Immunotherapy May Help Severe COVID-19 Patients

July 24, 2020

Interleukin 7 (IL-7) immunotherapy given to a small group of critically ill COVID-19 patients was associated with significantly restored lymphocyte counts, a case series in Belgium indicated.

A total of 12 critically ill COVID-19 patients with low lymphocyte count received IL-7, and compared with a control group of 13 patients given usual care, the IL-7 group was associated with lymphocyte levels more than twofold greater than controls at day 30, reported Pierre Francois Laterre, MD, of Université Catholique de Louvain in Brussels, and colleagues.

While the mortality rate was similar in both groups, the IL-7 group had a lower proportion of infections at day 30 compared with controls (50% vs 85%, respectively), the authors wrote in a research letter in JAMA Network Open.

They noted that COVID-19 has been called “a serial lymphocyte killer,” and that nearly all patients with severe forms of the disease experience lymphopenia, which also correlates with morbidity and mortality. CD4, CD8, and natural killer cells that play important antiviral roles are depleted in autopsies, leading to “immune collapse,” the team added.

“Clinical and pathological findings in patients with COVID-19 indicate that immunosuppression is a critical determinant of outcomes,” the authors wrote, with secondary hospital infections occurring in 50% of patients. “Impaired immune competence is an important pathogenic mechanism in COVID-19.”

IL-7 is currently being evaluated in randomized trials for both oncologic and infectious disorders, and the researchers noted that it is also being evaluated specifically for COVID-19 in a randomized trial in the U.K.

The therapy has previously shown that it can restore lymphocyte counts, leading to both “decreased viral load and clinical improvement in several life-threatening viral infections,” and is well tolerated in patients with bacterial sepsis, Laterre and co-authors said.

For inclusion in the study, patients at a medical center in Brussels who were critically ill with COVID-19, with severe lymphopenia and two consecutive absolute lymphocyte counts of less than 700/μL received an initial safety dose of 3 μg/kg of IL-7, followed by an intramuscular injection of 10 μg/kg twice a week for 2 weeks. The control group was matched to the IL-7 group based on severity of illness, comorbidities, and “other factors.”

Patients in the IL-7 group were a mean age of 62, while controls were slightly younger (age 59). Notably, 11 of 12 of the IL-7 group and nine of 13 of the control group were men.

IL-7 was well tolerated without inducing changes in temperature, blood pressure, or PaO2:FiO2 ratio, the researchers reported. Interestingly, they found no consistent association between IL-7 administration and concentration of pro-inflammatory IL-6.

While three patients had decreases in IL-6, and two had increases, “changes in concentration may have been because of changes in the underlying patient physiologic state than because of IL-7,” the researchers wrote, adding that the 30-day mortality rate was similar in both the IL-7 and control groups (five of 12 and six of 13, respectively).

While the investigators noted that no phenotypic or functional studies of immune cells were conducted, they said the findings suggested that IL-7 can be safely given to COVID-19 patients “without exacerbating inflammation or pulmonary injury” and should be studied further in COVID-19 patients with evidence of immunosuppression.

Disclosures

Laterre disclosed no conflicts of interest; one co-author disclosed being an investigator on a sepsis study evaluating interleukin 7, and support from the NIH.

RevImmune provided recombinant human interleukin 7 to the investigators.

Primary Source

JAMA Network Open

Source Reference: Laterre PF, et al “Association of Interleukin 7 Immunotherapy With Lymphocyte Counts Among Patients With Severe Coronavirus Disease 2019 (COVID-19)” JAMA Netw Open 2020; DOI: 10.1001/jamanetworkopen.2020.16485.

https://www.medpagetoday.com/infectiousdisease/covid19/87695

As Schools Weigh Reopening, Dearth of Data on COVID in Kids

As school districts, teachers, parents, and clinicians weigh reopening schools for in-classroom learning next month, it’s not helping that useful data about COVID-19 in children and teens is lacking in many states — especially since case counts in certain age brackets have been rapidly rising in recent weeks.

Many counties and states, and even the National Center for Health Statistics, lump infants, children, and teens into one or two groupings — for example, from 0 to 4 and from 5 to 17. Ohio and a few other states don’t separate them at all, with a single line for those age 0 to 19.

How each state defines a “child” is all over the map. Alabama, for example, reports that 21.7% of its 58,225 COVID cases so far are in youth, but divides them into two groups, 0-4, which has 1,123 cases, and 5-24, which has 11,493. Some of the latter, perhaps most, are adults by any measure.

Yvonne Maldonado, MD, chair of the Committee on Infectious Diseases for the American Academy of Pediatrics (AAP), which has produced weekly reports on the issue of “substantial” discordance in state-by-state pediatric COVID reporting, said the situation is far from optimal.

“All states should provide more granular data regarding symptomatic and asymptomatic infections in children, as well as age breakdown, number of hospitalizations, and deaths. Exposure history would also be helpful,” she said in an e-mail.

“While we would prefer that all states provide a standardized age range for children, we are limited by what the states are making publicly available,” Blake Sisk, senior research associate for the AAP and an author of the AAP’s reports, told MedPage Today in an e-mail.

Few states disclose the setting in which children or adolescents tested positive, what percentage of children were tested, whether they were sick or required hospitalization, or whether they died.

Child COVID Data Essential

Yet some experts say this information is essential to control the spread of SARS-CoV-2 as increasing numbers of reports suggest that not only can children become seriously ill with COVID-19, but they can transmit it to other children, their teachers, and other school support staff and their families. Against the common belief that pediatric infections are of little clinical concern, reports have emerged about multisystem inflammatory syndrome in children, and long-lasting effects on the brain.

To date, 66 children have died in the U.S., according to an AAP report issued Monday (which didn’t define “children” either). Another report, issued Wednesday by the Coronavirus in Kids Tracking and Education Project, has documented a total of 77 deaths in children and teens in 23 states, as well as 805 COVID-19 admissions to pediatric intensive care units. That report also included an estimate of 1.9 million pediatric coronavirus infections in the U.S., including undiagnosed cases not counted in official data.

In California, for example, the percentage of children and teens infected with COVID has been rapidly increasing. On April 1, the percentage of all children and teens 17 and younger was just 1.1% of all patients diagnosed with COVID-19. By June 1, it was 5.7%. In the 3 weeks beginning July 1, the percentage increased from 8.03% to 8.7% as California broke records on overall case counts and new pediatric cases in one day.

Irwin Redlener, MD, a pediatrician and founding director of the National Center for Disaster Preparedness at Columbia University, called the discordance in COVID-19 reporting of children and teens “a mess, just a mess. The restriction of data, especially around children right now, is a terribly bad idea.”

He added that these case reports by age bracket are important: “We actually don’t know that much about the disease and the way the virus behaves in children and it would be extremely helpful to have a more precise breakdown.”

“It’s difficult to understand why states aren’t reporting this more precisely, or why they aren’t reporting in ways that are consistent across all states,” he added.

All Over the Map

One state, Florida, seems to be more transparent than most. Florida breaks down pediatric COVID cases not only into five brackets of ages, but also how many in each bracket were hospitalized and how many died. Its report is updated Fridays.

Last week’s report revealed that 6,373 Florida children and teens were diagnosed with COVID-19 in the previous week — July 9 to July 16 — for a total of 23,170 among children age 0-17 since reporting began — and that 246 of those children and teens had been sick enough to be hospitalized (33 in the last seven days). The second highest number of hospitalizations, 51, was among infants less than one year old.

Two deaths were reported in 10- to 14-year-olds and two in those ages 15-17. Of the total new cases, 317 were infants younger than 1, for a total of 1,412.

New York was much less forthcoming. Asked for its pediatric COVID data, Evan Frost, a spokesman for the New York Department of Health, provided data only through May 10, in which 15,515 cases of COVID-19 in people under age 21 were reported to the state.

“All the currently available data related to COVID-19 in New York State can be found on the Department of Health’s COVID-19 tracker,” Frost said. He advised a reporter wanting more current, granular information to file a freedom of information request: “We do not have any other publicly available data.”

Nationally, according to the latest AAP report (prepared with the Children’s Hospital Association), case counts are rising rapidly, with a 46% increase during July 2-16, from 165,845 to 241,904. The report also noted that about 80% of new pediatric cases are in states in the South and West. The report is updated every week.

Howard Taras, MD, a pediatrician and advisor for the large San Diego County Unified School District, said more precise data on COVID in children and teens would be helpful. “For example, if elementary schools in one area opened and not in another, it would be great to compare just elementary school age trends between those two areas,” he said.

But variation in pediatric COVID reporting has been going on for so long that school officials and pediatricians “just try to follow general trends,” Taras said. He noted that “age groups in our buildings are also not clear and consistent,” with a variety of different sets of grade levels among schools.

Diagnosed Cases Likely to Be Sick

Since there is little to no systematic testing of these populations, it’s likely that children who have been tested were those who developed symptoms severe enough to warrant medical attention.

“We don’t have a lot of random testing of children yet because it requires a deep nasal pharyngeal probe, and a lot of kids aren’t going to tolerate that, and without their parents there, that’s not going to happen,” said Redlener.

He said it’s logical to assume that the majority of those children were tested either because they developed COVID symptoms, or were exposed to someone who became ill.

Joshua Sharfstein, MD, of the Johns Hopkins Bloomberg School of Public Health, said that while data granularity for children could improve — Maryland and Baltimore County report pediatric cases from 0 to 9 and 10 to 19, which total 9% of all cases — “it’s probably going to be more important, as more kids get sick, to understand what’s going on.”

Sharfstein said a key point is whether the children are hospitalized or not, and where, exactly, the outbreaks are occurring.

Many policy makers and educators fear a repeat of what happened in Israel, where schools reopened May 17 under a belief the pandemic in their country was over. In the first two weeks of July, a total of 2,026 students, teachers, and staff have contracted COVID-19, and 28,147 are under quarantine.

It’s also important to produce better information to inform policy makers, such as Missouri Gov. Mike Parson (R), who recently belittled the risk to children from the coronavirus.

“And if they do get COVID-19, which they will — and they will when they go to school — they’re not going to the hospitals,” Parson told a radio show host. “They are going to go home and they’re going to get over it.”

Redlener said what’s needed is a uniform reporting system for all states and the CDC to report age-bracketed data the same way.

“So far I don’t see how that’s going to happen unless there’s a federal directive that is telling the schools, you need to do this, you must do this,” Redlener said. “But we’ve had history since February of incompetency and lack of a clear message — lack of consistent guidelines that would apply to the whole country, and that’s why we’re in the mess we’re currently in.”

https://www.medpagetoday.com/pediatrics/generalpediatrics/87711

COVID-19 Tests Will Soon Cover Flu Too, Giroir Says

Future COVID-19 tests will also be able to test for influenza A and B, according to Trump administration “testing czar” Adm. Brett Giroir, MD.

“Most of these tests will be multiplex by flu season — one PCR test will diagnose both influenza A/B or COVID,” Giroir, who is assistant secretary for health in the Department of Health and Human Services (HHS), told MedPage Today during a phone call with reporters Thursday afternoon. “Everybody’s going down that developmental pathway.”

He urged everyone to get their flu vaccine in order to lessen the spread of influenza, which kills 30,000 to 70,000 people each year. “I’m a pediatric ICU doctor; I lost children from influenza every single year of my career, and most of those children — the great majority — didn’t get vaccinated,” he said. “That’s a tragedy.”

Giroir also gave an update on COVID-19 testing nationwide, noting that 51.7 million tests have been administered to date, and that an average of 770,000 tests per day are being conducted. The average positivity rate over the past week stands at 9.08%, Giroir said, adding that the administration “is very concerned about outbreaks occurring across the country, particularly in the Sun Belt states.” He tried to put a positive spin on the situation, however, noting that “our public health measures are starting to make a difference and we are making progress … We are starting to see the 7-day rolling averages of cases starting to turn downwards,” although “no one is declaring victory about this.”

Half of the tests now being done are administered either at the point of care — with a turnaround of 15 minutes — or at local hospitals, where “in general, we know that’s done on one shift, or within 24 hours in general,” he said. The other half is performed by major commercial labs, where “the average turnaround time is 4.27 days.” Giroir added that this number “is not as bad of a number as many people talk about, it’s up 0.8 days from what it was in June, but we’re trying to drive that down” through use of surge testing sites to reduce commercial laboratory burden, and through “pooled” testing, in which the lab combines samples from a group of people in a single test. Pooled testing increases efficiency by 20%-to-30% in the labs that use it, he said.

The administration also is moving more and more to point-of-care testing to reduce demand on commercial labs. “This week we sent 654 point-of-care testing machines to 635 nursing homes, and that’s 196,000 tests,” said Giroir. “Over the next 2 to 3 weeks, we’ll be sending instruments to an additional 1,790 nursing homes; that includes an additional over 806,000 tests.” Overall, he said, based on manufacturer projections, “in August, we expect the availability — it doesn’t mean we’re going to use them all — of approximately 51 million tests, of which 13 million will be point-of-care; in September, it’s approximately 65 million, of which we expect approximately 20 million to be point-of-care.”

In response to a question from MedPage Today, Giroir acknowledged that the point-of-care tests were less sensitive than those performed in clinical labs. “Almost every test has a tradeoff, so it has to be applied in the right surroundings and the right venue,” he said. “The point-of-care tests in general have slightly less sensitivity than the laboratory-based molecular tests, but new data is showing that may not even be true, that we may have one or two of these that are equivalent to those. So the sensitivity might be a little bit less, meaning you have a potential for more false negatives. Every test has a potential for false negatives, including the laboratory tests.”

So if the point-of-care tests are less sensitive, why is HHS still sending them to 15,400 nursing homes? “When you do the mathematical analysis with everything built in, if you have a point-of-care test that’s a little bit less sensitive, that beats a more sensitive test that you have to wait 2 days for, every single day, because you can act on that right there,” he said. “Ideally you have a 100% sensitive, 100% specific test that’s available in 2 minutes; we don’t have that, so we’re applying this ecosystem in the optimum way for the use case that we have.”

As for testing supplies, such as swabs and media, “we had a huge mobilization to get where we are, states tell us what we need every month and we send it,” he said. “The federal government purchases that; they get four shipments to a central location once a week for that month. We rely on the states to make sure they’re summing up their entire state needs.”

Giroir was also asked about colleges and universities that are considering testing students before allowing them to return to school. “In general, testing people before going back to the university is not a strategy we recommend, because you’re only negative for that one moment,” he said. “You could be positive the next day, and it doesn’t relieve any responsibility about wearing a mask and doing all those kinds of things.”

In addition, “many universities we’ve talked to are doing a strategy which I think is much better — doing surveillance, not diagnostic testing, but surveillance in their university research labs using excess reagents that would not burden the system,” he said. “We’ve been working a long time to make this possible and support universities in doing this, and several universities are doing this exactly.” One advantage of this strategy is that the university doesn’t need an Emergency Use Authorization to do surveillance, which is done through pooled testing.

https://www.medpagetoday.com/infectiousdisease/covid19/87723

FDA OKs Gilead CAR T for rare type of lymphoma

Under Priority Review status, the FDA approves Gilead Sciences (GILD -2.5%) unit Kite Pharma’s CAR T cell therapy Tecartus (brexucabtagene autoleucel) for the treatment of mantle cell lymphoma, a rare and aggressive type of non-Hodgkin lymphoma.

The product’s labeling has a Boxed Warning regarding the risks of cytokine release syndrome (CRS) and neurotoxicities. The Risk Evaluation and Mitigation Strategy (REMS) has been combined with the REMS for Yescarta (axicabtagene ciloleucel).

https://seekingalpha.com/news/3594908-fda-oks-gilead-car-t-for-rare-type-of-lymphoma

Indivior cheers agreement to resolve SUBOXONE Film criminal, civil liability

July 24, 2020

Indivior (OTCPK:INVVY +21.0%) reached an agreement with the U.S. Department of Justice, the Federal Trade Commission, and U.S. state attorneys for resolving its April 2019 criminal and civil liability.

Indivior Solutions, wholly-owned subsidiary of Indivior, pleaded guilty to one count of making a false statement relating to health care matters in 2012.

Over a period of seven years, Indivior will pay $600M to federal and state authorities; also agreed to a stipulated injunction with the FTC.

A five-year Corporate Integrity Agreement with the Office of Inspector General of the Department of Health and Human Services states that Solutions will be excluded from participation in government health programs.

Also, Indivior and subsidiaries will distribute a $100M payment in the week the plea is finalized and approved by a judge.

https://seekingalpha.com/news/3594902-indivior-cheers-agreement-to-resolve-suboxone-film-criminal-and-civil-liability

Mallinckrodt debt plunges after Franklin sale

Mallinckrodt (MNK -10.0%) unsecured bonds are trading at an all-time low of 10 cents on the dollar after Franklin Advisors sold a $500M stake ahead of a coupon payment due July 30. The debt was trading at 80 cents on the dollar two months ago.

The company previously announced that it may use bankruptcy to offload liabilities related to its role in the opioid crisis.

https://seekingalpha.com/news/3594898-mallinckrodt-debt-plunges-after-franklin-sale

Cel-Sci up 5% on positive data on COVID-19 conjugates

CEL-SCI (CVM +4.7%) bucks the broad market’s softness, albeit on below-average volume, after reporting encouraging results from animal studies on its LEAPS COVID-19 conjugates that, it says, showed faster and “much higher than expected” antibody responses against a non-mutating region of SARS-CoV-2 after only one injection. IgG antibody response was noted within 10 days.

Animal challenge studies are next up.

https://seekingalpha.com/news/3594885-cel-sci-up-5-on-positive-data-on-covidminus-19-conjugates