Innate immunity is activated after viral entry into the body. This activation triggers two parallel processes:
- It begins with the synthesis of a broad range of signaling proteins that recruit immune cells to sites of infection. These immune cells act rapidly but nonspecifically – destroying both viral replication foci and healthy host tissues.
- Regulation of inflammatory intensity and activation of adaptive immunity. These processes begin with the production of type I interferons (IFN-I). Adaptive immunity acts precisely – targeting only sites of viral replication.
Severe forms of respiratory viral infections result from an imbalance between these two processes. This imbalance arises because inflammation is initiated, but its intensity is not regulated, as viruses suppress endogenous interferon synthesis. As a result, proinflammatory signaling proteins are uncontrolledly amplified.
The situation is further aggravated by the fact that IFN-I synthesis does eventually begin, but only several days after infection. This substantial delay enhances the inflammatory response. Consequently, patients develop excessive lung inflammation, which may lead to acute respiratory distress syndrome, respiratory failure, and dysfunction of other organs.
Because the underlying cause of immune imbalance is insufficient endogenous interferon production at disease onset, the primary strategy for IFN-I therapy is early use during respiratory viral infection.
Interferon at Disease Onset
Respiratory viruses enter the body through the nasal mucosa. Therefore, local – intranasal – administration of IFN-I protects against severe disease and shortens illness duration by an average of three days compared with conventional therapy. In addition to reducing disease duration, intranasal interferon alleviates catarrhal symptoms and systemic intoxication.
Optimal treatment efficacy is achieved when therapy is initiated within the first 48 hours after symptom onset. Nasal sprays are more effective than drops, as interferon is distributed more evenly across the mucosal surface and penetrates deeper into the respiratory tract.
An additional strategy to prevent severe disease is prophylactic use of intranasal IFN-I. This approach reduces the risk of complications via two mechanisms. First, direct prevention, as IFN-I stimulates antiviral activity in nasal epithelial cells. Second, intranasal IFN-I compensates for insufficient endogenous interferon synthesis at the early stage of infection, if exposure has already occurred.
Another advantage of intranasal IFN-I preparations is the absence of systemic side effects, since high concentrations of the active substance are achieved only in the nasal cavity and do not affect the body as a whole. For this reason, nasal interferon formulations are included in national clinical guidelines in several countries. For example, in the recommendations of the Ministry of Health of the Russian Federation for the prevention and treatment of coronavirus infection, intranasal interferon is approved for pregnant women at any gestational age and for newborns.
If infection spreads to the lower respiratory tract, IFN-I can also be administered clinically via nebulization. During the COVID-19 pandemic, for example, intrapulmonary interferon inhalations were prescribed within the first 14 days after symptom onset. This route accelerated recovery and was well tolerated, without serious adverse effects.
Interferon in Hyperinflammation
Severe respiratory viral infections develop when the body experiences prolonged deficiency of type I interferons during illness. Such sustained immune imbalance leads to hyperinflammation and increased mortality. Hyperinflammation results from excessive production of signaling proteins driven by increasing viral load.
If a severe form of infection has already developed, additional interferon therapy may exacerbate the condition, as the immune system is already responding excessively. In this scenario, therapeutic strategies are reversed – aiming to suppress the production of signaling proteins, including IFN-I. Monoclonal antibodies are used for this purpose. They rapidly reduce fever and restore respiratory function.
Initial clinical trials of monoclonal antibodies were conducted under emergency conditions at the onset of the COVID-19 pandemic, when urgent treatment was required for patients with respiratory distress syndrome. However, clinical studies of monoclonal antibodies are still ongoing.
Conclusion
Severe forms of respiratory viral infections are associated with an immune imbalance. On one hand, inflammation develops in response to increasing viral load. On the other hand, viruses suppress endogenous interferon production, preventing proper regulation of inflammation and leading to hyperinflammation. Therefore, IFN-I use must be aligned with the stage of the infectious process.
Interferon accelerates recovery when administered during the first days after disease onset, optimally within the first three days. To suppress infection at the site of viral entry – the nasal epithelium – intranasal interferon formulations are appropriate. If infection has already progressed, IFN-I inhalations may reduce catarrhal symptoms and systemic intoxication.
However, the treatment strategy must be reversed once severe disease has developed – when respiratory distress syndrome or respiratory failure is present. In such cases, monoclonal antibodies are used to suppress the production of signaling proteins, thereby reducing hyperinflammation.
Reference
Перспективы цитокинотерапии острых респираторных вирусных инфекций, включая коронавирусную инфекцию
