Findings from separate, large observational consortium studies appear to offer contradictory results regarding the efficacy of immunomodulatory therapy in the treatment of children and adolescents hospitalized with multisystem inflammatory syndrome related to severe Covid-19.
Initial treatment with intravenous immune globulin (IVIG) plus glucocorticoids was associated with risk of new or persistent cardiovascular dysfunction, compared to IVIG alone, in an analysis of short-term outcomes among 518 pediatric multisystem inflammatory syndrome (MIS-C) cases treated at 58 U.S. hospitals identified through the CDC’s Overcoming Covid-19 surveillance registry.
However, data from the international Best Available Treatment Study (BATS) consortium trial on just over 600 children with MIS-C from 32 countries showed no evidence of differences in outcomes following primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.
The researchers noted that the confidence intervals for inferences about treatment effect “admit the possibility of actual benefit from one or more of the treatments relative to the others.”
Findings from both studies were published online June 16 in The New England Journal of Medicine.
In an accompanying editorial, Roberta DeBiasi, MD, of Children’s National Hospital and Research Institute, Washington DC, wrote that key differences in both the patient populations and the trial dates may at least partly explain the seemingly discordant findings.
DeBiasi further noted that while both groups of researchers used propensity-score adjustment and other statistical methods in an attempt to control for confounding related to treatment or variations in care, “these modeling approaches cannot fully compensate for such variations.”
“Among the most important of these variations are the criteria used for initiating immunomodulatory treatments, which could potentially lead to unavoidable differences in the interpretation of efficacy,” she wrote.
DeBiasi noted that nearly 4,000 cases of MIS-C and 35 related deaths have been reported in the U.S. alone since the multisystem inflammatory presentation of Covid-19 was first identified in pediatric patients.
“In a triumph of collaboration, experts achieved consensus about diagnostic criteria and the need to induce rapid immunomodulation aimed at limiting the course of illness. However, in the absence of randomized, controlled clinical trials, consensus around specific immunomodulatory therapies has been more elusive, given the speed with which centers have had to establish cohorts and deliver treatment,” she wrote.
Treatments used in patients with MIS-C have included IVIG, glucocorticoids, and biologic agents in various combinations.
In the Overcoming Covid-19 consortium trial, researchers analyzed surveillance data on MIS-C patients younger than age 21 treated at 58 U.S. hospitals from March 15 to Oct. 21, 2020.
The efficacy of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with IVIG plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics.
The primary outcome was cardiovascular dysfunction, which was a composite of left ventricular dysfunction or shock resulting in the use of vasopressors, on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2.
The mean age of the 518 patients included in the analysis was 8.7 years and 3-out-of- 4 (75%) had been previously healthy. Nine of the patients died.
Among the main findings:
- Initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% versus 31%; risk ratio, 0.56; 95% CI, 0.34-0.94).
- The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19-1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29-1.00).
- The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% versus 70%).
The international BATS Consortium trial involved pediatricians worldwide who were invited to join the study by uploading data from patients with suspected MIS-C onto a web-based electric data capture database.
“Since the accuracy of current MIS-C definitions in unknown and emerging experience suggests a wide spectrum of inflammatory illnesses after SARS-CoV-2 infection, our study invited pediatricians to enroll not only children who met the published criteria for MIS-C but also those with any suspected inflammatory illness after SARS-CoV-2 infection,” the researchers wrote.
Weighted logistic-regression was used, and the study included children with suspected MIS-C treated from June 2020 through February 2021.
Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy.
Among the main findings:
- Inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% CI, 0.33-1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22-1.33).
- The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone).
- The time until a reduction in disease severity was similar in the three groups.
In her editorial, DeBiasi wrote that while the value of early immunomodulatory therapy in MIS-C is now evident, “neither of these studies definitively answered the question about the most effective single or combination treatment.”
“Specifically, neither study was powered to included an evaluation of approaches that steer away from broad immunosuppression with glucocorticoids and that focus on more targeted and titratable treatments with biologic agents, such as anakinra and infiximab,” she wrote, adding that, “In this regard, clinicians must avoid the pitfall of interpreting a lack of data as a lack of efficacy.”
DeBiasi further noted that neither trials examined long-term outcomes related to the treatments, writing that systematic and comprehensive long-term follow-up trials for cardiac and non-cardiac outcomes “are sorely needed in the pediatric population and will launch soon.”
- Initial treatment with IVIG plus glucocorticoids was associated with risk of new or persistent cardiovascular dysfunction, compared to IVIG alone, in an analysis of data from the CDC’s Overcoming Covid-19 surveillance registry.
- The international Best Available Treatment Study (BATS) consortium showed no evidence of short-term differences in outcomes following primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.
Salynn Boyles, Contributing Writer, BreakingMED™
The study by Randolph et al. was funded by the CDC.
The BATS Consortium trial was funded by the European Union’s Horizon 2020 Program and others.
DeBiasi had no relevant relationships to disclose.
Cat ID: 926
Topic ID: 79,926,933,926,138,927
