COVID-19: The combination of antiviral and anti-inflammatory drugs improves the therapeutic effect

SARS-CoV-2 infection continues to cause hospitalization. The Robert Koch Institute estimates that the current COVID-19 hospitalization rate is about 6-7 per 100,000 resident population. Hospitalized COVID-19 patients now have access to a variety of medications that can reduce the severity of the disease and, in the most severe cases, the risk of death. Some of these drugs target the virus itself. Others fight inflammation associated with infection.

First-line treatment includes monoclonal antibodies and dexamethasone, a drug with strong anti-inflammatory properties. Antibody treatment attaches to the surface of the peplomer protein, neutralizes the virus, and prevents the virus from invading human cells. This type of treatment is used within 7 days after the onset of symptoms. Inpatients with COVID-19 who require oxygen therapy are usually given the glucocorticoid dexamethasone. It has been used for about 60 years to treat inflammatory conditions caused by an excessive immune response. COVID-19 has also been shown to definitely reduce the body’s inflammatory response. However, the drug is associated with a variety of side effects, including an increased risk of fungal infections, and should only be used in a specific and targeted manner.

Researchers at Charite, the Berlin Institute for Medical Systems Biology (BIMSB) at MDC, and FU Berlin are currently studying the mechanism of action of both types of treatment. “We have found evidence suggesting that the combination of antibody and dexamethasone is more effective than any of these therapies alone,” said researchers in the BIMSB’s RNA Biology and Post-Transcribing Regulation research group. The lead author, Dr. Emanuel Wyler, said. Dr. Marcus Land Thaler.

Not all lung compartments can be studied using lung tissue samples taken from patients, so the first step in last year’s research group was to find a suitable model. The task was entrusted to the co-final author, Dr. Jakob Trimpert, Veterinary and Research Group Leader at the Virology Institute in Berlin, who subsequently developed the COVID-19 hamster model. Hamsters have proven to be the most important non-transgenic model for COVID-19 research as animals that infect the same viral variants as humans and develop symptoms of similar diseases. However, symptoms and progression depend on the type of hamster. For example, Syrian hamsters usually have moderate symptoms, but Roborovski hamsters develop serious illnesses that are reminiscent of those found in COVID-19 patients who require intensive care.

“The current study tested the effects of single and combined antiviral and anti-inflammatory therapies on COVID-19, that is, using existing models with monoclonal antibodies, dexamethasone, or a combination of the two.” Explains Dr. Triplet. Next, FU Berlin’s veterinary pathologist examined the infected lung tissue under a microscope to determine the extent of lung tissue damage. Dr. Trimpert and his team also measured the amount of infectious virus and viral RNA present in tissues at various times. This allowed researchers to see if and how viral activity changed during the course of treatment. “Thanks to the detailed analysis of the various COVID-19 parameters available only in animal models, we were able to gain a better understanding of the basic mechanism of action of the two important COVID-19 drugs. We have found clear evidence of the potential benefits associated with the combination of antibodies and dexamethasone, “says Dr. Trimpert.

Using single-cell analysis, researchers have demonstrated the effect of drugs on complex interactions between different cellular signaling pathways and the number of immune cells present. Individual cells from a particular sample were loaded onto a chip, where they were first barcoded and then encapsulated in fine droplets of aqueous humor. When ready, the single cell underwent an RNA sequence. This is the process used to establish the sequence of gene building blocks that cells have just read. Thanks to the barcode, this RNA can later be identified as coming from a particular cell, allowing researchers to determine cell function with high accuracy at the single cell level. “We were able to observe that the antibody was effective in reducing the amount of virus present,” explains Dr. Wyler. “But this wasn’t used much in our models,” he adds. This is because it is not the virus that damages the lung tissue, but the strong inflammatory response caused by the virus. Immune cells that fight invading pathogens release messenger substances to call for strengthening. When a large amount of these defenses arrive, the lungs can become clogged. “Occclused vessels and unstable vessel walls can then cause acute lung failure,” explains Dr. Wyler.

Surprise came in the form of the famous drug dexamethasone. “This anti-inflammatory effect is particularly strong on certain types of immune cells known as neutrophils,” said the research group leader of the Department of Respiratory Medicine, Charite Infectious Diseases, co-author of the study. Dr. Geraldine Aille said. Neutrophils are a type of white blood cell that initiates a rapid response to viral and bacterial infections. “Corticosteroids suppress the immune system and prevent neutrophils from producing messenger substances that attract other immune cells,” explains Dr. Nouailles. She continues: “This makes the drug very effective in preventing the escalation of the immune response.”

Best treatment results were achieved when researchers administered a combination of antiviral and anti-inflammatory treatments. “This type of combination therapy is not included in existing clinical guidelines,” emphasizes Dr. Nouailles. “In addition, current guidance stipulates that in high-risk patients, antibody therapy can only be given during the first 7 days after the onset of symptoms. In clinical practice, dexamethasone requires patients to receive oxygen therapy. That is, it is used only in the very advanced stages of the disease, but when used in combination, it opens up a whole new treatment time frame. ”This new approach is before clinical adoption. , Should be evaluated in clinical trials.

reference: The major benefits of dexamethasone and antibody treatment in the COVID-19 hamster model revealed by Wyler E, Adler JM, Eschke K and others by single cell transcription. Mol. there. 2022. doi: 10.1016 / j.ymthe.2022.03.014

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