麻豆传媒

Empirical treatment with immunomodulators has worked quickly for severe cases of the apparently connected to COVID-19, according to some reports, although other groups suggest a more conservative approach is just as effective.

The condition, which has been emerging over the past several weeks in the U.S. and since late April in Europe, bears some features in common with the collection of symptoms that define Kawasaki disease. But the differences -- older age, more prominent GI symptoms, higher levels of cardiac injury biomarkers -- have been substantial enough to raise questions about whether treatments should be different, too.

"There are practice variations everywhere," said Nadine Choueiter, MD, of the Children's Hospital at Montefiore in New York City. "That's because there is very little data and people are using their best clinical judgment to treat those patients."

The standard first-line treatment for Kawasaki disease -- intravenous immunoglobulin (IVIG) -- and other immunomodulating therapies used in rheumatoid arthritis (RA) that suppress inflammation have also been used anywhere from 100% to a minority of cases.

IVIG makes sense given that MIS-C has a lot of clinical features that overlap with Kawasaki disease and that it has broad anti-inflammatory action, noted Kevin Friedman, MD, who has been seeing patients with this condition at Boston Children's Hospital. "And this is a highly inflammatory disease with all these elevated inflammatory markers and cytokines."

The NIH has for mechanically-ventilated COVID-19 patients without acute respiratory distress syndrome and only low-dose use for those with refractory shock.

Their use in MIS-C is not recommended unless in a trial, said Vincent Marconi, MD, of Emory University in Atlanta.

But one-third to 70% of MIS-C cases have been treated with steroids, according to a on Tuesday, at which several groups presented their experience.

A smattering of other targeted immune drugs have been used as well, said Friedman. "It's all based on principles of knowing what inflammatory markers are elevated, not that we know it 100% works in this disease."

Clinical presentations vary as well, with many milder cases along with the severe cases that have drawn the most attention in the popular media, noted Friedman, a member of the American Heart Association's and its Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee.

Following are highlights from the CDC webinar on how the groups treated MIS-C patients under the urgent circumstances prevailing at the time -- meaning that diagnoses and treatments weren't standardized, and there were no control groups to shed light on the therapies' comparative effectiveness.

U.K. Experience

A -- in which most have mild or no symptoms; some are febrile with inflammation; a few have Kawasaki disease temporally associated with infection; and an even smaller group have MIS-C temporally associated with infection -- was proposed by Michael Levin, MBE, PhD, of Imperial College London.

He reported on a series of 38 British cases identified between March 25 and May 1. While all were admitted for supportive care and required fluid resuscitation (70% also required inotropes), 62% got IVIG and 51% got corticosteroids. Anakinra (Kineret), an interleukin-1 receptor antagonist used in rheumatoid arthritis and for neonatal-onset multisystem inflammatory disease, was used in 8%.

The majority have responded to treatment, with 43% discharged from the ICU already, although one child who did not get immunosuppression was noted to have coronary artery dilation on follow-up echocardiography.

The U.K. cases emerged a month behind the COVID-19 curve there, Levin noted.

are elevated troponin, D-dimer, C-reactive protein, and brain natriuretic peptide, suggesting prominent cardiac injury compared with other syndromes, Levin noted.

French and Swiss Cardiac Cases

A series of 35 children seen for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state at pediatric ICUs in 14 centers over a 2-month period contemporary with the SARS-CoV-2 pandemic in France and Switzerland was reported in Circulation on Monday.

At admission, 80% were in cardiogenic shock and required inotropes. None met classical criteria for Kawasaki disease, although clinical signs suggestive of it -- skin rash, cheilitis, cervical adenopathy, meningism -- were frequent.

All of them received IVIG, and one-third got adjunctive steroids because of symptoms similar to an incomplete form of Kawasaki disease. Three got anakinra because of persistent severe inflammation.

Therapeutic-dose heparin was used for 23 of the 35. None had thrombotic or embolic events.

Complete recovery of left ventricular function was seen in 71% of patients at a median 2 days after admission. Seven were still in the hospital or had residual ventricular dysfunction when the paper was submitted.

Damien Bonnet, MD, PhD, of Hôpital Necker-Enfants Malades in Paris, and colleagues wrote that the "rapid resolution of systolic dysfunction together with mild to moderate troponin elevation suggests that the mechanism of heart failure is not consistent with myocardial damage as seen in adults associated with acute infection with SARS-CoV-2."

New York City

Cohen Children's Medical Center of Northwell Health in suburban New York City had 33 cases from April 17 to May 13, among whom 64% met complete Kawasaki disease criteria and 76% had shock, according to James Schneider, MD. About half had coronary artery abnormalities, 58% had myocardial dysfunction.

All got IVIG, with second doses in 30%. Fully 70% received steroids, 12% anakinra, 9% the anti-IL-6 drug tocilizumab (Actemra), and 3% the tumor necrosis factor inhibitor infliximab (Remicade). Enoxaparin was used for 42% and aspirin for 88%.

For the 82% discharged already, 18% had depressed cardiac function that normalized and 27% had persistent mildly depressed function.

On the other hand, Choueiter noted that for the 35 MIS-C cases admitted at her center in the Bronx, only the half of children who met criteria for Kawasaki disease received IVIG.

"When it doesn't fit Kawasaki criteria, then what we're doing is supportive therapy -- inotropes, ventilation, antibiotics -- as indicated for the individual," she said. "In some rare cases when we have supported the organs, when we have given the medications we can give, then we start discussing with rheumatology the role of immunomodulators."

Downsides to Immune Treatments

Marconi cautioned that there's an unclear impact of the biologic anti-inflammatory drugs on virus control, secondary infections, thromboses, or cytopenias in short-term use.

"We are very hesitant to give those medications upfront, because it's a fine balance between suppressing the inflammation and suppressing the immune system to a point where the body can no longer fight an infection," Choueiter said. "Since we are unclear about the mechanism of this disease yet, we are reserving those medications to children who are very sick [in whom] we have confirmed this is not a bacterial infection and...we have tried every option whether medication or supportive treatment."

Avoiding IVIG for patients who don't have Kawasaki disease might be preferable because, like any therapy, it has risks, Choueiter suggested.

"IVIG is a volume load. In someone whose heart function is down, we have to be very judicious in the amount of fluids we give," she said. Also, clotting and transfusion-related lung injury are possible. "If we don't know it works, then we can't really justify it. And in those patients we have not given it, they've done great."

Even with this conservative approach, "so far, our results are very similar to the study that came from France and Switzerland," she said. "These children are recovering anywhere between 3 days to a week. Their heart function is recovering. We are able to calm down the inflammation. And we have seen up to 10 of them in clinic a week or 2 weeks later and they have not shown signs of getting worse again or their heart function of getting worse or of coronary artery inflammation."

What is clear is that a multidisciplinary team needs to be involved, however a center chooses to treat, and that data should be collected to develop evidence on what works best, she concluded.

"I think it's going to shed light on a whole bunch of problems we haven't understood, like what's the environmental or infectious trigger that's causing these inflammatory responses in genetically susceptible people," Friedman said. "We're going to learn a lot about Kawasaki disease and a bunch of other inflammatory illnesses, autoimmune vasculitises, through this."

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