The current coronavirus disease 2019 (COVID-19) pandemic bears witness to devastating morbidity and mortality associated with this illness, at upwards of 95.54 million global cases and 2.04 million deaths at the time of this writing.1 Of its many manifestations, hypercoagulability and venous thromboembolisms (VTE) often lead to dire complications such as pulmonary embolism (PE).2 In adult case series, 20–30% of critically ill patients manifested PE despite thromboprophylaxis3–5 at a rate higher than that seen in controls identified before the pandemic. In contrast, PE as an initial finding in the pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patient has not been previously reported.6 This report identifies 2 adolescent patients presenting with PE, and whether their cases illustrate mechanisms leading to PE in pediatric patients with SARS-CoV-2 remain to be determined.
CASE REPORT 1
A 15-year-old female with obesity (body mass index 46.6) presented to the emergency department with sudden onset of nonradiating chest pain and associated shortness of breath of 1-hour duration. The patient denied fever, cough, dizziness, sick contacts, palpitations or paresthesias. She denied a history of thrombi or any recent prolonged immobility. There was no family history of hypercoagulable disorders or known COVID-19 exposures. Of note, the patient had taken oral contraceptives (OCPs) for 3 months but discontinued these 1 month before presentation.
Vital signs revealed tachycardia with slightly increased respiratory rate (heart rate 124 bpm, respiratory rate at 24 breaths/min, oxygen saturation at 94% on room air). On examination, the patient had no respiratory distress. Laboratories revealed an elevated D-dimer of 5.1 with normal prothrombin time (13.6 seconds), aPTT (26.3 seconds) and international normalized ratio (1.04). A rapid nasopharyngeal antigenic test for SARS-CoV-2 was also positive. Cardiac enzymes were elevated (troponin-I 0.92 ng/mL). A comprehensive metabolic panel, complete blood count with differential, urine drug screen, lower extremity ultrasound and electrocardiogram were normal. A computed tomography (CT) and angiography of the chest (Fig. 1A) revealed moderate thrombus in the distal left and right pulmonary artery extending into the upper and lower lobes bilaterally, with right heart strain. There was a mild opacity in the right lower lobe consistent with developing pneumonia or atelectasis. An echocardiogram demonstrated mildly depressed right ventricular systolic function. The patient received a heparin infusion that was titrated to an aPTT goal of 60–90 seconds. She also received nasal cannula oxygen at 2 L/min and was transferred to the pediatric intensive care unit for monitoring.
Adult interventional cardiology was consulted for potential thrombectomy and recommended continuing medical management. Mechanical thrombectomy or catheter-directed thrombolysis was deferred because of the distal locations of the thrombi and mild symptoms. Her cardiac enzyme elevation improved over 2 days, and her symptoms manifest only as chest pain on exertion. An echocardiogram on hospital day 2 showed improvement to normal right ventricular systolic function and size, although a repeat CT and angiography of the chest showed persistent significant PE burden. Given her improved heart function and clinical stability, she transitioned to enoxaparin on day 3. The patient improved and was transferred to the hospital floor on day 6 of admission. She demonstrated a hepatic transaminitis (alanine aminotransferase 112, aspartate aminotransferase 52) but was otherwise asymptomatic from an abdominal standpoint. Hypercoagulability evaluations for systemic lupus erythematosus, antiphospholipid antibody syndrome, factor V Leiden thrombophilia and prothrombin gene mutation were negative. Levels of protein C, S and antithrombin III were deferred to follow-up because of the effect of heparin on these anticoagulants and are not available at the time of this report.
She initially tested positive for SARS-CoV-2 infection via nasopharyngeal PCR and demonstrated IgG antibodies to the virus upon admission. Daily multisystem inflammatory syndrome in children (MIS-C) screening was performed using lactate dehydrogenase, ferritin, fibrinogen and procalcitonin, and these values were normal. C-reactive protein was elevated at 26.9 mg/L as well as sedimentation rate at 35 mm/h. She received 5 days of dexamethasone, and remdesivir was deferred. From a respiratory standpoint, the patient transitioned to room air on day 3 and maintained normal oxygen saturations. She remained afebrile and without any respiratory, inflammatory or gastrointestinal symptoms of COVID-19 throughout her hospital stay. She was discharged 10 days after admission, receiving enoxaparin with planned 3-month hematology follow-up. No new COVID-19 cases among her contacts were reported to her care team.
CASE REPORT 2
A 16-year-old female with obesity (body mass index 42.7) and a history of uncontrolled diabetes mellitus (HgbA1C 11.6%) presented with 2 weeks of fatigue leading to bedrest, several days of shortness of breath with productive cough presented to the emergency department with hypoxia and tachycardia (heart rate 127 bpm, respiratory rate 29 bpm, weight 125.6 kg). She described “feeling bad” and was largely bed-bound aside from eating and hygienic self-care. At hospital admission, she became syncopal while receiving a delivery. She was found by a bystander and was brought to the emergency department. Although her glucose level was elevated at 358 mg/dL, she did not demonstrate acidosis, an anion gap or ketosis.
Given her hypoxia to 86% saturation on room air, a chest CT was obtained and showed a significant pulmonary saddle embolus, as well as distal branch pulmonary emboli and right ventricular/left ventricular ratio diameter ratio > 1.0 indicating right ventricular strain. She did not endorse the recent use of regular OCPs. There were patchy ground glass opacities in the right upper and bilateral lower lobes consistent with viral infection or pulmonary edema.
Based on her symptomatology, right heart strain and proximal pulmonary emboli burden, she underwent pulmonary embolectomy via median sternotomy under cardiopulmonary bypass. Two emboli were removed, the larger being 8.3 × 5.1 × 1.2 cm (Fig. 1B). A postoperative transesophageal echocardiogram revealed no additional emboli and moderately depressed right ventricular systolic function. After this, she recovered in the pediatric ICU, was extubated by postoperative day 1 and progressively weaned from noninvasive positive pressure ventilation to room air by the time of discharge. No deep vein thrombosis was discovered on ultrasound imaging on postoperative day 0. Serial echocardiographic assessments of right ventricular function proved too technically difficult. A predischarge cardiac CT was obtained and revealed resolution of right ventricular dilatation and otherwise no clear evidence of persistent thrombosis or right ventricular dysfunction.
During her stay, rapid COVID-19 antigen tests were performed however returned negative, and a COVID-19 IgG assay was positive on postoperative day 2 however. She remained afebrile through her stay and improved from a pulmonary standpoint. MIS-C screening was performed although on postoperative day 3 and demonstrated elevated levels of fibrinogen ranging from 619 to 748 mg/dL, interleukin 6 at 22.57 pg/mL, lactate dehydrogenase at 302 units/L, ferritin at 520 ng/mL, erythrocyte sedimentation rate of 97 mm/h, C-reactive protein at 209 mg/L and procalcitonin of 0.39 ng/mL. In light of a lack of symptoms, MIS-C specific immunomodulatory therapies were not initiated. An admission blood culture remained negative, and a urine culture revealed Escherichia coli for which she was treated with ceftriaxone and transitioned to cephalexin on day 2 of a 7-day course.
From a thrombophilia standpoint, her functional protein S level was low at 36 m, and antithrombin III level was depressed at 67 consistent with consumption because of extensive thrombosis and heparin use, respectively. Protein C activity was normal at 82 as well as total protein S at 114%. D-dimer at admission was elevated 0.76 μg/mL. Lupus anticoagulant, factor V Leiden and prothrombin gene mutation were not measured and were to be evaluated at hematology follow-up 3 months after discharge which is not available at the time of this writing. Anticardiolipin and β-2 glycoprotein assays were normal. She was initially managed with heparin infusion titrated to an activated coagulation time of 160–180 and then transitioned to apixaban on postoperative day 3. She was discharged 11 days after admission, and no new COVID-19 cases among her contacts were reported to her care team.
This is the first report of pediatric patients presenting with submassive PE as primary issues in the setting of concomitant SARS-CoV-2 infection without MIS-C. One previous report7 describes the case of a 15-year-old female who demonstrated SARS-CoV-2 IgG antibodies after manifesting massive PE and cardiopulmonary failure while recovering from a laparoscopic appendectomy. In contrast to the patient in Case 1, the patient described by Kotula et al8 consistently demonstrated negative rapid SARS-CoV-2 antigen tests, and she also demonstrated MIS-C which the patient in Case 1 did not. With regard to her OCP history, antithrombin III and fibrinogen levels normalize within 2–6 weeks after discontinuation of OCPs. There is a case report of a 61-year-old man who was found to have died from fatal saddle PE in the absence of SARS-CoV-2 symptoms or rapid COVID-19 assay positivity 5 and 3 days before death although there were 2 sick contacts who demonstrated positivity.9 This suggests that this phenomenon is not isolated to children.
Neither patient manifested classic symptoms of MIS-C: fever, gastrointestinal symptoms, neurologic symptoms, rash, conjunctivitis, oral mucosal changes, extremity erythema or swelling or cervical lymphadenopathy. While inflammatory biomarkers were elevated, they were not diagnostic of MIS-C. Their lack of symptoms and inflammation contrasted starkly to the severity of their VTE.
It is unclear as to what thrombosis prophylaxis is warranted in children exposed to SARS-CoV-2 given a dearth of evidence. Given that 31% of hospitalized adults with infection demonstrate evidence of VTE in some series,4,10 considering older adolescents’ risk for COVID-19–related comorbidities including PE seems reasonable. Current recommendations on thrombosis prevention in pediatric patients with COVID-19 infection11 are based on a strong family/personal history of VTE or presence of a central venous catheter with 2 risk factors or 4 or more total risk factors. These risk factors include postpubertal age, decreased motility, burns, malignancy, venous stasis or low cardiac output state, estrogen therapy, active systemic infection, inflammatory disease flare, obesity, severe dehydration or recent surgery/trauma. Considering these risk factors, these patients were postpubertal and obese. It is unclear how nuances in the OCP history of the patient in Case 1 or bedrest of the patient in Case 2 influenced development of deep vein thrombosis; however, the severity of VTE symptoms they experienced appear disproportionate to those factors.
This case illustrates the potential for bilateral symptomatic submassive PE in functional adolescents with concurrent SARS-CoV-2 infection. Clinicians caring for such populations benefit from recognizing this risk and should consider adult management guidelines for patients with these clinical features.
1. COVID-19 Map - Johns Hopkins coronavirus resource center. 2021. Available at: https://coronavirus.jhu.edu/map.html
. Accessed January 18, 2021.
2. Helms J, Tacquard C, Severac F, et al.; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020; 46:1089–1098.
3. Cui S, Chen S, Li X, et al. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020; 18:1421–1424.
4. Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020; 18:1995–2002.
5. Poissy J, Goutay J, Caplan M, et al.; Lille ICU Haemostasis COVID-19 Group. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation. 2020; 142:184–186.
6. Simoni P, Bazzocchi A, Boitsios G, et al. Chest computed tomography (CT) features in children
with reverse transcription-polymerase chain reaction (RT-PCR)-confirmed COVID-19: a systematic review. J Med Imaging Radiat Oncol. 2020; 64:649–659.
7. Kotula JJ, Balakumar N, Khan D, et al. Bilateral pulmonary emboli in a teenager with positive SARS-CoV-2 antibody. Pediatr Pulmonol. 2020; 28:1023.
8. Robinson GE, Burren T, Mackie IJ, et al. Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgery. BMJ. 1991; 302:269–271.
9. Del Nonno F, Colombo D, Nardacci R, et al. Fatal pulmonary arterial thrombosis in a COVID-19 patient, with asymptomatic history, occurred after swab negativization. Thromb J. 2021; 19:1.
10. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020; 191:145–147.
11. Loi M, Branchford B, Kim J, et al. COVID-19 anticoagulation recommendations in children
. Pediatr Blood Cancer. 2020; 67:e28485.