18 August 2020

Frank van de Veerdonk, Mihai Netea and Roger Brüggemann, theme Infectious diseases and global health, wrote in JAMA Network Open that Corona patients with severe oxygen deficiency react positively to treatment with icatibant. Amongst others, these results have led to a follow-up study in ten Dutch hospitals into the effect of a drug that may be even more effective. The research is funded by ZonMw.

The rapid 'filling' of the lungs (pulmonary edema) is a characteristic of a serious infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In an earlier article, Nijmegen researchers suggested that this has to do with the ACE2 receptor. The coronavirus penetrates the cells through this receptor, after which the virus can multiply.
However, the ACE2 receptor is not only the gateway for the coronavirus, it also controls vasodilating quinines. As a result of the infection, the ACE2 receptors disappear massively from the lung cells. Without ACE2 these quinines have free play and - by binding to bradykinin receptors - can make the blood vessels leak. Internist Frank van de Veerdonk and Roger Brüggemann and colleagues had the idea that this process plays an important role in serious coronavirus infection.

Patient survey

To determine whether a hypothesis is correct, you need to test her. After consultation with the Committee on Human Subjects Research (CMO) and the Inspectorate for Health Care and Youth (IGJ) and with the consent of the participating patients, this was done with the medicine icatibant. Van de Veerdonk: "This medicine is used in patients with the rare condition hereditary angioedema. These patients sometimes suddenly develop severe subcutaneous fluid accumulation because their blood vessels start leaking locally. Icatibant blocks the bradykinine receptor B2R so that the leakage is quickly eliminated. To assess whether the drug is also suitable for the specific group of corona patients with fluid in the lungs, we administered it in the first half of this year to nine patients in the Internal Medicine department and one patient in the Intensive Care department".

Oxygen deficiency

The results are now published in JAMA Network Open. All patients with severe oxygen deficiency due to fluid in the lungs were given icatibant subcutaneous injections three times every six hours. The patient on the ICU could go to the ward 24 hours later and was discharged after 7 days. Eight of the remaining nine patients were admitted within 24 hours with less oxygen and the ninth after 38 hours. In eighteen comparable patients who were used as controls, the decrease in oxygen delivery was significantly less.

Support hypothesis

Brüggemann: "Although it is not a randomised study, the results support our hypothesis. In an early phase of the infection in case of severe oxygen deficiency we see that icatibant improves the situation. A drawback is the short duration of action of the drug. In two hours half of the medication is broken down, so the effect diminishes rapidly. After treatment, three patients had to be given oxygen again because the drug had worn off".

Other medicine

The research published in JAMA Network Open in fact provides a proof of concept, which has already been built on in the meantime. More insight into the functioning of the so-called kallikreine-kinine system (KKS) has ensured that the researchers expect even better effects from another medicine. Brüggemann: "Compared to icatibant, the lanadelumab drug remains active much longer, so you probably only need to administer it once or twice". Van de Veerdonk: "Moreover, it has a much wider effect. It inhibits the activation of the entire system that causes the leakage of blood vessels. In short: it works longer and more comprehensively."

Research in ten hospitals

Based on the initial results published in JAMA Network Open and these new insights, Van de Veerdonk and Brüggemann received a grant from ZonMw for a phase 2 clinical trial with lanadelumab for this specific group of COVID-19 patients. Ten hospitals are participating in the study. Brüggemann and van de Veerdonk are of the opinion that if this approach works, the research can be rolled out on an international scale immediately. This is not only important for patients with severe oxygen deficiency, but can also reduce the pressure on the IC capacity. Global organizations such as the World Health Organization (WHO) and REMAP-CAP are directly involved in this research and this strategy is currently being considered by several organizations. Van de Veerdonk and Brüggemann aim with this strategy to ensure that patients who are admitted with a lack of oxygen recover quickly and prevent them from being admitted to ICU.

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