Complement Inhibition in Severe COVID-19 Acute Respiratory Distress Syndrome

Abstract

Most children with COVID-19 have asymptomatic or mild illness. Those who become critically ill suffer from acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). The rapid deterioration of lung function has been linked to microangiopathic and immune-mediated processes seen in the lungs of adult patients with COVID-19. The role of complement-mediated acute lung injury is supported by animal models of SARS-CoV, evaluation of lung tissue in those who died from COVID-19 and response of COVID-19 ARDS to complement inhibition. We present a summary of a child with COVID-19 disease treated with convalescent plasma and eculizumab and provide a detailed evaluation of the inflammatory pathways.

Keywords: COVID - 19; SARS-CoV-2; acute respiratory distress syndrome (ARDS); children; complement; eculizumab; pediatric.

Figure 1

A graphic representation of laboratory and treatment measures. Graphs A-C illustrate various laboratory information throughout the patient's clinical course. Selected clinical interventions (respiratory support, renal replacement therapy, steroids, plasma and eculizumab) are shown along the bottom of this figure, and correspond to the timing of these interventions in relation to the graphs. (A) Hemoglobin (HGB), platelet and D-dimer trends throughout hospital course. Patient was admitted to intensive care unit on day 1. As shown in the graph, hemoglobin rapidly trended down along with thrombocytopenia which reached a nadir on day 5 and then steadily recovered following eculizumab and transfusion of platelets. His hemoglobin remained largely stable with a slow decline requiring packed red blood cell transfusions on days 15, 23, and 41. D-dimer was initially 565 ng/mL on day 1 of hospitalization, which rose rapidly over the next few days to peak at 10,000 ng/mL (upper limit of local laboratory analyses). The levels of D-dimer trended downwards around day 30, coinciding with the 3rd dose of eculizumab. The doses of eculizumab are indicated with arrows along the x-axis on days 9, 17, and 29. (B) Organ (renal and hepatic) function during COVID-19. Creatinine, Alanine Transaminase (ALT) and Aspartate Transaminase (AST) are shown in relation to the hospital stay of the patient. The peak in creatinine to 5.91 mg/dL on day 5 prompted the use of continuous veno-venous hemofiltration (CVVH) as shown in (C). The fall in creatinine was most appreciated with CVVH, and remained stable during his stay even after CVVH was discontinued on day 22. A brief rise in creatinine was noted after discontinuation of CVVH, which was not sustained, and creatinine levels decreased promptly without any additional intervention except continued eculizumab therapy. Hepatic function steadily improved following convalescent plasma and repeated doses of eculizumab. (C) Complement and cytokine analyses during hospital stay. Detailed analyses of multiple markers are in Table 1. This figure depicts the anaphylatoxin complement C5a over 40 ng/mL (red arrow, normal range 2.74–16.33 ng/mL) on day 5 coinciding with respiratory compromise. This level remained high in spite of administration of C5 inhibitor, eculizumab on day 9. The levels started to decline slowly with continue C5 blockade (doses on days 17 and 29). Elevated free C5 level on day 11 (see Table 1), after eculizumab dose on day 9 suggests incomplete blockade of C5 or continued complement activation upstream to C5. Plasma membrane attack complex (C5b9) of 1272 ng/mL which was five times the upper limit of normal (<244 ng/mL) dropped precipitously following eculizumab dose on day 9, and remained well-controlled through the stay. Levels of C3a followed a similar trajectory of C5a. An interesting phenomenon observed was significant drop in interleukin-6 (IL-6) levels following the second dose of eculizumab on day 17, which was closely followed by weaning of mechanical ventilation.