Combination therapy can reduce the morbidity and mortality associated with influenza

Many hospitalized patients with influenza develop complications of severe respiratory syndrome, driven by virus-induced cytopathic effects as well as a host immune response. Reporting The American Journal of Pathology, published by Elsevier, researchers have found that treatment with an immune receptor blocker in combination with an antiviral agent significantly improves the survival of mice with deadly flu and ‘reduced lung pathology in pigs with swine fever. Their research also gives us an insight into the best time to treat to prevent lung injury.

Previously, the researchers found that excessive flow of neutrophils, infections fighting immune cells, and the networks they form to kill pathogens, called extracellular neutrophil receptors (NETn), contribute to acute lung injury in influenza infection. The formation of NETn by activated neutrophils occurs via a cell death mechanism called NETosis and the released NETs contain chromatin fibers that harbor toxic components.

A mouse model, commonly used in the study of influenza pathophysiology and drug therapies, was used in the current study. Since mice are not natural hosts for flu, further testing is needed in larger animals before testing in humans. Therefore, researchers also tested pigs with swine flu virus infection. The animals were treated with a combination of CXCR2 antagonist, SCH527123, along with an antiviral agent, oseltamivir.

The combination of SCH527123 and oseltamivir significantly improved survival in mice compared with one of the drugs administered alone. The combination therapy also reduced lung pathology in pigs.

Combination therapy reduces lung inflammation, alveolitis, and vascular pathology, indicating that worse neutrophil activity and release in NETs adversely affects lung pathology in severe influenza. These findings support the evidence that antagonizing CXCR2 may alleviate lung pathology and that antiviral treatment may have significant synergistic effects to reduce influenza-related morbidity and mortality. “

Narasaraju Teluguakula, PhD, Principal Investigator, Center for Medical Health Sciences, Oklahoma State University, Stillwater, OK, USA

Balancing excessive neutrophil flow can be challenging without compromising the beneficial host immunity that neutrophils provide. Therefore, the researchers studied the temporal dinamics of NETn transmission in relation to pathological changes during the course of disease in mice. In the early inflammatory phase, three to five days after infection, significant neutrophil activation and NETn release were observed with minimal hemorrhagic lesions. In the late hemorrhagic exudative phase, severe vascular lesions with declining neutrophil activity were observed.

Dr. Teluguakula also confirms that these findings provide the first evidence to support the strategy of testing a combination of mixtures in a large model of animal flu. “Despite the similarities in lung pathology and immune responses between pigs and humans, models of swine flu pneumonia can be a common platform in understanding pathophysiology and drug-led therapies. hosts in human influenza diseases and may be useful in promoting their translation. the impact of drug treatment studies in human influenza infections. “