Multisystem inflammatory syndrome in children (MIS-C) is a serious, sometimes life-threatening late complication of coronavirus disease 2019 (COVID-19) with multiorgan involvement and evidence of immune activation. The pathogenesis of MIS-C is not known, nor is the pathogenesis of the severe organ damage that is the hallmark of MIS-C. Human herpesvirus 6 (HHV-6), the virus responsible for roseola, is a ubiquitous herpesvirus that causes close to universal infection by the age of 3 years. HHV-6 remains latent for life and can be activated during inflammatory states, by other viruses, and by host cell apoptosis. HHV-6 has been associated with end-organ diseases, including hepatitis, carditis, and encephalitis. In addition, ∼1% of people have inherited chromosomally integrated human herpesvirus 6 (iciHHV-6), which is HHV-6 that has been integrated into chromosomal telomeric regions and is transmitted through the germ line. iciHHV-6 can be reactivated and has been associated with altered immune responses. We report here a case of MIS-C in which an initial high HHV-6 DNA polymerase chain reaction viral load assay prompted testing for iciHHV-6, which yielded a positive result. Additional research may be warranted to determine if iciHHV-6 is commonly observed in patients with MIS-C and, if so, whether it may play a part in MIS-C pathogenesis.

Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory process that is observed in a small number of children convalescing from coronavirus disease 2019 (COVID-19).16  The MIS-C case definition includes at least 2 of the following features: rash, conjunctivitis, or mucocutaneous inflammation; hypotension; cardiac disease; coagulopathy; or acute gastrointestinal problems.7  Some patients exhibit neurologic or neuropsychiatric symptoms with associated imaging abnormalities.8,9  MIS-C has several hyperinflammatory features. Patients can exhibit high levels of circulating proinflammatory cytokines (interleukin 6, interleukin 17A, and interleukin 18, interferon-γ, and tumor necrosis factor β), and lymphocytes of patients with MIS-C typically have increases in activation markers.10,11  Therapy for MIS-C includes corticosteroids and often includes monoclonal antibodies directed against proinflammatory cytokines and/or their receptors.10  MIS-C typically appears days to a week or more after infection, often when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral loads (VLs) have become undetectable.6  The incidence of MIS-C is difficult to establish because many children experience asymptomatic SARS-CoV-2 infection.5  Although there are many descriptions of the features of MIS-C, including important immunologic associations,12  the detailed pathogenesis is not well established, although some reports have suggested an association between high levels of antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein and a higher risk for MIS-C.1315  Particular anti-SARS-CoV-2 antibody profiles and inflammatory marker and immune signatures have been associated with MIS-C.13,16 

Human herpesvirus 6 (HHV-6), the causative agent of roseola (also known as sixth disease or exanthem subitem, a syndrome that can be caused by human herpesvirus 7 also17 ), is a ubiquitous human pathogen1820  with 2 strains, HHV-6A and HHV-6B.21  HHV-6 infects almost all children in the first few years of life; infection is close to universal by age 3 to 4 years.22  HHV-6 is also neurotropic, and primary HHV-6 infections can be associated with seizures and encephalitis. HHV-6 infects a variety of cell types, including B and T lymphocytes, monocytes, natural killer cells, dendritic cells, astrocytes, megakaryocytes, glial cells, and epithelial cells. As with other herpesviruses, HHV-6 can remain latent within an individual’s cells throughout life.18,20  Primary disease due to HHV-6 is generally self-limited and is not typically treated, although several antiviral agents, including approved antiviral agents, have activity against HHV-6.23  The cellular receptor for HHV-6A is CD46,24  which is found on all nucleated cells, whereas the primary cellular receptor for HHV-6B is CD134,25  a tumor necrosis factor superfamily member found on activated T cells. HHV-6 can integrate into a cell’s telomeric region, yielding inherited chromosomally integrated human herpesvirus 6 (iciHHV-6), which can be transmitted in a Mendelian fashion.2629  The presence of iciHHV-6 has been associated with altered and, in some instances, increased antibody responses to certain viruses30  and has been associated with an increased risk of acute graft-versus-host disease and cytomegalovirus activation in hematopoietic cell transplant recipients.31,32 

Antiviral agents approved for other indications with in vitro activity against HHV-6 and with reports of clinical response include cidofovir, ganciclovir and valganciclovir, and foscarnet, although the clinical utility of some agents can be problematic given their toxicity profiles.18  An investigational cidofovir prodrug, brincidofovir, is under investigation for HHV-6 in hematopoietic cell transplant settings.33 

Both episomal HHV-6 and iciHHV-6 can be reactivated from latency.28 . HHV-6 reactivation, accompanied by end-organ disease affecting many systems, has been observed in association with solid-organ and bone marrow transplantation.20,34  High-level HHV-6 reactivation has also been observed in association with drug rash with eosinophilia and systemic symptoms,35,36  which has been linked to elevated proinflammatory cytokine levels.36  A study of the kinetics of proinflammatory cytokine production and HHV-6 activation in a small cohort of patients with drug-induced hypersensitivity syndrome suggested that high levels of proinflammatory cytokines preceded HHV-6 activation, suggesting a possible causal link.37  HHV-6 activation by proinflammatory cytokines may be difficult to establish directly but has been often observed in the presence of human herpesvirus 7, which itself readily responds to inflammatory activation signals.38  HHV-6 reactivation, particularly in transplant patients, can be associated with clinically significant disease, with features such as fever, bone marrow suppression, interstitial pneumonitis, and encephalitis.

Here we report a case of a patient with MIS-C who was initially found to have a high HHV-6 VL and then subsequently determined to have iciHHV-6.

In late December 2020, a 12-year-old boy with obesity presented to an outside hospital emergency department after 3 days of headache and vomiting and 1 day of altered mental status. He was febrile, hypotensive, and tachycardic on presentation and was ultimately transferred to their PICU for worsening mental status. Because of the initial concern for sepsis, the patient received broad-spectrum antibiotics. Assays for multiple infectious agents, including viral pathogens that could help explain his altered mental status, were conducted. Several of these assays were sent to referral laboratories, which returned results after some time. The pathogen testing results are summarized in Table 1. The result of an initial reverse transcription polymerase chain reaction (RT-PCR)–based assay for SARS-CoV-2 was negative. The patient continued to have fevers as high as 40.8°C despite receiving antibiotic and antipyretic treatment. Laboratory studies revealed elevated levels of inflammatory markers, thrombocytopenia, coagulopathy, acute kidney injury, and transaminitis (Table 1). Elevation of troponin and brain natriuretic peptide levels was concerning for cardiac involvement (Table 1). An echocardiogram confirmed reduced cardiac function, with an initial ejection fraction of 44% that worsened to 25% on a repeat echocardiogram, and the patient was placed on continuous vasoactive infusions to maintain adequate perfusion. He had severe cardiac dysfunction and acute respiratory failure requiring intubation. Given multisystem involvement, with increasing suspicion for MIS-C, he was treated with intravenous immunoglobulin. Although the patient had no known history of COVID-19 infection or any other recent illnesses, a COVID-19 immunoglobulin G serological test, by using a pre–intravenous immunoglobulin serum sample, was obtained, and the result was found to be positive, confirming suspicion for MIS-C. He was transferred from the referring hospital to the University of Virginia for further management.

TABLE 1

Selected Laboratory Values Obtained on Admission

Laboratory TestPatient’s ResultsReference Levels
HHV-6 DNA quantification, copies per mL 1 123 094 <500 
Epstein-Barr virus antibody VCA IgM, U/mL <36 <36 
Epstein-Barr Virus antibody VCA IgG, U/mL <18 <18 
Cytomegalovirus IgM antibody, AU/mL <30 <30 
Cytomegalovirus IgG antibody, U/mL <0.60 <0.60 
HIV 1 and 2 p24 Nonreactive Nonreactive 
Parvovirus IgM antibody Negative Negative 
Parvovirus IgG antibody Negative Negative 
Herpes simplex virus 1 and 2 PCR result Negative Negative 
IgG, mg/dL 822 685–1620 
IgM, mg/dL 75 27–151 
Rheumatoid factor, IU <10 <10 
Antinuclear antibody screen results by ELISA Negative Negative 
Anti-streptolysin O titer, IU 100 <100 
Thyroid-stimulating hormone, mIU/L 0.39 0.30–5 
Free T4, ng/dL 0.78 0.73–1.80 
BUN, mg/dL 36 7–17 
Creatinine, mg/dL 2.3 0.5–0.8 
Aspartate aminotransferase, U/L 926 <35 
Alanine transaminase, U/L 384 <55 
White blood cell count, ×1000 per μL 14.04 4.40–9.50 
Hemoglobin, g/dL 12 11.5–15.5 
Hematocrit, % 34.8 40–52 
Platelet count, ×1000 per μL 107 150–450 
Prothrombin time, s 22.2 9–13 
INR 2.0 0.8–1.2 
Partial thromboplastin time, s 49.6 25.0–36.0 
D-dimer, ng/mL 3203 ≤230 
Fibrinogen, mg/dL 734 151–402 
Ferritin, ng/mL 6907 20–275 
C-reactive protein, mg/dL 41.6 <0.5 
Erythrocyte sedimentation rate, mm/h 80 0–30 
Lactate dehydrogenase, U/L 1158 127–287 
γ-glutamyl transferase, U/L 18 <55 
Lipase, U/L 24 8–78 
B-type natriuretic peptide, pg/mL 618 <13 
Troponin I, ng/mL 1.76 <0.02 
Laboratory TestPatient’s ResultsReference Levels
HHV-6 DNA quantification, copies per mL 1 123 094 <500 
Epstein-Barr virus antibody VCA IgM, U/mL <36 <36 
Epstein-Barr Virus antibody VCA IgG, U/mL <18 <18 
Cytomegalovirus IgM antibody, AU/mL <30 <30 
Cytomegalovirus IgG antibody, U/mL <0.60 <0.60 
HIV 1 and 2 p24 Nonreactive Nonreactive 
Parvovirus IgM antibody Negative Negative 
Parvovirus IgG antibody Negative Negative 
Herpes simplex virus 1 and 2 PCR result Negative Negative 
IgG, mg/dL 822 685–1620 
IgM, mg/dL 75 27–151 
Rheumatoid factor, IU <10 <10 
Antinuclear antibody screen results by ELISA Negative Negative 
Anti-streptolysin O titer, IU 100 <100 
Thyroid-stimulating hormone, mIU/L 0.39 0.30–5 
Free T4, ng/dL 0.78 0.73–1.80 
BUN, mg/dL 36 7–17 
Creatinine, mg/dL 2.3 0.5–0.8 
Aspartate aminotransferase, U/L 926 <35 
Alanine transaminase, U/L 384 <55 
White blood cell count, ×1000 per μL 14.04 4.40–9.50 
Hemoglobin, g/dL 12 11.5–15.5 
Hematocrit, % 34.8 40–52 
Platelet count, ×1000 per μL 107 150–450 
Prothrombin time, s 22.2 9–13 
INR 2.0 0.8–1.2 
Partial thromboplastin time, s 49.6 25.0–36.0 
D-dimer, ng/mL 3203 ≤230 
Fibrinogen, mg/dL 734 151–402 
Ferritin, ng/mL 6907 20–275 
C-reactive protein, mg/dL 41.6 <0.5 
Erythrocyte sedimentation rate, mm/h 80 0–30 
Lactate dehydrogenase, U/L 1158 127–287 
γ-glutamyl transferase, U/L 18 <55 
Lipase, U/L 24 8–78 
B-type natriuretic peptide, pg/mL 618 <13 
Troponin I, ng/mL 1.76 <0.02 

ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; IgM, immunoglobulin M; INR, international normalized ratio; PCR, polymerase chain reaction; SUN, serum urea nitrogen; T4, thyroxine; VCA, viral capsid antibody.

At the University of Virginia, the result of one repeat SARS-CoV-2 RT-PCR assay was positive at a high cycle threshold value of 40 cycles, and the result of another repeat SARS-CoV-2 RT-PCR was negative. After initiation of anakinra, an interleukin 1 inhibitor, and high-dose methylprednisolone, he showed improvement in laboratory markers and clinical status. He was weaned from his vasopressor support and extubated to room air and showed return of his end-organ function. Antibiotics were discontinued after results of bacterial cultures remained negative. Results of viral pathogen testing sent by the referring hospital at the time of his initial admission returned negative for cytomegalovirus, Epstein-Barr virus, HIV, herpes simplex virus, and parvovirus (Table 1). However, an HHV-6 polymerase chain reaction result sent by the referring hospital, conducted by Quest Diagnostics Nichols Institute Chantilly (Chantilly, VA) later revealed a high VL of 1 123 094 viral DNA copies per mL (reference range <500 viral DNA copies per mL). The methodology used to determine the HHV-6 VL at the reference laboratory was reviewed, and it was determined that the test was conducted on a whole-blood specimen, which raised the possibility that the high VL resulted not from high-level HHV-6 replication but rather because the assay was detecting iciHHV-6 DNA from the patient’s leukocytes. A sample of hair follicles was sent to Coppe Laboratories (Waukesha, WI), which tested the hair follicles for the U94 genes of HHV-6A and HHV-6B. HHV-6A was not detected, but HHV-6B was detected, indicating that the patient had iciHHV-6B. There were no other complications during his recovery.

To our knowledge, an association of MIS-C with iciHHV-6 has not been previously reported. Hyperinflammatory states similar to those seen in MIS-C are known to be associated with HHV-6 activation, including in patients with iciHHV-6. In addition, proapoptotic signals activate herpesviruses and retroviruses out of latency.39,40  The end-organ dysfunction seen in MIS-C has substantial similarities to that seen in other hyperinflammatory states associated with HHV-6 activation,20,3436  so it is plausible that in some patients with MIS-C, HHV-6 activation could contribute to the pathologies associated with MIS-C. This single case may prompt an interest in additional studies of HHV-6 in patients with MIS-C, either iciHHV-6 or activation of conventional episomally latent HHV-6. If HHV-6 is a common feature in MIS-C, that observation would constitute another contrast between MIS-C and Kawasaki disease, in which high-level HHV-6 activation has not been commonly observed.

Here we report a single case of iciHHV-6 in association with MIS-C. Although no definitive conclusions can be drawn from a single case, it may be useful to study larger numbers of patients with MIS-C to determine if iciHHV-6 is commonly observed in association with MIS-C, particularly considering the observations that patients with MIS-C can demonstrate enhanced antibody responses to SARS-CoV-21315  and that iciHHV-6 has been associated with increases in antibody responses to certain viruses.30  Further study may reveal, in additional patients, an association between iciHHV-6 and MIS-C or an additional association between the activation of conventional HHV-6 and MIS-C or no real further associations at all. Additional studies, however, may be warranted in efforts to better understand the pathogenesis of the disease. Currently available assays for iciHHV-6 require several days’ turnaround time for results to become available, so iciHHV-6 assays in patients with MIS-C would be considered in the context of a research study. If iciHHV-6 proved to be a common feature of MIS-C, it would be necessary to scale up and widely deploy the assay for it to be clinically useful. Although there are no US Food and Drug Administration–approved antiviral agents for HHV-6, some agents have been employed off label in patients with HHV-6-associated disorders.41,42  If iciHHV-6 is commonly associated with MIS-C, it may be of interest to design a clinical trial of an antiviral agent to determine if antiviral therapeutics may improve management of MIS-C.

We thank the patient and his family for their willingness in agreeing to publish this case report. We thank Kristin Loomis of the HHV-6 Foundation for her thoughtful and helpful comments and input.

Dr Biswas drafted part of the initial manuscript, contributed to the analysis and interpretation of the data, and critically reviewed and revised the manuscript; Drs Crain and Spaeder reviewed and revised the manuscript and contributed to the analysis and interpretation of the data; Dr Gomez contributed initial clinical observations, reviewed the manuscript, and contributed to the analysis and interpretation of the data; Dr Starolis supervised certain laboratory testing, troubleshooting, and confirmatory assays, reviewed the manuscript, and contributed to the analysis and interpretation of the data; Dr Poulter reviewed and consulted on laboratory results, reviewed the manuscript, and contributed to the analysis and interpretation of the data; Dr Zeichner conceptualized the study, drafted part of the initial manuscript, reviewed and revised the manuscript, and contributed to the analysis and interpretation of the data; and all authors helped to critically revise the manuscript for important intellectual content, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work and in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved.

FUNDING: Supported by the Pendleton Pediatric Infectious Disease Laboratory and by the funding provided to Dr Zeichner via the McLemore Birdsong endowed chair. The HHV-6 Foundation provided in-kind support for inherited chromosomally integrated human herpesvirus 6 assays and shipping. Quest Diagnostics conducted additional confirmatory assays that were not billed to the patient in an effort to better understand the case. The funding had no influence on the work or conclusions.

     
  • COVID-19

    coronavirus disease 2019

  •  
  • HHV-6

    human herpesvirus 6

  •  
  • iciHHV-6

    inherited chromosomally integrated human herpesvirus 6

  •  
  • MIS-C

    multisystem inflammatory syndrome in children

  •  
  • RT-PCR

    reverse transcription polymerase chain reaction

  •  
  • SARS-CoV-2

    severe acute respiratory syndrome coronavirus 2

  •  
  • VL

    viral load

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Zeichner is an associate editor of Pediatrics. Dr Starolis is an employee of Quest Diagnostics Nichols Institute Chantilly; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Zeichner is an associate editor of Pediatrics. Dr Starolis is an employee of Quest Diagnostics Nichols Institute Chantilly; the other authors have indicated they have no financial relationships relevant to this article to disclose.