Immune cell activation in severe COVID-19 resembles lupus

In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of immune cells, resembling acute flares of systemic lupus erythematosus (SLE), an autoimmune disease.

Their findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. They also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.

The results were published online on Oct. 7 in Nature Immunology.

The Emory team’s results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an “extrafollicular” pathway outside germinal centers—looking similar to they had observed in SLE.

B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection. In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.

Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz, MD and his lab were focused on studying SLE and how the disease perturbs the development of B cells.

Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Co-senior author Frances Eun-Hyung Lee, MD is associate professor of medicine and director of Emory’s Asthma/Allergy Immunology program.

“We came in pretty unbiased,” Sanz says. “It wasn’t until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE.”

In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of “autoantibodies” that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.

Whether severe COVID-19 leads to autoantibody production with clinical consequences is currently under investigation by the Emory team. Sanz notes that other investigators have observed autoantibodies in the acute phase of the disease, and it will be important to understand whether long-term autoimmune responses may be related to the fatigue, joint pain and other symptoms experienced by some survivors.

“It’s an important question that we need to address through careful long-term follow-up,” he says. “Not all severe infections do this. Sepsis doesn’t look like this.”

In lupus, extrafollicular B cell responses are characteristic of African-American patients with severe disease, he adds. In the new study, the majority of patients with severe infection were African-American. It will be important to understand how underlying conditions and health-related disparities drive the intensity and quality of B cell responses in both autoimmune diseases and COVID-19, Sanz says.

The study compared 10 critically ill COVID-19 patients (4 of whom died) admitted to intensive care units at Emory hospitals to 7 people with COVID-19 who were treated as outpatients and 37 healthy controls.

People in the critically ill group tended to have higher levels of antibody-secreting cells early on their infection. In addition, the B cells and the antibodies they made displayed characteristics suggesting that the cells were being activated in an extrafollicular pathway. In particular, the cells underwent fewer mutations in their antibody genes than seen in a focused immune response, which is typically honed within germinal centers.

The Nature Immunology paper was the result of a collaboration across Emory. The co-first authors are Matthew Woodruff, Ph.D., an instructor in Sanz’s lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital.

Ramonell notes that the patients studied were treated early during the COVID-19 pandemic. It was before the widespread introduction of the anti-inflammatory corticosteroid dexamethasone, which has been shown to reduce mortality.

The team’s findings could inform the debate about which COVID-19 patients should be given immunomodulatory treatments, such as dexamethasone or anti-IL-6 drugs. Patients with a greater expansion of B cells undergoing extrafollicular activation also had higher levels of inflammatory cytokines, such as IL-6.

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Blood pressure medications decrease death and severe disease in COVID-19 patients

At the start of the pandemic, there was concern that certain drugs for high blood pressure might be linked with worse outcomes for COVID-19 patients.

Because of how the drugs work, it was feared they would make it easier for the coronavirus to get inside the body’s cells. Nevertheless, many national medical societies advised patients to continue taking their medication.

With the potential for a second wave, it was essential to investigate whether patients could safely continue using these drugs. So, our team at the University of East Anglia set out to discover what effect they have on the progress of COVID-19.

Instead of putting patients at risk, we found that these medications actually lower the risk of death and severe disease in COVID-19 patients.

Bad outcomes cut by one-third

We pooled data from 19 relevant COVID-19 studies that included patients taking two particular types of blood pressure medication: angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). This allowed us to look at the outcomes of more than 28,000 COVID-19 patients to assess the effects of these drugs.

ACEIs and ARBs work by acting on the renin-angiotensin-aldosterone system (RAAS), which is essential for regulating blood pressure and the balance of fluids and electrolytes. These drugs were also thought to potentially increase the expression of a protein found on the surface of cells called angiotensin-converting enzyme 2 (ACE2).

Apart from helping regulate blood pressure, the ACE2 protein is also what allows the coronavirus to enter the body’s cells. This is why there were concerns about patients using these drugs. If the medications increased the amount of ACE2 present on cells, it was suspected they would make it easier for the virus to infect them, worsening a patient’s condition.

But when we looked at the outcomes of patients taking ACEIs and ARBs compared with those not on these medications, this wasn’t the case.

We found no evidence that these medications might increase the severity of COVID-19 or the risk of death. On the contrary, among patients taking ACEIs and ARBs that had been prescribed to treat high blood pressure, there was actually a significantly lower risk of death, being admitted to intensive care or being put on ventilation. We observed a reduction of such events by one-third in this group.

It may be that these medications actually have a protective role—particularly in patients with high blood pressure.

What’s behind this effect?

It’s not clear why patients taking ACEIs and ARBs experienced less severe disease, but there are a couple of points to consider.

The first is that while theoretically these drugs were thought to increase ACE2 levels, there’s no convincing evidence that this actually happens. We don’t have any clinical data on the effects of these drugs on ACE2 expression in human tissue.

And even if these drugs do increase ACE2 levels in cells, not all of it is surface-bound. Additional ACE2 that appears elsewhere in the cell might not function as an entry point for SARS-CoV-2.

There’s also a second potentially relevant piece of information. Infection with SARS-CoV-2 may also lead to an overreaction of the RAAS pathway – which is what these blood pressure drugs target—and inflammation. This increased inflammatory process is thought to be the culprit for acute lung injury and can lead to worsening pneumonia and acute respiratory distress syndrome. Hence, it might be that taking medications that inhibit the RAAS system prevents such a sequence of events and improves clinical outcomes in COVID-19.

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Elevated clotting factor V levels linked to worse outcomes in severe COVID-19 infections

Patients hospitalized with severe COVID-19 infections who have high levels of the blood clotting protein factor V are at elevated risk for serious injury from blood clots such as deep vein thrombosis or pulmonary embolism, investigators at Massachusetts General Hospital (MGH) have found.

On the other hand, critically ill patients with COVID-19 and low levels of factor V appear to be at increased risk for death from a coagulopathy that resembles disseminated intravascular coagulation (DIC), a devastating, often fatal abnormality in which blood clots form in small vessels throughout the body, leading to exhaustion of clotting factors and proteins that control coagulation, report Elizabeth M. Van Cott, MD, investigator in the deparment of pathology at MGH and colleagues.

Their findings, based on studies of patients with COVID-19 in MGH intensive care units (ICUs), point to disturbances in factor V activity as both a potential cause of blood clotting disorders with COVID-19, and to potential methods for identifying at-risk patients with the goal of selecting the proper anticoagulation therapy.

The study results are published online in the American Journal of Hematology.

“Aside from COVID-19, I’ve never seen anything else cause markedly elevated factor V, and I’ve been doing this for 25 years,” Van Cott says.

Patients with severe COVID-19 disease caused by the SARS-CoV-2 virus can develop blood clots in medical lines (intravenous lines, catheters, etc), and in arteries, lungs, and extremities, including the toes. Yet the mechanisms underlying coagulation disorders in patients with COVID-19 are still unknown.

In March 2020, in the early days of the COVID-19 pandemic in Massachusetts, Van Cott and colleagues found that a blood sample from a patient with severe COVID-19 on a ventilator contained factor V levels high above the normal reference range. Four days later, this patient developed a saddle pulmonary embolism, a potentially fatal blood clot occurring at the junction of the left and right pulmonary arteries.

This pointed the investigators to activity of factor V as well as factor VIII and factor X, two other major clotting factors. They studied the levels of these clotting factors and other parameters in a group of 102 consecutive patients with COVID-19, and compared the results with those of current critically ill patients without COVID-19, and with historical controls.

They found that factor V levels were significantly elevated among patients with COVID-19 compared with controls, and that the association between high factor V activity and COVID-19 was the strongest among all clinical parameters studied.

In all, 33 percent of patients with factor V activity well above the reference range had either deep vein thrombosis or a pulmonary embolism, compared with only 13 percent of patients with lower levels. Death rates were significantly higher for patients with lower levels of factor V (30 percent vs. 12 percent), with evidence that this was due to a clinical decline toward a DIC-like state.

Van Cott and colleagues also found that the clinical decline toward DIC was foreshadowed by a measurable change in the shape or “waveform” of a plot charting light absorbance against the time it takes blood to coagulate (waveform of the activated partial thromboplastin time, or aPTT).

“The waveform can actually be a useful tool to help assess patients as to whether their clinical course is declining toward DIC or not,” Van Cott explains. “The lab tests that usually diagnose DIC were not helpful in these cases.”

Importantly, the MGH investigators note that factor V elevation in COVID-19 could cause misdiagnosis of some patients, because under normal circumstances factor V levels are low in the presence of liver dysfunction or DIC. Physicians might therefore mistakenly assume that patients instead have a deficiency in vitamin K.

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Experts make weak recommendation for remdesivir in severe COVID-19

In The BMJ today, a panel of international experts make a weak recommendation for the use of remdesivir in patients with severe covid-19, and strongly support continued enrolment of patients into ongoing clinical trials of remdesivir.

Their advice is part of The BMJ‘s Rapid Recommendations initiative—to produce rapid and trustworthy guidelines for clinical practice based on new evidence to help doctors make better decisions with their patients.

The antiviral medication remdesivir has received worldwide attention as a potentially effective treatment for severe covid-19 and is already being used in clinical practice.

Today’s recommendation is based on a new evidence review comparing the effects of several drug treatments for covid-19 up to 20 July 2020.

It shows that remdesivir may be effective in reducing recovery time in patients with severe covid-19, although the certainty of the evidence is low. But remdesivir probably has no important effect on the need for mechanical ventilation and may have little or no effect on length of hospital stay.

The authors stress that “the effectiveness of most interventions is uncertain because most of the randomised controlled trials so far have been small and have important study limitations.”

After thoroughly reviewing this evidence, the expert panel says that most patients with severe covid-19 would likely choose treatment with remdesivir given the potential reduction in time to clinical improvement.

But given the low certainty evidence, and allowing for different patient perspectives, values, and preferences, they issued a weak recommendation with strong support for continued recruitment in trials.

They suggest that future research should focus on areas such as optimal dose and duration of therapy, and whether there are specific groups of patients most likely to benefit from remdesivir.

The authors also sound a note of caution about the potential opportunity cost of using remdesivir while the evidence base is still uncertain. As a relatively costly drug that is given intravenously, use of remdesivir may divert funds, time, attention, and workforce away from other potentially worthwhile treatments.

The study that today’s recommendation is based on is called a living systematic review.

In a linked editorial, The BMJ editors explain that living systematic reviews are useful in fast moving research areas such as covid-19 because they allow authors to update previously vetted and peer reviewed evidence summaries as new information becomes available.

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