10.5826/dpc.1203a146
Introduction: It has been reported that the use of oral isotretinoin may have positive and negative effects on the course of COVID-19 and the risk of transmission.
Objectives: The purpose of our study is to evaluate how our patients that took oral isotretinoin during the pandemic were affected by COVID-19.
Methods: The clinical processes of moderate-to-severe acne vulgaris patients between March 2020 and February 2021 were evaluated.
Results: Of 102 moderate-to-severe acne patients, 67 were using oral isotretinoin and 35 were using a topical treatment. Of 27 patients who tested positive for COVID-19, 16 (59.3%) were using oral isotretinoin and 11(40.7%) were using topical treatment, there was no statistical difference in the rates of COVID-19 positivity between the two groups (P = 0.412). The rates of positive tests for COVID-19 were similar between contacted patients of two groups (P = 0.391). Loss of smell/taste was lower in patients using oral isotretinoin compared to patients receiving topical treatment (46.7% and 72.7%, respectively.). Headache symptoms were less common in patients using oral isotretinoin (P = 0.047).
Conclusions: The use of oral isotretinoin did not cause an increase or decrease in the risk of COVID-19 transmission. The patients using oral isotretinoin had a lower incidence of taste/smell loss and headache.
text/xml
2160-9381
2111
en
Mehmet Kamil Mülayim
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
COVID-19; isotretinoin; smell; taste, headache.
How are Acne Vulgaris Patients Using Oral Isotretinoin Affected by COVID-19?
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-07-28
2021-10-18
2022-07-28
2022-09-13
e2022146
Dermatol Pract Concept
Introduction: It has been reported that the use of oral isotretinoin may have positive and negative effects on the course of COVID-19 and the risk of transmission.
Objectives: The purpose of our study is to evaluate how our patients that took oral isotretinoin during the pandemic were affected by COVID-19.
Methods: The clinical processes of moderate-to-severe acne vulgaris patients between March 2020 and February 2021 were evaluated.
Results: Of 102 moderate-to-severe acne patients, 67 were using oral isotretinoin and 35 were using a topical treatment. Of 27 patients who tested positive for COVID-19, 16 (59.3%) were using oral isotretinoin and 11(40.7%) were using topical treatment, there was no statistical difference in the rates of COVID-19 positivity between the two groups (P = 0.412). The rates of positive tests for COVID-19 were similar between contacted patients of two groups (P = 0.391). Loss of smell/taste was lower in patients using oral isotretinoin compared to patients receiving topical treatment (46.7% and 72.7%, respectively.). Headache symptoms were less common in patients using oral isotretinoin (P = 0.047).
Conclusions: The use of oral isotretinoin did not cause an increase or decrease in the risk of COVID-19 transmission. The patients using oral isotretinoin had a lower incidence of taste/smell loss and headache.
Mehmet Kamil Mülayim
2022/07/28
10.5826/dpc.1203a146
e2022146
Kahramanmaraş Sütçü İmam University, Faculty of Medicine, Department of Dermatology, Kahramanmaraş, Turkey
2160-9381
COVID-19; isotretinoin; smell; taste, headache.
en
e2022146
Kartal D, Yaşar M, Kartal L, Özcan I, Borlu M. Effects of isotretinoin on the olfactory function in patients with acne. An Bras Dermatol. 2017;92(2):191-195. DOI: 10.1590/abd1806-4841.20175483. PMID: 28538877. PMCID: PMC5429103.
How are Acne Vulgaris Patients Using Oral Isotretinoin Affected by COVID-19?
https://dpcj.org/index.php/dpc/article/download/2111/1667
             How are Acne Vulgaris Patients Using Oral
                Isotretinoin Affected by Covid-19?
      Mine Müjde Kuş1, Perihan Öztürk1, Tutku Bulut1, Celal Kuş2, Mehmet Enes Güner1,
                          Hülya Nazik1, Mehmet Kamil Mülayim1


1 Kahramanmaraş Sütçü İmam University, Faculty of Medicine, Department of Dermatology, Kahramanmaraş, Turkey
2 Kahramanmaraş Sütçü İmam University, Faculty of Medicine, Department of Family Medicine, Kahramanmaraş, Turkey



Key words: COVID-19, isotretinoin, smell, taste, headache
Citation: Kuş MM, Öztürk P, Bulut T, et al. How are Acne Vulgaris Patients Using Oral Isotretinoin Affected by Covid-19? Dermatol Pract
Concept. 2022;12(3):e2022146. DOI: https://doi.org/10.5826/dpc.1203a146
Accepted: December 26, 2021; Published: July 2022
Copyright: ©2022 Kuş et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: Concept: M.M.K., P.Ö., Design: M.M.K., P.Ö., C.K., Data Collection or Processing: T.B.,M.E.G., H.N., M.K.M., Analysis or
Interpretation: M.M.K., T.B., C.K., Literature Search: M.M.K., T.B., M.E.G., C.K., H.N., M.K.M., Writing: M.M.K., P.Ö.,M.E.G., H.N.,
M.K.M.
Corresponding author: Mine Müjde Kuş MD, Kahramanmaraş Sütçü İmam University, Department of Dermatology, Kahramanmaraş,
Turkey– 0 (507) 204 55 36 E-mail: mmujde_ozdemir@hotmail.com




  ABSTRACT             Introduction: It has been reported that the use of oral isotretinoin may have positive and negative
                       effects on the course of COVID-19 and the risk of transmission.
                       Objectives: The purpose of our study is to evaluate how our patients that took oral isotretinoin
                       during the pandemic were affected by COVID-19.
                       Methods: The clinical processes of moderate-to-severe acne vulgaris patients between March 2020
                       and February 2021 were evaluated.
                       Results: Of 102 moderate-to-severe acne patients, 67 were using oral isotretinoin and 35 were using
                       a topical treatment. Of 27 patients who tested positive for COVID-19, 16 (59.3%) were using oral
                       isotretinoin and 11 (40.7%) were using topical treatment, there was no statistical difference in the
                       rates of COVID-19 positivity between the two groups (P = 0.412). The rates of positive tests for
                       COVID-19 were similar between contacted patients of two groups (P = 0.391). Loss of smell/taste
                       was lower in patients using oral isotretinoin compared to patients receiving topical treatment (46.7%
                       and 72.7%, respectively.). Headache symptoms were less common in patients using oral isotretinoin
                       (P = 0.047).
                       Conclusions: The use of oral isotretinoin did not cause an increase or decrease in the risk of COVID-19
                       transmission. The patients using oral isotretinoin had a lower incidence of taste/smell loss and headache.




Original Article | Dermatol Pract Concept. 2022;12(3):e2022146                                                                         1
Introduction                                                     smoking, additional disease, additional treatments, pneu-
                                                                 mococcal and influenza vaccines, history of contact with
The coronavirus disease 19 (COVID-19) pandemic was de-           someone with COVID-19, whether patients had COVID-19,
clared by the World Health Organization in March 2020,           if they had, symptoms, treatment of choice (without treat-
and COVID-19 was the leading cause of death in many              ment, with medication at home, inpatient, in intensive care),
countries in 2020 [1]. No specific treatment has yet been        whether there were any sequelae.
found for COVID-19. In addition, as in other branches of            The obtained data were transferred to the computer.
medicine, the positive and/or negative effects of the drugs we   SPSS version 20.0 statistical package program was used
frequently use in dermatology on the course of COVID-19          in the analysis of the data. In the representation of the de-
remain unclear.                                                  scriptive statistics of the study, mean ± standard deviation
    Oral isotretinoin (13-cis-retinoic acid), a synthetic ana-   (SD), minimum-maximum values for
                                                                                              ​​ continuous numerical
log of vitamin A, is a first-generation retinoid used for the    variables, number (N), and percentage (%) were used for
treatment of acne vulgaris [2]. Nasal mucosal dryness is         categorical variables. Pearson chi-square and Fisher tests
observed in two-thirds of patients during oral isotretinoin      were used to compare categorical variables. According to
treatment [3].                                                   the normality evaluation made by Kolmogorov-Smirnov and
    The COVID-19 agent SARS-CoV-2 enters the human               Shapiro-Wilk tests; Parametric tests (paired sample t-test and
body through Angiotensin-Converting Enzyme-2 (ACE2) re-          t-test in independent groups) were used where continuous
ceptors. ACE-2 receptor expression was found in the basal        variables fit the normal distribution, and nonparametric
layer of nonkeratinized squamous epithelium in the nasal         tests (Mann-Whitney U test, Kruskal Wallis test) were used
mucosa. Isotretinoin has the effect of revealing ACE-2 recep-    where they did not fit the normal distribution. Statistical sig-
tors by causing nasal mucosa dryness and down-regulating         nificance level was accepted as P < 0.05.
ACE-2 receptors at the same time [4-6]. Biological pro-
cesses showing the pharmacological functions of vitamin A
                                                                 Results
for the treatment of COVID-19 have been defined and its
therapeutic mechanisms have been proven by signaling path-       The study included 102 moderate-to-severe acne patients aged
ways and it is thought that it can be used in the ­treatment     16 years and older who were followed up and treated in our
of COVID-19 [7]. However, some authors suggested that            clinic, using oral isotretinoin at a dose of 0.5-1mg/kg or topi-
COVID-19 is a hypervitaminosis of vitamin A and that all         cal treatment (topical retinoid or topical benzoylperoxide plus
drugs metabolized in the liver should be discontinued [8].       clindamycin) for at least two months. The clinical processes
                                                                 between March 2020 and February 2021 were evaluated.
Objectives                                                          Of the 67 patients who took oral isotretinoin during the
                                                                 pandemic, 52 (77.6%) were female and 15 (61%) were male,
According to these data in the literature, the effects of oral   mean age was 22.64 ± 6.62. Of 35 patients who used topical
isotretinoin, a vitamin A derivative, on the transmission and    treatment, 19 (54.3%) were female and 16 (61%) were male,
course of COVID-19 are not clear. The aim of our study           the mean age was 25.74 ± 8.16.
is to evaluate whether the use of oral isotretinoin affects         Twenty (74.1%) of the women and 7 (25.9%) of the men
the findings and symptoms of COVID-19 and the risk of            had a history of 27 COVID-19 positivity confirmed by poly-
transmission.                                                    merase chain reaction (PCR) in the nasal swab sample. The
                                                                 mean age of those who were positive for COVID-19 was
                                                                 24.88 ± 8.65, and there was no statistical difference in age
Methods
                                                                 and gender between those who were positive for COVID-19
Our study was a retrospective, descriptive and cross-sectional   and those who were negative for COVID-19 (P = 0.773 and
study. The clinical processes of moderate-to-severe acne vul-    P = 0.556, respectively). There was no statistical difference
garis patients aged 16 years and older who were followed up      between COVID-19 positive and COVID-19 negatives in
in our clinic between March 2020 and February 2021 and           terms of body mass index (BMI) average, smoking, addi-
using oral isotretinoin at a dose of 0.5-1mg/kg or topical       tional disease status, acne severity, pneumococcal and influ-
treatment (patients who do not accept systemic treatment),       enza vaccination status (Table 1).
were evaluated.                                                     Of the 27 patients who were positive for COVID-19, 16
    The data form was filled via file scanning, during con-      (59.3) were using oral isotretinoin and 11 (40.7%) were us-
trol examination, or by teleconference interview method.         ing a topical treatment. There was no statistical difference
In the data, form followings were questioned: patients age,      in COVID-19 positivity rates between patients using oral
gender, body mass index, treatment received, disease severity,   isotretinoin and patients using topical treatment (P = 0.412).



2                                                                    Original Article | Dermatol Pract Concept. 2022;12(3):e2022146
            Table 1. Sociodemographic and clinical characteristics of the acne vulgaris patients
                      (comparison between COVID-19-positive and negativepatients)
                                         COVID (+)                               COVID (-)
                                      mean é SD / N (%)                       mean é SD / N (%)                       P
 Age                                      24.88 ± 8.65                            23.28 ± 6.76                     0.773a
 BMI                                      23.25 ± 2.88                            22,64 ± 3.01                     0.201a
 Gender
 Male                                        7 (25.9)                               24 (32.0)                      0.556b
 Female                                     20 (74.1)                               51 (68.0)
 Smoking
 Yes                                         4 (14.8)                               15 (20.0)                      0.553b
 No                                         23 (85.2)                               60 (80.0)
 Additional disease
 Yes                                          1 (3.7)                                7 (9.3)                       0.678b
 No                                         26 (96.3)                               68 (90.7)
 Pneumococcal vaccine
 Yes                                          0 (0.0)                                4 (5.3)                       0.571b
 No                                          27 (100)                               71 (94.7)
 Influenza Vaccine
 Yes                                          1 (3.7)                                2 (2.7)                       0.607b
 No                                         26 (96.3)                               73 (97.3)

BMI = body mass index; SD = standard deviation.
a
 Mann-Whitney u test; bChi-squared or Fisher test for the comparison between the groups.




    Considering the rates of COVID-19 transmission after             to those using topical treatment (33.3%, 72.7%, respec-
contact with a COVID-19 positive person, COVID-19 posi-              tively), and there was a statistically significant difference
tivity in 14 of 29 patients, who were using oral isotretinoin        (P = 0.047). Taste\smell loss developed in 7 (46.7%) of
and came into contact with someone that tested positive for          16 COVID-19-positive patients using oral isotretinoin and
COVID-19 was confirmed by PCR test; COVID-19 positiv-                8 (72.7%) of 11 COVID-19-positive patients using topical
ity in 11 of 18 patients who were using the topical treatment        treatment, but there was no statistical difference (P = 0.246)
and came into contact with someone that tested positive for          (Table 2).
COVID-19 was confirmed by PCR test. There was no statis-                 Among the gastrointestinal (nausea, vomiting, abdom-
tical difference in the rates of being positive for COVID-19         inal pain) and respiratory symptoms (dyspnea, chest pain)
between contacted patients using oral isotretinoin and con-          associated with severe COVID-19, only shortness of breath
tacted patients using topical treatment (P = 0.391).                 was seen in 4 of our patients, other severe symptoms were
    Of the 27 patients who were positive for COVID-19,               not encountered. Dyspnea was observed in one patient
26 had symptoms, only one patient using oral isotretinoin            (6.7%) using oral isotretinoin and 3 (27.3%) patients receiv-
was asymptomatic, and there was no statistical difference            ing topical treatment. There was no statistically significant
in the rates of asymptomatic COVID-19 positivity between             difference between the two groups (P = 0.279).
patients using oral isotretinoin and patients using topical              No patient with COVID-19 needed hospitalization or
treatment (P = 0.593).                                               intensive care. Of the 16 COVID-19-positive patients who
    In order of frequency, the symptoms associated with              took oral isotretinoin, 10 recovered with medical treatment
COVID-19 were: taste\smell loss (15), headache (13), fever           at home and 6 without treatment. All 11 COVID-19-positive
(12), malaise (12), arthralgia\myalgia (11), cough (8), sore         patients who received topical treatment recovered with med-
throat (6), shortness of breath (4). There was no statisti-          ical treatment at home. There was no statistical difference
cal difference between patients using oral isotretinoin and          between the two groups in terms of the need for medical
patients using topical treatment in terms of the incidence           treatment (P = 0.054).
of symptoms other than headache. Headache was seen at                    Six of the patients with COVID-19 had partial taste\
a lower rate in patients using oral isotretinoin compared            smell loss that continued 1 month after they had the disease,



Original Article | Dermatol Pract Concept. 2022;12(3):e2022146                                                                   3
                    Table 2. Symptoms of COVID-19-positive patients (comparison between
                                oral retinoid users and topical treatment users)
 Symptom                         Oral retinoid users N (%)                Topical treatment users N (%)                    P
 Taste\smell loss                          7 (46.7)                                    8 (72.7)                          0.246
 Headache                                  5 (33.3)                                    8 (72.7)                          0.047
 Fever                                     7 (46.7)                                    5 (45.5)                          0.951
 Malaise                                   7 (46.7)                                    5 (45.5)                          0.951
 Artralgia/myalgia                         4 (26.7)                                    7 (63.9)                          0.109
 Cough                                     6 (40.0)                                    2 (18.2)                          0.395
 Sore throat                               4 (26.7)                                    2 (18.2)                          0.999
 Shortness of breath                        1 (6.7)                                    3 (27.3)                          0.279



2 (12.5%) were receiving oral isotretinoin and 4 (36%) were        thanks to their antioxidant and surfactant-mediated proper-
receiving topical treatment. There was no statistical differ-      ties [9]. We did not see ARDS symptoms in any of our pa-
ence between the patients using oral isotretinoin and the          tients. We could not associate this with the protective use of
patients using topical treatment in terms of taste/smell loss      oral isotretinoin, because our patients had a low mean age
sequela (P = 0.350).                                               and a very low rate of possible risk factors for ARDS.
                                                                      Gastrointestinal (nausea, vomiting, abdominal pain)

Discussion                                                         and respiratory symptoms (shortness of breath, chest pain)
                                                                   have been associated with severe COVID-19 [10]. Severe
It has been reported that the use of oral isotretinoin may have    COVID-19-associated dyspnea was seen at a lower rate in
positive and negative effects on the course of COVID-19 and        patients using oral isotretinoin compared to patients receiv-
the risk of transmission (Table 3).                                ing topical treatment 6.7%, and27.3%, respectively), we
    Mawson et al. found that COVID-19 disease is very s­ imilar    thought that this might be related to the protection of oral
to an endogenous form of a hypervitaminosis of vitamin A,          isotretinoin against severe COVID-19, but we did not detect
that liver damage caused by the SARS-CoV-2 virus causes            a statistically significant difference (P = 0.279).
toxic concentrations of retinoic acid and stored retinyl esters       ACE2 has been shown to be a functional receptor for
to be released into the circulation, including the lungs, heart,   SARS-CoV to enter host target cells [11]. ACE2 receptor ex-
blood vessels, and skin, without binding to protein. They          pression has been found in the basal layer of the squamous
claimed it caused damage to organs. They recommended that          epithelium in the nasal mucosa. The use of oral isotretinoin,
treatment strategies focus on reducing circulating retinoid        which causes dryness in the nasal mucosa, causes mucosal
concentrations. They argued that all nonessential drugs that       fragmentation, and may facilitate the adhesion of the coro-
are metabolized in the liver should be discontinued, and also      navirus to the nasal mucosa by exposing the basal layer [4,5].
that all drugs that damage the liver should be avoided during      On the other hand, since isotretinoin is one of the strongest
the acute phase of treatment [8]. However, the patients using      down-regulators of ACE-2 receptors, it was thought that
oral isotretinoin included in our study did not need hospi-        the use of isotretinoin may be protective against the trans-
talization or intensive care even though they continued their      mission of COVID-19 in that it reduces the possibility of
medication when they became COVID-19-positive.                     cellular entry of the virus [6]. To evaluate these hypotheses,
    Retinoic acid and carotenoids exert many physiological         we looked at the rates of being positive for COVID-19 after
effects, along with the enhancement of T-cell function, which      contact with a COVID-19(+) person, and we did not find any
develops an inducible immune response against pathogens            difference in the rates of being COVID-19-positive between
such as viruses [9]. Bioinformatics computational findings         contact patients using oral isotretinoin and contact patients
showed that vitamin A has anti-viral, anti-inflammatory, and       using topical treatment (P = 0.391). Öğüt et al also found
immunomodulatory effects through different biological pro-         that oral isotretinoin treatment was not associated with an
cesses and cell signaling pathways. As a result of these find-     increased risk of contracting COVID-19 [12]. These results
ings, the therapeutic mechanisms of vitamin A for the clinical     suggest that oral isotretinoin use increases the risk of trans-
treatment of COVID-19 have been defined [7]. Therefore,            mission by exposing ACE2 receptors, while reducing the risk
contrary to Mawson et al, it is thought that vitamin A de-         of transmission by down-regulating ACE2 receptors, leading
rivatives may have a protective role in the pathogenesis of        to a similar risk of transmission with people who do not use
ARDS, which is a complication of severe COVID-19 cases,            isotretinoin.



4                                                                      Original Article | Dermatol Pract Concept. 2022;12(3):e2022146
                    Table 3. Possible associations between oral isotretinoin and COVID-19
 COVID-19 transmission             Oral isotretinoin may increase the risk of transmission by exposing ACE-2 receptors in the
 risk and oral isotretinoin        nasal mucosa.
 use                               Oral isotretinoin can reduce the risk of transmission by down-regulating ACE-2 receptors.
 Severe COVID-19 and use           Because COVID-19 disease resembles an endogenous form of hypervitaminosis of
 of oral isotretinoin              ­vitamin A, the use of oral isotretinoin may worsen the disease severity.
                                   Thanks to its antioxidant and surfactant-mediated properties, oral isotretinoin may be pro-
                                   tective in the pathogenesis of ARDS, which is a complication of severe COVID-19 cases.
 COVID-19 treatment and            Oral isotretinoin can be used in the treatment of COVID-19 as it has anti-viral, anti-in-
 oral isotretinoin use             flammatory, and immunomodulatory effects.
 Symptoms due to                   Oral isotretinoin can alleviate COVID-19-related headache with its down-regulating effect
 COVID-19 and use of oral          on ACE-2 receptors and anti-inflammatory-immunomodulatory effects.
 isotretinoin                      Since oral isotretinoin increases the sense of smell and improves the lost sense of smell, it
                                   can reduce the level of taste-smell loss due to COVID-19 and accelerate its recovery.


    During the course of COVID-19, the most common clin-            loss of taste/smell, which persisted 1 month after recovery,
ical symptoms were reported as fever, cough, headache, and          was lower in patients using oral isotretinoin compared to
sore throat, in decreasing order of frequency [13]. In our pa-      patients receiving topical treatment (12.5% and 36%, re-
tients, this order was taste\smell loss, headache, fever, mal-      spectively), which may be related to the faster recovery of
aise, arthralgia\myalgia, cough, sore throat, and shortness of      olfactory function by isotretinoin, but again, no statistical
breath. We found that the headache symptom decreased with           difference was observed (P = 0.350). The main weakness of
the use of oral isotretinoin (P = 0.047). Various mechanisms        this study is that the small number of patients. Smell/taste
have been described for headaches due to COVID-19. The              loss levels could not be evaluated objectively because it is a
first of these mechanisms has been reported to be the inva-         retrospective study.
sion of the trigeminal nerve endings of the virus that is bound         In conclusion, the use of oral isotretinoin did not cause
to ACE2 receptors in the nasal cavity. We thought that the          an increase or decrease in the risk of COVID-19 transmis-
use of oral isotretinoin may cause a less frequent occurrence       sion. Headache symptom was seen less frequently in oral
of headache due to COVID-19, with the down-regulating ef-           isotretinoin users. In patients using oral isotretinoin, the
fect of isotretinoin on ACE2 receptors [6,11,14].                   rates of taste/smell loss were lower, although not statistically
    Although taste\smell loss is one of the most commonly           significant. The rates of complete recovery of taste/smell loss
known symptoms of COVID-19 in the non-medical com-                  were higher in oral isotretinoin users, although it was not
munity, its incidence varies between 0% and 98% [15]. We            statistically significant.
found the rate of taste\smell loss to be 55%, this rate was
higher in patients using a topical treatment (72.7%).               References
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