Results
Case 1: 13 year-old female, treated for Ewing Sarcoma of the left proximal femur at 2 years old per Children’s Oncology Group (COG) protocol AEWS0031 (375mg/m2 doxorubicin, no dexrazoxane) along with left above the knee amputation, presented with abdominal pain and nausea 11 weeks after testing positive for COVID-19. An echocardiogram showed severely diminished left ventricular systolic dysfunction with a 28% ejection fraction (EF) along with a large thrombus in the right atrium and right ventricle with elevated pulmonary vascular resistance and severe tricuspid regurgitation. One week prior, her annual echocardiogram revealed a 57% EF. She tested negative for acute COVID-19 infection (PCR test), but had a positive IgG for SARS-CoV-2. She was treated with milrinone, aggressive diuresis, and enalapril. A cardiac MRI showed myocarditis by MRI Lake Louise criteria, scarring characteristic of ischemia, and bilateral non-occlusive and subsegmental pulmonary embolisms in addition to the intra-cardiac thrombi. She was treated with methylprednisolone (2d) but not with IVIG, as she did not meet diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C). Unfractionated heparin and aspirin were administered for her thrombi. She was weaned off milrinone; started on digoxin, spironolactone, furosemide, and enoxaparin; and eventually discharged home. Six months later, her EF remained diminished at 35%.
Case 2: 19 year-old male, treated two years prior for low risk central nervous system (CNS) positive acute myelogenous leukemia (AML) per COG protocol AAML1031 (342mg/m2 doxorubicin equivalents with dexrazoxane), presented with fever and cough, found to be COVID-19 positive without respiratory distress. Neutropenia and thrombocytopenia were noted. One month later, he presented with fevers and hypotension with evidence of heart failure and coagulopathy, requiring brief inotropic support. Echocardiogram revealed 24% EF, compared to 67% EF nine months earlier. He responded to IVIG (3d) and methylprednisolone (4d) treatment for MIS-C. A bone marrow biopsy for persistent neutropenia and thrombocytopenia revealed relapse of his AML. His heart failure improved 8 days later to 67% EF, but currently, he continues on lisinopril.
Case 3: 4 year-old male with a history of congenital CMV was treated for low risk CNS negative AML per COG protocol AAML1031 (342mg/m2 doxorubicin equivalents with dexrazoxane), but relapsed three months off therapy. He underwent re-induction per COG protocol AAML1421 consisting of vyxeos (liposomal daunorubicin, 29.7 mg/m2 doxorubicin equivalents) followed by fludarabine, cytarabine, and gemtuzumab. He had a bone marrow with residual disease of 0.37% by flow cytometry prior to undergoing a matched unrelated cord transplant with anti-thymocyte globulin, busulfan, and fludarabine conditioning. He was intubated from D+18 through +37 due to complications of engraftment syndrome, eventually weaned to room air. On day +62, he was found to have 0.27% residual disease by flow cytometry after developing peripheral blasts. Immunosuppression was weaned; he received decitabine days +65 through +69 for relapse therapy. He became febrile with a blood culture positive for coagulase-negative Staphylococcus on day +68 and hypoxic on day +76 with a subsequent positive test for COVID-19. Multiple family members tested positive for COVID-19, and this was deemed to be hospital acquired from family members. Due to worsening respiratory status, he was intubated on D+87. An echocardiogram showed diffuse dilation of his left main and left anterior descending coronary arteries, but stable systolic function with a 30% SF compared to 28% three months prior. However, on a repeat echo three days later, his coronary arteries were normal, and he did not require IVIG treatment. He underwent treatment with remdesivir (10d), dexamethasone (3d), tocilizumab, and convalescent plasma without clinical improvement. On day +114, routine adenovirus testing was positive by PCR on blood and respiratory viral panel, after being negative 7 days prior, and he was started on cidofovir. His COVID-19 PCR remained positive until day +119 and on day +121, he succumbed to respiratory failure secondary to his prolonged COVID-19 infection with superimposed adenovirus infection.
During this time, we also cared for five pediatric oncology patients in active treatment who tested positive for COVID-19 infection, all with acute lymphoblastic leukemia (ALL) (Table 1). None of these patients developed severe cardiorespiratory complications and were thus classified as the non-severe group for this study. One patient within this group developed a cerebral sinus venous thrombosis presumed to be from a combination of his COVID-19 infection and recent pegylated aspargase treatment, but did not develop any serious sequelae or cardiorespiratory symptoms.
Comparison of potential risk factors for infectious complications of COVID-19 (including age, WBC, neutrophils, lymphocytes, platelets, or type-A blood) showed no significant differences between the severe and non-severe groups (Table 1, Fig. 1A-E). In contrast, anthracycline exposure was significantly increased in the severe group (mean 362.9+ 10.49 SEM vs 80 + 18.37 mg/m2doxorubicin dose equivalents, p<0.001, t-test, Fig 1F). Baseline cardiac function (as defined by echocardiogram shortening fraction) was also significantly lower in the severe group (mean 32%+ 1.5 vs 39.8% + 2.2, p= 0.036, Mann-Whitney) (Fig 1G).