A 21-year-old young adult presented to the ED with a 1-week history of high fever, vomiting, diarrhea, and abdominal pain. His mother was SARS-CoV-2 positive by polymerase chain reaction approximately 3 weeks prior; his PCR was negative for SARS-CoV-2.
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Following admission, he became hypotensive and tachycardic with evidence of myocarditis. His chest x-ray was normal and his O2 saturation was 100% on room air. His clinical presentation was initially suggestive of toxic shock syndrome without a rash, but despite aggressive fluid resuscitation and broad-spectrum antibiotics, he continued to clinically deteriorate with persistent high fever and increasing cardiac stress. Echocardiography revealed biventricular dysfunction. His laboratory abnormalities included rising inflammatory markers and troponin I and B-type natriuretic peptide (BNP). A repeat PCR for SARS-CoV-2 was negative on day 2 of illness. He was diagnosed as likely having macrophage-activation syndrome (MAS) despite the atypical features (myocarditis), and he received Anakinra with no apparent response. He also was given intravenous immunoglobulin (IVIg) for his myocarditis and subsequently high-dose steroids. He became afebrile, his blood pressure stabilized, his inflammatory markers declined, and over several days he returned to normal. His COVID-19 antibody test IgG was positive on day 4 of illness.
This case challenged us for several reasons. First, the PCR from his nasopharynx was negative on two occasions, which raises the issue of how sensitive and accurate these PCR tests are for SARS-CoV-2 or are patients with COVID-19–associated hyperinflammatory syndrome still PCR positive? Second, although we have seen many adult cases with a cytokine storm picture similar to this patient, nearly all of the prior cases had chest x-ray abnormalities and hypoxia. Third, the severity of the myocardial dysfunction and rising troponin and BNP also was unusual in our experience with COVID-19 infection. Lastly, the use of antibody detection to SARS-CoV-2 enabled us to confirm recent COIVD-19 disease and see his illness as part of the likely spectrum of clinical syndromes seen with this virus.
Dr. Stephen I. Pelton
The Lancet reported eight children, aged 4-14 years, with a hyperinflammatory shock-like syndrome in early May.1 The cases had features similar to atypical Kawasaki disease, KD shock syndrome, and toxic shock syndrome. Each case had high fever for multiple days; diarrhea and abdominal pain was present in even children; elevated ferritin, C-reactive protein, d-dimer, increased troponins, and ventricular dysfunction also was present in seven. Most patients had no pulmonary involvement, and most tested negative for SARS-CoV-2 despite four of the eight having direct contact with a COVID-positive family member. All received IVIg and antibiotics; six received aspirin. Seven of the eight made a full recovery; one child died from a large cerebrovascular infarct.
Also in early May, the New York Times described a “mysterious” hyperinflammatory syndrome in children thought to be linked to COVID-19. A total of 76 suspected cases in children had been reported in New York state, three of whom died. The syndrome has been given the name pediatric multisystem inflammatory syndrome. The syndrome can resemble KD shock syndrome with rash; fever; conjunctivitis; hypotension; and redness in the lips, tongue and mucous membranes . It also can resemble toxic shock syndrome with abdominal pain, vomiting, and diarrhea. However, the degree of cardiac inflammation and dysfunction is substantial in many cases and usually beyond that seen in KD or toxic shock.
The syndrome is not limited to the United States. The Royal College of Pediatrics and Child Health has created a case definition:2
- A child presenting with persistent fever, inflammation (elevated C-reactive protein, neutrophilia, and lymphopenia) and evidence of single or multiorgan dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurologic) with additional features.
- Exclusion of any other microbial causes such as bacterial sepsis or staphylococcal or streptococcal shock syndromes, infections known to be associated with myocarditis (such as enterovirus).
- SARS-CoV-2 testing may or may not be positive.
Dr. Ingrid Camelo
As with our young adult, treatment is supportive, nonspecific, and aimed at quieting the inflammatory response. The current thinking is the syndrome is seen as antibody to SARS-CoV-2 appears and frequently the nasopharyngeal PCR is negative. It is hypothesized that the syndrome occurs in genetically predisposed hosts and potentially is a late-onset inflammatory process or potentially an antibody-triggered inflammatory process. The negative PCR from nasopharyngeal specimens reflects that the onset is later in the course of disease; whether fecal samples would be COVID positive is unknown. As with our case, antibody testing for IgG against SARS-CoV-2 is appropriate to confirm COVID-19 disease and may be positive as early as day 7.
The approach needs to be team oriented and include cardiology, rheumatology, infectious diseases, and intensive care specialists working collaboratively. Such cases should be considered COVID positive despite negative PCR tests, and full personal protective equipment should be used as we do not as yet know if live virus could be found in stool. We initiated treatment with Anakinra (an interleukin-1 type-1 receptor inhibitor) as part of our treatment protocol for MAS; we did not appreciate a response. He then received IVIg and high-dose steroids, and he recovered over several days with improved cardiac function and stable blood pressure.
What is the pathogenesis? Is SARS-CoV-2 causative or just an associated finding? Who are the at-risk children, adolescents, and adults? Is there a genetic predisposition? What therapies work best? The eight cases described in London all received IVIg, as did our case, and all but one improved and survived. In adults we have seen substantial inflammation with elevated C-reactive protein (often as high as 300), ferritin, lactate dehydrogenase, triglycerides, fibrinogen, and d-dimers, but nearly all have extensive pulmonary disease, hypoxia, and are SARS-CoV-2 positive by PCR. Influenza is also associated with a cytokine storm syndrome in adolescents and young adults.3 The mechanisms influenza virus uses to initiate a cytokine storm and strategies for immunomodulatory treatment may provide insights into COVID-19–associated multisystem hyperinflammatory syndrome.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and public health and senior attending physician in pediatric infectious diseases at Boston Medical Center. Dr. Camelo is a senior fellow in pediatric infectious diseases at Boston Medical Center. They have no relevant financial disclosures. Email them at [email protected].
References
1. Riphagen S et al. Lancet. 2020 May 6. doi: 10.1016/S0140-6736(20)31094-1.
2. Royal College of Paediatrics and Child Health Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19.
3. Liu Q et al.Cell Mol Immunol. 2016 Jan;13(1):3-10.
