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\begin{document}

\title{Which immunosuppressive drug is preferred in the treatment of toxic
epidermal necrolysis during COVID-19 outbreak?}



\author[1]{Saeedeh  Farajzadeh}%
\author[2]{Najmeh Ahramiyanpour}%
\affil[1]{Kerman University of Medical Sciences}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{June 02, 2024}


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\selectlanguage{english}
\begin{abstract}
Toxic epidermal necrolysis (TEN) is a serious drug reaction. Its proper
cure would be challenging during COVID-19 outbreak because of a dilemma
regarding selecting the immunosuppressive drug. In this case
presentation, we report a case of TEN who treat successfully with
cyclosporine during COVID-19 outbreak in a referral COVID-19 hospital.%
\end{abstract}%



\sloppy


\textbf{Title:} Which immunosuppressive drug is preferred in the
treatment of toxic epidermal necrolysis during COVID-19
outbreak?\textbf{Authors:} Saeedeh Farajzadeh \textsuperscript{1} M.D.,
Najmeh Ahramiyanpour \textsuperscript{1} M.D.\textbf{Affiliations:}

Department of Dermatology, Afzalipoor Hospital, Kerman University of
Medical Sciences, Kerman, Iran

\textbf{Corresponding Author:} Najmeh Ahramiyanpour, M.D., Department of
Dermatology, Afzalipoor Hospital, Kerman University of Medical Sciences,
Kerman, Iran. Tel: +989173703643, E-mail:
najmeh.pour@gmail.com\textbf{Abstract:} Toxic epidermal necrolysis (TEN)
is a serious drug reaction. Its proper cure would be challenging
especially during COVID-19 outbreak because of a dilemma regarding
selecting the immunosuppressive drug. In this case presentation, we
report a case of TEN who treat successfully with cyclosporine during
COVID-19 outbreak in a referral COVID-19 hospital.\textbf{Keywords:}
Toxic epidermal necrolysis, COVID-19, immunosuppressant, cyclosporine,
calcineurin inhibitors.\textbf{Introduction:} Toxic epidermal necrolysis
(TEN) is a rare drug reaction associated with high mortality rate
\textsuperscript{{[}1{]}}. TEN presents with erythematous and dusky
maculopapular rash that progresses to flaccid blisters, epidermal
erosion, necrosis and skin detachment. \textsuperscript{{[}1-3{]}} Drug
hypersensitivity is the most common cause of TEN. TEN can be associated
with infections, systemic diseases, malignancies and autoimmune
conditions\textsuperscript{{[}4-6{]}}. While there is no gold standard
treatment for TEN, systemic corticosteroid, intravenous immunoglobulin
(IVIG), cyclosporine, and tumor necrosis factor (TNF) inhibitors are
optional drugs for the management of TEN \textsuperscript{{[}1-4{]}}.
Management of TEN is always challenging especially during COVID-19
outbreak because use of the immunosuppressive drugs might have both
beneficial and harmful effects on COVID-19
course\textsuperscript{{[}7{]}}. As we know there is not any study to
compare the effects of different immunosuppressive drugs such as
cyclosporine or prednisolone on TEN patients who are predispose to
COVID-19. Selecting an immunosuppressive drug in a patient with TEN is
challenging and troublesome. Here, we report a case of TEN who treat
successfully with cyclosporine during COVID-19 outbreak in a referral
corona hospital.\textbf{Case Synopsis:} A 24-year-old man came into the
emergency department with a 4-days history of painful generalized dusky
rash on his body associated mucosal surface involvement. His past
medical history was positive for bipolar mood disorder. He was on
carbamazepine and valproate sodium for the last two years and
lamotrigine during the last two weeks. On arrival to the emergency room,
the patient was oriented and his vital signs were stable (Bp: 130/80
mmHg, pulse rate: 80 beats per minute, temperature: 36.9, respiratory
rate: 16 per minute, and O2 saturation: 99\%). Physical examination
described more than 50\% of body surface area involvement. skin lesions
were as painful, dusky and purpuric macules and patches of irregular
size and shape on the trunk and extremities. Flaccid blisters with
serosal fluid and detached epidermal surface on the neck and chest
detected (Figure 1). The Nikolsky sign was positive. Hemorrhagic crust,
lips erosion, erythema of buccal mucosa, conjunctivitis, and facial
edema is seen He also complained of photophobia and painful dysphagia.
His SCORTEN (SCORs of Toxic Epidermal Necrolysis) was 2. Laboratory
tests revealed exclusively a mild leukopenia while other results were
negative or in normal ranges: potassium: 4 mmol/L, serum creatinine: 1.1
mg/dl, serum urea: 12 mmol/l, serum bicarbonate: 22 mmol/l, serum
glucose: 10 mmol/l, white blood cells: 3.5 \selectlanguage{greek}μ\selectlanguage{english}l, hemoglobin: 13.7 g/dL,
platelets: 420,000, aspartate transaminase: 24 U/L, alanine
aminotransferase: 16 U/L, albumin: 36 g/L. The patient was admitted with
a diagnosis of TEN into the dermatology ward of Afzalipour hospital, of
Kerman University of Medical Sciences, Iran that also is a referral
COVID-19 center hospital in Kerman. Lamotrigine was stopped and he was
managed with supportive care, wound care, thrombotic prophylaxis. As
corticosteroid is rather controversial during covid-19 outbreak and IVIG
which is the first choice of treatment was not afforded for the patient,
we worked up to start cyclosporine. The blood pressure, electrolytes and
cholesterol were normal. Therefore, we started cyclosporine 4mg/kg/day.
Within the first 36 hours after starting cyclosporine, the patient
showed a dramatic response to the treatment. No new bullae formation was
detected and there was a reduction in erythema and erosion. The evidence
of re-epithelization was observed on the third day and the Nikolsky sign
became negative (Figure 2). Meanwhile, blood pressure and kidneys'
function were normal. Eventually, he discharged after one week with
prescription of the cyclosporin 2mg/kg/day for another one week. He
informed respecting the possibility of relapse. One week later the
patient referred to our clinic. Skin and mucosal lesions improved and
the cyclosporine therapy was discontinued.\textbf{Discussion:} Although
systemic corticosteroid, IVIG, cyclosporine, and TNF inhibitors are
optional drugs in managing TEN, it is still controversial about the gold
standard treatment for TEN\textsuperscript{{[}1, 4{]}}. During COVID-19
outbreak, the management of TEN has encountered an additive challenge.
Because use of the immunosuppressive drug, especially like prednisolone
and cyclosporine, are controversial \textsuperscript{{[}8{]}}. It seems
IVIG is the best option for the management of TEN, because IVIG is human
immunoglobulin and can strengthens the immune system
\textsuperscript{{[}9{]}}. An important issue in patients that IVIG is
not affordable, as it is the case in our patient, or is contraindicated,
is which one of immunosuppressive drugs can be use in the management of
TEN during covid-19 outbreak. As we know, there is not any study in
COVID-19 outbreak to compare the effects of different immunosuppressive
drugs such as cyclosporine and prednisolone on TEN patients. Use of
corticosteroid, which is the routine choice in treating TEN patients, is
controversial in COVID-19 outbreak especially amongst critical patients,
\textsuperscript{{[}10, 11{]}}. Albeit, it appears that corticosteroids
can be effective in severe COVID-19 cases, its routine use is not
supported in the literature\textsuperscript{{[}12-14{]}}. On the other
hand, due to the increasing mortality of seasonal epidemic of influenza
among corticosteroid users, administrating corticosteroids in TEN
patients would be of concern\textsuperscript{{[}15{]}}. Therefore, we
discarded the use of corticosteroid. We decided to start cyclosporine,
as it can be a good treatment option in COVID-19 outbreak due to several
reasons. First, in Kirchhof et al.\textsuperscript{{[}16{]}} cohort
study the relative mortality of TEN patients who were treated with
cyclosporine was lower than those with IVIg. Second, cyclosporine might
be associated with a rapid re-epithelialization
\textsuperscript{{[}17{]}} and reduce duration of hospitalization
\textsuperscript{{[}17, 18{]}}, which can reduce the risk of COVID-19 in
critical patients during hospitalization. Third, cyclosporine can
inhibit influenza A virus \textsuperscript{{[}19{]}}. forth, in-vitro
studies showed that cyclosporine can inhibit immunophilin pathway and by
this way it can inhibit replication of coronavirus
\textsuperscript{{[}8, 19-22{]}}. Fifth, COVID-19 mortality is highly
linked to the cytokine storm and cyclosporine can be beneficial during
the inflammatory phase of COVID-19\textsuperscript{{[}21, 22{]}}. Sixth,
Cavagana et al.\textsuperscript{{[}22{]}} reported that clinical course
of COVID-19 patients on calcineurin inhibitors (CNIs) is generally mild
with a low risk of superinfection. Finally, although cyclosporine is an
immunosuppressant agent, infections are not one of its common side
effects \textsuperscript{{[}23{]}}.\textbf{Conclusion:} IVIG is the best
treatment option in the management of TEN during COVID-19 outbreak. For
those IVIG is contraindicated or is not affordable, cyclosporine can be
a better choice than other immunosuppressant drugs. As, patients on
cyclosporine can benefit its antiviral effects and have a shorter
hospital admission stay.\textbf{Potential conflicts of interest:} The
authors declare no conflicts of interest.\textbf{References:}

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\textbf{Figure legends:}Figure 1: On arrival skin lesions Figure 2:
Improved skin lesions at day 4 of admission after starting cyclosporine\selectlanguage{english}
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