A 9-year-old female of eastern Indian origin with no significant past medical history presented to the emergency room with abdominal pain, fever, nausea, and vomiting for 3 days. She had completed the 2-dose Pfizer-BioNTech COVID-19 immunization series 31 days before presentation to the emergency department. She had a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) test done for travel purposes 16 days prior to presentation which was positive. She was asymptomatic at the time of the test. A rapid antigen test was negative before leaving for travel.
The patient traveled with her family to the US Virgin Islands for several days and was feeling well through her return. Parents did not notice any tick bites but did report multiple mosquito bites. A few days after returning to the United States, she developed persistent fever, emesis, nausea, and abdominal pain. Respiratory viral PCR panel (RVP) at the primary pediatrician's office was negative including for SARS-CoV-2. While waiting for the results of the RVP patient was given a dose of oseltamivir. She continued to have nausea, emesis, and decreased intake, as well as painful area at the tip of her tongue.
Polymerase chain reaction tests remain the gold standard for COVID-19 testing. Home rapid antigen tests are intended to be used in serial testing. This patient had a positive PCR test and only one negative home rapid antigen test.
Owing to persistent symptoms, she presented to the emergency department on her third day of illness. There, she was found to be persistently febrile, with maximum temperature of 40 C, heart rate between 124 and 133 beats per minute, respiratory rate between 20 and 30 breaths/min, with oxygen saturation 96% to 100%, and blood pressure 94 to 102/44 to 54 mm Hg. Her exam was unremarkable except for mild conjunctival injection and epigastric abdominal tenderness.
Initial laboratory work-up was notable for mild hyponatremia, leukopenia, thrombocytopenia, lymphopenia, and elevated inflammatory markers (Table 1). Severe acute respiratory syndrome coronavirus 2 PCR was negative. Rapid streptococcal antigen test was negative. Urinalysis was notable for trace ketones, protein, small leukocyte esterase with white blood cell (WBC) 10 to 19, and few bacteria seen.
On admission, the patient was started on 2 g/kg IVIG in addition to empiric ceftriaxone and doxycycline for possible bacterial infection. Antibiotics were discontinued after 72 hours once cultures were negative. Parasite and viral testing for diseases endemic to the United States Virgin Islands and northeastern United States were sent. This included Anaplasma, Babesia, dengue, Erlichia chaffeensis, Leptospira, tuberculosis, Parvovirus B19, Shigella species, enteroinvasive E. coli, Shiga-toxin producing genes, Campylobacter species (jejuni and coli), and Salmonella species. She developed a macular, nonpruritic, nonpetechial rash over the neck and hands with sparing of palm and soles approximately 5 hours after starting her IVIG treatment, and this did not abate until after IVIG was completed. She was also noted to have bilateral conjunctival injection without discharge on day 1 of admission which resolved by discharge. She was afebrile 24 hours after completion of IVIG treatment to the time of discharge. In addition to IVIG, the patient was started on 2 mg/kg/day prednisone due to continued symptoms. She also had intermittent episodes of confusion and agitation for the first few days of her admission, possibly related to the combination of systemic inflammation and/or known side effects of IVIG infusion and steroids.
Owing to elevated d-dimer approximately 20x above normal at 10.87 ug/mL FEU, deep venous thrombosis (DVT) prophylaxis with low-molecular weight heparin was initiated. Anticoagulation was discontinued with decreasing d-dimer and worsening thrombocytopenia. Aspirin was discussed with cardiology but was not started while patient was thrombocytopenic, with an unremarkable echocardiogram.
Her inflammatory markers trended downward after completion of IVIG; however, her pancytopenia persisted and reached a nadir of hemoglobin 9.7 g/dL, red blood cell count 3.61 M/uL, platelet count 30,000/uL, white blood cell count 2580 cells/uL, absolute lymphocyte count 240 (Figure 1). BNP increased to a peak of 4114 pg/mL on hospital day 3, and down trended to 429 pg/mL by day of discharge. Echocardiography remained normal at time of admission, after IVIG treatment, and after discharge.
Because her hematologic abnormalities did not improve as expected with IVIG and steroid therapy, additional laboratory studies were obtained to exclude rheumatological conditions. Complement (C3 and C4) levels were normal; anti-nuclear antibody (ANA) was positive with titer 1:320; however, dsDNA and Smith antibodies were normal. Proinflammatory markers IL-6 and CXCL-9 were elevated at 284 pg/mL and 13 122 pg/mL, respectively.
Hematologic workup included negative direct antibody test (DAT) which decreases the likelihood of autoimmune cytopenia. Her initial peripheral smear prior to the initiation of steroids was negative for blasts, and repeat smear while on steroids remained negative. A bone marrow aspiration to further evaluate the pancytopenia was considered but was not performed due to her parents' request. Thrombocytopenia began to improve on hospital day 7 and her platelet count was 104 000/uL at the time of discharge.
The patient met criteria for MIS-C as defined by the American Academy of Pediatrics and Centers for Disease Control and Prevention: (1) she is under 21 years of age, with laboratory evidence of inflammation, requiring hospitalization, and had at least 2 systems involved; (2) other causes of her symptoms had been ruled out with extensive testing; and (3) she had a recent positive RT-PCR test for COVID-19.