Long-Term Microvascular Changes in Multisystem Inflammatory Syndrome in Children

Abstract

This case-control study investigates changes in microcirculation and endothelial function in the acute phase of multisystem inflammatory syndrome in children and 3 to 6 months after onset.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe postinfection reaction to SARS-CoV-2 requiring intensive care treatment in 48% of patients.¹ The precise pathogenesis and long-term clinical impact of MIS-C remain poorly understood. Various SARS-CoV-2–related vascular molecular mechanisms imply potentially acute and lasting key roles of the endothelium and microcirculation.² In vivo microvascular impairment has been described in patients with COVID-19.³ Furthermore, there is sparse evidence of microvascular damage in MIS-C during the acute and immediate postacute phases.^4,5 Given limited data on MIS-C’s pathogenesis and long-term outcomes with a potential link to microcirculation and endothelial function, we investigated these aspects longitudinally during the acute phase and 3 to 6 months after symptom onset.

Methods

This prospective case-control study was conducted between April 8 and December 16, 2022, following the Declaration of Helsinki after approval by the Ludwig Maximilian University of Munich ethics committee. We followed the STROBE guideline. Children diagnosed with MIS-C according to World Health Organization criteria and without significant comorbidities were included in the study after acquisition of written informed consent from parents or guardians and were matched for age and sex to healthy control participants.

Clinical data and vital signs were collected. Videos of sublingual microcirculation were obtained with a handheld MicroScan video microscope based on sidestream dark field imaging technology. Offline analysis using AVA software, version 3.2, quantified total vessel density (TVD), microvascular flow index (MFI), proportion of perfused vessels (PPV), and vessel diameter distribution (Video). Endothelial function (reactive hyperemia index) and arterial stiffness (augmentation index [AI]) were measured by digital arterial plethysmography using the EndoPAT device.

Video. Sublingual Microcirculation in MIS-C During the Acute Phase and Follow-Up Compared With Controls.

Download video file ^{(69.5MB, mp4)}

In multisystem inflammatory syndrome in children (MIS-C), both the acute phase and follow-up examinations reveal reduced microvascular flow index, total vessel density, and portion of perfused vessels along with a loss of capillaries and a relative increase in larger vessels compared with healthy controls.

Data analysis was conducted blinded using SPSS and included the Shapiro-Wilk test, t test, χ² test, Mann-Whitney U test, and multivariate linear regression. 2-sided P < .05 was significant.

Results

Eighteen patients with MIS-C were recruited (7 [38.9%] female; 11 [61.1%] male; mean [SD] age, 10.6 [4.0] years; 1 was excluded due to comorbidities) and matched with 17 controls (6 [35.3%], female; 11 [64.7%], male; mean [SD] age, 10.96 [4.2] years) (Figure). They were examined during the acute phase and after a median of 114.5 days (IQR, 94.5-136.0 days). During the acute phase, patients with MIS-C compared with controls exhibited significantly damaged microcirculation, including lower median MFI (2.36 [IQR, 2.23-2.72] vs 2.80 [IQR, 2.69-2.86]; P = .01), TVD (16.14 [IQR, 14.61-17.85] mm/mm² vs 19.61 [IQR, 19.22-20.66] mm/mm²; P = .004), and PPV (12.31% [IQR, 11.46%-15.59%] vs 18.10% [IQR, 17.67%-19.70%] P = .004). Vessel diameter distribution was altered with significant capillary rarefication (Table).

Figure. Study Flowchart.

MIS-C indicates multisystem inflammatory syndrome in children; SDF, sidestream dark field.

Table. Microcirculation, Endothelial Function, and Arterial Stiffness During the Acute Phase of MIS-C and Follow-Up.

Measure	Median (IQR)		P valuea	Linear regressionb
	Patients with MIS-C	Controls		β	P value
Acute phase, SDF (n = 7 per group)
MFIc
Small vesselsd	2.40 (2.08 to 2.67)	2.92 (2.83 to 3.00)	.004	NA	NA
All vessels	2.36 (2.23 to 2.72)	2.80 (2.69 to 2.86)	.01	NA	NA
TVD, mm/mm2
Small vesselsd	4.28 (3.36 to 7.27)	9.15 (8.45 to 11.02)	.009	NA	NA
All vessels	16.14 (14.61 to 17.85)	19.61 (19.22 to 20.66)	.004	NA	NA
PPV, %
Small vesselsd	2.97 (2.44 to 6.66)	8.94 (8.22 to 11.02)	.004	NA	NA
All vessels	12.31 (11.46 to 15.59)	18.10 (17.67 to 19.70)	.004	NA	NA
Vessel diameter, %d
Small	32.01 (22.55 to 41.66)	48.23 (44.68 to 54.79)	.009	NA	NA
Medium	58.90 (47.18 to 64.16)	47.02 (41.34 to 47.14)	.02	NA	NA
Large	10.96 (9.08 to 12.40)	6.28 (3.86 to 8.19)	.009	NA	NA
Acute phase, EndoPAT (n = 8 per group)
RHI	1.16 (0.84 to 1.34)	1.17 (1.07 to 1.71)	.46	NA	NA
AIx75e	−13.32 (−20.99 to 0.22)	−16.10 (−19.24 to −6.99)	.67	NA	NA
Follow-up, SDF (n = 14 per group)
MFIc
Small vesselsd	2.48 (2.31 to 2.82)	2.90 (2.73 to 3.00)	.01	−0.353	.03
All vessels	2.30 (2.20 to 2.72)	2.79 (2.63 to 2.92)	.01	−0.422	.01
TVD, mm/mm2
Small vesselsd	5.06 (3.47 to 6.20)	10.27 (8.82 to 11.33)	<.001	−0.799	<.001
All vessels	15.96 (14.07 to 17.41)	19.65 (19.12 to 20.63)	<.001	−0.689	<.001
PPV, %
Small vesselsd	4.04 (3.27 to 5.04)	9.61 (8.02 to 11.06)	<.001	−0.826	<.001
All vessels	12.14 (11.24 to 14.26)	17.85 (16.63 to 19.82)	<.001	−0.752	<.001
Vessel diameter, %d
Small	31.69 (26.96 to 36.61)	52.19 (46.77 to 56.90)	<.001	−0.823	<.001
Medium	53.83 (50.55 to 57.26)	42.39 (40.47 to 47.21)	<.001	0.763	<.001
Large	12.50 (9.12 to 18.04)	4.03 (3.34 to 8.05)	<.001	0.706	<.001
Follow-up, EndoPAT (n = 16 per group)
RHI	1.52 (1.11 to 2.08)	1.19 (1.06 to 1.77)	.27	0.216	.12
AIe	−7.05 (−15.72 to 0.54)	−18.01 (−30.46 to −10.03)	.009	0.448	.007

Abbreviations: AIx75, augmentation index normalized for a heart rate of 75 beats/min; MFI, microvascular flow index; MIS-C, multisystem inflammatory syndrome in children; NA, not applicable; PPV, proportion of perfused vessels; RHI, reactive hyperemia index; SDF, sidestream dark field; TVD, total vessel density.

^a Mann-Whitney U test.

^b Adjusted for age, sex, and body mass index.

^c MFI of 0 indicates no flow; 1, intermittent; 2, sluggish; and 3, continuous.

^d Small vessels were defined as vessels with a diameter less than 10 μm; medium, from 10 μm to less than 25 μm; and large, 25 μm or larger.

^e Normalized to a heart rate of 75 bpm.

Impaired microcirculatory parameters persisted during follow-up, even without ongoing inflammation. These findings remained significant when adjusting for known confounders as age, body mass index, and sex. Furthermore, AI was significantly increased in MIS-C but only during follow-up (median, −7.05 [IQR, −15.72 to 0.54] vs −18.01 [IQR, −30.46 to −10.03]; P = .009). Subanalyses did not reveal any association of disease severity (myocardial dysfunction, need of intensive care, or use of catecholamines) or laboratory parameters (C-reactive protein, ferritin, leukocytes, or fibrinogen) with persisting microcirculatory alterations.

Discussion

This study found significant, persistent microvascular damage with redistribution of the vessel architecture (ie, loss of capillaries with relative increase in larger vessels) in patients with MIS-C and suggests a long-term association with arterial stiffness. Our findings suggest that MIS-C’s pathogenesis may go beyond the acute hyperinflammatory reaction, possibly involving independent effects of SARS-CoV-2 on the endothelium and vascular system. Supporting this idea, microvascular perturbations have been observed in children recovering from COVID-19.³ Patients with long COVID have likewise demonstrated significantly reduced vessel density.⁶ Even in this small, single-center cohort, significant vascular alterations that persisted over several months may indicate that MIS-C is associated with increased risk for future cardiovascular complications.

This study emphasizes the importance of understanding the vascular impact of MIS-C during the acute phase and follow-up period to provide appropriate medical care and interventions. A limitation was the small study population owing to the rarity of MIS-C.

Supplement.

Data Sharing Statement