Sex: M
Vaccine: COVID19
Symptoms: Computerised tomogram, Coronary artery aneurysm, Echocardiogram, Fibrin D dimer, Haemoglobin
Clinical narrative: MIS-C; delayed giant coronary aneurysm; This is a literature report.  A 5-year-old male patient received BNT162b2 (BNT162B2), as dose 1, single (Batch/Lot number: unknown) for covid-19 immunisation. The patient's relevant medical history included: "COVID-19" (unspecified if ongoing), notes: 55 days before receipt of 1st dose of BNT162B2. The patient's concomitant medications were not reported. The following information was reported: MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (hospitalization, medically significant, life threatening), 15 days after the suspect product(s) administration, outcome "recovering", described as "MIS-C"; CORONARY ARTERY ANEURYSM (hospitalization, medically significant, life threatening), 15 days after the suspect product(s) administration, outcome "recovering", described as "delayed giant coronary aneurysm". The patient underwent the following laboratory tests and procedures: Antibody test: Positive; Blood albumin (3.5-4.5): 3.1 g/dl, notes: On day 3; 3 g/dl, notes: On day 4; 3 g/dl, notes: On day 7; 2.6 g/dl, notes: On day 22; 2.3 g/dl, notes: On day 23; 2.9 g/dl, notes: On day 27; 4.2 g/dl, notes: On day 55; Body temperature: 102 Fahrenheit; 100 Fahrenheit, notes: day 5; Brain natriuretic peptide: within normal limits; Brain natriuretic peptide (normal high range 100): 103.7 pg/mL, notes: On day 3; 177.8 pg/mL, notes: On day 4; 30.3 pg/mL, notes: On day 9; 62.4 pg/mL, notes: On day 22; Computerised tomogram: showed mild RCA dilation, notes: on day 94 showed mild RCA dilation with 3 small  to medium-sized right coronary aneurysms in the mid and distal segments; C-reactive protein (normal high range 1): 19.3 mg/dl, notes: On day 3; 21.0 mg/dl, notes: On day 4; 8.7 mg/dl, notes: On day 5; 4.4 mg/dl, notes: On day 9; 16.3 mg/dl, notes: On day 11; 2.9 mg/dl, notes: On day 13; 6.1 mg/dl, notes: On day 22; 17.5 mg/dl, notes: On day 23; 0.2 mg/dl, notes: On day 27; 11.1 mg/dl, notes: On day 55; 0.2 mg/dl, notes: On day 85; 1 mg/dl, notes: less than 1, On day 117; Echocardiogram: no coronary artery dilation, notes: reassuring with normal cardiac function and no coronary artery dilation; moderately dilated coronary arteries, notes: day 10 significant for new moderately dilated coronary arteries with no obvious aneurysms; severe dilation, notes: significant for severe dilation to his coronary arteries; severe coronary artery dilation, notes: On day 24 show severe coronary artery dilation, most significant for the LAD (4.4 mm, z-score 7.98); showed  improvement in the diffuse coronary artery, notes: On day 64 showed  improvement in the diffuse coronary artery dilation to the mildly dilated range except for the LAD artery at the takeoff of the first diagonal branch in the moderate range; not visible on echocardiogram, notes: on day 94; slight improvement, notes: day 139; Fibrin D dimer (0-220): 412 ng/ml, notes: On day 3; 405 ng/ml, notes: On day 9; 268 ng/ml, notes: On day 23; Haemoglobin: 10.6 g/dl, notes: On day 3; 10.5 g/dl, notes: On day 4; 11.3 g/dl, notes: On day 9; 10.3 g/dl, notes: On day 11; 10.8 g/dl, notes: On day 13; 10.3 g/dl, notes: On day 22; 9.4 g/dl, notes: On day 23; 10.1 g/dl, notes: On day 27; 9.3 g/dl, notes: On day 55; 9.9 g/dl, notes: On day 60; 10.9 g/dl, notes: On day 85; Inflammatory marker test: elevated; increased; improved, notes: on day 27 on enoxaparin, daily aspirin and a 30-day steroid taper; increasing, notes: after discharge on day 55; notably improved, notes: on day 117; cardiac biomarkers: elevated; 6.5, notes: right coronary artery; 15.59, notes: left anterior descending artery; Platelet count: 478 x10 3/mm3, notes: On day 3; 450 x10 3/mm3, notes: On day 4; 644 x10 3/mm3, notes: On day 9; 551 x10 3/mm3, notes: On day 11; 612 x10 3/mm3, notes: On day 22; 532 x10 3/mm3, notes: On day 23; 611 x10 3/mm3, notes: On day 27; 899 x10 3/mm3, notes: On day 55; 739 x10 3/mm3, notes: On day 85; Red blood cell sedimentation rate: more than 40, notes: Unit: mm/h; SARS-CoV-2 test: Positive; Serum ferritin (13.7-78.8): 96.97 ng/ml, notes: On day 4; 39.77 ng/ml, notes: On day 9; 65.28 ng/ml, notes: On day 22; 107.29 ng/ml, notes: On day 23; 52.75 ng/ml, notes: On day 27; 106 ng/ml, notes: On day 55; 23 ng/ml, notes: On day 85; Troponin I: within normal limits; Troponin I (normal high range 0.03): 0.036 ng/ml, notes: On day 3; 0.010 ng/ml, notes: less than 0.010, On day 9; 0.010 ng/ml, notes: less than 0.010, On day 22; White blood cell count (4.3-12.4): 15.55 x10 3/mm3, notes: On day 3; 15.21 x10 3/mm3, notes: On day 4; 25.60 x10 3/mm3, notes: On day 8; 23.69 x10 3/mm3, notes: On day 11; 25.83 x10 3/mm3, notes: On day 13; 30.82 x10 3/mm3, notes: On day 22; 27.38 x10 3/mm3, notes: On day 23; 20.66 x10 3/mm3, notes: On day 27; 12.3 x10 3/mm3, notes: On day 55; 16.95 x10 3/mm3, notes: On day 60; 6.3 x10 3/mm3, notes: On day 85. Therapeutic measures were taken as a result of multisystem inflammatory syndrome in children, coronary artery aneurysm. The clinical course was as follows: A previously healthy 5-year-old male was hospitalized with fever up to 102 F for 4 days (day 0 = first day of fever), sore throat, myalgias, abdominal pain, conjunctival injection and rash 55 days after onset of a mild COVID-19 illness that did not require hospitalization and 15 days after receiving the first dose of BNT162b2. The workup was notable for elevated inflammatory markers [white blood cell (WBC) count 15.55 10 3/uL (reference: 4.3-12.4), C-reactive protein (CRP) 19.3 mg/dL (reference: <1)], mildly elevated cardiac biomarkers including brain natriuretic peptide [103.7 pg/mL (reference: <100.0)] and troponin-I [0.036 ng/mL [reference: <0.03]) with evidence of SARS-CoV-2 infection, including positive SARS-CoV-2 polymerase chain reaction (PCR) and antinucleocapsid antibody. Although he had features suggestive of incomplete Kawasaki disease (KD), given a positive COVID-19 test on both PCR and antinucleocapsid antibody the child met CDC case definition for MIS-C and was diagnosed as such. Per hospital protocol for management of MIS-C with KD features, he was treated with intravenous immunoglobulin (IVIG) 2 g/kg, steroids (methylprednisolone 1mg/kg intravenously twice daily for one day followed by prednisone 1 mg/kg orally twice daily for four days) and daily aspirin 81 mg. Echocardiography during the initial hospitalization was reassuring with normal cardiac function and no coronary artery dilation. The patient demonstrated clinical improvement with resolution of symptoms, and on day 6 of MIS-C illness, he was discharged home with low-dose aspirin for 6 weeks and 1 day of prednisone. A day after completing the prescribed 5-day course of steroids, the patient was readmitted on day 9 with slightly elevated temperature (100 F), fatigue, cough, faint blanching macular rash on the chest and abdomen, conjunctivitis and dry, cracked lips. Laboratory studies were notable for elevations in WBC count (25.6 10 3/uL), CRP (4.4 mg/dL), and D-dimer [405 ng/mL (reference: 0-220)]. His troponin and brain natriuretic peptide were within normal limits. He was diagnosed with recrudescence of MIS-C with KD features and started on methylprednisolone 1 mg/kg IV q12h and low-dose aspirin with resolution of symptoms. Echocardiography on day 10 was significant for new, moderately dilated coronary arteries with no obvious aneurysms, and the patient was promptly given a second dose of IVIG 2g/kg, following which he remained afebrile. On day 13, he was discharged with a 2-week taper of prednisolone and low-dose aspirin. Until day 19 of illness, he took 1 mg/kg of prednisolone twice daily. On day 20, the patient started his planned prednisolone taper of 1 mg/kg daily. He then presented with tactile fever, dry cracked lips, conjunctivitis, and abdominal pain on day 22. Inflammatory markers had increased since previous discharge (WBC 30.82 10 3/uL), CRP 6.1 mg/dL). Echocardiography was significant for severe dilation to his coronary arteries: right coronary artery (RCA) (4.5 mm, z-score 6.5) and left anterior descending artery (LAD) (6.7 mm, z-score 15.59). He was admitted for the third time and began treatment for refractory MIS-C with infliximab 10 mg/kg IV and methylprednisolone 30 mg/kg IV for 5 days. As the LAD dimensions met criteria for a giant coronary aneurysm, he was also given enoxaparin for his coronary artery dilation per the Heart Association Kawasaki guidelines. On day 24, echocardiography continued to show severe coronary artery dilation, most significant for the LAD (4.4 mm, z-score 7.98). His inflammatory markers and clinical course improved, and he was discharged on day 27 on enoxaparin, daily aspirin and a 30-day steroid taper. Nearly a month after discharge, on day 55, the patient remained asymptomatic, but his inflammatory markers began increasing (CRP 11.1 mg/dL), and his steroid taper was further extended. On day 64, a repeat echocardiogram showed improvement in the diffuse coronary artery dilation to the mildly dilated range except for the LAD artery at the takeoff of the first diagonal branch in the moderate range. A cardiac computed tomography study on day 94 showed mild RCA dilation with 3 small- to medium-sized right coronary aneurysms in the mid and distal segments, not visible on echocardiogram. The left main coronary artery and left anterior descending coronary artery were improved to normal, except for aneurysmal dilation at the left anterior descending at the level of the first diagonal branch takeoff, which was like what was seen by echocardiogram. On day 112, his prednisolone was discontinued and on day 117 his inflammatory markers were notably improved with a CRP < 1 mg/dl. His last echocardiogram (day 139) before the article submission showed slight improvement. The authors reported a case of MIS-C with three unusual features: development of a delayed giant coronary aneurysm, multiple recrudescent episodes resulting in hospital readmissions and occurrence after COVID-19 vaccination with a recent history of SARS-CoV-2 infection.  MIS-C has been associated with cardiac manifestations in >80 percent of cases, but reports of giant coronary aneurysms (z-score >/= 10 or diameter >/= 8 mm) and delayed coronary dilation in MIS-C are scarce. In this patient, coronary aneurysms developed after the administration of IVIG, and much later in his disease course - nearly 3 weeks after he was initially symptomatic. Infliximab has been shown to improve coronary aneurysms in refractory MIS-C and in other types of vasculitis including KD and Behcet Disease.  The patient was admitted 3 times for MIS-C refractory to initial treatment with IVIG, corticosteroids and anti-inflammatory agents, most likely due to rebound inflammation. Readmission for the same episode of MIS-C is rare. Among the 456 cases of MIS-C at the child's institution, he is the only patient to date to require two readmissions for MIS-C. Notably, his MIS-C symptoms first resurfaced a day after he completed his course of prednisone and then again a day after his prednisone taper was decreased to 1 mg/kg daily. It appeared this patient needed a longer course with higher dosing to achieve suppression of his inflammation. Glucocorticoids have been shown to reduce the need for adjuvant therapy, decrease the duration of fevers and reduce the need for hemodynamic support. A month after, he was discharged from the hospital, his inflammatory markers were rising and his steroid taper was adjusted accordingly.  Given the timing of this patient's MIS-C onset relative to his first dose of COVID-19 vaccination and the severity of his MIS-C illness, questions regarding further COVID-19 vaccination were raised. First, the care team had concerns regarding the potential contribution of COVID-19 vaccine to the occurrence of MIS-C. Published literature and CDC MIS-C surveillance activities suggest that (1) COVID-19 vaccine is highly effective in preventing MIS-C; (2) MIS-C after COVID-19 vaccination is rare, with most cases having evidence of SARS-CoV-2 infection; and (3) the contribution of vaccination to these cases, if any, is unknown. The CDC Interim Clinical Considerations advise patients with SARS-CoV-2 infection to wait until after they have recovered from acute COVID-19 illness and have met criteria to discontinue isolation before obtaining COVID-19 vaccination. CDC guidance further advises, however, that individuals may consider delaying vaccination by 3 months from the onset of COVID-19 symptoms (or positive test if no symptoms) given possibility of improved immune response and observed low risk of reinfection in the weeks to months after SARS-CoV-2 infection. Whether our patient's COVID-19 vaccine 6 weeks after COVID-19 illness contributed to his MIS-C is unknown. Pediatricians should be aware that the option for an extended interval between SARS-CoV-2 infection and COVID-19 vaccination exists. The second question regarding vaccination was whether the patient should receive a second dose of vaccine to complete his primary series of COVID-19 vaccination. Current CDC guidance recommends that further COVID-19 vaccine doses in children with MIS-C within 90 days after vaccination should be deferred until more safety data are available, unless there is strong evidence that the episode of MIS-C was a complication of a recent SARS-CoV-2 infection. Given the complexities of this case, consultation was requested from the CDC-funded Safety Assessment Project regarding future vaccinations. Project is a collaboration between CDC and 7 medical research centers with expertise in vaccine safety and multiple medical specialties that provides consultation to healthcare providers with complex patient vaccine safety questions. Advice from project is meant to assist in decision-making, rather than provide direct patient management. Project experts advised deferring COVID-19 vaccine at the current time and suggested review of the risks and benefits of the COVID-19 vaccine and available vaccine formulations in the CDC Interim Clinical Considerations when the child is fully recovered. The child's care team agreed, opting to recommend that the family not seek further doses of COVID-19 vaccine at this time. However, the care team committed to reconsidering administration of COVID-19 vaccine at least three months after his inflammatory markers normalized, considering such factors at that time as community prevalence of SARS-CoV-2, latest data on benefit and safety of further doses of vaccines (particularly in those with prior history of COVID-19), and effectiveness of available vaccines against prevailing strains of SARS-CoV-2.; Sender's Comments: Based on the available information in the case, the causal association between the events Multisystem Inflammatory Syndrome in  Children and coronary artery aneurysm  and the suspect drug BNT162B2  cannot be excluded.  The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to regulatory authorities, Ethics Committees, and Investigators, as appropriate