In April 2020, professionals first noted a temporal association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-4 infection and multisystem inflammatory syndrome in children (MIS-C) as a rare but serious complication.5-8 Since then, MIS-C has been reported to occur 2 to 6 weeks after infection with SARS-CoV-2 and is characterized by persistent fever and nonspecific symptoms including abdominal pain, vomiting, headache and fatigue.
Conjunctival injection (hyperemia) and rashes resembling Kawasaki disease have been observed in a high percentage of children with this condition.4,6,9-11 Severely affected children present with multiple organ failure and shock requiring inotropic support.
Laboratory studies have shown intense inflammation with elevated levels of C-reactive protein, ferritin, troponin, and N-terminal pro-B-type natriuretic peptide and reduced levels of hemoglobin, platelets, and lymphocytes.
Faced with a new disease with no proven treatment, pediatricians have treated patients using their "best guess" about what might be beneficial.
Based on the similarity of MIS-C with Kawasaki disease,2,4,9,11 macrophage activation syndrome,12 and staphylococcal toxic shock syndrome,13,14 professionals have preferentially chosen immunomodulatory agents that have shown benefit in these diseases, with such medications often used in combination or sequentially when initial treatments have failed.15-17
Since coronary artery aneurysm is an important overlapping feature of both MIS-C and Kawasaki disease, intravenous immunoglobulin (IVIG), the proven treatment for Kawasaki disease,18 has been widely adopted as a therapy, and its suspension is considered unacceptable by some doctors. However, some
Children with MIS-C recover only with supportive treatment,3,15 so such aggressive attempts to suppress the inflammatory response may not necessarily translate into clinical benefit.
Randomized trials are needed to establish the most effective treatment for MIS-C. However, due to its rapid emergence during the coronavirus disease 2019 (Covid-19) pandemic – and concerns that it may lead to death, multiple organ failure or long-term heart damage – doctors have adopted the use of a variety of immunomodulators, which are now being recommended in local and national treatment guidelines.19,20
The authors conducted the Best Available Treatment Study (BMTD) to provide evidence for recommendations on the treatment of MIS-C by collecting and analyzing results of treatments chosen by individual pediatricians for the care of their patients.
| Methods |
> Study design
Pediatricians from around the world were invited to join this study by uploading data from their patients with suspected MIS-C to a web-based research electronic data capture database.21
Since the precision of current definitions of MIS-C is unknown and emerging experience suggests a broad spectrum of inflammatory diseases following infection with SARS-CoV-2,22,23 pediatricians were invited to enroll not only children who met the criteria for MIS-C24-26 but also those with any suspected inflammatory disease after SARS-CoV-2.
De-identified longitudinal data were collected on presenting characteristics, demographic characteristics, laboratory findings, immunomodulatory treatments (IVIG, glucocorticoids, or biologic agents), and supportive therapies. Daily and treatment data were collected according to calendar day. The length of stay, required organ support, and health status at discharge were also recorded.
> Treatment comparison
Three primary treatment groups were large enough to be considered for comparison: IVIG alone, IVIG plus glucocorticoids, and glucocorticoids alone. IVIG alone was chosen as the standard of care as it is the accepted treatment for Kawasaki disease and has been widely adopted in the management of MIS-C. Therefore, IVIG plus glucocorticoids and glucocorticoids alone were compared with IVIG.
The first calendar day of each of the three treatments was defined as day 0, and subsequent treatment and outcomes were defined relative to this onset. Additional immunomodulators that were administered on the same calendar day as the primary treatment were defined as coprimary treatments, while immunomodulators that were administered on subsequent days were considered secondary treatments.
> Primary and secondary results
There were two primary outcomes. The first was a composite of inotropic support or mechanical ventilation (invasive or noninvasive) for day 2 or later or death. The second was a reduction in disease severity on a seven-point ordinal scale between day 0 and day 2; disease severity levels from worst to least were as follows: receipt of mechanical ventilation and inotropic support, receipt of mechanical ventilation alone, receipt of inotropic support alone, receipt of oxygen alone, no supportive therapy with a protein C level reactive protein of 50 mg/L or more, without supportive therapy with a C-reactive protein level less than 50 mg/L and hospital discharge.
Key secondary outcomes were the temporal dynamics of blood markers of inflammation and organ damage; an escalation of immunomodulator administration, which was defined as the addition of a separate immunomodulator or (if initial treatment included glucocorticoids) an incremental increase of 5 mg/kg body weight or its equivalent in the daily dose of prednisolone; the time to a 1-point reduction in disease severity on the ordinal scale; left ventricular dysfunction on echocardiography; coronary artery aneurysm after treatment (coronary artery z-score ≥ 2.5 or documented aneurysm)27; any increase in cardiorespiratory support therapy after day 0; and other therapeutic complications or death.
For the primary outcomes, a subgroup analysis was performed that included only patients who met the World Health Organization (WHO) criteria for MIS-C26 and a sensitivity analysis in which the primary treatments were defined. as those received during the first two calendar days of immunomodulatory treatment.
> Statistical analysis
Weighted logistic regression methods were used to analyze dichotomous outcomes, and time-to-event analyzes were performed using weighted Cox regression, with weights determined by inverse probability based on covariate balancing propensity scores to account for baseline differences between the three groups. main treatment regimens (IVIG alone, IVIG plus glucocorticoids, and glucocorticoids alone).
These analyzes included the same covariates that were used for the propensity scores to produce doubly robust estimates. The average treatment effect was calculated unless otherwise described. Results were reported as odds ratios or average risk ratios with 95% confidence intervals, using IVIG only as the reference category.
Inflammatory markers were represented as percentages of each patient’s maximum value. Weighted generalized additive models were fitted to produce smoothed curves with confidence intervals.
Weights were produced as described above; However, in comparing patients who were treated with immunomodulatory drugs with those who did not receive such treatment, the average treatment effect in the untreated group was estimated to preserve the sample size of this smaller and distinct subgroup.
| Results |
> Patients
From June 20, 2020 to February 24, 2021, practitioners from 81 hospitals in 34 countries uploaded data from 651 patients with suspected MIS-C to the study database. Data from 37 patients were excluded due to incomplete information or duplicate entries.
Of the remaining 614 patients, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; another 22 patients received other immunomodulators, and 39 did not receive immunomodulatory therapy. In the three primary treatment groups, 136 of 552 patients (25%) received additional immunomodulators at day 2, and 238 patients (43%) received secondary agents at some point.
> Clinical and laboratory measurements
Clinical and laboratory findings were similar between treatment groups. However, troponin levels and the percentage of patients receiving inotropes on day 0 were higher in the group receiving IVIG plus glucocorticoids. Of the 614 patients, 490 (80%) met the WHO criteria for MIS-C.
The most common missing criterion among patients who did not meet WHO criteria was evidence of exposure to SARS-CoV-2. SARS-CoV-2 antibody measurements were not performed in 14% of patients, and results were negative in 14%. Bacteria were cultured in blood samples from 6 patients.
The percentage of patients who met the American Heart Association (AHA) definition for Kawasaki disease18 was 37% in the general population and 39% among those who met the WHO criteria for MIS. c.
> Primary results
A total of 50 of 553 patients (9%) had received immunomodulators before being referred to the reporting hospital and were excluded from the weighted analyses.
Receipt of inotropic support or mechanical ventilation on day 2 or later or death (the first primary outcome) occurred in 56 patients who received initial treatment with IVIG plus glucocorticoids (adjusted odds ratio for comparison with IVIG alone, 0.77; range 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33).
In a subgroup analysis that included only patients who met WHO criteria for MIS-C, a first primary outcome event occurred in 40 patients who received initial treatment with IVIG plus glucocorticoids (adjusted odds ratio for comparison with IVIG alone, 0.95; 95% CI, 0.37 to 2.45) and in 12 patients who received treatment with glucocorticoids alone (adjusted odds ratio, 0.30; 95% CI, 0.10 to 0.85).
A reduction in the disease severity score on the ordinal scale on day 2 (the second primary outcome) occurred in 54 patients who received IVIG plus glucocorticoids (adjusted odds ratio for comparison with IVIG alone, 0.90; 95% CI %, 0.48 to 1.69) and in 20 patients who received glucocorticoids alone (adjusted odds ratio, 0.93; 95% CI, 0.43 to 2.04).
When the WHO criteria for MIS-C were considered in a subgroup analysis, a second primary outcome event occurred in 52 patients who received IVIG plus glucocorticoids (adjusted odds ratio for comparison with IVIG alone, 1.09; CI 95%, 0.53 to 2.23) and in 16 patients who received glucocorticoids alone (adjusted odds ratio, 1.95; 95% CI, 0.83 to 4.60).
The results for the two primary outcomes showed an acceptable degree of balance with respect to covariates. Analyzes that were performed using standardized weights did not change the interpretation of the primary results.
> Secondary results
Intensification of immunomodulatory treatment was less common among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (odds ratio, 0.18; 95% CI, 0.10 to 0.33).
The comparison was inconclusive between patients receiving glucocorticoids alone and IVIG alone (odds ratio, 1.31; 95% CI, 0.64 to 2.68). No clear group differences in blood markers, inotropic support, or mechanical ventilation were observed between patients who had escalation to other treatments by day 2 and those who continued receiving initial treatment.
Left ventricular dysfunction was reported in 12% of 538 patients undergoing echocardiography from day 2 onwards, with no substantial differences between treatment groups. Coronary artery aneurysm was observed on the last echocardiogram 2 days after initiation of treatment or later in 6% of the 326 patients for whom data were available.
The low number of coronary artery aneurysms detected precluded statistical comparisons between treatment groups, although among patients with data, the incidence of aneurysm was not higher among those who did not receive IVIG as part of primary treatment than among those who received IVIG. .
Death was reported in 3 of 238 patients (1%) who received IVIG alone, in 5 of 192 patients (3%) who received IVIG plus glucocorticoids, and in 4 of 91 patients (4%) who received glucocorticoids alone; status regarding death was not reported for 32 patients.
In the analysis of time to improvement in disease severity on the ordinal scale, the mean hazard ratio for the comparison with IVIG alone was 0.89 (95% CI, 0.67 to 1.19) for IVIG plus glucocorticoids and 1.03 (95% CI, 0.72 to 1.46) for glucocorticoids alone.
Physicians reported drug complications in 16 of 411 patients (4%) who received glucocorticoids in any combination and in 9 of 408 (2%) who received IVIG in any combination. Glucocorticoid-related complications were predominantly hypertension and hyperglycemia.
> Effect of immunomodulation on blood markers
C-reactive protein levels decreased more rapidly in patients who received immunomodulators than in those who did not receive such treatment.
Changes in C-reactive protein, troponin, and ferritin levels followed a similar temporal decline in all three groups, although there was some variation in the rate of decline, which was more obvious in patients who did not change treatment before day 3. .
To investigate whether the inclusion of children with Kawasaki disease in the present study could have influenced responses to treatment, changes in blood markers were explored separately in children with a probable diagnosis of Kawasaki disease and those without such a diagnosis. .
Since Kawasaki disease is generally more common in children before age 6 years and MIS-C is usually reported in older children, patients who met the AHA criteria for Kawasaki disease and all those below were compared. of 6 years of age (whose disease can be described as Kawasaki disease) with the rest of the MIS-C patients.
Among children who received IVIG alone, smoothed curves showed rates of decline in C-reactive protein levels among those younger than 6 years who met AHA criteria for Kawasaki disease that were similar to the rates among the remaining children. .
However, among children who received glucocorticoids with or without IVIG, there was a more rapid decline in C-reactive protein level in the group of children who did not meet AHA criteria for Kawasaki disease or who were older than 6 years. .
| Discussion |
In a pragmatically defined international cohort of patients with suspected MIS-C, we found no evidence of substantial differences in the two primary outcomes among children who received the three most common treatments for this disorder (IVIG alone, IVIG plus glucocorticoids, and glucocorticoids alone). ).
However, when the analyzes were restricted to patients meeting WHO criteria for MIS-C, we found modest evidence of a benefit with glucocorticoids alone over IVIG alone for both primary outcomes.
Analyzes of secondary outcomes showed a lower frequency of escalation in immunomodulatory therapy (i.e., addition of secondary agents) in patients receiving IVIG plus glucocorticoids than in those receiving IVIG alone or glucocorticoids alone.
We found no clear evidence of an association between initial treatment with any of the three treatments and changes in organ failure, inflammation, or hospital discharge. The frequency of coronary artery aneurysm was also similar in the three groups, but the percentage of patients with data on this was too low to draw firm conclusions.
In a French national surveillance study involving patients with MIS-C,28 researchers found that patients receiving IVIG plus glucocorticoids had a lower frequency of treatment escalation than those receiving IVIG alone, along with a reduced need for support. hemodynamic and a shorter stay in the intensive care unit. However, this study did not include a glucocorticoid-only group and had a smaller enrollment of patients than the present study.
The high rates of escalation to additional treatments in patients receiving single agents may be explained by failure of initial treatment or disease severity, as well as a greater willingness to intensify therapy when a single treatment was administered. A greater percentage of patients receiving IVIG plus glucocorticoids were also receiving inotropes on day 0.
These patients had higher troponin levels than those in the other two groups, suggesting that patients who were more severely ill may have received IVIG plus glucocorticoids. However, patients who were receiving additional treatment by day 2 did not receive further inotropic or ventilatory support or had higher troponin levels than those who did not undergo treatment intensification.
C-reactive protein and ferritin levels were measured to explore how different agents may have affected inflammation as surrogates for a determination of overall inflammation, and troponin was measured as a marker of cardiac injury. After adjustment for baseline differences in disease severity, the rate of reduction in the C-reactive protein level appeared to be more rapid in patients receiving immunomodulators.
Because the clinical features of MIS-C overlap with those of Kawasaki disease, a major dilemma in treatment decisions for MIS-C has been whether treatment regimens that do not include IVIG (the proven treatment for Kawasaki disease Kawasaki) can delay recovery and increase the risk of coronary artery aneurysm.
No evidence of delayed recovery from organ failure was found in patients receiving glucocorticoids alone as initial treatment. When the analysis was restricted to patients meeting WHO criteria for MIS-C, a possible benefit of glucocorticoids alone in reducing the frequency of organ failure and a reduction in ordinal scale score was found, although this comparison was confounded by the high percentage of patients with treatment escalation to IVIG plus glucocorticoids.
The frequency of coronary artery aneurysm in the three treatment groups was low (6%), so no firm conclusions could be drawn regarding this complication.
The authors explored whether the inadvertent inclusion of Kawasaki disease patients in the MIS-C cohort may have prevented detection of benefit from non-IVIG treatments. We found suggestive evidence that the rate of decline in the level of C-reactive protein in response to immunomodulators may have differed between younger children who met AHA criteria for Kawasaki disease and other children with suspected MIS. c. This finding supports the concern that the challenge of making a clinical distinction between these two diseases may increase the difficulty in identifying differences between treatments for MIS-C.
This study included patients who met the WHO definition of MIS-C and patients with one or more missing criteria for this diagnosis. Current criteria are imperfect, as antibody testing is not always available and a history of exposure to SARS-CoV-2 lacks specificity because asymptomatic infection is common.
Because MIS-C includes a broad spectrum of diseases, until a diagnostic test is developed, physicians will face difficult treatment decisions when faced with a broader group of inflammatory diseases that occur after SARS-C infection. CoV-2 than those identified by the WHO criteria.
MIS-C has emerged as an important complication of SARS-CoV-2 infection in children in low- and middle-income countries.29,30 IVIG and biological agents are expensive and have limited availability in many countries, for example. so evidence is needed to support its use instead of cheaper anti-inflammatory agents such as glucocorticoids.
Since this study does not provide conclusive evidence of equivalence or superiority of any of the three treatments that were evaluated, continued recruitment and analysis of a larger number of patients is necessary to provide definitive evidence.
This study has some limitations. Since the data did not come from randomized studies, a major concern was whether treatment selection was biased by disease severity. The use of propensity score weighting reduced bias. However, bias may also have been introduced by the fact that some patients received additional treatments after their primary treatment. The higher treatment escalation rates in the monotherapy groups may have masked efficacy differences.
Additionally, aneurysm status at day 2 and thereafter was not available for 35% of study patients, and follow-up data on coronary artery aneurysms were not specifically collected. Therefore, the current findings are insufficient to suggest the equivalence of glucocorticoids with IVIG in the prevention of coronary artery aneurysms.
Overall, we found no evidence of differences in outcomes between treatment with single-agent glucocorticoids or IVIG or between single-agent and double-agent primary treatments. Confidence intervals for inferences about treatment effect allow for the possibility of an actual benefit with one or more of the treatments relative to the others.
