A previously healthy 2-year-old female from Minnesota presented in March to the Emergency Department with 1 week of fever and cough associated with emesis and diarrhea. Her family of 5 had been ill for the past week with upper respiratory symptoms. The patient was unimmunized and had no previous hospitalizations. Upon initial examination, she was noted to be febrile (temperature of 39.2 °C), tachycardic (heart rate of 210 beats/min), hypotensive (blood pressure of 85/40 mm Hg), tachypneic (respiratory rate of 68 breaths/min) and hypoxic (oxygen saturation of 87%). She appeared acutely ill and had supraclavicular retractions, decreased breath sounds over the left lower lung and capillary refill of 4 seconds in her distal extremities, which were noted to be warm. Initial laboratory results demonstrated a white blood cell count of 6.1 × 109/L (normal: 5.5–15.5), platelet count of 313 109/L (normal: 150–450), C-reactive protein of 215 mg/L (normal: 0–8), creatinine of 1.68 mg/dL (normal: 0.15–0.53), lactic acid of 10.4 mmol/L (normal: 0.7–2.1), international normalized ratio of 1.75 (normal: 0.86–1.14) and partial thromboplastin time of 48 seconds (normal: 22–37). A rapid nasopharyngeal influenza antigen test was negative. Further microbiologic evaluation included blood and urine cultures, and a respiratory viral polymerase chain reaction panel. A chest radiograph demonstrated a left lower lobe opacity with left pleural effusion.
The patient was aggressively fluid resuscitated with approximately 30 mg/kg of isotonic fluid, and was empirically treated with cefepime and vancomycin. She was admitted to the pediatric intensive care unit where she continued to have poor perfusion. Due to concern for severe sepsis, she was intubated and started on norepinephrine and dopamine. On hospital day 2, the patient continued to have delayed capillary refill in her distal extremities, despite hemodynamic stabilization and a significant decrease in vasopressor support. A 4-extremity arterial and venous ultrasound with duplex demonstrated right and left ulnar artery thromboses, left radial artery thrombosis and venous thromboses of the right subclavian, axillary, cephalic and left iliac veins. Further laboratory results at this time revealed a reduced protein S free of 13% (normal: 60–135), reduced protein C chromogenic of 25% (normal: 40–92) and reduced antithrombin III of 30% (normal: 85–135) with abnormally elevated Von Willebrand factor (VWF) activity of >390% (normal: 50–180) and D-dimer of 15.6 µg/dL (normal: 0–0.5).
Interventional radiology and pediatric orthopedics were consulted for emergent management of the diffuse thromboses. Thrombectomy and catheter directed thrombolytics were contraindicated due to the caliber, multiplicity and size of vasculature affected. After consultation with pediatric hematology, systemic thrombolytics with tissue plasminogen activator, factor replacement with activated protein C and fresh–frozen plasma and medicinal leech therapy were started (Fig. 1). She transitioned to heparin infusion on hospital day 4.
Her hospital course was also complicated by prolonged acute respiratory failure. An endotracheal aspirate obtained shortly after intubation returned a negative Gram stain. Lung ultrasound demonstrated a moderate left lung effusion, and computed tomography scan of the chest identified a left lower lobe consolidation with a cystic intraparenchymal structure consistent with necrosis. Pleural fluid analysis revealed an exudative process with a neutrophilic differential. All microbiologic evaluations returned negative including blood cultures, endotracheal aspirate cultures, pleural fluid culture and urine culture.
Another diagnostic test revealed the underlying pathogen.
For Denouement see P. 953.
(Pediatr Infect Dis J 2021;40:953–954)
Continued from P. 952.
Although the rapid influenza A/B antigen test on admission was negative, the respiratory viral panel detected influenza A (IAV) 2009 H1N1 on hospital day 2 via polymerase chain reaction analysis. Other viral targets, including influenza B, respiratory syncytial virus A/B, parainfluenza 1–3, human metapneumovirus, human rhinovirus and adenovirus were negative. Her dramatic presentation of severe sepsis complicated by diffuse arterial and venous thromboses was presumed to be secondary to influenza A H1N1 subtype with severe systemic inflammatory response. The patient completed a 5-day course of oseltamivir and 10-day course of ceftriaxone, the latter given concern for possible superimposed bacterial infection.
Despite aggressive therapeutic interventions to reduce vascular occlusion and improve perfusion, the patient developed dry gangrene of her distal upper extremities due to prolonged thrombotic associated ischemia (Fig. 2). She was discharged on enoxaparin for 6 months duration and underwent an outpatient amputation of 4 full phalanges on her left hand, and partial phalanges on her right hand.
Arterial and venous thromboses have not been previously described as a complication of influenza in children. Currently, pediatric thrombosis complications are not tracked on FluNet, the global web-based influenza surveillance system.1 However, adult patients with influenza have an increased risk of venous thromboembolism. Retrospective reviews of critically ill adults with IAV H1N1 found a 25% risk of significant thromboembolic events, including pulmonary embolism, deep venous thrombosis, acute myocardial infarct and cerebral ischemic stroke.2 Although rare, adult patients with arterial thrombosis have also been described, often postmortem.3 In fact, in an observational study, adult patients with pandemic H1N1 and thrombotic complications carried a significantly higher mortality rate than those without thromboses, 30% versus 8%, respectively.4 It can be postulated that the literature is more robust among adults given the tendency of this population to have chronic conditions, including diabetes, hypertension and atherosclerosis, which may predispose them to endothelial injury and thrombosis during influenza infections.
The pathogenesis of thrombosis in influenza is incompletely understood; however, playing a role is the complex relationship between the virion, endothelial cells and an aggressive inflammatory response. Influenza primarily targets the lung epithelium by binding sialic acid residues via hemagglutinin on the virion surface.5 Intracellular viral RNA thus activates toll-like receptors which stimulate the innate immune system and the production of proinflammatory cytokines including IL-6, IL-8, TNF-alpha, monocyte chemoattractant protein, macrophage inflammatory protein and downstream IL-1beta.6 Endothelial disruption and apoptosis can occur via direct IAV infection of endothelial cells or via cytokine release leading to vascular hyperpermeability and cellular damage. In vivo mouse studies demonstrate IAV infected endothelial cells express tissue factor and VWF which in turn lead to thrombin production and platelet adhesion.7 Anticoagulant pathways are also disrupted including a reduced ability to activate protein C via disruption of endothelial thrombomodulin, thus clinically predisposing the study mice to venous and atherothrombotic events.7 Hence, it can be hypothesized that our patient’s abnormal laboratory results including increased VWF, D-dimer and decreased protein S, protein C and antithrombin may be explained by severe endothelial disruption from influenza infection and inflammatory response.
Other respiratory viruses including influenza B, parainfluenza and respiratory syncytial virus have been shown to similarly activate the extrinsic coagulation system via tissue factor.8 Although this patient’s case, which occurred in March 2019, preceded the global pandemic, certainly SARS-CoV-2 and Multisystem Inflammatory Syndrome in Children would now be at top of the differential diagnosis. Macro and microvascular thrombotic complications are associated with severe presentations of COVID-19 in adult patients, including pulmonary embolisms, deep venous thromboses and diffuse microvascular angiopathic complications detected on autopsies. Similar to the pathogenesis of influenza-associated thrombosis, SARS-CoV-2 is thought to activate the coagulation pathway indirectly by producing endothelial injury.9 SARS-CoV-2 enters endothelial cells through the ACE2 receptors which through complex pathways stimulates aggressive cytokine release and subsequent activation of the extrinsic clotting cascade via tissue factor.10
In conclusion, this case of influenza A with systemic inflammatory response complicated by diffuse arterial and venous thromboses is the first to be described in a pediatric patient. As explored in the pathophysiology above, these thromboembolisms are likely less a direct complication of IAV, and rather are a reflection of a severe infection with aggressive inflammatory response, endothelial injury and activation of the extrinsic coagulation pathway. Given the rarity of such presentations in children, the possibility of an underlying hyperinflammatory genetic predisposition should be considered, which was not explored in our patient. Further epidemiologic surveillance and basic research is needed to understand this complex process to help identify risk factors and define management of thromboses in severe influenza and other respiratory viruses.
1. World Health Organization, Global Influenza Surveillance and Response Systems (GISRS). (2020). FluNet. Available at: https://www.who.int/influenza/gisrs_laboratory/flunet/en/
. Accessed December 12, 2019.
2. Dimakakos E, Grapsa D, Vathiotis I, et al. H1N1-induced venous thromboembolic events? Results of a single-institution case series. Open Forum Infect Dis. 2016;3:ofw214.
3. Harms PW, Schmidt LA, Smith LB, et al. (2010). Autopsy findings in eight patients with fatal H1N1 CME / SAM. 27–35. Available at: https://doi.org/10.1309/AJCP35KOZSAVNQZW
. Accessed October 10, 2019.
4. Bunce PE, High SM, Nadjafi M, et al. Pandemic H1N1 influenza infection and vascular thrombosis. Clin Infect Dis. 2011;52:e14–e17.
5. Armstrong SM, Darwish I, Lee WL. Endothelial activation and dysfunction in the pathogenesis of influenza A virus infection. Virulence. 2013;4:537–542.
6. Yang Y, Tang H. Aberrant coagulation causes a hyper-inflammatory response in severe influenza pneumonia. Cell Mol Immunol. 2016;13:432–442.
7. Keller TT, van der Sluijs KF, de Kruif MD, et al. Effects on coagulation and fibrinolysis induced by influenza in mice with a reduced capacity to generate activated protein C and a deficiency in plasminogen activator inhibitor type 1. Circ Res. 2006;99:1261–1269.
8. Visseren FL, Bouwman JJ, Bouter KP, et al. Procoagulant activity of endothelial cells after infection with respiratory viruses. Thromb Haemost. 2000;84:319–324.
9. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033–2040.
10. Jayarangaiah A, Kariyanna PT, Chen X, et al. COVID-19-associated coagulopathy: an exacerbated immunothrombosis response. Clin Appl Thromb Hemost. 2020;26:1076029620943293.