N-terminal of probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels are often elevated in multisystem inflammatory syndrome in children (MIS-C) secondary to inflammation, myocardial dysfunction, or increased wall tension. Intravenous immunoglobulin (IVIG), accepted treatment of MIS-C, may transiently increase myocardial tension and contribute to an increase in NT-proBNP. We sought to study the association between pre- and post-IVIG levels of NT-proBNP and CRP and their clinical significance.
This single-center, retrospective, cohort study included consecutive children, aged ≤21 years, with diagnosis of MIS-C who received IVIG from April 2020 to October 2021. Data collection included clinical characteristics, laboratory tests, management, and outcomes. Study cohort consisted of patients who received IVIG and had NT-proBNP levels available pre- and post-IVIG.
Among 35 patients with MIS-C, 30 met inclusion criteria. Twenty-four, 80%, showed elevation in NT-proBNP post-IVIG. The median NT-proBNP level pre-IVIG was 1921 pg/mL (interquartile range 548–3956), significantly lower than the post-IVIG median of 3756 pg/mL (interquartile range 1342–7634)) (P = .0010). The median pre-IVIG CRP level was significantly higher than the post-IVIG level (12 mg/dL vs 8 mg/dL, P = .0006). All but 1 recovered before discharge, and none had signs of worsening cardiac function post-IVIG. In those who recovered, NT-proBNP had normalized by discharge or 1-week follow-up.
Our study shows that NT-proBNP levels often transiently increase immediately after IVIG therapy without signs of worsening myocardial function. These values should be interpreted in the context of CRP levels and clinical recovery.
The incidence of multisystem inflammatory syndrome in children (MIS-C) related to coronavirus disease 2019 has been increasing since the start of the pandemic, mirroring the coronavirus disease 2019 infection rates.1 MIS-C generally occurs 2 to 6 weeks after severe acute respiratory syndrome coronavirus 2 infection and has features overlapping with Kawasaki disease (KD).2,3 It is characterized by persistent fever, abdominal pain, vomiting, fatigue, conjunctival injection, and typically a blanching erythematous macular rash.2,4 In severe cases, children may develop multiorgan failure, shock requiring vasoactive support, and ICU admission.4,5 Although the precise pathophysiology of MIS-C is unclear, it is thought to be a delayed immunologic response to viral invasion and is characterized by severe inflammation with elevation of inflammatory biomarkers, including C-reactive protein (CRP) and ferritin.4,5 Biomarkers of cardiac inflammation, dysfunction, and/or injury including troponin and N-terminal of probrain natriuretic peptide (NT-proBNP) may also be elevated.6,7 NT-proBNP is produced by cardiac myocytes as a response to increased wall tension and is commonly elevated in congestive heart failure (HF), ventricular hypertrophy, and volume overload.8
Intravenous immunoglobulin (IVIG) is recommended by the American College of Rheumatology to treat MIS-C.9 Trending laboratories, including NT-proBNP and CRP, have been common ways to assess response to treatment in MIS-C.9 There have been case reports in patients with KD that IVIG can lead to subclinical left ventricular dysfunction because of volume overload and/or increased viscosity.10 It is unclear if the same phenomenon is observed in patients with MIS-C. We hypothesized that NT-proBNP levels would transiently increase after IVIG treatment without worsening of underlying inflammatory pathology as reflected by CRP levels. Our objectives were to clarify the association between pre- and post-IVIG NT-proBNP and CRP levels. We looked at these changes in relationship to clinical improvement.
Methods
This single-center, retrospective, cohort study included all consecutive pediatric patients, aged ≤21 years, with diagnosis of MIS-C who received IVIG from April 1, 2020, to October 31, 2021, and had pre- and post-IVIG NT-proBNP levels. Data were obtained from the electronic medical record. Available NT-proBNP levels, CRP levels, and echocardiogram results were recorded and noted if pre- or post-IVIG therapy. Laboratory values were considered post-IVIG if obtained after the IVIG infusion was complete; typically, this was the following calendar day. The study was approved by the institutional review board.
For the diagnosis of MIS-C, patients had to meet the Centers for Disease Control and Prevention definition.3 All children underwent serial evaluation, including blood counts, metabolic panel, markers of inflammation, and echocardiogram to guide treatment response.9 Data collection consisted of demographics including self-identified race, sex assigned at birth, clinical characteristics, laboratory tests, echocardiogram results, management, and outcomes. MIS-C patients received the standard 2 g/kg of IVIG with a maximum of 100 g per dose. IVIG was given per hospital protocol over 8 to 12 hours, with an initial rate of 0.6 mL/kg of body weight per hour that could be doubled every 15 minutes as tolerated to a maximum infusion rate of 4.8 mL/kg/hr. When concerned for cardiac dysfunction or volume overload, the dose was split into 2 infusions (1 g/kg, maximum 50 g) given at least 12 hours apart at the discretion of the treating provider.
Descriptive statistics for nonparametric data were used because of small sample size and skewed data distribution. Differences between median values pre- and post-IVIG administration were assessed using a Wilcoxon signed rank test for paired observations. Statistical significance was determined using an α = .05 threshold for significance. Multiple comparison adjustments were not included because of the small number of comparisons being made in this analysis. Data were analyzed using R version 4.1.2 and Microsoft Excel software.
Results
Among 35 patients with MIS-C diagnosis, 30 of those had NT-proBNP levels obtained pre- and post-IVIG therapy. The demographics and characteristics are shown in Table 1. The median age was 12.5 (range: 1–21) years. There were slightly more males (56.7%) than females (43.3%). The majority of participants self-identified as White (63.3%, n = 19), followed by Hispanic/Latino (20%, n = 6). Two patients had underlying cardiac disease (6.67%), 1 had cancer (3.33%), and none had kidney disease. Almost half of the participants required ICU admission (40%, n = 12) and a similar proportion had hypotension (43.3%, n = 15). Two deaths occurred which could have been related to MIS-C: 1 medically complex patient with a history of recurrent supraventricular tachycardia recovered and then died 3 months after discharge; the other had preexisting hepatoblastoma undergoing chemotherapy and experienced cytokine storm, metastases, and died in hospice the day after discharge.
The median pre-IVIG NT-proBNP level of 1921 (interquartile range 548–3956) was significantly lower than the post-IVIG 3756 (interquartile range1342–7634) (P = .0010). Five patients had normal NT-proBNP levels (<207 pg/mL) before IVIG; after IVIG, 5 of the 5 had elevated levels. For all patients who recovered before discharge, the NT-proBNP levels had normalized by discharge or follow-up 1 week later. Fig 1 shows a scatter plot of the individual NT-proBNP levels. Twenty-four (80%) had an increase in their NT-proBNP level after IVIG administration without clinical worsening cardiac function. All patients had echocardiograms pre- and post-IVIG. Six patients had depressed left ventricular ejection fraction, <45%, pre-IVIG, and all had normal ejection fractions post-IVIG. Fourteen (46.7%) were given IVIG as divided doses and 13 of those had an increase in NT-proBNP after the first and/or second dose of IVIG, depending on when the laboratory was obtained. The median pre-IVIG CRP level was significantly higher than the post-IVIG level, with normal being <0.5 mg/dL, (12 mg/dL vs 8 mg/dL, P = .0006). Twenty-six patients had a decrease in CRP post-IVIG (86.7%) and all CRP levels had decreased by discharge. Fig 2 shows the NT-proBNP and CRP levels over time in relationship to IVIG administration.
Five patients had treatment intensification after IVIG and all recovered. One patient was initially diagnosed with KD but, after recurrent fevers, was determined to have MIS-C and was given steroids. One was given an additional 0.5 g/kg IVIG dose for increasing troponin and chest pain without echocardiogram or electrocardiogram correlation. One was given tocilizumab for recurrent fevers. Treatment of 2 patients was intensified after an increase in NT-proBNP without fevers or increased CRP, 1 received steroids, and the other a higher dose of anakinra for 1 day. No patients had signs of clinical deterioration after IVIG. There were no serious adverse events related to IVIG.
Discussion
Our study confirmed the previous observation seen with KD, that NT-proBNP levels increase immediately after IVIG therapy in the majority of patients with MIS-C without clinical worsening.11 This was not unexpected because IVIG increases intravascular viscosity and volume.12 This increase appears to be independent of whether the IVIG is given as a divided or full dose. Our study population was comparable with previous reports showing similar rates of ICU admission and need for vasopressor support in MIS-C patients.13,14
NT-proBNP levels are useful in supporting the diagnosis of acute decompensated HF and serial measurements can establish treatment response.15 Adult literature shows improvement in NT-proBNP can be seen within 24 to 48 hours after reduction of myocardial tension, such as in mitral valve repair and electrocardioversion in atrial fibrillation.16–18 The rapidity to normalization of NT-proBNP in children with HF is not well studied.
The increase in NT-proBNP described in patients with KD indicates NT-proBNP is only a good indicator of left ventricular function before IVIG treatment.19 Echocardiogram findings in these studies suggest that the increase in NT-proBNP after IVIG may represent transient left ventricular wall tension.19,20 The additional volume and viscosity of IVIG is often given to a patient who already has increased left ventricular wall tension as evidenced by a baseline elevated NT-proBNP. Our findings imply the limited utility of NT-proBNP immediately after IVIG therapy but support that subsequent values align with clinical improvement and decreasing inflammation. Of note, the 2 patients in our study who required treatment intensification because of increasing NT-proBNP levels were hospitalized before development of our institutional MIS-C guideline and standardized treatment regimen. Clinical improvement was seen for patients post-IVIG, despite the transient increase in NT-proBNP. To the best of our knowledge, our study is the first to report an increase in NT-proBNP levels after IVIG treatment in MIS-C patients.
Our study has limitations. This was a single-center, retrospective, observational study with a relatively small sample size, which may limit generalizability. We did not have a control group because all MIS-C patients received standard treatment with IVIG. We did not evaluate if different pharmaceutical preparations of IVIG have the same effect. We did not stratify by disease severity, so we do not know if NT-proBNP levels varied with disease severity and degree of cardiac involvement. We did not measure the exact time elapsed after IVIG therapy and the laboratory result, which may have influenced the absolute values but was unlikely to impact the overall change observed.
NT-proBNP levels in MIS-C are often transiently higher after IVIG therapy, without other signs of worsening myocardial function or inflammation. These increased values should be interpreted with caution and in the context of clinical improvement and CRP values so as to avoid misinterpretation because disease progression and escalation of additional treatment interventions.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLAIMER: The authors have indicated they have no conflicts of interest relevant to this article to disclose.
Drs Schmitz, Koestner, Wood, Sharathkumar, and Badheka conceptualized the study, designed the data collection instruments, collected data, carried out the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript; Mr Burghardt and Mr Wendt collected data, carried out analyses, and contributed to the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
