Study: There’s an Effective Treatment for the Inflammatory Syndrome in Kids With Covid-19
A pediatrician unpacks the latest research
Until recently, little was understood about how to treat multisystem inflammatory syndrome in children (MIS-C). Considered among the most serious complications of Covid-19 in kids, MIS-C was first described about nine months ago. For more on the characteristics and diagnosis of MIS-C check out this story:
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Because MIS-C is similar to another inflammatory syndrome seen in children called Kawasaki disease, pediatric providers have treated the condition similarly. Let’s take a look at what’s been discovered.
Design and setting
An article published at the beginning of February in the Journal of the American Medical Association by Naïm Ouldali, MD, PhD, and colleagues compared the two most common treatments for MIS-C. The first was intravenous immunoglobulin (IVIG), and the second was a combination of IVIG and an intravenous corticosteroid, methylprednisolone.
IVIG is a compound obtained from the plasma of blood donors. It contains immune proteins called antibodies that help humans fight infection. Unlike convalescent plasma, which is a collection of antibodies that act against one specific pathogen, IVIG contains a mixture of antibodies that work against many various diseases. IVIG has been used successfully to treat a number of immune conditions including Kawasaki disease, immune thrombocytopenia, and Guillain-Barre syndrome. Kawasaki disease is usually treated with IVIG alone, but sometimes a steroid is added in refractory cases or for certain high-risk patients.
This retrospective observational study was conducted with 106 children using data from the French National Public Health Agency. The average age was 8.6 years, and 52% were female. Seventy-two patients received IVIG alone (monotherapy group) while 34 received a combination of IVIG and methylprednisolone (dual treatment group). IVIG was given as a single 2 gram per kilogram body weight dose for all patients. Patients receiving methylprednisolone were given similar, but not identical, doses over an average of 4.8 days.
The study’s primary endpoint was defined by its authors as persistent fever for two days after treatment initiation or a recurrence of fever within seven days of starting treatment. At first, this decision surprised me because fever, as miserable as it can feel sometimes, is far from the most troubling outcome that can occur from MIS-C. As I read more, however, the decision began to make sense.
The authors justified their choice by explaining, “This outcome [fever] was similar to the primary outcome used in therapeutic studies of Kawasaki disease and has been associated in Kawasaki disease with increased risk of further cardiovascular complications.” Furthermore, 90% of patients with MIS-C have been found to experience at least four days of fever over the course of their illness. This information suggests fever is indeed a good method of assessing the efficacy of a treatment in the setting of MIS-C.
In addition to fever, the study also evaluated secondary endpoints such as acute heart failure as measured by the capacity of the heart’s main pumping chamber, the left ventricle. Other secondary endpoints included length of stay in the pediatric intensive care unit (PICU) as well as the need for hemodynamic support with medications called vasopressors or inotropes that serve to increase a patient’s blood pressure or cardiac output during a critical illness.
Among those receiving IVIG monotherapy, 51% failed to respond to treatment, meaning that just over half of this group continued to have a fever for at least two days after starting the treatment or had a recurrence of fever within the first week. In comparison, only 9% of children receiving dual treatment (IVIG and steroid) failed to respond. The authors calculated that the odds of fever (after two days or recurring within a week) were four-fold less in the dual treatment group compared with the monotherapy group.
A similar effect was seen when looking at secondary outcomes. The dual treatment group had a five-fold lower chance of acute heart failure or the need for hemodynamic support. Length of stay in the PICU was also significantly shorter in the dual treatment group with a median of four days versus six days for those receiving monotherapy.
These results align with other smaller studies that suggest an association of dual treatment with shorter time to cardiac recovery as well as studies that have associated steroids with shorter hospital stays in patients with MIS-C.
The main limitation of the study is that it was retrospective, and, therefore, the patients were not randomized. The study incorporates two types of statistical analysis tools called propensity score matching and inverse probability of treatment weighting. The details of these methods are beyond the scope of this story (and beyond the brain of this simple country doctor), but they are designed to decrease the bias inherent in an observational study.
Presumably, it would be unethical to conduct a true randomized placebo-controlled trial (RCT) on children with MIS-C because those in the placebo group would be denied a likely effective treatment. In addition, RCTs are difficult to design for rare diseases like MIS-C since so few individuals develop the condition. The authors note, “Given the rarity and severity of MIS-C, conducting randomized trials may be highly challenging, and observational methods such as these may provide the best level of evidence.”
Conclusions and future direction
This study provides arguably the best evidence compiled to date to guide clinicians in the treatment of MIS-C and strongly suggests a combination of IVIG and a corticosteroid are ideal. Our knowledge of MIS-C is expected to grow, not only as more studies are conducted but also as patients with a history of MIS-C are followed over longer periods of time. Moreover, studying MIS-C will undoubtedly increase our understanding of Kawasaki disease as well as other post-infectious or inflammatory syndromes in children.