Multisystem inflammatory syndrome in children (MIS-C) is a severe inflammatory response described in children after infection with severe acute respiratory syndrome coronavirus 2. We present a case of a 9-year-old African American boy with 2 distinct illnesses that were both consistent with MIS-C. He first presented in the early stages of our understanding of MIS-C with predominantly neurologic and gastrointestinal symptoms and demonstrated elevated inflammatory markers consistent with MIS-C. He was treated with intravenous immunoglobulin with complete resolution of signs and symptoms. After 7 months of good health, he returned with a second, distinct illness characterized by fever, rash, gastrointestinal symptoms, and elevated inflammatory markers that met the criteria for MIS-C. In addition, we identified new dilatation of the left anterior descending coronary artery. He improved rapidly after treatment with intravenous immunoglobulin, aspirin, and steroids. Our report highlights the need to achieve a better understanding of this entity’s pathogenesis and clinical course and to improve anticipatory guidance for children with MIS-C.

In spring 2020, pediatricians in Europe reported a novel multisystem inflammatory disease related to coronavirus disease 2019 (COVID-19).1  Similar reports ensued from the New York City Health Department,2  leading to a case definition for multisystem inflammatory syndrome in children (MIS-C) published by the Centers for Disease Control and Prevention on May 14, 2020.3  Knowledge of this disease has been bolstered by numerous case series that describe clinical characteristics, laboratory findings, and management.4,5  However, our understanding of its pathogenesis and clinical outcomes continues to evolve. We report a case of a 9-year-old African American male who presented to our freestanding children’s hospital in the southeastern United States with 2 distinct clinical illnesses 7 months apart, each consistent with MIS-C. He presented initially with primarily gastrointestinal and neurologic symptoms and, later, with a rapidly progressive illness with predominant cardiovascular manifestations. During both illnesses, he had laboratory evidence of inflammation and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology.

A 9-year-old, previously healthy male presented in June 2020 with 1 day of diplopia, trunk rash, altered gait, somnolence, urinary incontinence, headache, neck pain, epigastric pain, vomiting, and 6 days of fever. He had suspected exposure to COVID-19 at an indoor day camp, but there was no known exposure to animals or ticks and no travel. The physical examination was significant for fever, macular rash, erythematous lips, nonpurulent conjunctival injection, and bilateral posterior cervical adenopathy. He appeared unwell but nontoxic, with a normal sensorium and unsteady gait. SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) was negative. Head computerized tomography (CT) scan was normal. Cerebrospinal fluid (CSF) examination showed mild pleocytosis, elevated protein, and a negative meningoencephalitis panel. The differential diagnosis included meningitis, encephalitis, tick-borne illness, atypical Kawasaki disease (KD), MIS-C, toxic shock syndrome, rheumatologic diseases, and isolated central nervous system hemophagocytic lymphohistiocytosis. He was started on vancomycin and ceftriaxone for 48 hours until blood and CSF culture results were negative and received a 10-day course of doxycycline.

Infectious diseases, neurology, rheumatology, oncology, and cardiology services were consulted. An extensive workup for alternative diagnoses was found to be negative (Table 1). Brain MRI on day 2 of hospitalization revealed a 1 cm T2 hyperintense lesion in the splenium of the corpus callosum (Fig 1). Transthoracic echocardiogram (TTE) was normal, and electrocardiogram (ECG) demonstrated sinus bradycardia with prolonged PR interval for age (183 ms). SARS-CoV-2 immunoglobulin G (IgG) tested against the nucleocapsid protein6  yielded positive results (1.81 index units). A chest CT scan revealed bilateral lower lobe tree-in-bud ground glass opacities, and a respiratory viral panel was negative, thus raising concern for MIS-C or a recent COVID-19 infection as has been described.7 Ehrlichia chaffeensis polymerase chain reaction (PCR) and Rocky Mountain spotted fever serologies done early in the hospitalization and a week into clinical course yielded negative results.

FIGURE 1

MRI brain images demonstrating splenium lesion and resolution. White arrow indicates splenium lesion.

FIGURE 1

MRI brain images demonstrating splenium lesion and resolution. White arrow indicates splenium lesion.

Close modal
TABLE 1

Additional Diagnostic Laboratory Studies From Each Episode of MIS-C

Study
First illnessResultReference
Immunology studies   
 Cytokine panel, pg/mL   
  TNF-α <1.7 ≤7.2 
  IFN- γ 4.7 ≤4.2 
  IL-1β <6.5 ≤6.7 
  IL-2 <2.1 ≤2.1 
  Soluble IL-2Ra 8260 622–1619 
  IL-4 <2.2 ≤2.2 
  IL-5 <2.1 ≤2.1 
  IL-6 3.3 ≤2.0 
  IL-8 32.7 ≤3.0 
  IL-10 7.2 ≤2.8 
  IL-12 2.0 ≤1.9 
  IL-13 3.3 ≤2.3 
  IL-17 <1.4 ≤1.4 
 Lymphocyte panel, cells/µL   
  Absolute CD3 471 770–4000 
  Absolute CD4 358 400–2500 
  Absolute CD8 100 200–1700 
  Absolute NK cells 56 70–590 
  Absolute CD19 162 100–800 
  Absolute CD45RA 261 250–2000 
  Absolute CD45RO 98 100–510 
  CD107a (MCF) 717 207–678 
 NK function, %   
  NK 50:1 52 ≥20 
  NK 25:1 47 ≥10 
  NK 12:1 39 ≥5 
  NK 6:1 20 ≥1 
  NK lytic units 40 ≥2.6 
  Interpretation Normal Normal 
Rheumatologic studies   
 ACE (unit/L) 48 13–100 
 ANA Negative  
 Anti-dsDNA 1.0 ≤4.0 
 C3 (mg/dL) 149 92–161 
 Anti-Smith <0.2 ≤0.9 
 Anti-RNP <0.2 ≤0.9 
 Anti-SSA <0.2 ≤0.9 
 Anti-SSB <0.2 ≤0.9 
Immunoglobulins (mg/dL)   
 IgA 78 33–225 
 IgG 977 550–1425 
 IgM 46 40–190 
Infectious disease and neurologic studies   
 Serum studies   
 RMSF IgM and IgG Negative Negative 
Rickettsia typhi IgM and IgG Negative Negative 
Ehrlichia chaffeensis DNA PCR Not detected Not detected 
Ehrlichia chaffeensis IgM and IgG Negative Negative 
 Arbovirus Antibody Panel Negative Negative 
 EBV nuclear antibody (IgG) Negative Negative 
 EBV IgG antibody Negative Negative 
 EBV IgM antibody Negative Negative 
 EBV antibody to early-D antigen Negative Negative 
Cerebrospinal Fluid Studies   
 Biofire film array meningitis encephalitis panel Negative Negative 
 West Nile virus IgM and IgG Negative Negative 
 Autoimmune encephalopathy panel Negative Negative 
Nasopharyngeal study   
 Respiratory viral panel PCR Negative Negative 
Stool study   
 Gastrointestinal pathogen PCR panel Negative Negative 
Second illness   
 Histoplasmosis yeast phase and mycelial phase antibody, CSF Negative <1:8 Negative <1:8 
 Histoplasmosis antibody, immunodiffusion Negative Negative 
 Histoplasmosis antigen (blood and urine) Negative Negative 
 QuantiFERON-TB gold plus Negative Negative 
Study
First illnessResultReference
Immunology studies   
 Cytokine panel, pg/mL   
  TNF-α <1.7 ≤7.2 
  IFN- γ 4.7 ≤4.2 
  IL-1β <6.5 ≤6.7 
  IL-2 <2.1 ≤2.1 
  Soluble IL-2Ra 8260 622–1619 
  IL-4 <2.2 ≤2.2 
  IL-5 <2.1 ≤2.1 
  IL-6 3.3 ≤2.0 
  IL-8 32.7 ≤3.0 
  IL-10 7.2 ≤2.8 
  IL-12 2.0 ≤1.9 
  IL-13 3.3 ≤2.3 
  IL-17 <1.4 ≤1.4 
 Lymphocyte panel, cells/µL   
  Absolute CD3 471 770–4000 
  Absolute CD4 358 400–2500 
  Absolute CD8 100 200–1700 
  Absolute NK cells 56 70–590 
  Absolute CD19 162 100–800 
  Absolute CD45RA 261 250–2000 
  Absolute CD45RO 98 100–510 
  CD107a (MCF) 717 207–678 
 NK function, %   
  NK 50:1 52 ≥20 
  NK 25:1 47 ≥10 
  NK 12:1 39 ≥5 
  NK 6:1 20 ≥1 
  NK lytic units 40 ≥2.6 
  Interpretation Normal Normal 
Rheumatologic studies   
 ACE (unit/L) 48 13–100 
 ANA Negative  
 Anti-dsDNA 1.0 ≤4.0 
 C3 (mg/dL) 149 92–161 
 Anti-Smith <0.2 ≤0.9 
 Anti-RNP <0.2 ≤0.9 
 Anti-SSA <0.2 ≤0.9 
 Anti-SSB <0.2 ≤0.9 
Immunoglobulins (mg/dL)   
 IgA 78 33–225 
 IgG 977 550–1425 
 IgM 46 40–190 
Infectious disease and neurologic studies   
 Serum studies   
 RMSF IgM and IgG Negative Negative 
Rickettsia typhi IgM and IgG Negative Negative 
Ehrlichia chaffeensis DNA PCR Not detected Not detected 
Ehrlichia chaffeensis IgM and IgG Negative Negative 
 Arbovirus Antibody Panel Negative Negative 
 EBV nuclear antibody (IgG) Negative Negative 
 EBV IgG antibody Negative Negative 
 EBV IgM antibody Negative Negative 
 EBV antibody to early-D antigen Negative Negative 
Cerebrospinal Fluid Studies   
 Biofire film array meningitis encephalitis panel Negative Negative 
 West Nile virus IgM and IgG Negative Negative 
 Autoimmune encephalopathy panel Negative Negative 
Nasopharyngeal study   
 Respiratory viral panel PCR Negative Negative 
Stool study   
 Gastrointestinal pathogen PCR panel Negative Negative 
Second illness   
 Histoplasmosis yeast phase and mycelial phase antibody, CSF Negative <1:8 Negative <1:8 
 Histoplasmosis antibody, immunodiffusion Negative Negative 
 Histoplasmosis antigen (blood and urine) Negative Negative 
 QuantiFERON-TB gold plus Negative Negative 

ACE, angiotensin converting enzyme; ANA, antinuclear antibodies; C3, complement C3; CD, cluster of differentiation; CF, complement fixation; dsDNA, double-stranded DNA; EBV, Epstein-Barr virus; IFN, interferon; Ig, immunoglobulin; IL, interleukin; NK, natural killer cell; PCR, polymerase chain reaction; RNP, ribonucleoprotein; RMSF, Rocky Mountain spotted fever; SSA, Sjögren’s-syndrome-related antigen A; SSB, Sjögren’s-syndrome-related antigen B; TNF, tumor necrosis factor.

Extensive studies were completed during the first episode; workup during the second episode was tailored to this child’s clinical presentation and course. A full description of laboratory panels is described in the Supplemental Information.

Given the unrevealing extensive workup and the constellation of clinical and laboratory markers (Table 2) suggestive of MIS-C3,8  in the context of a global pandemic, we assigned a diagnosis of MIS-C. He was treated with intravenous immunoglobulin (IVIG) 2 g/kg on day 5 of hospitalization (day 11 of symptoms) and promptly defervesced. Generalized weakness, headache, and hypersomnolence continued for 2 to 3 days. Repeat lumbar puncture showed an opening pressure of 28 cm H2O and elevated protein. He received acetazolamide until his headaches improved. A brain MRI on day 6 of hospitalization showed resolution of the abnormality in the splenium of the corpus callosum. The symptoms resolved and he was discharged on hospital day 14. Ehrlichia chaffeensis serology obtained at the end of hospitalization yielded negative results. Although an empirical course of doxycycline was continued, clinical improvement was noted only after IVIG therapy, arguing against the diagnosis of tick-borne illness. At an outpatient follow-up with cardiology and rheumatology 3 weeks after discharge, he reported full symptomatic recovery. D-dimer, ECG, and TTE were normal.

TABLE 2

Pertinent Laboratory Studies for Each Episode

Laboratory Study (Reference Range)First Episode, June 2020Second Episode, January 2021
White blood cells (5–13 thou/mcL) 2.2 4.9 
Hemoglobin (11–16 g/dL) 9.0 8.9 
Platelets (140–450 thou/mcL) 112 156 
Absolute neutrophil count (1.8–7.1 thou/mcL) 1.43 3.71 
Absolute lymphocyte count (1.45–7.67 thou/mcL) 0.57 0.77 
Neutrophil/lymphocyte ratio 2.5 4.8 
Interleukin-6 (≤2.0 pg/mL) 3.3 — 
Sodium (134–142 mmol/L) 125 127 
Albumin (3.5–5.4 g/dL) 2.7 3.4 
Aspartate aminotransferase (15–40 U/L) 116 68 
Alanine aminotransferase (10–41 U/L) 90 62 
Erythrocyte sedimentation rate (0–13 mm/hr) 25 
C-reactive protein (≤ 9 mg/L) 7.5 55.5 
Procalcitonin (0.5–2 ng/mL) — 4.34 
Ferritin (10–300 ng/mL) 386 185 
Lactate dehydrogenase (420–750 unit/L) 1648 1040 
D-dimer (0–0.44 mcg FEU/mL) 3.75 1.52 
Fibrinogen (181–446 mg/dL) 188 492 
Prothrombin time (11.7–14.5 s) 15.5 15.5 
International normalized ratio (0.85–1.16) 1.26 1.26 
Partial thromboplastin time (32.8–39 s) 30.7 32.8 
Troponin-I (0–0.034 ng/mL) <0.01 0.14 
B-type natriuretic peptide (≤100 pg/mL) 45.5 211.4 
SARS-CoV-2 RT-PCR Negative Negative 
IgG, index valuea 1.81 7.91 
Total IgG, IgA, IgM, index valueb — 24.8 
Laboratory Study (Reference Range)First Episode, June 2020Second Episode, January 2021
White blood cells (5–13 thou/mcL) 2.2 4.9 
Hemoglobin (11–16 g/dL) 9.0 8.9 
Platelets (140–450 thou/mcL) 112 156 
Absolute neutrophil count (1.8–7.1 thou/mcL) 1.43 3.71 
Absolute lymphocyte count (1.45–7.67 thou/mcL) 0.57 0.77 
Neutrophil/lymphocyte ratio 2.5 4.8 
Interleukin-6 (≤2.0 pg/mL) 3.3 — 
Sodium (134–142 mmol/L) 125 127 
Albumin (3.5–5.4 g/dL) 2.7 3.4 
Aspartate aminotransferase (15–40 U/L) 116 68 
Alanine aminotransferase (10–41 U/L) 90 62 
Erythrocyte sedimentation rate (0–13 mm/hr) 25 
C-reactive protein (≤ 9 mg/L) 7.5 55.5 
Procalcitonin (0.5–2 ng/mL) — 4.34 
Ferritin (10–300 ng/mL) 386 185 
Lactate dehydrogenase (420–750 unit/L) 1648 1040 
D-dimer (0–0.44 mcg FEU/mL) 3.75 1.52 
Fibrinogen (181–446 mg/dL) 188 492 
Prothrombin time (11.7–14.5 s) 15.5 15.5 
International normalized ratio (0.85–1.16) 1.26 1.26 
Partial thromboplastin time (32.8–39 s) 30.7 32.8 
Troponin-I (0–0.034 ng/mL) <0.01 0.14 
B-type natriuretic peptide (≤100 pg/mL) 45.5 211.4 
SARS-CoV-2 RT-PCR Negative Negative 
IgG, index valuea 1.81 7.91 
Total IgG, IgA, IgM, index valueb — 24.8 

IL-6, interleukin 6; Ig, immunoglobulin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RT-PCR, real time polymerase chain reaction; —, not collected (IL-6 and procalcitonin) or not available (total IgG, IgA, IgM) during the specific episode of illness.

a

Abbott architect SARS-CoV-2 IgG assay.6 

b

Vitros total anti-SARS-CoV-2 antibodies assay.9 

In January 2021, he presented with 3 days of rash, emesis, abdominal pain, and headache. He reported no known direct exposure to acute COVID-19 and had not been tested for SARS-CoV-2 during the preceding 2 months. His initial examination revealed a pruritic macular rash involving his trunk and upper extremities. SARS-CoV-2 IgG against nucleocapsid protein6  and total antibody against spike protein9  were elevated at 7.91 index units and 24.8 index units, respectively. Although a second episode of MIS-C was highest on the differential diagnosis, other diagnoses considered were atypical KD, infections such as toxic shock syndrome, tuberculosis, and histoplasmosis and systemic viral infections such as adenovirus, or tick-borne illnesses. Neurologic examination and brain MRI were normal. Diagnostics for histoplasmosis and tuberculosis were obtained because of the previous abnormal CT chest findings and the results were negative (Table 1). A paucity of respiratory symptoms, negative evaluation for respiratory infections, and improvement with a return to baseline between episodes also argued against a long-standing untreated infectious etiology.

He subsequently developed fevers up to 39.5°C, cracked lips, conjunctival erythema, hand swelling, and unilateral submandibular lymphadenopathy. An ECG showed sinus tachycardia, and TTE (Fig 2) demonstrated mild proximal left anterior descending coronary artery dilatation (3.4 mm, z-score: + 2.38) and mild mitral valve regurgitation. These findings and abnormal laboratory studies (Table 2) led to a diagnosis of MIS-C. Treatment was initiated with high-dose aspirin, IVIG 2 g/kg, and methylprednisolone 1 mg/kg every 12 hours. He defervesced after IVIG administration. By hospital day 5, all laboratory results except D-dimer had returned to normal values. He was discharged from the hospital on low-dose aspirin daily and prednisolone 1 mg/kg every 12 hours to complete 10 total doses. At a follow-up with cardiology 2 weeks after discharge, coronary dilation had resolved on TTE. Low-dose aspirin was continued until his 3-month follow-up visit, at which time all laboratories were normal.

FIGURE 2

Two-dimensional echocardiogram demonstrating dilated coronary artery. Downward arrow indicates the mild dilation of left anterior descending coronary artery (3.4 mm, z-score: +2.38). Upward arrow indicates the left main coronary artery.

FIGURE 2

Two-dimensional echocardiogram demonstrating dilated coronary artery. Downward arrow indicates the mild dilation of left anterior descending coronary artery (3.4 mm, z-score: +2.38). Upward arrow indicates the left main coronary artery.

Close modal

Our patient exhibited 2 distinct illnesses, both of which met the clinical and laboratory case definitions of MIS-C (Table 2),3,8  and could not be unambiguously explained by another etiology. In the interim between illnesses, he returned to his usual state of good health and demonstrated resolution of laboratory abnormalities. This case is not consistent with previous reports that have described rebound MIS-C symptoms after the completion of therapy10  and reinfection with SARS-CoV-2 without recurrence of MIS-C.11  Our case introduces the possibility that a subset of children may be genetically predisposed or at high risk for repeat MIS-C. Alternatively, or perhaps in parallel, some high-risk SARS-CoV-2 variants may be more likely to trigger MIS-C. On the basis of the current literature on MIS-C and other postinfectious hyperinflammatory syndromes, we offer some possible mechanisms by which this may have occurred.

KD and MIS-C share upregulation of the NF-κ B and interleukin-1 β pathways and the interleukin-12/interferon γ (IFN-γ) axis, which initiate multifactorial cascades through both innate and adaptive immune responses.12  Growing evidence shows that, like KD, MIS-C pathogenesis is associated with activation of inflammasomes secondary to a recent and/or residual viral insult.1315  Genome-wide studies of KD have established associations between specific single nucleotide polymorphisms, human leukocyte antigen types, and KD recurrence and severity.14  Individuals with defects in any component of these implicated inflammatory pathways may be at increased risk for severe or repeated episodes of MIS-C. Genetic analyses of this patient are in progress.

It is possible that the separate illnesses consistent with MIS-C in our patient were triggered by different variants of SARS-CoV-2. Unfortunately, no specimens are available for viral sequencing or detection of variant-specific antibodies from his first hospitalization for comparison. Based on the limited data available in our region, the dominant SARS-CoV-2 variant profiles were different in June and December 2020 (C. Jonsson, PhD, unpublished data). Evidence to date, including the safety profile of SARS-CoV-2 antibody treatment of COVID-19, refutes the likelihood of antibody-dependent enhancement of subsequent SARS-CoV-2 infections with a different variant.16  However, case reports and other literature suggest that certain variants may confer a higher risk of development of MIS-C, including the predominant variant circulating in the United States in the spring of 2020, D614G.17 

We acknowledge certain limitations in our report. During his first illness, our patient had a significant neurologic presentation, which is less common, but recent evidence has demonstrated that as many as 20% of patients present with neurologic symptoms.18  Notably, the most common neurologic imaging finding in MIS-C patients is reported to be reversible lesions of the splenium of the corpus callosum.19  Such lesions can also be caused by bacterial or viral infections such as influenza, underlying seizure disorder, or systemic illnesses such as KD or systemic lupus erythematosus.20  In our patient, our extensive evaluation excluded these etiologies (Table 1). We admit that the first episode is unusual because neither C-reactive protein nor erythrocyte sedimentation rate were elevated as is typically seen in MIS-C. However, our patient did have an elevation of multiple inflammatory markers including D-dimer, ferritin, and lactate dehydrogenase as well as lymphopenia and a cytokine profile including elevated IL-6, IL-8, IL-10, and IFN- γ consistent with COVID-19 and MIS-C.8,2123  We considered that the antibody titers measured in the second episode in January 2021 could have been influenced by the IVIG infused during the first episode in June 2020; however, studies show that SARS-CoV-2 antibodies were first detected in IVIG products manufactured from plasma collected in the United States in September 2020.24  Lastly, as KD and MIS-C have similar presentations4,5  and presumed mechanisms, we cannot completely exclude recurrent KD. Overall, a thorough workup for alternative diagnoses (Table 1), a failure to improve on antibiotics, and subsequent improvement after IVIG tend to support a diagnosis of MIS-C given the constellation of clinical, laboratory, and imaging findings otherwise unexplained during a pandemic.

There may be factors intrinsic to individuals, higher-risk populations, or SARS-CoV-2 variants that are more likely to cause MIS-C. Additional immunologic and virologic characterization of cases of MIS-C is warranted, and clinicians should be aware of the possibility that repeat MIS-C illness can occur in their patients.

Supported by the Children's Foundation Research Institute at Le Bonheur Children’s Hospital and the Children's Foundation of Memphis.

Drs Hancock, Green, and Bagga conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Moyen and Creel contributed to sections of the case report and reviewed and revised the manuscript; Drs Finkel, Pishko, and Collins assisted with conceptualization and design of the study and critically reviewed and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

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

     
  • COVID-19

    coronavirus disease 2019

  •  
  • CSF

    cerebrospinal fluid

  •  
  • CT

    computerized tomography

  •  
  • ECG

    electrocardiogram

  •  
  • IFN- γ

    interferon γ

  •  
  • IgG

    immunoglobulin G

  •  
  • IVIG

    intravenous immunoglobulin

  •  
  • KD

    Kawasaki disease

  •  
  • MIS-C

    multisystem inflammatory syndrome in children

  •  
  • RT-PCR

    real-time polymerase chain reaction

  •  
  • SARS-CoV-2

    severe acute respiratory syndrome coronavirus 2

  •  
  • TTE

    transthoracic echocardiogram

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Supplementary data