OBJECTIVES:

Multisystem inflammatory syndrome in children (MIS-C) has spread through the pediatric population during the coronavirus disease 2019 pandemic. Our objective for the study was to report the prevalence of conduction anomalies in MIS-C and identify predictive factors for the conduction abnormalities.

METHODS:

We performed a single-center retrospective cohort study of pediatric patients <21 years of age presenting with MIS-C over a 1-month period. We collected clinical outcomes, laboratory findings, and diagnostic studies, including serial electrocardiograms, in all patients with MIS-C to identify those with first-degree atrioventricular block (AVB) during the acute phase and assess for predictive factors.

RESULTS:

Thirty-two patients met inclusion criteria. Median age at admission was 9 years. Six of 32 patients (19%) were found to have first-degree AVB, with a median longest PR interval of 225 milliseconds (interquartile range 200–302), compared with 140 milliseconds (interquartile range 80–178) in patients without first-degree AVB. The onset of AVB occurred at a median of 8 days after the initial symptoms and returned to normal 3 days thereafter. No patients developed advanced AVB, although 1 patient developed a PR interval >300 milliseconds. Another patient developed new-onset right bundle branch block, which resolved during hospitalization. Cardiac enzymes, inflammatory markers, and cardiac function were not associated with AVB development.

CONCLUSIONS:

In our population, there is a 19% prevalence of first-degree AVB in patients with MIS-C. All patients with a prolonged PR interval recovered without progression to high-degree AVB. Patients admitted with MIS-C require close electrocardiogram monitoring during the acute phase.

What’s Known on This Subject:

A novel disease known as multisystem inflammatory syndrome in children (MIS-C) has been increasingly prevalent in pediatric patients with coronavirus disease 2019. Few data are available on the incidence of arrhythmia and cardiac involvement in children with MIS-C.

What This Study Adds:

Pediatric patients with MIS-C may develop conduction anomalies, particularly first-degree atrioventricular block. Patients have elevated levels of cardiac and inflammatory markers, which are not associated with development of conduction abnormalities. First-degree atrioventricular block typically returns to normal after the acute illness phase.

Since the first report of coronavirus disease 2019 (COVID-19) on December 31, 2019, new disease manifestations and complications are continuing to appear in pediatric patients. Early studies in China revealed that children of all ages were susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral etiology of COVID-19.1  Compared with adults, pediatric patients were more commonly asymptomatic or had benign respiratory and gastrointestinal symptoms.1  Recently, a new study revealed an emergence of Kawasaki disease–like presentations in pediatric patients with an active or recent diagnosis of COVID-19.2  The new syndrome, now known as multisystem inflammatory syndrome in children (MIS-C), has been most prevalent in regions highly burdened with COVID-19.24 

As a large academic institution in New York City at the epicenter of the COVID-19 pandemic, our institution has cared for multiple patients with MIS-C. During the clinical assessment and treatment of patients with MIS-C, a subset of pediatric patients with PR prolongation on the electrocardiogram (ECG), consistent with first-degree atrioventricular block (AVB), emerged. Although a recent case report described an adult with a high-degree AVB and a confirmed diagnosis of COVID-19 in the absence of MIS-C symptoms, to our knowledge there has not been a similar report in pediatric patients.5 

Our primary aim for this study was to report the frequency of conduction anomalies in MIS-C and to characterize the presentation and clinical course for the subset of patients who develop these abnormalities. We also sought to identify predictive factors for conduction abnormalities in patients with MIS-C.

The study was approved by the Columbia University Irving Medical Center Institutional Review Board. We conducted a retrospective cohort study of all patients <21 years of age presenting to NewYork-Presbyterian Morgan Stanley Children’s Hospital in New York City, New York, with a clinical diagnosis of MIS-C between April 15, 2020, and May 15, 2020. A diagnosis of MIS-C was made by using the case definition per the US Centers for Disease Control and Prevention guidelines.3,4  The diagnosis of MIS-C was made in patients <21 years old presenting with fever (≥38.0°C for ≥24 hours or report of subjective fever lasting ≥24 hours), laboratory evidence of inflammation (≥1 of the following: elevated C-reactive protein level, erythrocyte sedimentation rate, fibrinogen level, procalcitonin level, d-dimer level, ferritin level, lactic acid dehydrogenase level, or interleukin 6 level or elevated neutrophil count), and clinical severity requiring hospitalization. Patients had multisystem (≥2) organ involvement, including the cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurologic system. Patients did not have a plausible alternative diagnosis and had to have tested positive for current or recent SARS-CoV-2 infection by reverse transcription polymerase chain reaction (PCR), serology, or an antigen test.3,4  At our institution, the serology testing does not differentiate between immunoglobulin M and immunoglobulin G; thus, a positive serology test result does not clearly define a resolved infection. ECGs were routinely obtained after admission according to our institution’s guidelines for workup of all patients with MIS-C.6  First-degree AVB on the ECG was defined as a PR interval on a surface ECG >200 milliseconds without associated disruption of atrial-to-ventricular conduction.7  All ECGs were read by a pediatric cardiologist using electronic calipers. All patients suspected of having MIS-C were placed on continuous telemetry monitoring during admission, which was reviewed daily by a pediatric cardiologist. All statistical analyses were conducted in Stata software version 16 (Stata Corp, College Station, TX). Clinical and demographic variables were described by using summary statistics. All continuous data were presented as medians with ranges or interquartile ranges (IQRs). Categorical variables were presented as number (%). The Wilcoxon rank test was used for univariable analyses. Variables with a P value <.05 were considered statistically significant.

Thirty-two patients were diagnosed with MIS-C. Demographic details of the study population are listed in Table 1. The median age was 9 years (range 1–20), and there were 17 (53%) male patients. A majority of patients (n = 22; 69%) were found to have negative results on the SARS-CoV-2 PCR testing but positive results on the COVID-19 serology testing. The remaining patients (n = 10; 31%) had positive results on PCR testing. The majority of patients received both glucocorticoid (n = 30; 94%) and intravenous immunoglobulin (IVIg) therapy (n = 29; 91%) during hospitalization, whereas 13% (n = 4) of patients received anakinra, a recombinant human interleukin-1 receptor antagonist.

TABLE 1

Patient Characteristics

Patient Characteristics
Total No. patients 32 
Age, y, median (range) 9 (1–20) 
Male sex, n (%) 17 (53) 
COVID-19 laboratory testing, n (%)  
 PCR negative result and serology positive result 22 (69) 
 PCR positive result and serology positive result 7 (22) 
 PCR positive result and serology result unknown 3 (9) 
Treatment, n (%)  
 IVIg 29 (91) 
 Glucocorticoids 30 (94) 
 Anakinra 4 (13) 
Initial ECG intervals, median (IQR)  
 HR, beats per minute 128 (102–143) 
 PR, ms 135 (121–160) 
 QRS, ms 77 (72–86) 
 QTc, ms 421 (398–434) 
Patient Characteristics
Total No. patients 32 
Age, y, median (range) 9 (1–20) 
Male sex, n (%) 17 (53) 
COVID-19 laboratory testing, n (%)  
 PCR negative result and serology positive result 22 (69) 
 PCR positive result and serology positive result 7 (22) 
 PCR positive result and serology result unknown 3 (9) 
Treatment, n (%)  
 IVIg 29 (91) 
 Glucocorticoids 30 (94) 
 Anakinra 4 (13) 
Initial ECG intervals, median (IQR)  
 HR, beats per minute 128 (102–143) 
 PR, ms 135 (121–160) 
 QRS, ms 77 (72–86) 
 QTc, ms 421 (398–434) 

HR, heart rate.

Of the 32 total patients, 6 had first-degree AVB (19%) during hospitalization, including 2 patients with PR prolongation on the initial ECG at presentation. None of the 6 patients progressed to advanced AVB while on telemetry monitoring. The median of the longest PR interval for patients who did not develop first-degree AVB versus the patients who developed first-degree block, was 140 milliseconds (range: 80–178) vs 225 milliseconds (range: 200–302), respectively (P ≤ .01). No patients developed tachyarrhythmias during hospitalization. None of the patients with first-degree AVB received medications that prolonged the PR interval, including β-blockers, calcium channel blockers, or other antiarrhythmic medications.

Figure 1 reveals chronological PR changes for the 6 patients with MIS-C who developed first-degree AVB. All patients underwent an ECG every 24 to 48 hours until discharge. The onset of first-degree AVB occurred at a median of 8 days after the initial onset of symptoms (range: 5–10). The time to resolution of PR prolongation occurred at a median of 3 days after the initial first-degree AVB (range: 1–5). One patient’s prolonged PR interval did not resolve by the conclusion of the study. Other ECG findings in patients with first-degree AVB included a prolonged QTc interval (n = 2), ectopic atrial rhythm (n = 2), ST elevation in inferior leads (n = 2), and nonspecific ST and T wave abnormalities (n = 5). Notably, 1 patient developed a new-onset right bundle branch block (RBBB) along with first-degree AVB on day 3 of hospitalization, both of which subsequently resolved by day 5 (Fig 2). There was 1 patient who was found to have profound PR prolongation of 302 milliseconds (Fig 3). Two of the 6 patients with PR prolongation had an initial QTc interval of 476 milliseconds and a QTc interval of 473 milliseconds in the absence of medications prolonging the QTc interval. At the conclusion of the study, both patients’ QTc values became normal.

FIGURE 1

PR interval changes on serial ECGs during MIS-C from onset of illness.

FIGURE 1

PR interval changes on serial ECGs during MIS-C from onset of illness.

Close modal
FIGURE 2

ECG findings in a 9-year-old boy. A, Initial 12-lead ECG on presentation revealing normal sinus rhythm with narrow QRS complexes. B, Twelve-lead ECG on day 3 of hospitalization revealing first-degree AVB (PR of 200 milliseconds) with RBBB.

FIGURE 2

ECG findings in a 9-year-old boy. A, Initial 12-lead ECG on presentation revealing normal sinus rhythm with narrow QRS complexes. B, Twelve-lead ECG on day 3 of hospitalization revealing first-degree AVB (PR of 200 milliseconds) with RBBB.

Close modal
FIGURE 3

Twelve-lead ECG revealing significant first-degree AVB with a PR interval of 302 milliseconds and nonspecific T wave abnormalities in a 12-year-old boy.

FIGURE 3

Twelve-lead ECG revealing significant first-degree AVB with a PR interval of 302 milliseconds and nonspecific T wave abnormalities in a 12-year-old boy.

Close modal

Additionally, abnormal ECG findings in patients without first-degree AVB included a prolonged QTc interval (n = 4), ectopic atrial rhythm (n = 1), ST elevation or depression (n = 3), T wave inversions (n = 5), nonspecific ST and/or T wave abnormalities (n = 14), nonspecific intraventricular conduction delay or right ventricular conduction delay (n = 5), right axis deviation (n = 5), and intermittent premature ventricular complexes (n = 1). Four patients without first-degree heart block had QTc intervals of 474, 486, 488, and 494 milliseconds, which all normalized by the conclusion of the study.

There was no statistical difference in the rate of ICU admission during hospitalization between those with first-degree AVB and those without (4 of 6 [67%] and 21 of 26 [81%], respectively; P = .46).

All patients diagnosed with MIS-C underwent echocardiography during hospitalization, and the left ventricular ejection fraction (LVEF) was measured. Univariable analyses were completed by using the lowest ejection fraction during the patient’s hospitalization (Table 2). There were 2 patients with a significantly decreased LVEF (30% and 35%) in the group without conduction anomalies and none in the group with PR prolongation. Despite these outliers, the median LVEF for patients who had first-degree AVB, compared with patients without, was not significantly different (53.5% [IQR: 45–57] and 56.5% [IQR: 48–59], respectively; P = .32).

TABLE 2

Laboratory and Diagnostic Findings

MIS-C Without First-Degree AVBMIS-C With First-Degree AVBPNormal Laboratory Values
Total patients, n 26 — — 
Age, y, median (range) 7.5 (1–20) 11.5 (9–17) — — 
Male sex, n (%) 12 (46) 5 (83) .11 — 
ICU admission, n (%) 21 (81) 4 (67) .46 — 
Progression to advanced AVB, n (%) — — 
Longest PR interval, ms 140 (80–178) 225 (200–302) <.01 — 
Lowest LVEF percentile, median (IQR) 56.5 (48–59) 53.5 (45–57) .32 — 
High-sensitive troponin T, ng/L, median (IQR) 44 (13–88) 89 (49–217) .11 <14 
NT-proBNP, pg/mL, median (IQR) 7236 (3117–27 552) 5438 (1809–35 255) .90 10–242 
CRP, mg/L, median (IQR) 201 (48–300) 211 (163–255) .77 <0.9 
ESR, mm/h, median (IQR) 69 (47–79) 78 (58–90) .48 0–20 
Procalcitonin, ng/mL, median (IQR) 1.9 (0.7–16.3) 2.6 (0.8–2.8) .79 <0.08 
Ferritin, ng/mL, median (IQR) 595 (344–866) 559 (378–752) .96 13–150 
IL-6, pg/mL, median (IQR) 227 (80–315) 124 (102–315) .85 <5 
Manual absolute band count percentile, median (IQR) 4.5 (0–10) 4.5 (0–7) .71 
D-dimer, μg/mL, median (IQR) 3.8 (2.5–8.1) 2.9 (2.2–3.9) .21 <0.8 
Fibrin, mg/dL, median (IQR) 571 (426–680) 709 (660–750) .18 191–430 
LDH, U/L, median (IQR) 373 (285–444) 308 (288–523) .99 140–280 
Albumin, g/dL, median (IQR) 2.9 (2.5–3.5) 2.6 (2.2–3.5) .50 3.9–5.2 
MIS-C Without First-Degree AVBMIS-C With First-Degree AVBPNormal Laboratory Values
Total patients, n 26 — — 
Age, y, median (range) 7.5 (1–20) 11.5 (9–17) — — 
Male sex, n (%) 12 (46) 5 (83) .11 — 
ICU admission, n (%) 21 (81) 4 (67) .46 — 
Progression to advanced AVB, n (%) — — 
Longest PR interval, ms 140 (80–178) 225 (200–302) <.01 — 
Lowest LVEF percentile, median (IQR) 56.5 (48–59) 53.5 (45–57) .32 — 
High-sensitive troponin T, ng/L, median (IQR) 44 (13–88) 89 (49–217) .11 <14 
NT-proBNP, pg/mL, median (IQR) 7236 (3117–27 552) 5438 (1809–35 255) .90 10–242 
CRP, mg/L, median (IQR) 201 (48–300) 211 (163–255) .77 <0.9 
ESR, mm/h, median (IQR) 69 (47–79) 78 (58–90) .48 0–20 
Procalcitonin, ng/mL, median (IQR) 1.9 (0.7–16.3) 2.6 (0.8–2.8) .79 <0.08 
Ferritin, ng/mL, median (IQR) 595 (344–866) 559 (378–752) .96 13–150 
IL-6, pg/mL, median (IQR) 227 (80–315) 124 (102–315) .85 <5 
Manual absolute band count percentile, median (IQR) 4.5 (0–10) 4.5 (0–7) .71 
D-dimer, μg/mL, median (IQR) 3.8 (2.5–8.1) 2.9 (2.2–3.9) .21 <0.8 
Fibrin, mg/dL, median (IQR) 571 (426–680) 709 (660–750) .18 191–430 
LDH, U/L, median (IQR) 373 (285–444) 308 (288–523) .99 140–280 
Albumin, g/dL, median (IQR) 2.9 (2.5–3.5) 2.6 (2.2–3.5) .50 3.9–5.2 

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IL-6, interleukin 6; LDH, lactate dehydrogenase; NT-proBNP, N-terminal pro–brain natriuretic peptide; —, not applicable.

Cardiac and inflammatory markers were also obtained for all patients during hospitalization, illustrated in Table 2. No laboratory variable was significantly associated with the development of first-degree AVB. At the time of the initial first-degree AVB development, all patients had normal electrolyte levels.

Since the initial report of COVID-19 in December 2019, children with severe complications requiring hospitalization were relatively rare during the first several months of the pandemic. A recent surge in pediatric patients with significant systemic inflammatory response and multiorgan dysfunction, with symptoms overlapping with Kawasaki disease, has shifted the diagnostic and treatment paradigm for the pediatric population.8,9  At our institution, >30 patients were admitted with a diagnosis of MIS-C during the study period. From a cardiovascular perspective, some patients were noted to have decreased cardiac function and conduction abnormalities.

Early reports in adult patients revealed direct cardiac complications of COVID-19, including arrhythmias, acute myocardial injury, and myocarditis with circulatory failure.10,11  In a recent study, an adult patient was found to have high-degree AVB in the setting of COVID-19 illness in the absence of MIS-C symptoms.5  In our study, we analyzed pediatric patients with a COVID-19–related inflammatory disease; our patients with MIS-C exhibited conduction abnormalities, including first-degree AVB and RBBB.

AVB has been associated with multiple infectious and inflammatory diseases, such as Lyme disease, acute rheumatic fever, and myocarditis.1214  Occurring in 15% to 20% of patients, a prolonged PR interval is a minor criteria for diagnosis of acute rheumatic fever.13,15  Our study revealed a similar 19% incidence of a prolonged PR interval in pediatric patients with MIS-C. Previous studies revealed that patients with a PR interval >300 milliseconds were more likely to progress to having complete AVB from an infectious etiology process, such as Lyme disease.16  In our study, 1 patient developed significant PR prolongation of 302 milliseconds, which improved without progression to advanced AVB. Additionally, AVB in patients with Lyme carditis and myocarditis typically resolved within 7 and 5 days, respectively.17,18  In our study, we found that most patients’ PR intervals returned back to baseline in a median of 3 days from the initial diagnosis of first-degree AVB.

The exact pathogenic mechanism underlying the development of conduction abnormalities remains unknown. In patients with rheumatic carditis, there is evidence suggesting molecular mimicry as the etiology of myocardial injury.19  During an acute infection (such as group A Streptococcus), the immune response leads to production of antibodies or cytotoxic T cells directed against human valvular endothelium because of the antigenic similarities of the infectious agent and the glycoproteins of cardiac valves.19  This process may result in mitral or aortic valvulitis as well as pancarditis. A similar pathophysiology of AVB has not yet been clearly established. Cristal et al20  showed that advanced AVB can occur in the absence of rheumatic carditis, suggesting an alternative mechanism of acquired AVB. In this vein, conduction abnormalities of MIS-C may be an isolated finding separate from the myocardial injury documented in patients actively infected with SARS-CoV-2.10 

Although the clinical presentation and conduction abnormalities found in patients with MIS-C share similarities with other disease entities, there are a few notable distinctions. Despite similar presenting characteristics with Kawasaki disease, including limbic sparing conjunctivitis and oral mucosal changes, patients with MIS-C exhibited a prolonged PR interval, which is not regularly seen in Kawasaki disease.21  More commonly, PR interval prolongation is seen in infections such as Lyme disease.16  In addition to the first-degree AVB found in our cohort of patients with MIS-C, 1 patient developed a new-onset RBBB with PR prolongation during the acute illness phase. Although first-degree AVB is commonly seen in patients with Lyme disease and acute rheumatic fever, involvement of the bundle branches is uncommon.22 

At our institution, patients with MIS-C and first-degree AVB did not progress to high-degree AVB. This may be explained by the initiation of immunosuppression, including glucocorticoids and IVIg early in the acute phase of illness. Previous data regarding the efficacy of immunosuppression for acquired AVB are limited. In one study, a review of the literature indicated that complete heart block associated with acute myocarditis resolved in all 3 children in whom steroids and IVIg treatment were used.12  Literature has also revealed that glucocorticoids downregulate the activation of the proinflammatory response and have been used to treat congenital heart block in fetuses and neonates.23,24  We suspect that the early initiation of high-dose steroids and IVIg treatment may have curtailed the inflammatory effects on the myocardium and conduction system and, therefore, the progression of first-degree AVB to advanced AVB.

This study is inherently limited by its retrospective design and small sample size. Furthermore, the diagnosis of MIS-C continues to evolve, and the symptoms may also overlap with other viral illnesses in pediatric patients, making the diagnosis challenging.

Although no patients in our study progressed to advanced AVB, 1 patient developed significant PR prolongation and 1 patient had new-onset RBBB. Previous studies have revealed a progression of PR interval prolongation to advanced AVB in other infectious or inflammatory conditions, such as Lyme disease.14,16  It is possible that disease in patients with MIS-C may theoretically have progressed to advanced AVB in the absence of treatment. Given the relative lack of knowledge and prospective studies regarding the MIS-C disease process, conclusions about the natural history are necessarily limited. In this vein, all patients with MIS-C should be monitored closely during hospitalization with frequent ECGs and telemetry monitoring, and follow-up should be established to document normalization of the PR interval.

This study reveals a 19% prevalence of first-degree AVB in patients diagnosed with MIS-C. In our subset of patients, first-degree AVB associated with MIS-C improved without progression to advanced AVB. Cardiac enzymes, inflammatory markers, and cardiac function were not associated with first-degree AVB development. Future multicenter studies are warranted to further elucidate conduction abnormalities associated with the novel MIS-C.

Drs Choi and Liberman conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Fremed, Starc, Weller, Cheung, Ferris, and Silver critically reviewed and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted.

FUNDING: No external funding.

     
  • AVB

    atrioventricular block

  •  
  • COVID-19

    coronavirus disease 2019

  •  
  • ECG

    electrocardiogram

  •  
  • IQR

    interquartile range

  •  
  • IVIg

    intravenous immunoglobulin

  •  
  • LVEF

    left ventricular ejection fraction

  •  
  • MIS-C

    multisystem inflammatory syndrome in children

  •  
  • PCR

    polymerase chain reaction

  •  
  • RBBB

    right bundle branch block

  •  
  • SARS-CoV-2

    severe acute respiratory syndrome coronavirus 2

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.