The study was led by Prof. David Gurwitz, Prof. Noam Shomron, and MSc candidate Guy Shapira of TAU’s Sackler Faculty of Medicine, and published in The FASEB Journal on September 22, 2020.

The researchers analyzed data from 67 countries on all continents. Comparisons revealed a highly significant positive correlation between the prevalence of the two mutations in the population and COVID-19 mortality rates (adjusted to size of the population) in many countries, such as the USA, the UK, Belgium, Spain, Italy, and more.

Consequently, the researchers suggest that these mutations may be additional risk factors for severe COVID-19. They now propose that their findings should be corroborated by clinical trials, and if validated should lead to population-wide screening for identifying carriers of the PiS and/or PiZ mutations. Such individuals should then be advised to take extra measures of social distancing and later be prioritized for vaccination once vaccines are available. According to the researchers, these steps can be effective in reducing COVID-19 morbidity and fatality rates.

[Editor’s note: Please see the paper, referenced below, for precise figures of mutation and mortality rates.]

Prof. Gurwitz, Prof. Shomron, and Shapira conclude, “Our data analysis reveals a strong correlation between these mutations and severe illness and death from COVID-19. We call upon the research community to test our hypothesis against clinical data, and also call upon decision makers in every country to conduct population-wide screening for identifying mutation carriers and prioritize them for vaccination once COVID-19 vaccines have been approved. In the meantime, carriers should be notified that they may belong to a high-risk group and advised to maintain strict social isolation.”

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The 1,035 patients in the study faced a staggeringly high risk of death, as ventilators and other care failed to support their lungs. But after they were placed on ECMO, their actual death rate was less than 40%. That’s similar to the rate for patients treated with ECMO in past outbreaks of lung-damaging viruses, and other severe forms of viral pneumonia.

The new study published in The Lancet provides strong support for the use of ECMO — short for extracorporeal membrane oxygenation — in appropriate patients as the pandemic rages on worldwide.

It may help more hospitals that have ECMO capability understand which of their COVID-19 patients might benefit from the technique, which channels blood out of the body and into a circuit of equipment that adds oxygen directly to the blood before pumping it back into regular circulation. Small studies published early in the pandemic had cast doubt on the technique’s usefulness.

Still, the international team of authors cautions that patients who show signs of needing advanced life support should receive it at hospitals with experienced ECMO teams, and that hospitals shouldn’t try to add ECMO capability mid-pandemic.

Global cooperation to achieve results

The study was made possible by a rapidly created international registry that has given critical care experts near real-time data on the use of ECMO in COVID-19 patients since early in the year.

Hosted by the organization called ELSO, for Extracorporeal Life Support Organization, the registry includes data submitted by the 213 hospitals on four continents whose patients were included in the new analysis. The paper includes data on patients age 16 or older who were started on ECMO between January 16 and May 1, and follows them until death, discharge from the hospital, or August 5, whichever occurred first. The team will present the findings at the ELSO Annual Meeting on Sept. 26.

“These results from hospitals experienced in providing ECMO are similar to past reports of ECMO-supported patients, with other forms of acute respiratory distress syndrome or viral pneumonia,” says co-lead author Ryan Barbaro, M.D., M.S., of Michigan Medicine, the University of Michigan’s academic medical center. “These results support recommendations to consider ECMO in COVID-19 if the ventilator is failing. We hope these findings help hospitals make decisions about this resource-intensive option.”

Co-lead author Graeme MacLaren, MBBS, of the National University Health System in Singapore, notes, “Most centers in this study did not need to use ECMO for COVID-19 very often. By bringing data from over 200 international centers together into the same study, ELSO has deepened our knowledge about the use of ECMO for COVID-19 in a way that would be impossible for individual centers to learn on their own.”

Insights into patient outcomes

Seventy percent of the patients in the study were transferred to the hospital where they received ECMO. Half of these were actually started on ECMO — likely by the receiving hospital’s team — before they were transferred. This reinforces the importance of communication between ECMO-capable hospitals and non-ECMO hospitals that might have COVID-19 patients who could benefit from ECMO.

The new study could also help identify which patients will benefit most if they are placed on ECMO.

“Our findings also show that mortality risk rises significantly with patient age, and that those who are immunocompromised, have acute kidney injuries, worse ventilator outcomes or COVID-19-related cardiac arrests are less likely to survive,” continues Barbaro, who chairs ELSO’s COVID-19 registry committee and provides ECMO care as a pediatric intensive care physician at U-M’s C.S. Mott Children’s Hospital. “Those who need ECMO to replace cardiac function as well as lung function also did worse. All of this knowledge can help centers and families understand what patients might face if they are placed on ECMO.”

“The lack of reliable information early in the pandemic hampered our ability to understand the role of ECMO for COVID-19,” says co-senior author Daniel Brodie, M.D., of New York Presbyterian Hospital. “The results of this large-scale international registry study, while hardly definitive evidence, provide a real-world understanding of the potential for ECMO to save lives in a highly selected population of COVID-19 patients.” Brodie shares senior authorship with Roberto Lorusso, M.D. of the Maastricht University Medical Center in the Netherlands and Alain Combes, M.D. of Sorbonne University in Paris.

A robust statistical approach

Because the ELSO database does not track what happens to patients once they are discharged to home, other hospitals, and long-term acute care or rehabilitation facilities, the study used a statistical approach based on in-hospital mortality up to 90 days after the patient was put ECMO. This also allows the team to account for the 67 patients who were still in the hospital as of August 5, whether they were still on ECMO, in the ICU or in step-down units.

Philip Boonstra, Ph.D., of the U-M School of Public Health, helped design the study using a “competing risk” approach, based on his experience handling the statistical design and analysis of long-term data from clinical trials for cancer.

“We used 90-day in-hospital mortality because this is the highest-risk period, and because it allows us to use the information we have to the fullest, even if we don’t know the final outcome for every patient,” he says.

Having data through August, when only a small number of the patients in the study remained in the hospital, was important — though data are missing on a small number of patients. And even though patients who were discharged to their homes or a rehabilitation facility will likely have a long recovery ahead after the intensive level of care involved in ECMO, they are likely to survive based on past data. However, the fate of those who went to LTAC facilities, which provide long-term care at a near-ICU level, is less certain.

More about the study and next steps

More than half of the patients in the study were treated in hospitals in the United States and Canada, including Michigan Medicine’s own hospitals. U-M’s Robert Bartlett, M.D., emeritus professor of surgery and a co-author of the new paper, is considered a key figure in the development of ECMO, including the first use in adults in the 1980s. Bartlett led the development of the initial guidance for the use of ECMO in COVID-19.

“ECMO is the final step in the algorithm for managing life-threatening lung failure in advanced ICUs,” says Bartlett. “Now we know it is effective in COVID-19.”

As of August 5, 380 of the patients in the study had died in the hospital, more than 80% of them within 24 hours of a proactive decision to discontinue ECMO care because of a poor prognosis. Of the remaining patients 57% had gone home or to a rehabilitation center (311 patients); had been discharged to another hospital or a long-term acute care center (277 patients). The rest were still in the hospital but had reached 90 days after start of ECMO.

The new study adds to the information used to create the ECMO COVID-19 guidelines published by ELSO, which is in part based on past randomized controlled trials of ECMO’s use in ARDS.

Barbaro and others are studying the longer-term effects of ECMO care for any patient; he leads a team that has recently received a National Institutes of Health grant for a long-term study of children who have survived after treatment with ECMO.

Meanwhile, the ELSO registry continues to track the care of patients placed on ECMO because of COVID-19. Christine Stead, the chief executive officer of ELSO, credits the rapid pivot and intense teamwork among ECMO centers and their staff for the strength of the new paper.

“We started with a WeChat dialogue with teams in China, who were able to share knowledge and help their counterparts in Japan be ready for the spread to their country,” she says. “We asked all the centers that take part in ELSO to change their practice, and begin entering data about patients as soon as they were placed on ECMO, rather than waiting until they were discharged from the hospital. This has allowed us to achieve something that will help hospitals make more informed decisions, based on meaningful data, as the pandemic continues.”

In collaboration with the Medical University of South Carolina, researchers at the National Institute of Standards and Technology (NIST) analyzed urine samples from pregnant women to look for the presence of DINCH, which is short for di(isononyl)cyclohexane-1,2-dicarboxylate. They found concentrations of DINCH in most of the urine samples but no evidence of effects in lab assays on two hormones, progesterone and estrogen. The researchers have published their findings in the journal Chemosphere.

Phthalates are often called plasticizers and can be found not only in personal care products to help them maintain a gel-like consistency but also in garden hoses, inflatable toys and medical tubing. “They are used to provide flexibility in plastics. Think of a rubber ducky and how squishy it is. That’s because of phthalates in vinyl,” said NIST researcher John Kucklick.

However, phthalates can disrupt the hormonal or endocrine system, which may cause pregnancy loss, infertility and harmful effects on the delivery of a baby.

As a result, many manufacturers have replaced phthalates with chemicals such as DINCH, another type of plasticizer, but less is known about the effects of this chemical compound on humans. DINCH has been used since 2002 in commercial products such as toys, medical devices and food packaging.

“People are exposed to different compounds, and we find out about some of them, such as phthalates, which are being replaced by industry,” said NIST researcher Jessica Reiner. “We may or may not know a lot of information about these new compounds, but studies like this one are always looking to understand if they’re a good substitute compared with other ones.”

Once DINCH enters the human body, it is processed and broken down into compounds called metabolites and excreted in the urine. The researchers collected urine samples over a period of four years from a total of 100 pregnant women living in the Charleston, South Carolina, area who planned to deliver at the Medical University of South Carolina medical center. The samples were then analyzed to check for DINCH metabolites.

Plasticizers are found everywhere, and it is challenging to measure the compound by itself because of all the possible contamination sources in the lab. “So, we look at the metabolites that have gone through a person, and they’re only found in urine and not found anywhere else. It’s much easier to measure than the unmetabolized compound,” said Kucklick.

At the Hollings Marine Laboratory in Charleston, NIST researchers analyzed urine samples for three DINCH metabolites using liquid chromatography (a technique that separates a sample into its individual parts) and tandem mass spectroscopy (which measures the mass-to-charge ratio of ions). Results showed that one type of DINCH metabolite, OH-MINCH, was detected in 98% of the urine samples. But the concentration levels of the metabolite were low and 275 times less than the most prevalent phthalate metabolite, monoethyl phthalate, suggesting that levels of human exposure to DINCH are smaller. But researchers weren’t just looking at concentration levels of DINCH.

Another aspect of the study was to analyze DINCH exposure by race. Of the 100 pregnant women, half were African American, while the others were Caucasian. Concentrations of OH-MINCH were 50% higher in African American women compared to Caucasian women, which was consistent with a 2017 study that looked at phthalate levels, led by Abby Wenzel, a NIST postdoctoral researcher at the time.

Researchers hypothesized the difference in concentration levels could be attributed to the type of personal care products that African American women use compared with Caucasian women and that these products are also replacing phthalates with DINCH. But further follow-up studies are needed to understand the reasons for this discrepancy, the researchers said.

The researchers did not find evidence that the DINCH metabolites interfered with regulating the signaling of specific hormones required for pregnancy. Using a method called transactivation assay, they added the metabolites to chemical receptors in test tubes for two types of hormones: estrogen, which is involved in sexual reproduction, and progesterone, which is involved in pregnancy. The researchers monitored whether the DINCH metabolites acted in ways similar to the hormones or interfered with the regulation of the hormones. No effects were observed in this study, but, according to Kucklick, that doesn’t mean they aren’t there.

This work may lay the foundation for future standard reference materials that could benefit research by organizations such as the Centers for Disease Control and Prevention, which is also studying these compounds, especially phthalates in urine. Another area of interest is how DINCH works in the body. But more immediately, additional testing and analysis needs to be conducted to make sure the use of DINCH does not have long-term consequences.

“We’re always trying to learn about the chemicals we don’t know about. It’s good to understand what we’re being exposed to and what some of the downsides of what these chemicals might be,” said Kucklick.

“Our study shows that patients from Hispanic neighborhoods did not have the same rebound in non-COVID-19 admissions as other groups, which points to a much broader issue of healthcare access and equity for lower-income and minority patients,” said senior author and health economist Jonathan Skinner, a professor at the Dartmouth Institute for Health Policy and Clinical Practice at the Geisel School of Medicine, and the James O. Freedman Presidential Professor in Economics at Dartmouth. As a result, these barriers may have contributed to higher in-hospital mortality rates in April for this group than for others,” he added.

The study drew on data from 1 million hospital admissions (from hospital administrative data and electronic medical and billing records) from Sound Physicians, a large nationally distributed medical group with hospitals throughout the U.S. The data came from 201 hospitals in 36 states, including areas hit hard early on by the pandemic, including Wash., Mich., Ohio, and the greater metropolitan area of New York.

The research team looked at non-COVID-19 admissions for the top 20 acute medical conditions, from early February through early July. They found that non-COVID-19 admissions fell in March and reached its lowest point in April. The rebound leveled off in June/July, which was when there was a resurgence of COVID-19 cases in some regions.

The study’s results reports the following:

• From February to April 2020, declines in non-COVID-19 admissions were similar across all demographic subgroups exceeding 20 percent for all primary admission diagnoses.
• The lowest point in non-COVID-19 admissions was in April during which the overall decline was 43 percent.
• By late June/early July 2020, non-COVID-19 admissions had only made a partial rebound at 16 percent below pre-pandemic baseline volume. (Updated data suggests this partial rebound continued through the summer.)
• During the June/July rebound period, non-COVID-19 admissions were substantially lower for patients from majority-Hispanic neighborhoods (32 percent below baseline) and remained well below baseline for patients with pneumonia (44 percent below baseline), chronic obstructive pulmonary disease/asthma (40 percent below baseline), sepsis (25 percent below baseline), urinary tract infection (24 percent below baseline) and acute ST-elevation myocardial infarction/heart attack (22 percent below baseline).

These particular diseases are reported in the results, as these were the acute conditions for which the declines were the highest. Most of the majority-Hispanic neighborhoods in this dataset were located in the Southwest and South — Calif., Ariz., Texas, and Fla.

The research team speculate that the declines in medical admissions may have been due in part to a fear of contracting COVID-19 by both physicians and patients, greater use of telemedicine, and possibly lower transmission rates of non-COVID-19 diseases following stay-at-home orders.

Authors include: Jonathan Skinner, senior author; John Birkmeyer, lead author and chief clinical officer of Sound Physicians, and an adjunct professor at Dartmouth Institute for Health Policy and Clinical Practice at the Geisel School of Medicine at Dartmouth; Amber Barnato and Nancy Birkmeyer at the Dartmouth Institute for Health Policy and Clinical Practice at the Geisel School of Medicine at Dartmouth; and Robert Bessler from Sound Physicians. The study was funded by the National Institute on Aging.

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