An augmented immune response explains the adverse course of COVID-19 in patients with hypertension

January 11, 2021

This most likely explains the augmented response of the immune system and the more severe disease progression. However, certain hypertension-reducing drugs known as ACE inhibitors can have a beneficial effect. They not only lower blood pressure, but also counteract immune hyperactivation. The scientists have now published their findings in the journal Nature Biotechnology.

More than one billion people worldwide suffer from high blood pressure, or hypertension. Of the more than 75 million people around the world who have become infected with the SARS-CoV-2 virus worldwide so far, more than 16 million also have hypertension. These patients are more likely to become severely ill, which in turn results in an increased risk of death. It was previously unclear to what extent treatment with antihypertensive drugs could be continued during a SARS-CoV-2 infection - and whether they were more likely to benefit or harm the patients. This is because antihypertensives interfere with the exact same regulatory mechanism that the novel coronavirus SARS-CoV-2 uses to enter the host cell and trigger COVID-19.

Professor Ulf Landmesser is Medical Director of the CharitéCenter 11 for Cardiovascular Diseases, Director of the Medical Department of Cardiology and BIH Professor of Cardiology on the Charité's Campus Benjamin Franklin in Berlin. He recognized early on that patients with hypertension or cardiovascular diseases often experienced a particularly critical disease progression with COVID-19. "The virus uses the receptor ACE2 as an entry portal into the cells, and the formation of this receptor is potentially influenced by the administration of antihypertensive drugs," explains Landmesser. "We had therefore initially feared that patients receiving ACE inhibitors or angiotensin receptor blockers might have more ACE2 receptors on their cell surfaces and thus become more easily infected."

Certain drugs that lower blood pressure could also help with COVID-19

To clarify this suspicion, the scientists analyzed individual cells from the respiratory systems of COVID-19 patients who were also taking medication for high blood pressure. Dr. Sören Lukassen, a scientist in Professor Christian Conrad's group at the BIH Digital Health Center, explains that they were subsequently able to give the all-clear: "We found that the drugs do not seem to cause more receptors to form on the cells. As a result, we do not believe that they make it easier for the virus to enter the cells in this way and thus cause the more severe course of COVID-19." On the contrary, cardiovascular patients taking ACE inhibitors actually displayed a lower risk of becoming severely ill with COVID-19. In fact, they displayed almost the same level of risk as COVID-19 patients without cardiovascular problems.

Severe course of COVID-19 linked to pre-activation of the immune system

The blood of hypertensive patients usually shows elevated levels of inflammation, which can be fatal in the case of a SARS-CoV-2 infection. "Elevated inflammation levels are always a warning signal that COVID-19 will be more severe, regardless of any cardiovascular issues," explains Landmesser. The scientists therefore employed single-cell sequencing methods to investigate the immune response of hypertensive patients with COVID-19.

"We analyzed a total of 114,761 cells from the nasopharynx of 32 COVID-19 patients and 16 non-infected controls, with both groups including cardiovascular patients as well as people without cardiovascular problems," reports Dr. Saskia Trump, research group leader in the lab of Irina Lehmann, who is BIH Professor for Environmental Epigenetics and Lung Research. "We found that the immune cells of the cardiovascular patients displayed strong pre-activation even before infection with the novel coronavirus," explains Lehmann. "After contact with the virus, these patients were more likely to develop an augmented immune response, which was associated with the severe disease progression of COVID-19. However, our results also showed that treatment with ACE inhibitors, though not with angiotensin receptor blockers, could prevent this augmented immune response following infection by the coronavirus. ACE inhibitors could thus reduce the risk of patients with hypertension from experiencing severe disease progression."

Delayed reduction in viral load

Furthermore, the scientists found that the anti-hypertensive drugs can also impact how quickly the immune system is able to reduce the viral load, i.e., the concentration of the virus in the body. "Here, we observed a clear difference between the different forms of treatment for high blood pressure," notes Roland Eils, Director of the BIH Digital Health Center. "In the patients treated with angiotensin II receptor blockers, the reduction in viral load was significantly delayed, which could also contribute to a more severe course of COVID-19. We did not observe this delay in the patients who were receiving ACE inhibitors to treat their hypertension."

Interdisciplinary collaboration speeds up research

More than 40 scientists have been working at a breakneck pace on this extensive study. "The ability to quickly provide answers to urgent questions during the ongoing pandemic requires interdisciplinary collaboration among many committed individuals," explains Eils. "COVID-19 is such a complex disease that we brought together experts from cardiology, immunology, virology, pulmonary medicine, intensive care and computer science for this study. Our goal was to provide a scientifically sound answer as quickly as possible to the question of whether simultaneous treatment with ACE inhibitors or angiotensin receptor blockers could have beneficial or even adverse effects during the COVID-19 pandemic."

No evidence of increased risk of infection

Thanks to the study, the teams from the BIH, Charité and collaborating institutions in Leipzig and Heidelberg can now reassure both patients and the physicians treating them: "Our study provides no evidence that treatment with anti-hypertensive drugs increases the risk of infection by the novel coronavirus," says Ulf Landmesser, summarizing the results. "However, treating hypertension with ACE inhibitors could be more beneficial for patients suffering from COVID-19 than treatment with angiotensin II receptor blockers - a hypothesis that is currently being further investigated in randomized trials."
Original publication:

Saskia Trump#, Soeren Lukassen#, Markus S. Anker#, Robert Lorenz Chua#, Johannes Liebig#, Loreen Thürmann#, Victor Corman#, Marco Binder#, Jennifer Loske, Christina Klasa, Teresa Krieger, Bianca P. Hennig, Marey Messingschlager, Fabian Pott, Julia Kazmierski, Sven Twardziok, Jan Philipp Albrecht, Jürgen Eils, Sara Hadzibegovic, Alessia Lena, Bettina Heidecker, Christine Goffinet, Florian Kurth, Martin Witzenrath, Maria Theresa V.lker, Sarah Dorothea Müller, Uwe Gerd Liebert, Naveed Ishaque, Lars Kaderali, Leif- Erik Sander, Christian Drosten, Sven Laudi*, Roland Eils*, Christian Conrad*, Ulf Landmesser*, Irina Lehmann*, Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19, Nat. Biotechnology DOI: 10.1038/s41587-020-00796-1

About the Berlin Institute of Health (BIH)

The mission of the Berlin Institute of Health (BIH) is medical translation: transferring biomedical research findings into novel approaches to personalized prediction, prevention, diagnostics and therapy and, conversely, using clinical observations to develop new research ideas. The aim is to deliver relevant medical benefits to patients and the population at large. The BIH is also committed to establishing a comprehensive translational ecosystem as translational research area at the Charité - one that places emphasis on a system-wide understanding of health and disease and that promotes change in the biomedical research culture. The BIH is funded 90 percent by the Federal Ministry of Education and Research (BMBF) and 10 percent by the State of Berlin. The two founding institutions, Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), were independent member entities within the BIH until 2020. As of 2021, the BIH has been integrated into the Charité as the so-called third pillar; the MDC is privileged partner of the BIH.

BIH at Charité

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to