The novel coronavirus SARS-CoV-2, the viral etiology of the COVID-19 illness, affects adults more severely than children. Approximately 2% of documented cases occur in patients >20 years old, with only 0.6%–2% of children requiring intensive care unit admission.1,2 However, with the emergence of the COVID-19-associated multisystem inflammatory syndrome in children (MIS-C), it is now apparent that children too may have severe and life-threatening complications related to SARS-CoV-2 infection. Many cases of MIS-C have been described with Kawasaki disease-like symptoms. This, at times, has led to conflation of MIS-C and Kawasaki disease (KD).3,4 However, patients with MIS-C often have characteristics different than most patients with KD.5 The apparent temporal link between MIS-C and acute SARS-CoV-2 infection, as well as differences in patient population, age, symptoms, and ancillary studies, have led many to suspect a separate and distinct pathology for the inflammation of MIS-C than that seen in KD.6
On May 12, 2020, an 11-year-old obese (weight, 75 kg; body mass index, 30.9) African American female was admitted to the pediatric ICU of a children’s hospital in Northern New Jersey with pneumonia and respiratory distress. That same day, her mother was admitted to a different hospital with acute respiratory failure secondary to SARS-CoV-2 infection.
The patient presented with fever for 3 days and increasing tachypnea. On admission to the intensive care unit, she was febrile, tachycardic, and tachypneic with accessory muscle use. On auscultation, she had decreased aeration. Oxygen saturation was 93% while on supplemental oxygen via face mask. Her initial laboratory findings were notable for lymphopenia [absolute lymphocyte count of 1150 × 10 (3) mcL], hypoalbuminemia (3.1 g/dL), elevated D-Dimer 8.4 mcg/mL, and elevated C-reactive protein 44.34 mg/dL. She had SARS-CoV-2 detected via nasopharyngeal polymerase chain reaction (PCR). Chest radiograph showed dense infiltrates of both the right and left lungs.
During the first 24 hours of admission, she required increased respiratory support, progressing to intubation. On day 1 of her admission, she was started on a 10-day course of remdesivir, obtained via compassionate use investigational new drug protocol, and prophylactic enoxaparin. On day 2 of her admission, she was diagnosed with acute respiratory distress syndrome. She was started on methylprednisolone and was positioned prone to improve oxygenation. Fever subsequently resolved, and inflammatory markers improved.
Her early hospital course was complicated by a right lower lobe pulmonary embolism and a small pneumothorax and pneumomediastinum. On the eighth day of her admission, fever recurred, and inflammatory markers increased. She was started on broad spectrum antibiotics for empiric treatment of ventilator-associated pneumonia. Fever and labs subsequently improved. On day 18 of her hospitalization, she was extubated, although she still required supplemental oxygen support for the duration of her hospitalization. She completed a methylprednisolone taper on day 19 of hospitalization. Oral feeding started on day 21. Three days later, she developed new fever, abdominal pain, and difficulty eating. Labs showed neutrophilia, decreased lymphocyte count, and increased inflammatory markers (C-reactive protein, ferritin) and D-dimer (see Figs. 1 and 2).
Evaluation for other infectious etiologies, including cultures of blood and urine and evaluation of stool and including PCR studies and Clostridium difficile testing, was unremarkable. Nasopharyngeal SARS-CoV-2 PCR remained positive, and she also developed detectable SARS-CoV-2 IgG. Recrudescence of fever, new gastrointestinal symptoms, and increasing inflammatory markers 4 weeks after initial diagnosis of SARS-CoV-2, were consistent with a putative diagnosis of MIS-C. Methylprednisolone was restarted on day 28 of admission, and, on day 32, intravenous immunoglobulin (IVIG) was administered. Twenty-four hours after initiation of the IVIG, the patient defervesced, followed by resolution of gastrointestinal symptoms. Echocardiography was unremarkable, and brain natriuretic peptide and troponin remained normal throughout the admission.
This case reports a child with SARS-CoV-2 infection who developed complications that have been previously described in other pediatric COVID-19 case series.7,8 These include acute hypoxemic respiratory failure requiring mechanical ventilation and hematologic anomalies characteristic of COVID-19 (lymphopenia, neutrophilia). Unlike previously reported patients, our patient subsequently developed MIS-C. Our patient is African American and obese, both factors associated with a more severe course of COVID-19 infection, and perhaps also with an increased risk for MIS-C.8,9
The newly described syndrome, MIS-C has emerged as a diagnostic challenge for clinicians. It was first described in Europe, with initial guidelines for diagnosis and treatment published by The Royal College of Paediatrics and Child Health in May 2020.10 The CDC in the United States issued its own case definition in May 2020, highlighting an apparent link to the current pandemic.11 The exact nature and timing of that link, however, remains uncertain. Previously, most cases of MIS-C have been described in children without antecedent symptoms of severe illness suggestive of acute COVID-19.12 Data are lacking as to whether treatment of the acute COVID-19 infection would have any impact on the development of MIS-C. Our patient was treated with investigational remdesivir on initial presentation because of her severe acute COVID-19 manifestations. Despite this treatment, she still developed MIS-C. Her clinical course is evidence that all children, whether presenting with severe, mild, or asymptomatic COVID-19 infection, are at risk of developing MIS-C.
Laboratory testing did assist in diagnosis of this patient’s MIS-C. During her acute infection, her IL-6 level was normal but increased to 7.1 pg/mL (normal <2) when MIS-C was suspected. As Figure 1 illustrates, initial lab abnormalities had resolved or improved, only to worsen later, supporting the clinical diagnosis of MIS-C rather than suggesting that this latter part of the illness represented a prolonged extension of acute COVID-19.
Optimal treatment of MIS-C has not been fully elucidated and is the subject of ongoing discussion and debate among pediatric providers in the acute care setting. Various modalities have been used, but efficacy data are lacking or incomplete. Our patient received both methylprednisolone and IVIG for treatment of this inflammatory condition with subsequent improvement suggesting a good response. More investigation into the optimal treatment is needed.
The care of patients, particularly pediatric patients, with SARS-CoV-2 infection, has evolved over the course of the pandemic. There is still much to learn regarding the pathophysiology of this illness and risk factors for development of both severe disease and postinfectious manifestations such as MIS-C. This case illustrates that MIS-C can develop despite aggressive treatment of acute COVID-19 pneumonia with remdesivir and systemic glucocorticoids. A patient with such severe acute illness followed by development of MIS-C has not to our knowledge been previously described in the literature, including in a recent analysis of 58 UK patients with MIS-C (PIMS-TS).12 Our patient illustrates that those who have severe COVID-19 illness, including those treated with antivirals or glucocorticoids, remain at risk for developing MIS-C. Her course also strengthens the link between infection with SARS-CoV-2 virus and development of this postinfectious syndrome. Continued efforts to better understand this illness will allow for more rapid diagnosis and treatment and will likely be critical for improving treatment of our pediatric patients in the future.
We would like to thank our institution for their support as well as the patient and family for their permission to present this case. We also thank Drs. Saranga Agarwal, Amy Chirico, Bruce Freidman, Ginger Janow, Rachel Lewis, Julia Piwoz, and Mark Siegel, along with the many nurses and support staff who helped in the care of this patient.
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