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\begin{document}

\title{Severe Hemolytic Exacerbations of Chinese PNH Patients infected
SARS-CoV-2 Omicron}



\author[1]{Hui Yang}%
\author[2]{Xingxing Chai}%
\author[1]{Yuemin Gong}%
\author[1]{Xinyu Zhang}%
\author[3]{Lingling Wang}%
\author[3]{Xin Zhou}%
\author[1]{Xiaoyu Chen}%
\author[4]{Jinge Xu}%
\author[5]{Dan Xu}%
\author[1]{Jianyong Li}%
\author[1]{Guangsheng He}%
\affil[1]{Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital}%
\affil[2]{second people’s hospital of Lianyungang}%
\affil[3]{Wuxi People's Hospital}%
\affil[4]{The Second Affiliated Hospital of Xuzhou Medical University}%
\affil[5]{Funing People's Hospital}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolytic
anemia, bone marrow failure, thrombophilia. COVID-19, caused by a novel
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with many
variants including Omicron. This study depicted demographic and clinical
characteristics of 20 PNH patients with SARS-Cov2 Omicron infection. All
the patients hadn't previously been administrated with complement
inhibitors. They all were with high disease activity (HDA), and LDH
level exceeded any documented since the diagnosis of PNH, and those
reported in the literature for previously stable treatment with
complement inhibitors. D-dimer level elevated in 10 patients. 2 patients
developed mild pulmonary artery hypertension. Glomerular filtration rate
(GFR) declined in 5 patients. 1 patient developed acute renal failure
and underwent hemodialysis. Anemia and hemolysis were improved in 5
patients treated with eculizumab. Hemolytic exacerbation of PNH with
COVID-19 is severe and eculizumab may be an effective treatment.%
\end{abstract}%



\sloppy


\textbf{Severe Hemolytic Exacerbations of Chinese PNH Patientsinfected
SARS-CoV-2 Omicron}

Hui Yang\textsuperscript{1}\#, Xingxing Chai\textsuperscript{2}\#,
Yuemin Gong\textsuperscript{1}, Xinyu Zhang\textsuperscript{1}, Lingling
Wang\textsuperscript{3}, Xin Zhou\textsuperscript{3}, Xiaoyu
Chen\textsuperscript{1}, Jinge Xu\textsuperscript{4}, Dan
Xu\textsuperscript{5}, Guangsheng He\textsuperscript{1*}, Jianyong
Li\textsuperscript{1}

\textsuperscript{1}Department of Hematology; The First Affiliated
Hospital of Nanjing Medical University, Jiangsu Province Hospital in
Nanjing, Key Laboratory of Hematology of Nanjing Medical University,
Collaborative Innovation Center for Cancer Personalize

300\# Guangzhou Road, Nanjing, Jiangsu Province, China (210029)

\textsuperscript{2}Department of Hematology; The second people's
hospital of Lianyungang

41\# Hailiandong Road, Lianyungang, Jiangsu Province, China (222000)

\textsuperscript{3}Department of Hematology; Wuxi People's Hospital
affiliated to Nanjing Medical University

299\# Qingyang Road, Wuxi, Jiangsu Province, China (214002)

\textsuperscript{4}Department of Hematology, The Second Affiliated
Hospital of Xuzhou Medical University

32\# Meijian Road, Xuzhou, Jiangsu Province, China (221004)

\textsuperscript{5}Department of Hematology; Funing People's Hospital

109\# Fucheng Street, Yancheng, Jiangsu Province, China (224400)

*Correspondence:

Guangsheng He, Department of Hematology; The First Affiliated Hospital
of Nanjing Medical University, Jiangsu Province Hospital in Nanjing, Key
Laboratory of Hematology of Nanjing Medical University, Collaborative
Innovation Center for Cancer Personalize

300\# Guangzhou Road, Nanjing, Jiangsu Province, China (210029)

Email: heguangsheng1972@sina.com

\#These authors contributed equally to this work and shared first
authorship.

\textbf{Abstract}

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolytic
anemia, bone marrow failure, thrombophilia. COVID-19, caused by a novel
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with many
variants including Omicron. This study depicted demographic and clinical
characteristics of 20 PNH patients with SARS-Cov2 Omicron infection. All
the patients hadn't previously been administrated with complement
inhibitors. They all were with high disease activity (HDA), and LDH
level exceeded any documented since the diagnosis of PNH, and those
reported in the literature for previously stable treatment with
complement inhibitors. D-dimer level elevated in 10 patients. 2 patients
developed mild pulmonary artery hypertension. Glomerular filtration rate
(GFR) declined in 5 patients. 1 patient developed acute renal failure
and underwent hemodialysis. Anemia and hemolysis were improved in 5
patients treated with eculizumab. Hemolytic exacerbation of PNH with
COVID-19 is severe and eculizumab may be an effective treatment.

\textbf{Keyword}

Paroxysmal nocturnal hemoglobinuria; COVID-19; Omicron; complement
inhibitor therapy; hemolysis;

\textbf{Introduction}

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired and clonal
disease characterized by hemolytic anemia, bone marrow failure,
thrombophilia and multi-organ damage, which results from the mutation of
the \emph{X} -linked \emph{PIGA} gene. The blockade of
glycosylphosphatidylinositol (GPI) synthesis caused by mutation results
in the absence of GPI-anchored protein (such as CD55 and CD59), and
CD55-deficient and CD59-deficient blood cells are more susceptible to
complement attack and lysis\textsuperscript{{[}1,2{]}}. Coronavirus
disease 2019 (COVID-2019) first emerged in Wuhan, Hubei, China, by
severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2)\textsuperscript{{[}3{]}}. SARS-CoV-2 was reported multiple
variants, including Alpha, Beta, Gamma, Delta, Omicron, and Omicron
shows a 13-fold increase in viral infectivity than Delta
variant\textsuperscript{{[}4{]}}. SARS-CoV-2 activate the complement
system through the classical pathway, lectin pathway and the alternative
pathway. Specific antibody directed against the receptor-binding domain
of the spike protein initiates the classical pathway, the binding of
mannose-binding lectin (MBL) with SARS-CoV-2 spike protein triggers the
lectin pathway and SARS-CoV-2 spike protein may dysregulate the
alternative pathway by binding heparan sulfate and competing with factor
H, which is a negative regulator of complement
activity\textsuperscript{{[}5,6{]}}. After SARS-CoV-2 infection,
patients with PNH more likely suffered the
hemolysis\textsuperscript{{[}7--16{]}}, patients usually presented
visible hemoglobinuria and a small number patients showed
pancytopenia\textsuperscript{{[}17{]}}. Terminal complement inhibitors
(such as eculizumab) are promising in COVID-19 treatment by blocking the
formation of membrane attack complex (MAC) and reducing pro-inflammatory
and prothrombotic influence\textsuperscript{{[}5,6,18{]}}. Due to the
rarity of PNH, the clinical features of patients infected with
SARS-CoV-2 were mostly case reports. China has been heavily affected by
the SARS-CoV-2 Omicron outbreak with the peak in mid-December 2022. We
collected clinical data from 20 PNH patients infected with SARS-CoV-2
Omicron and treated 5 patients with eculizumab.

\textbf{2. Patients and Methods}

2.1 Patients

The study enrolled 20 patients with PNH infected SARS-CoV-2 Omicron
prospectively registered in the Chinese Eastern Collaboration Group of
Anemia (ChiCTR2100050945), which was conducted by four centers: the
First Affiliated Hospital with Nanjing Medical University (Nanjing,
China), the second people's hospital of Lianyungang (Lianyungang,
China), Wuxi People's Hospital (Wuxi, China) and Funing People's
Hospital (Funing, China) from December 2022 to February 2023. Patients
signed informed consent. The study was conducted according the
Declaration of Helsinki and approved by the hospital ethics committee.

2.2 Diagnostic criteria

All the patients developed fever, cough, nasal congestion, sore throat,
or other uncomfortable symptoms. Reverse transcription polymerase chain
reaction (RT-PCR) or antigen testing for SARS-Cov-2 was positive.

High disease activity (HDA) was defined as evidence of hemolysis
(elevated lactate dehydrogenase {[}LDH{]}[?]1.5 times upper limit of
normal {[}ULN{]}) and a history of at least 1 of the following signs or
symptoms--- fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia
(hemoglobin \textless{} 100 g/L), MAVEs (including TEs), dysphagia, or
erectile dysfunction\textsuperscript{{[}19{]}}.

2.3 Methods

A collection on 20 patients with PNH registered in 4 centers is to
evaluate the occurrence and clinical characteristics of SARS-CoV-2
infection, and the efficacy of eculizumab.

\textbf{3. Statistics analysis}

Categorical variables were described using frequencies and percentages,
and continuous variables were described using median, minimum and
maximum. Shapiro-Wilk test is used to test whether the data conform to a
normal distribution. The degree of SARS-CoV-2-induced hemolysis compared
with the literature was examined by Mann-Whitney U test. Paired samples
conformed to a normal distribution use paired sample T test, otherwise
Wilcoxon test is used for examination. All of the analyses were
performed using the statistical package SPSS 26.0, p<0.05 was
considered statistically significant.

\textbf{4. Results}

4.1 Status of hemolytic episodes with SARS-CoV-2 Omicron infection

A total of 20 PNH patients diagnosed with SARS-CoV-2 Omicron infection
were enrolled in this study. 6 (30\%, 6/20) were male, 14 (70\%, 14/20)
were female and the median age was 37 years (range 15--75years). Eleven
patients (55\%, 11/20) presented classical PNH and nine patients (45\%,
9/20) were diagnosed with PNH/AA. They accepted glucocorticoid
maintenance and transfusion in the past. None of them were treated with
complement inhibitors. The median time to episode occurred is three days
after SARS-CoV-2 Omicron infection (1-5 days).

10 patients (50\%, 10/20) complained of hemoglobinuria. Other 10
patients (50\%, 10/ 20) presented with worsen fatigue and cytopenia.
Although no thrombotic event happened, D-dimer (median 2.55mg/L, range
0.57-- 4.47mg/L) was elevated in 10 patients, and all of them received
prophylactic low molecular weight heparin.

Mild pulmonary hypertension was found in two patients (32mmHg and
35mmHg, respectively). The glomerular filtration rate in five patients
(25\%, 5/20) was lower than 60ml/min/1.73m\textsuperscript{2}. One
patient underwent hemodialysis due to acute renal failure.

The level of LDH (2555U/L vs 1542U/L, 9.43\selectlanguage{ngerman}×ULN vs 5.62×ULN, p=0.011),
total bilirubin (TBIL) (49.56\selectlanguage{greek}μ\selectlanguage{english}mol/L vs 28.92 \selectlanguage{greek}μ\selectlanguage{english}mol/L, p=0.031) and
indirect bilirubin (IBIL) (29.31 \selectlanguage{greek}μ\selectlanguage{english}mol/L vs 17.8\selectlanguage{greek}μ\selectlanguage{english}mol/L, p=0.017) were
higher than the most severe hemolysis previously recorded. Anemia became
worsened compared to the previous period --- RBC (2.17\selectlanguage{ngerman}×1012/L vs
2.42×1012/L, p=0.356), Hb (66 g/L vs 71 g/L, p=0.459) (Table 1). The
decrease in GFR was nearly statistically significant\selectlanguage{english}(113.65
ml/min/1.73m\textsuperscript{2} vs 118.3
ml/min/1.73m\textsuperscript{2}, p=0.055\selectlanguage{english}).

4.2 Efficacy of eculizumab

5 patients were administrated with eculizumab. After eculizumab
treatment, hemolysis was controlled (LDH 13.53xULN vs 3.38xULN,
p=0.028), and RBC count (1.96x10\textsuperscript{12}/L vs
2.45x10\textsuperscript{12}/L, p=0.01), and level of hemoglobin (64 g/L
vs 83 g/L, p=0.005) were also improved significantly (Table 2) (Figure
1). The improvement in IBIL was nearly statistically significant (31.7
1\selectlanguage{greek}μ\selectlanguage{english}mol/L vs 20.69 \selectlanguage{greek}μ\selectlanguage{english}mol/L, p=0.057). The elevated D-dimers in two patients
also decreased significantly after treatment--- 4.04 mg/L vs 1.47 mg/L,
2.15 mg/L vs 1.37 mg/L, respectively. During hemolysis, one patient had
a high IL-6 serum concentration, 31.29 times higher than the upper limit
of the normal ---165.83 pg/mL while after eculizumab treatment IL-6
drops to 4.98 pg/mL. Because of emergency use, the patients treated by
eculizumab could not be vaccinated against Neisseria meningitidis and
Streptococcus pneumoniae in advance, but infection did not occur with
the whole course of penicillin prophylaxis.

4.3 Outcomes of COVID-19 and PNH

In our study, 12 of 20 (60\%) were hospitalized. 2 (2/20, 10\%) patients
developed severe COVID-19---one with severe viral pneumonia but
recovered after two doses of eculizumab with oxygen support and the
other with acute renal failure but recovered after hemodialysis.

Of the 5 patients using eculizumab, 2 were not in HDA status. But 13 of
the other 15 patients remained in HDA status during the second week
after infection with SARS-CoV-2 Omicron.

\textbf{5. Discussion}

PNH is a complement-mediated hemolytic
anemia\textsuperscript{{[}1{]}}and SARS-CoV-2 activates complement and
inflammatory factor storm\textsuperscript{{[}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\textsuperscript{{[}5,6{]}}and on the other hand, coronavirus
infection activates monocyte, macrophage, and dendritic cell, then
releases IL-6 and amplifies cytokine cascade\textsuperscript{{[}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.\textsuperscript{{[}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\textsuperscript{{[}2,21,22{]}}. In our
cohort, there were 5 patients with severe renal function decline
(glomerular filtration rate [?] 60ml/min/1.73m\textsuperscript{2}), even
one accepted hemodialysis.

C5 inhibitors have been recommended as the first line treatment for
PNH\textsuperscript{{[}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\textsuperscript{{[}24--27{]}}. Meanwhile, eculizumab has been
used to treat severe COVID-19 \textsuperscript{{[}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\textsuperscript{{[}29{]}}. After eculizumab stops the cleavage of
C5, the production of C5a is reduced. In an Annane's
study\textsuperscript{{[}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\textsuperscript{{[}31{]}} administrated eculizumab to
4 patients with severe COVID-19, their inflammatory markers declined and
recovery time was cut short. The
literature\textsuperscript{{[}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\selectlanguage{ngerman}×ULN vs 2.04×ULN, p\selectlanguage{english}<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.

\textbf{6. Acknowledgements}

We thank everyone involved in medical care and epidemic prevention for
their efforts during the COVID-19 pandemic. We thank everyone at Jiangsu
Provincial People's Hospital, the second people's hospital of
Lianyungang, Wuxi People's Hospital affiliated to Nanjing Medical
University

and Funing People's Hospital. We thank patients' understanding and
support for study.

\textbf{7. Data availability statement}

This article contains all the data generated or analyzed during this
study. Any further queries should be directed to the corresponding
author.

\textbf{8. Funding}

This work was supported by the National Natural Science Foundation of
China (81900109), Jiangsu Innovative Talents Subsidized Project
{[}(2019)30357{]}, Jiangsu Province Capability Improvement Project
through Science, Technology and Education (ZDXK202209) and 2022 Research
Development Fund of Kangda College of Nanjing Medical University
(KD2022KYJJZD045).

\textbf{9. Conflict of interest}

The authors declare no conflict of interest.

\textbf{10. Author contributions}

Research idea and study design: Hui Yang and Xingxing Chai. Data
collection: Hui Yang, Yuemin Gong, Xinyu Zhang, Lingling Wang, Jinge Xu,
Dan Xu. Data analysis: Hui Yang, Xingxing Chai and Xiaoyu Chen. Wrote
the manuscript: Hui Yang and Xingxing Chai. Supervision or mentorship:
Xin Zhou, Jianyong Li and Guangsheng He.

\textbf{11. Ethics statement}

This study was approved by the First Affiliated Hospital of Nanjing
Medical University ethics committee (Ethics approval document
2020-SR-421) conducted following the principle of the Helsinki
Declaration.

\textbf{12. Consent to participate}

Informed consent was obtained from all individual participants included
in the study.

\textbf{13. Consent to publication}

The authors confirms that the work has not been published before and the
publication has been approved by all co-authors.

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\textbf{Table 1 Comparison of current hemolysis with the most severe
hemolysis previously}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Current Omicron-induced hemolysis & Previous most drastic hemolysis &
P value\tabularnewline
\midrule
\endhead
Gender, n (\%) & Gender, n (\%) & Gender, n (\%) & /\tabularnewline
Male & 5 (29.41\%) & 5 (29.41\%) &\tabularnewline
Female & 12 (70.59\%) & 12 (70.59\%) &\tabularnewline
Median age (range) (years) & 38 (17, 73) & 38 (17, 73) &
/\tabularnewline
Classification, n (\%) & Classification, n (\%) & Classification, n (\%)
& /\tabularnewline
Classical & 10 (58.82\%) & 10 (58.82\%) &\tabularnewline
Combined with BMD & 7 (41.18\%) & 7 (41.18\%) &\tabularnewline
Subclinical & 0 (0\%) & 0 (0\%) &\tabularnewline
WBC (\selectlanguage{ngerman}×109/L) (range) & 3.11 (1.54, 10.54) & 3.64 (2.23, 9.58) &
0.796\tabularnewline
ANC (\selectlanguage{ngerman}×109/L) (range) & 2.24 (0.68, 9.35) & 1.8 (0.5, 7.81) &
0.636\tabularnewline
RBC (\selectlanguage{ngerman}×1012/L) (range) & 2.17 (1.14, 3.28) & 2.42 (1.37, 3.27) &
0.356\tabularnewline
Hb (g/L) (range) & 66 (38, 88) & 71 (47, 94) & 0.459\tabularnewline
BPC (\selectlanguage{ngerman}×109/L) (range) & 140 (22, 306) & 141 (12, 310) &
0.446\tabularnewline
LDH (U/L) (range) & 2555 (672,8482) & 1542 (733, 4157) &
0.011\tabularnewline
LDH (\selectlanguage{ngerman}×ULN) (range) & 9.43 (2.48, 31.3) & 5.62 (2.7, 15.34) &
0.011\tabularnewline
Creatinine (\selectlanguage{greek}μ\selectlanguage{english}mol/L) (range) & 68 (35.8, 186) & 62 (38.3, 215) &
0.113\tabularnewline
GFR (ml/min/1.73m2) (range) & 113.65 (32.44, 136.3) & 118.3 (27.23,
143.59) & 0.055\tabularnewline
BUN (mmol/L) (range) & 4.59(2.4, 10.38) & 4.76(2.2, 11) &
0.623\tabularnewline
TBIL (\selectlanguage{greek}μ\selectlanguage{english}mol/L) (range) & 49.56(11, 104.3) & 28.92(12.4, 94.1) &
0.031\tabularnewline
IBIL (\selectlanguage{greek}μ\selectlanguage{english}mol/L) (range) & 29.31(7.5, 84.9) & 17.8(10.1, 72.2) &
0.017\tabularnewline
D-dimer (mg/L) (range) & 0.6(0.31, 4.15) & 0.59(0.12, 6.76) &
0.695\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BMD, bone marrow disease; WBC, white blood cell count;
ANC, absolute neutrophil count; RBC, red blood cell count; Hb,
hemoglobin; BPC, blood platelet count; LDH, lactate dehydrogenase; ULN,
upper limits of normal, GFR, glomerular filtration rate; BUN, blood urea
nitrogen; TBIL, total bilirubin; IBIL, indirect bilirubin

\textbf{Table 2 Improvement the of hemolysis by eculizumab}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Before eculizumab therapy & After eculizumab therapy & P
value\tabularnewline
\midrule
\endhead
Gender, n (\%) & & & /\tabularnewline
Male & 1 (20\%) & 1 (20\%) &\tabularnewline
Female & 4 (80\%) & 4 (80\%) &\tabularnewline
Median age (range) (year) & 59 (26, 67) & 59 (26, 67) & /\tabularnewline
Classification, n (\%) & & & /\tabularnewline
Classical & 3 (60\%) & 3 (60\%) &\tabularnewline
Combined with BMD & 2 (40\%) & 2 (40\%) &\tabularnewline
Subclinical & 0 (0\%) & 0 (0\%) &\tabularnewline
WBC (\selectlanguage{ngerman}×10\textsuperscript{9}/L) (range) & 2.85 (2.27, 10.54) & 3.09 (2.1,
5.64) & 0.504\tabularnewline
ANC (\selectlanguage{ngerman}×10\textsuperscript{9}/L) (range) & 2.24 (0.74, 9.35) & 1.79 (0.17,
4.62) & 0.686\tabularnewline
RBC (\selectlanguage{ngerman}×10\textsuperscript{12}/L) (range) & 1.96 (1.32, 2.47) & 2.45
(2.24, 2.66) & 0.01\tabularnewline
Hb (g/L) (range) & 64 (43, 80) & 83 (67, 87) & 0.005\tabularnewline
BPC (\selectlanguage{ngerman}×10\textsuperscript{9}/L) (range) & 74 (50, 306) & 81 (38, 319) &
0.448\tabularnewline
LDH (U/L) (range) & 3667 (1075.1, 4887) & 915 (460, 1822) &
0.028\tabularnewline
GFR (ml/min/1.73m\textsuperscript{2}) (range) & 84.47 (36.31, 130.54) &
85.53 (42.25, 129) & 0.742\tabularnewline
IBIL (\selectlanguage{greek}μ\selectlanguage{english}mol/L) (range) & 31.71 (14.7, 83.5) & 20.69 (4.3, 24.1) &
0.057\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1} Eculizumab improved the RBC count
(1.96\selectlanguage{ngerman}×10\textsuperscript{12}/L vs 2.45×10\textsuperscript{12}/L,
p=0.01), levels of Hb (64 g/L vs 83 g/L, p=0.005) and LDH (13.53×ULN vs
3.38×ULN, p=0.028) significantly.

\textbf{Hosted file}

\verb`figure.docx`  available at \url{https://authorea.com/users/724224/articles/708310-severe-hemolytic-exacerbations-of-chinese-pnh-patients-infected-sars-cov-2-omicron}

\selectlanguage{english}
\FloatBarrier
\end{document}

