avian influenza viruses (H7N9, H5N6) and the Middle East respiratory syndrome coronavirus (MERS-CoV) was high. Once 48 h passed the infection, neuraminidase inhibitors were ineffective for influenza virus infections. Currently, no proved effective antiviral treatment is available to treat and prevent MERS. MERS-CoV is highly homologous to severe acute respiratory syndrome (SARS), therefore, the experience gained from SARS treatment, including the use of IFNα, may be helpful in the treatment of MERS-CoV infection. Through in vitro studies, it was found that MERS-CoV was 50 to 100 times more sensitive to IFNα than SARS virus. Therefore, IFNα might be an effective treatment for MERS [6]. IFNα was shown to be effective in patients with chronic active Epstein-Barr virus disease [7, 8]. Sakai et al. reported the application of IFNα to patients with chronic active Epstein-Barr virus disease resulting in unremarkable suppression of lymphocyte proliferation [8]. An open-label trial of systemic IFN improved 28-day survival in patients with ARDS [9].

Interferons (IFNs) are a family of multifunctional cytokines with broad-spectrum antiviral, antiproliferative, and immunomodulatory activities. IFN has broad-spectrum antiviral and immunomodulatory effects and is classified as type I, type II or type III based on different binding receptors [10]. Among them, type I IFN (mainly IIB IFN) plays an important role in the control of viral infections. IFNα establishes an antiviral state by inducing cells to produce antiviral proteins, which prevents viral infection [11]. Aerosol inhalation is one route way for IFN administration, which could not only improve efficacy but also reduce the IFN blood concentration in normal tissues, thereby reducing adverse reactions [12]. In clinical practice, IFNα has been widely used to treat various viral diseases in children in some disease [13, 14], but few studies have been conducted to investigate its effect in the treatment of viral pneumonia in adults. Moreover, there were also no consensus on how to use IFNα in adults with viral pneumonia.

Therefore, we performed a multicenter, randomized controlled study to investigate the efficacy and safety of aerosol inhalation of recombinant human IFNα1b for noninfluenza viral pneumonia and to provide a basis for its rational use and dose in clinical practice.

The current study investigated the efficacy and safety of aerosol inhalation of recombinant human interferon α1b (IFNα1b) injection for noninfluenza viral pneumonia. It was found that aerosol inhalation of recombinant human IFNα1b could improve the ORRs of the clinical symptoms with our additional adverse events in noninfluenza viral pneumonia.

This study found that the ORRs of primary efficacy measures, including coughing, expectoration, pulmonary rales, respiratory rate, and chest pain were higher in the IFNα1b group than that in the control group, which received routine symptomatic treatment alone, suggesting that aerosol inhalation of recombinant human INFα1b effectively improves the overall response rate of the disease. IFNα is a recognized immunomodulatory therapy to suppress viral replication by inhibiting basal transcription processes.

Because of its antiviral effects, IFNα has been used in trials in combination with other antiviral agents to prevent and treat emerging and reemerging virus infections for which no approved drugs are available [15‐18]. However, results from these trials have yielded inconsistent results. In addition, other studies indicated that IFNα has pathogenic effects during acute and chronic infections [19‐23]. Together, these findings suggest that the relationship between virus replication and or related pathogenesis and the kinetics of IFN expression, whether endogenous or after exogenous administration, contributed to the variability of outcomes. IFNα therapy has been used to treat patients with severe respiratory disease caused by CoVs, with similarly inconsistent outcomes [24]. In particular, IFNα treatment of patients with MERS failed to improve survival [15, 25, 26]. For example, in one study, IFN treatment prolonged survival when assessed at 14 days, but not at 28 days [15]. Previous studies have demonstrated a critical role for MDA5 in sensing CoV RNA and thereby initiating the IFN response [27]. The majority of these studies used macrophages infected with a murine CoV, mouse hepatitis virus, which is macrophage tropic [28, 29]. Since human CoVs predominantly infect airway and alveolar epithelial cells and PRR expression is cell-type specific, we examined the PRRs necessary for IFN production specifically in airway and alveolar epithelial cells using mice transduced with Ad5-hDPP4 and then infected with the human EMC/2012 strain of MERS-CoV. Ad5 predominantly infects epithelial cells and not myeloid cells [30]. Although there was no significant difference of chest pain between the two groups. It could still be found that in early 4 days of the treatment, the average score of chest pain seemed to be lower than IFNα1b group. It was reported that the treatment of IFNα1b could lead to some adverse events, including pulmonary effusion cardiac insufficiency [31]. Therefore, the mechanism and reason of the early chest pain still needed to be further investigated.

Prophylactic or early therapeutic administration of IFNs during MERS-CoV infection in rhesus macaques provided significant protection [32]. However, studies in humans failed to conclusively establish the beneficial effects of rIFN therapy [25, 26, 33], possibly because of delayed administration relative to peak virus titers. In the early stage of treatment (days 2 to 3), expectoration, respiratory rate, and pulmonary rales were improved. Virus replication occurs in the early stage, therefore, early treatment may better inhibit virus replication. This study shows that IFN is more effective in patients diagnosed in the early stage, indicating that early treatment is advantageous for disease control and remission, although late treatment is also effective.

When used in the systemic therapy, IFNs are mostly administered by an intramuscular injection. The most frequent adverse effects are flu-like symptoms, especially increased body temperature. In current study, no significant difference of the adverse events was observed between the IFNα1b group and the control group, suggesting that aerosol inhalation of recombinant human IFNα1b injection was safe and well tolerated.

There were also some limitations in this study. First the analysis of viral pathogens could be uncertain, and not all cases have positive pathogen results. Second, the specimen was collected from the upper respiratory tract, which might not be the same pathogen as the lower respiratory tract.

In conclusion, aerosol inhalation of recombinant human IFNα1b combined with routine treatment is safe and well tolerated in the treatment of noninfluenza viral pneumonia. It significantly improves the ORRs of clinical symptoms and accelerates recovery compared with routine treatment.