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\begin{document}

\title{Severe hemolysis and vasoclusive crisis due to COVID-19 infection in a
Sickle Cell Disease patient improved after Red Blood Cells exchange}



\author[1]{Lina Okar}%
\author[1]{Mohamad Rezek}%
\author[1]{Amna Gamil}%
\author[1]{Yahya Mulkandathil}%
\author[2]{mohamed yassin}%
\affil[1]{Hamad Medical Corporation}%
\affil[2]{HMC  NCCCR}%


\vspace{-1em}



  
  \date{May 04, 2024}


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\begin{abstract}
As the clinical course of COVID-19 infection in SCD patients is not
clear, close monitoring is essential. We emphasize that RBC exchange
should be offered early to avoid possible deterioration. We present a
case of COVID-19 infection in a SCD patient causing severe hemolysis,
that improved after RBC exchange.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Sickle Cell disease (SCD) is one of the most common hemoglobinopathies,
it is due to mutation on the beta chain hemoglobin that causes deformity
in red blood cells (RBCs) shape. The sickle shape of RBCs affects their
function leading to hypoxia and sickle cell crisis including hemolysis
when triggers like infections happen{[}1{]}.

With the widely spread of Coronavirus infection, special population
needs close monitoring as the exact clinical course and prognosis is not
well known yet{[}2{]}. It was suggested that patients with SCD might
present with vaso-occlusive crisis (VOCs) or acute chest syndrome (ACS)
as first presentation of COVID-19 infection{[}3{]}. The overlap between
ACS and COVID-19 pneumonia made this an interesting area for
research{[}4{]}. However, hemolytic crisis was not very common among
previously reported cases{[}5{]}.

Management plan for patients with SCD presenting with COVID-19 infection
is not final yet{[}6{]}. However, following the recognized guideline for
painful crisis, ACS and hemolysis treatment is essential. Previous
studies showed the remarkable favorable impact of RBCs exchange in the
course of COVID-19 infection among patients with
hemoglobinopathies{[}7{]}. We believe it might prevent deterioration if
offered earlier in the course of the disease. Treatment with hydroxyurea
might or might not affect the susceptibility of COVID-19
infection{[}6{]}. Admission to the hospital is also required even if the
cases are asymptomatic or mild because acute complications seems to
happen after few days of infection.

Here we report a case of 48-year-old SCD patient compliant with HU who
underwent post travel screening for COVID-19 infection and tested
positive, admission and close monitoring were offered, he developed
painful crisis and sever hemolysis after few days thus needed ICU
admission and improved after RBCs exchange.

\textbf{Case presentation:}

A 48-year-old gentleman came back from a travel abroad and was tested
positive for COVID-19 while screening him as part of post travel
protocol. despite being asymptomatic, COVID-19 PCR from Nasopharyngeal
swab was positive with a CT value 15 on 15th November 2020. His past
medical history was remarkable for Diabetes mellitus type II, on
metformin and gliclazide, and Sickle Cell Disease on hydroxyurea 500 mg
BID. He had no previous surgeries. He has a history of recurrent pain
crisis; most of them were managed in the Emergency department. His last
blood transfusion in 2011. He has hypersplenism and avascular necrosis
of the left shoulder, on conservative therapy. His last painful crisis
was on 9the October 2020, for which he was managed with IV fluids, pain
management, and discharged later in the same day. After testing positive
for coronavirus, Labs (as shown in table 1) and Chest Xray (as shown in
table 2) were ordered.

He was started on treatment; Favipiravir + Amoxicillin/Clavulanic acid
for COVID-19 infection pneumonia, plus enoxaparin for deep vein
thrombosis (DVT) prophylaxis. On day 4, he started to have intolerable
back pain. Labs were repeated (Table 1) and the patient was transferred
to ICU to manage his pain crisis. Repeated Chest X ray showed Interval
progression of bilateral basal atelectasis and faint infiltrates more on
the right side, which worsened later. Amoxicillin/Clavulanic acid was
changed to Piperacillin/Tazobactam, hemoglobin was low (5.4) with
hemolysis picture, Exchange transfusion was done for the patient, with 6
PRBCs. Dexamethasone was also added. The patient became stable after the
transfusion and pain management. Another Chest x ray done 2 days later
showed incomplete resolution of the widespread consolidation distributed
over both lung fields when compared to a chest x-ray done 2 days ago his
condition was improving. A repeated HbS was 22. 3 days later, he was
discharged, with instructions about safety netting and home isolation,
with resumption of his home medications. Throughout his stay in the
Hospital, he did not need high oxygen flow nor intubation (the highest
oxygen requirement was 1 -- 2 L nasal cannula for one day).

\textbf{Discussion:}

Coronavirus family has multiple strain, the latest novel virus caused
the coronavirus disease 2019 (COVID-19) was called severe acute
respiratory syndrome coronavirus 2 (SARS-CoV2){[}8{]}. Data suggested
that this new virus acts through specific receptors on the erythrocytes
including ACE2, CD147 and CD26 causing pathological interaction with
hemoglobin molecule and sometimes resulting in hemolysis{[}9{]}.

Sickle cell disease (SCD) is a common inherited hemoglobinopathy. It is
due to a single amino acid substitution in the sixth residue of beta
globin subunit, this pathological change results in hemoglobin S (HBS).
HBS is an abnormal hemoglobin that causes structure deformity in red
blood cells (RBCs) changing it to crescent or sickle shape{[}10{]}.

SCD complications are categorized into acute and chronic. The acute
presentations are described as time-dependent which mean there should be
high suspension to diagnose them early and offer appropriate evaluation
and treatment, thus improving the prognosis. These complications include
ACS, vaso-oclusive crisis (VOC), acute anemia, hepatobiliary
complications, Stroke, splenic sequestration, and priapism. Whereas
chronic complications are pulmonary hypertension, hepatopathy due to
iron overload, avascular necrosis, retinopathy, renal disease and
peripheral ulcers {[}10{]}.

Hemolytic crisis is defined as drop of more than or equal to 2 g/dL from
the baseline patient's hemoglobin value. Acute anemia might present as a
single presentation or in accordance with splenomegaly or hepatomegaly
{[}10{]}. However, when aplastic crisis diagnosis is made it is
essential to rule out any possibility of delayed hemolytic transfusion
reaction as more cautions is required if RBCs transfusion is the
plan{[}1{]}.

ACS is the most cause of hospital admission and mortality among SCD
patients. The trigger for this condition is often infection, mostly
bacterial and sometimes viral. Both ACS and COVID-19 pneumonia share a
similar clinical feature such as fever, cough, shortness of breath and
chest pain. Evidence from previous studies suggests that SARS-CoV2 could
trigger ACS{[}11{]}. Due to this overlap between ACS and pneumonia, it
is important to recognize the effect of COVID-19 in SCD patients{[}7{]}.

Generally, patients with chronic comorbidities like diabetes,
hypertension, lung diseases and cardiovascular diseases are at increased
risk of COVID-19 complications. Noticeably, patients suffering from SCD
have a lot of complications as mentioned before. In the presence of this
multi-organ dysfunction,COVID-19 infection may trigger ACS or
VOC{[}12{]}. Also, the abnormality in endothelial and procoagulants
increase the risk of thromboembolic events, thus providing prophylactic
anticoagulants is essential {[}2{]}.

A recent retrospective study conducted in Bahrain reviewed 387 patients
with SCD screened for COVID-19 infection, 6 patients had COVID-19
infection, all patients had favorable outcome, 3 patients were
asymptomatic and 3 had mild to moderate symptoms. The study concluded
that there is no difference among patients with SCD and non-SCD patients
in term of COVID-19 clinical course, viral clearance, and infection
rate. Also, no remarkable increased risk for SCD crisis{[}9{]}. In
contrast to our case where the patient had asymptomatic presentation
then developed acute painful episode with severe hemolysis. A case
series of 10 patients with SCD infected with COVID-19 in UK also showed
a good prognosis as 9 out of 10 patients recovered fully. Interestingly,
7 patients received blood transfusion (4 RBCs exchange and 3 simple
transfusion). It is worthy to notice that one patients in this series
died and she didn't receive blood transfusion as she had delayed
hemolytic transfusion reaction as contraindication{[}13{]}. Another case
series for 4 patients with SCD and COVID-19 infection showed that all
patient presented with VOCs and had mild course, only one patient
deteriorated and needed Intensive Care Unit (ICU) admission where the
patient received RBCs exchange and improved remarkably. This case series
suggest good prognosis of COVID-19 infection and emphasize on the
importance of early RBCs exchange. However, none of the four patients
mentioned in this case had acute hemolytic anemia{[}3{]}. Nino
Balanchivadze et al published one center study that retrospectively
reviewed 24 patients with SCD anemia or trait infected with COVID-19, 4
patients had SCD, none of the included patients was taking hydroxyurea
(HU) the author concluded that patients with SCD generally had
unremarkable course of disease, low possibility of ICU admission and
intubation but hospitalization period might be longer {[}6{]}. It has
been hypothised that COVID-19 infection in patients with SCD precipitate
hemolysis because it affects hemoglobin beta chain, whereas others
suggested that patients with Thalassemia and SCD have immunity against
COVID-19 infection due to the defect in hemoglobin beta chain
{[}9{]}{[}14{]}{[}15{]}. The physiology behind this hypothesis as
published in one paper is that viral proteins like ORF1ab, ORF10 and
ORF3a might cause porphyrin-associated iron molecule in heme to
separate, this complex is located in the beta 1 chain, resulting in less
amount of Oxygen being carried by the hemoglobin in the blood
stream{[}15{]}. Patients with SCD as mentioned have mutation in beta
chain hemoglobin, whether this plays a role in the protection against
COVID-19 infection or not is still an area of research.

Red blood cells exchange is one way to treat severe ACS, a pervious data
suggested its use in the case of severe COVID-19 pneumonia overlapping
with ACS in patients with SCD. Moreover, it was noticed that whenever
RBCs exchange offered earlier, the prognosis and clinic course were
better{[}7{]}{[}3{]}. In our case the patient improved after the red
blood cells exchange and we suggest that it might play a role in the
prevention of painful episode and hemolysis crisis progression if
offered earlier in the course of infection.

While RBCs exchange form an important component in the acute management
plan of SCD crisis, hydroxyurea is the mainstone in the maintenance
therapy. However, it is not recognized yet if compliance with this
therapy affects the presentation of COVID-19, data in this regard are
conflicting, one retrospective study screened 40 patients with SCD for
coronavirus infection, only 24 were positive and all of them were not on
HU, thus the authors suggested that HU in treatment might have a
protective effect against the virus. This was not the case in our
patients as he was on long term HU treatment and still had moderate
course of illness{[}6{]}.

Admission of Patients with SCD and COVID-19 infection is essential even
if they are asymptomatic as they can develop acute painful episodes and
hemolytic crisis later in the course of infection like our reported
case. Although no final guideline is available now for the treatment of
SCD patients with COVID-19 infection, we believe that offering RBCs
exchange is an essential part of managing those population and we
recommend to offer it as earlier as possible to avoid deterioration.
Finally, the role of HU in the clinical course of coronavirus infection
is still not defined and form an area for further research.

\textbf{Conclusion:}

Even though previous studies suggested favorable outcome for COVID-19
infection among patients with hemoglobinopathies. SCD remains at risk of
acute deterioration even in the absence of any COVID-19 characteristic
symptoms. Thus, close monitoring is necessary. ACS was mentioned before
as a presentation of COVID-19 infection in those patients, yet acute
hemolysis crisis should also be in mind. Offering RBCs exchange and
admitting patients to the ICU until they are stable plays a role in
improving prognosis and the earlier this is done the better the outcome.
We believe that more studies are needed to form a clear guideline
regarding RBCs exchange role and time of administration and the role of
HU compliance on the course of infection\textbf{.}

\textbf{Acknowledgment}

We would like to acknowledge the Hematology section/ oncology
department, Intensive care unit as well as Family medicine residency
program at Hamad Medical Corporation for their support.

Open access fees offered by Qatar National Library (QNL).

\textbf{Statement of Ethics}

Consent was obtained from the patients.

Case approved by HMC Medical Research center

\textbf{Declaration of interest}

The authors report no conflicts of interest.

\textbf{Data availability statement:}

All data related to the article are available upon request.

\textbf{Authors contribution:}

Lina Okar and Mohamad Rezek wrote the manuscript.

Amna Gmeil, Yahya Mulikandayhil, and Mohamed A. Yassin reviewed the
literature and reviewed the manuscript.

\textbf{References:}

{[}1{]} Wali Y, Kini V, Yassin MA. Distribution of sickle cell disease
and assessment of risk factors based on transcranial Doppler values in
the Gulf region. Hematology. 2020 Jan 1;25(1):55-62.

{[}2{]} Menapace LA, Thein SL. COVID-19 and sickle cell disease.
Haematologica 2020;105:2501--4.
https://doi.org/10.3324/haematol.2020.255398.

{[}3{]} de Sanctis V, Canatan D, Corrons JL, Karimi M, Daar S, Kattamis
C, Soliman AT, Wali Y, Alkindi S, Huseynov V, Nasibova A. Preliminary
Data on COVID-19 in patients with hemoglobinopathies: A multicentre
ICET-A study. Mediterranean Journal of Hematology and Infectious
Diseases. 2020;12(1).

{[}4{]} Beerkens F, John M, Puliafito B, Corbett V, Edwards C, Tremblay
D. COVID-19 pneumonia as a cause of acute chest syndrome in an adult
sickle cell patient. Am J Hematol 2020;95:E154--6.
https://doi.org/10.1002/ajh.25809.

{[}5{]} Chakravorty S, Padmore-Payne G, Ike F, Tshibangu V, Graham C,
Rees D, et al. COVID-19 in patients with sickle cell disease -- A case
series from a UK tertiary hospital. Haematologica 2020;105:2691--3.
https://doi.org/10.3324/haematol.2020.254250.

{[}6{]} Balanchivadze N, Kudirka AA, Askar S, Almadhoun K, Kuriakose P,
Fadel R, et al. Impact of COVID-19 Infection on 24 Patients with Sickle
Cell Disease. One Center Urban Experience, Detroit, MI, USA. Hemoglobin
2020. https://doi.org/10.1080/03630269.2020.1797775.

{[}7{]} Okar L, Aldeeb M, Yassin MA. The role of red blood cell exchange
in sickle cell disease in patient with COVID-19 infection and pulmonary
infiltrates. Clin Case Reports 2020:ccr3.3526.
https://doi.org/10.1002/ccr3.3526.

{[}8{]} Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C,
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SARS-CoV-2. Nat Microbiol 2020;5:536--44.
https://doi.org/10.1038/s41564-020-0695-z.

{[}9{]} AbdulRahman A, AlAli S, Yaghi O, Shabaan M, Otoom S, Atkin SL,
et al. COVID-19 and sickle cell disease in Bahrain. Int J Infect Dis
2020;101:14--6. https://doi.org/10.1016/j.ijid.2020.09.1433.

{[}10{]} Yassin MA, Soliman AT, de Sanctis V, Abdula MA, Riaz LM, Ghori
FF, Yousaf A, Nashwan AJ, Abusamaan S, Moustafa A, Kohla S. Statural
growth and prevalence of endocrinopathies in relation to liver iron
content (LIC) in adult patients with beta thalassemia major (BTM) and
sickle cell disease (SCD). Acta Bio Medica: Atenei Parmensis.
2018;89(Suppl 2):33.

{[}11{]} Sivalingam T, Inusa B, Doyle P, Oteng-Ntim E. COVID-19 and the
pulmonary complications of sickle cell disease. EJHaem 2020:545--7.
https://doi.org/10.1002/jha2.105.

{[}12{]} Sheha D, El-Shayeb M, Eid Y, Amin M, Saeed A, Abdou D, et al.
Unfolding of sickle cell trait by coronavirus disease 2019 (COVID-19)
infection. Br J Haematol 2020;191:e38--40.
https://doi.org/10.1111/bjh.17089.

{[}13{]} London S, London S. Ase eports 2020;105:2691--3.

{[}14{]} Torti L, Maffei L, Sorrentino F, De Fabritiis P, Miceli R,
Abruzzese E. Impact of SARS CoV-2 in hemoglobinopathies: a protective
mechanism being from Beta chain Hemoglobin defects? Mediterr J Hematol
Infect Dis 2020;12:e2020052. https://doi.org/10.4084/mjhid.2020.052.

{[}15{]} wenzhong liu, hualan L. COVID-19: Attacks the 1-Beta Chain of
Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism
2020. https://doi.org/10.26434/CHEMRXIV.11938173.V7.

\textbf{List of figure and table legends:}

Table.1 Laboratory results upon admission, deterioration and discharge.

Table 2. Chest Xrays.

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