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.