5. Discussion
PNH is a complement-mediated hemolytic anemia[1]and SARS-CoV-2 activates complement and inflammatory factor storm[6]. PNH patients infected with SARS-CoV-2 are more likely to have hemolytic episodes. 20 patients all had HDA in this study and had severe hemolysis and anemia: LDH, indirect bilirubin increased and red blood cell count, hemoglobin declined significantly.
Current study found that Omicron-induced hemolysis was more intense than ever happened since diagnosis. On the one hand, SARS-CoV-2 triggered complement activation through three pathways[5,6]and on the other hand, coronavirus infection activates monocyte, macrophage, and dendritic cell, then releases IL-6 and amplifies cytokine cascade[20]. Under dual attack, it causes severe hemolysis in patients suffering from PNH.
In this study, there was no thromboembolism, but D-dimer values of a half of patients were beyond the upper limit of normal. Zlatko et al.[16] reported one PNH patient who presented with deep vein thrombosis as the first sign of COVID-19. SARS-CoV-2 may increase thrombophilia in PNH in the context of multiple triggers, such as increased inflammatory factors, endothelial injury, platelet and thrombin activations. Acute kidney injury of PNH will be caused by a variety of reasons, such as the direct toxicity of free hemoglobin released by broken red blood cells, the constriction of renal blood vessels caused by NO consumption, and the direct damage caused by the coronavirus and cytokine storm[2,21,22]. In our cohort, there were 5 patients with severe renal function decline (glomerular filtration rate ≤ 60ml/min/1.73m2), even one accepted hemodialysis.
C5 inhibitors have been recommended as the first line treatment for PNH[23], greatly improving the poor prognosis of PNH. C5 inhibitors protect PNH clone from attack by blocking the complement activation pathway and significantly improve hemolytic anemia, reduce events of thrombosis, and alleviate damage of renal function[24–27]. Meanwhile, eculizumab has been used to treat severe COVID-19 [28]. Excess C5a induces the release of pro-inflammatory cytokines from innate immune cells which is thought to play a key role in acute lung injury[29]. After eculizumab stops the cleavage of C5, the production of C5a is reduced. In an Annane’s study[30]of 80 patients with severe COVID-19, 35 patients treated with additional eculizumab showed higher survival rate (82.9% vs 62.2%, p=0.04) and improved tissue oxygenation compared with 45 patients who received supportive care alone. Another case reported that after Diurno[31] administrated eculizumab to 4 patients with severe COVID-19, their inflammatory markers declined and recovery time was cut short. The literature[10,12–14,16] documented less frequent hemolysis following SARS-CoV-2 infection in PNH patients who regularly used complement inhibitors. Compared with cases with LDH values reported in the literature, hemolysis in current study was more severe (LDH 7.47×ULN vs 2.04×ULN, p<0.001). In our study, 5 patients receiving eculizumab achieved improvement in hemolysis and anemia, and COVID-19 was also relieved. Eculizumab maybe a good choice for patients with PNH after SARS-CoV-2 infection.
In conclusion, our study preliminarily demonstrate SARS-CoV-2 infection could induce a hemolytic exacerbation in patients with PNH but eculizumab can effectively control acute hemolysis. A large amount of long-term follow-up data are still needed to assess the impact of SARS-CoV-2 on patients with PNH, evaluate the dose and duration of eculizumab, and develop better prevention and control plans.