Triplet Shows 'Promising' Activity in Unresectable/Metastatic CRC

Combining an EGFR inhibitor with a pair of checkpoint inhibitors can produce “promising” activity in certain patients with colorectal cancer (CRC), according to an investigator from a phase 2 trial.

The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.

Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).

Immune activation?

The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.

In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.

“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Lee said.

In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.

“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Lee said.

Single-arm study

Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.

The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.

Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.

As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.

Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.

The best response rate (confirmed and unconfirmed) at any time was 41%.

At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.

There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.

Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).

‘Disappointing PFS’

In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”

“These are great questions and thoughts I’ve had as well,” Lee replied.

He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.

Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.

Regarding PFS, Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.

The current study was funded by Amgen and Bristol Myers Squibb. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Biden Overturns Trump Ban on Transgender Troops

President Joseph R. Biden has overturned the ban on transgender people serving in the US military ordering that it must accept all Americans willing to serve and stating that gender identity should not prevent individuals from enlisting or serving.

The Executive Order reverses a Trump administration policy that prevented transgender individuals from joining the military and discharged anyone who sought to transition. Although it was announced in 2017, a flurry of lawsuits kept it from taking effect until 2019, soon after the US Supreme Court said enforcement could proceed while litigation in the lower courts continued.

“It is my conviction as Commander in Chief of the Armed Forces that gender identity should not be a bar to military service,” said Biden in the executive order. “Moreover, there is substantial evidence that allowing transgender individuals to serve in the military does not have any meaningful negative impact on the Armed Forces,” he said.

The Biden order will restore the policy that existed under President Barack Obama’s administration.

The American Medical Association (AMA) said it welcomed Biden’s order. “There is no medically valid reason to exclude” transgender individuals, said AMA President Susan R. Bailey, MD, in a statement. “Ending this discriminatory policy is a win for all patriotic Americans who want to serve their country,” Bailey noted.

The American Psychiatric Association has voiced its opposition to a ban on transgender service multiple times over the past few years, most recently in April 2019 when the Trump policy went into effect.

“We look forward to a speedy implementation of inclusive policy,” said Aaron Belkin in the same Palm Center statement. Belkin is director of the Palm Center, a nonpartisan research institute that conducts scholarly analysis of US military personnel policy, with a focus on LGBTQ populations.

“Incredible Victory”

The Palm Center issued a report in November that found the Trump administration policy had harmed recruitment, retention, unit cohesion, morale, medical care, and good order and discipline. The organization has estimated that just under 15,000 transgender individuals serve in the military.

“This is an incredible victory for our clients and sends a message that transgender people not only belong in our armed services, but in our country,” tweeted the American Civil Liberties Union, which represented multiple individuals who sued the Trump administration.

“President Biden’s order allows us to put this shameful episode behind us and marks the beginning of a much brighter era in which military service is once again based on a person’s qualifications, not on who they are,” Shannon Minter, legal director of another organization that sued over the Trump policy, the National Center for Lesbian Rights, said in a release.

Retired Army Lieutenant Colonel Ann Murdoch, president of the Transgender American Veterans Association (TAVA), said in a statement that “transgender and gender nonconforming patriots have been serving in the US Armed Forces since 1776 with great distinction and we celebrate the fact that they can now do so openly, without fear of politically driven discrimination.”

For years, transgender patriots were forced to continue to hide their identity while serving in our military, according to the Human Rights Campaign. However, today, thanks to President Joe Biden, Secretary Lloyd Austin, and pro-equality voters across America, they may live and serve openly as themselves. The government will begin the process to eliminate an arbitrary and discriminatory executive action that has not only harmed transgender service members but our entire military, said Alphonso David, president of the Human Rights Campaign.

At least one US politician, Sen. John Cornyn, a Texas Republican, seemed to take issue with Biden’s order, tweeting: “Another ‘unifying’ move by the new Administration?”

Service Members Reinstated

The Biden order not only allows anyone to enlist and serve if they meet the qualifications set by the various service branches, but it also directs the military to establish a process so that personnel can transition during service.

The order would also let service members seek reinstatement, “should they wish to do so and meet the current entry standards,” according to the order.

The order also gives protections to anyone currently serving, stating that it prohibits involuntary separations, discharges, and denials of reenlistment or continuation of service based on gender identity or under circumstances relating to gender identity.

Military officials should examine the records of any service members and correct any “injustice” that was meted out because of an individual’s gender identity, according to the order.

Biden gave the military 60 days to report on its progress. The newly sworn in Secretary of Defense, Lloyd Austin, reportedly said at his confirmation hearing that he supported overturning the ban on transgender service. 

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More Than One Third of COVID-19 Infections Are Asymptomatic

Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.

A systematic review suggests at least one third of SARS-CoV-2 infections occur in people who never develop symptoms, providing strong evidence for the prevalence of asymptomatic infections.

The finding that nearly one in three infected people remain symptom-free suggests testing should be changed, the investigators note.

“To reduce transmission from people who are presymptomatic or asymptomatic, we need to shift our testing focus to at-home screening,” lead author Daniel Oran, AM, told Medscape Medical News. “Inexpensive rapid antigen tests, provided to millions of people for frequent use, could help us significantly reduce the spread of the virus.”

The systematic review was published online January 22 in Annals of Internal Medicine.

The findings come at a dire time when the official number of COVID-19 cases in the United States exceeds 25 million for the first time. Public health officials have raised concerns about more transmissible, and possibly more deadly, variants of SARS-CoV-2, while a new presidential administration tries to meet the challenge of improving vaccine distribution and acceptance rates.

The results also build on earlier findings from the same research team — Oran and senior author Eric Topol, MD — that published a review article looking at asymptomatic COVID-19 cases. Even though initial data were more limited, they likewise suggested a broader scope of testing is warranted, pointing out that asymptomatic individuals can transmit SARS-CoV-2 for up to 14 days. Topol is also editor-in-chief of Medscape.

In the current systematic review, the highest-quality evidence comes from large studies in England and Spain. The nationally representative evidence included serologic surveys from more than 365,000 people in England and more than 61,000 in Spain. When analyzed separately, about the same proportion of asymptomatic cases emerged: 32.4% in England and 33% in Spain.   

“It was really remarkable to find that nationwide antibody testing studies in England and Spain — including hundreds of thousands of people — produced nearly identical results: about one third of the SARS-CoV-2 infections were completely asymptomatic,” said Oran, a researcher at Scripps Research Translational Institute in La Jolla, California.

The systematic review included 43 studies with PCR testing for active SARS-CoV-2 infection and another 18 with antibody results that indicated present or previous infection. The studies were published up until November 17, 2020.

An appreciation for asymptomatic transmission of SARS-CoV-2 infection has come a long way from initial dismissals about its importance, Topol noted via Twitter. “When Dr @camilla_rothe reported an asymptomatic transmission a year ago, the @NEJM report was refuted and disparaged. She was later named a TIME 100 Person of the Year.”

Not Symptomatic vs Never Symptomatic

The term “asymptomatic” could be misleading because some people in this group do progress to develop signs of infection. This “presymptomatic” group of patients is likely a minority, the authors note. Longitudinal studies indicate that about three quarters of people who are asymptomatic with SARS-CoV-2 remain so.

Topol anticipated the one-third asymptomatic finding could draw some feedback about distinguishing asymptomatic from presymptomatic individuals. He tweeted, “Some will argue that there is admixture with presymptomatic cases, but review of all the data supports this estimate as being a conservative one.”

The heterogeneity of the settings, populations and other features of the studies prevented the authors from performing a meta-analysis of the findings.

Home Is Where the Test Is?

Based on their findings, Oran and Topol believe “that COVID-19 control strategies must be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection,” they write. They suggest frequent use of inexpensive, rapid home tests to identify people who are asymptomatic or presymptomatic, along with programs and housing provided by the government to offer financial assistance and allow this group of people to isolate themselves.

Further research is warranted to determine if and how well vaccines for SARS-CoV-2 prevent asymptomatic infection.

Topol and Oran created a short video to highlight the findings from their systematic review.

The study was supported by a grant from the National Institutes of Health.

Ann Intern Med. Published online January 22, 2021. Full text

Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology, and critical care. Follow Damian on Twitter:  @MedReporter.

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The Changing Brain Signature of HIV

Combination antiretroviral therapy (cART) has shifted HIV infection from a fatal to a chronic condition. New evidence now suggests this has been accompanied by a shift in the profile of HIV-related brain abnormalities beyond the basal ganglia, frequently implicated in the pre-cART era, to limbic structures.

“This shift in subcortical signatures may be contributing to the increasing range of neuropsychiatric and cognitive outcomes,” write Neda Jahanshad, PhD, University of Southern California Keck School of Medicine, and colleagues.

The study was published online January 15 in JAMA Network Open.

Brain Signature of HIV

The researchers with the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium examined structural brain associations with CD4+ T cell counts and HIV viral load.

These clinical markers are the most consistently available in studies of HIV and generalize across demographically and clinically diverse HIV-infected individuals, they point out. However, the degree to which they capture central nervous system (CNS) injury is not fully understood.

In this cross-sectional study of 1203 HIV-infected adults from 13 HIV neuroimaging studies, a lower CD4+ T-cell count was associated with smaller hippocampal and thalamic volume independent of treatment status. However, in a subset of adults not on cART, a lower CD4+ T-cell count was associated with smaller putamen volume.

Across all participants, detectable viral load was associated with smaller hippocampal volume, but in the subset on cART, detectable viral load was also associated with smaller amygdala volume.

The findings indicate that plasma markers universally used to monitor immune function and response to treatment in patients with HIV infection are associated with subcortical brain volume.

“Our findings,” they add, “extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.”

A limitation of the analysis is that most of the participants were men (n = 880, 73%). “A more extensive international effort assessing the neurologic effects of HIV infection in women is needed,” they conclude.

This analysis, they add, demonstrates the feasibility and utility of a global collaborative initiative to understand the neurologic signatures of HIV infection. They invite other HIV researchers to join the ENIGMA-HIV consortium.

“With a greater collaborative effort, we will be able to assess factors that may modulate neurologic outcomes, including cART treatment regimens, comorbidities, coinfections, substance use, socioeconomic factors, and demographic factors, as well as the functional implications of such structural brain differences, in well-powered analyses,” the researchers say.

“Understanding the neurobiological changes that may contribute to neuropsychiatric and cognitive outcomes in HIV-positive individuals is critical for identifying individuals at risk for neurologic symptoms, driving novel treatments that may protect the CNS, and monitoring treatment response,” they add.

Support for this research was provided by grants from the National Institutes of Health, the SA Medical Research Council, the National Health and Medical Research Council and the European Research Council. Jahanshad received partial research support from Biogen Inc for work unrelated to the topic of this article. A complete list of author disclosures is in the original article.

JAMA Netw Open. 2021;4:e2031190. Full text

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Stem Cell Transplant Shows Long-term Benefit in MS

The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show.

The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.

Patients with relapsing-remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years

Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.

Dr Matilde Inglese

“This is the longest follow-up of AHSCT in MS patients so far to be reported,” study author Matilde Inglese, MD, University of Genoa, Genoa, Italy, told Medscape Medical News. “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”

The study was published online in Neurology on January 20.

“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors conclude in their article.

The study had no control group, so a direct comparison is not possible. Nevertheless, Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.

“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Inglese commented. “Younger patients with an aggressive form of relapsing-remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”

The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.

“We are effectively renewing the immune system,” Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”

Other results from the study show that among patients with relapsing-remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.

Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing-remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.

For patients with relapsing-remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.

Among those patients with relapsing-remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.

Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.

Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate ― about 0.3% ― thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.

However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.

In the Neurology article, the authors conclude: “Although patients with RRMS [relapsing-remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.

“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they write.

Commenting on these latest findings for Medscape Medical News, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis, the Cleveland Clinic, Cleveland, Ohio, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”

The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Cohen noted. He added, “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”

He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort,” he said.

To address that question, several randomized trials comparing AHSCT to high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Cohen is the lead investigator) and four European trials ― NET-MS (for which Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.

The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Inglese has disclosed no relevant financial relationships.

Neurology. Published online January 20, 2021. Abstract

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Myocarditis May Be Rare After COVID-19 in Elite Athletes

Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.

Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.

Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).

That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.

The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could potentially be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculate.

The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.

One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published January 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin-Madison.

“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, told theheart.org | Medscape Cardiology.

Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”

The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”

The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.

Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published December 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tennessee.

Reassurance and Concern

“The incidence is much lower than we feared, and so that’s reassuring,” Clark told theheart.org | Medscape Cardiology. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”

The study’s two non-COVID-19 control groups — elite athletes in one and nonathletes in the other — allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).

As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Clark said.

The LGE finding, write Clark and his Vanderbilt coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”

Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.

“And you get a little bit in the mid-septum, as well,” Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”

Conceivably, Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”

It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, observed for theheart.org | Medscape Cardiology.

“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Baggish, who directs the Cardiovascular Performance Program at his center and is unaffiliated with either study.

Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, cautions an accompanying editorial from Jonathan H. Kim, MD, MSc.

Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argues Kim, from Emory University School of Medicine, Atlanta.

There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”

Interestingly, the estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”

The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”

Routine CMR for Positive Cases

The University of Wisconsin group looked at all of their institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.

The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.

All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group writes. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.

Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report notes.

The Vanderbilt analysis from Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.

They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.

The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reports.

The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group writes. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.

At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Baggish noted, so their clinical implications are unknown.

“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”

Starekova had no disclosures. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other couthors are in the report. Clark and his coauthors had no disclosures. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.

Circulation. Published online December 17, 2020. Full text

JAMA Cardiol. Published online January 14, 2021. Full text, Editorial

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Health Experts Blame Rapid Expansion for Vaccine Shortages

Editor’s note: Find the latest COVID-19 news and guidance in Medscape’s Coronavirus Resource Center.

People who had appointments to get COVID-19 vaccinations talk to New York City healthcare workers, Thursday, January 21, outside a closed vaccine hub in the Brooklyn borough of New York City after they were told to come back in a week due to a shortage of vaccines.

Public health experts Thursday blamed COVID-19 vaccine shortages around the US in part on the Trump administration’s push to get states to vastly expand their vaccination drives to reach the nation’s estimated 54 million people age 65 years and over.

The push that began over a week ago has not been accompanied by enough doses to meet demand, according to state and local officials, leading to frustration and confusion and limiting states’ ability to attack the outbreak that has killed over 400,000 Americans.

Over the past few days, authorities in California, Ohio, West Virginia, Florida, and Hawaii warned that their supplies were running out. New York City began canceling or postponing shots or stopped making new appointments because of the shortages, which President Joe Biden has vowed to turn around. Florida’s top health official said the state would deal with the scarcity by restricting vaccines to state residents.

The vaccine rollout so far has been “a major disappointment,” said Eric Topol, MD, head of the Scripps Research Translational Institute.

Problems started with the Trump administration’s “fatal mistake” of not ordering enough vaccine, which was then snapped up by other countries, Topol said. Then, opening the line to senior citizens set people up for disappointment because there wasn’t enough vaccine, he said. The Trump administration also left crucial planning to the states and didn’t provide the necessary funding.

“It doesn’t happen by fairy dust,” Topol said. “You need to put funds into that.”

Last week, before Biden took over as president, the US Health & Human Services Department suggested that the frustration was the result of unrealistic expectations among the states as to how much vaccine was on the way.

But some public health experts said that the states have not been getting reliable information on vaccine deliveries and that the amounts they have been sent have been unpredictable. That, in turn, has made it difficult for them to plan how to inoculate people.

“It’s a bit of having to build it as we go,” said George Rutherford, MD, an epidemiologist at the University of California, San Francisco. “It’s a front-end supply issue, and unless we know how much vaccine is flowing down the pipe, it’s hard to get these things sized right, staffed, get people there, get them vaccinated, and get them gone.”

State health secretaries have asked the Biden administration for earlier and more reliable predictions on vaccine deliveries, said Washington state Health Secretary Umair Shah, MD, MPH.

Marcus Plescia, MD, MPH, of the Association of State and Territorial Health Officials was also among those who said opening vaccinations to senior citizens was done too soon, before supply could catch up.

“We needed steady federal leadership on this early in the launch,” Plescia said. “That did not happen, and now that we are not prioritizing groups, there is going to be some lag for supply to catch up with demand.”

Supply will pick up over the next few weeks, he said. Deliveries go out to the states every week, and the government and drugmakers have given assurances that large quantities are in the pipeline.

The rollout has proceeded at a disappointing pace. The US government has delivered nearly 38 million doses of vaccine to the states, and about 17.5 million of those have been administered, according to the Centers for Disease Control and Prevention.

About 2.4 million people have received the necessary two doses, by the CDC’s count — well short of the hundreds of millions who will have to be inoculated to vanquish the outbreak.

Biden, in one of his first orders of business, signed 10 executive orders to combat the coronavirus pandemic on January 21, including one broadening the use of the Defense Production Act to expand vaccine production. The 1950 Korean War-era law enables the government to direct the manufacture of critical goods.

He also mandated masks for travel — including in airports and on planes, ships, trains, buses, and public transportation — and ordered the Federal Emergency Management Agency to set up vaccination centers and the CDC to make vaccines available through pharmacies starting next month.

Biden has vowed to dispense 100 million shots in his first 100 days.

“We’ll move heaven and earth to get more people vaccinated for free,” he said.

Florida was one of the first states to open vaccine eligibility to members of the general public over age 65. Now uncertainty over the vaccine supply has prompted the state surgeon general, Scott Rivkees, MD, to advise counties to prioritize available doses for state residents, including so-called snowbirds who live there part-time. People seeking vaccination will have to provide a driver’s license or other document, such as rental leases and utility bills.

In New York, Mayor Bill de Blasio and Gov. Andrew Cuomo have been pleading for more doses. Appointments through January 24 for the first dose of the vaccine at 15 community vaccination hubs set up by the city health department were postponed to the following week.

Vaccinations in New York haven’t stopped, but demand for the shots now far exceeds the number of doses available, the mayor said.

“It’s just tremendously sad that we have so many people who want the vaccine and so much ability to give the vaccine, what’s happening?” de Blasio said. “For lack of supply, we’re actually having to cancel appointments.”

Rosa Schneider had jumped at the chance to make a vaccination appointment once she heard that educators like her were eligible in New York. A high school English teacher who lives in New York City but works in New Jersey, she said that a day before she was to be vaccinated at a city-run hospital, she got a call saying the supply had run out and the appointment was canceled.

“I was concerned, and I was upset,” said Schneider, 32, but she is trying daily to book another appointment. She is hopeful availability will improve in the coming weeks.

Associated Press writer Jennifer Peltz contributed to this report from New York.

New AHA Scientific Statement on Mind-Heart-Body Connection

Healthcare professionals should consider psychological health in adults with or at risk for cardiovascular disease (CVD), the American Heart Association (AHA) advises in a new scientific statement.

The statement, Psychological Health, Well-Being, and the Mind–Heart–Body Connection, notes that psychological health can positively or negatively impact a person’s health and risk factors for heart disease and stroke.

Glenn Levine

The AHA previously issued a scientific statement that dealt strictly with depression and one that dealt with meditation, but “this is the first such scientific statement to more broadly address the issue of psychological health,” writing group chair Glenn N. Levine, MD, chief of cardiology, Michael E. DeBakey VA Medical Center in Houston, told theheart.org | Medscape Cardiology.

“This was particularly important to do now given the COVID crisis and all the psychological stress people are under the past year,” said Levine, professor of medicine, Baylor College of Medicine, Houston.

“Irrespective of that, it is clearly time that we recognize that we should strive to treat not only the disease, but the patient and the person as a whole,” he added.

The statement was published online January 25 in Circulation.

Heart, Body, and Mind Interconnected

The task of the writing group was to evaluate, synthesize, and summarize available evidence on the relation between psychological and CV health and to offer simple steps to screen for and ultimately improve the psychological health of patients with or at risk for CVD.

Depression, chronic stress, anxiety, anger, pessimism, and life dissatisfaction are all associated with potentially harmful biologic responses. These include irregularities of heart rate and rhythm; increased digestive complaints, blood pressure and inflammation; and reduced blood flow to the heart, the writing group notes.

“A large body of study data now make it clear that psychological health can impact a patient’s heart health, just as diabetes, hypertension, and hyperlipidemia can, and that improving our patients’ psychological health is likely to lead to reduced cardiac risk down the road,” Levine said.

The cumulative effect of daily stressors and exposure to traumatic events can also increase the risk for CVD. Patients’ self-reports of general and work-related stress have been associated with an up to 40% increased risk of developing or dying from CVD, the writing group notes.

“Most studies of psychological health are observational, with many involving self-reporting from patients, which presents challenges to establishing specific cause and effect relationships,” Levine said in a news release.

“However, a preponderance of such studies is highly suggestive and allows one to make reasonable conclusions about an association between negative psychological health and cardiovascular risk,” he noted.

Negative psychological health is also associated with health behaviors that raise the risk for CVD, including smoking, lower levels of physical activity, unhealthy diet, being overweight, and not taking medications as prescribed.

The writing group advises regular mental health screening for people with or at risk for CVD, and notes that psychological therapy and mind–body programs can lead to better heart health.

Programs that improve psychological health include cognitive behavioral therapy, psychotherapy, collaborative care management approaches, stress reduction therapy, and meditation.

On a Positive Note

Studies have also shown that positive psychological health — including happiness, gratitude, sense of purpose, life satisfaction, and mindfulness — is associated with a lower risk for CVD and a greater likelihood of beneficial health behaviors.

These include smoking cessation, increased physical activity, heart-healthy eating, increased medication adherence, and regular check-ups and health screenings.

People with better mental health also tend to have positive social relationships, support, and connections, which can facilitate healthier adaptation to life’s challenges.

“We hope that clinicians will understand and recognize that we need to consider not only the patient’s specific disease, but the patient’s psychological health as well,” Levine told theheart.org | Medscape Cardiology.

“For example, depressed patients are less likely to take the medications we prescribe. Just as we assess and treat more standard cardiac risk factors, such as hypertension and hyperlipidemia, so should we assess and address psychological factors, which can also impact our patients cardiac risk and prognosis,” he said.

The writing group has no relevant disclosures. This s cientific statement was prepared by the volunteer writing group on behalf of the AHA Council on Clinical Cardiology; the Council on Arteriosclerosis, Thrombosis and Vascular Biology; the Council on Cardiovascular and Stroke Nursing; and the Council on Lifestyle and Metabolic Health.

Circulation. Published online January 25, 2021. Abstract