In a recent study posted to medRxiv* pre-print server, researchers evaluated the effectiveness of isotretinoin (13-cis retinoic acid) to improve the outcomes of coronavirus disease 2019 (COVID-19).
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have increased rapidly across the globe due to the emergence of recombinant mutant variants. These variants have shown improved viral spike (S) protein and angiotensin-converting enzyme 2 (ACE2) binding, increasing viral transmissibility.
Previous studies have reported that the receptor binding domain (RBD) of S protein binds strongly to the STRA6 (retinol / Vitamin A) receptors. For this purpose, isotretinoin effectively downregulates ACE2 receptors. In addition, it has potent anti-inflammatory properties that facilitate improvement in COVID-19 patients by reducing the ‘cytokine storm’ associated with elevated interleukin-6 (IL-6) in COVID-19.
About the study
In this study, researchers conducted a randomized controlled trial (RCT) to evaluate the effectiveness of isotretinoin to improve COVID-19 results.
A total of 40 hospitalized COVID-19 patients over the age of 18 were recruited for the study. They were hospitalized for less than two days after the COVID-19 diagnosis. Data were obtained on patients’ medical history, age, sex, body mass index (BMI); and radiological and laboratory examinations such as computed tomography (CT) and complete blood count, respectively.
Subjects were clinically examined for the presence of COVID-19-associated signs and symptoms such as fever, cough, anosmia, abdominal painsdiarrhea and their oxygen saturation was measured. COVID-19 diagnosis was confirmed by polymerase chain reaction (PCR) and absolute lymphocyte counts below 1.0 x 109/ L. The severity of the disease severity was categorized as mild, moderate, and severe based on the presence of upper respiratory tract complications and the need for oxygen supplementation, mechanical ventilation, and intensive care unit (ICU) admissions.
The study participants were divided into two groups of 20 patients each. Group I received aerosolized and oral forms of isotretinoin with standard therapy, while group II received only standard therapy (control group). The duration of treatment was two weeks for both groups. Group I received isotretinoin orally as 20 mg / day doses and as inhaled aerosol sprays with concentrations ranging from 0.2 to 4 mg / kg / day. The standard of care therapy set by the Egyptian Ministry of Health (MOH) was provided to all patients.
The assessed clinical outcomes were mortality, number of days required for clinical improvement and hospital discharge, ICU admissions, and oxygen saturation levels. The serological results evaluated were IL-6, D-dimer, ferritin, C-reactive protein (CRP), dihydrotestosterone (DHT), tumor necrosis factor-alpha (TNF-α), cholesterol and immunoglobulin A (IgA).
The study results showed a high statistically significant difference between the two groups two weeks after treatment with higher effect in group I.
On clinical examination, patients showed persistent fever (26%), intermittent fever (37%), cough (69%), anosmia (32%) and abdominal pain (22%). Oxygen saturation levels varied between 90 and 95, 90 and 85 and below 85 for 52.6%, 16% and 31.6% patients, respectively.
On X-ray examination, the CT thoracic scans usually revealed tissue, blurred glass, confluent opacities, consolidation, and extensive consolidation in 31.6%, 21.1%, 15.5%, 15.8%, and 15.7%, respectively, patients.
Only 10.5% of group I patients required ICU admissions compared to 28.6% controls. In addition, no deaths were reported in group I, while group II showed 14% mortality. Mortality was significantly associated with comorbidities such as obesity and diabetes mellitus. In addition, patients with abdominal pain and low oxygen saturation were more likely to die due to COVID-19. This indicated that isotretinoin therapy was associated with decreased COVID-19 severity.
In group I, the time it took to obtain a negative PCR report was 13 days compared to 24 days in group II. Similarly, group I patients showed clinical improvement at 16 days and received hospital discharge at 22 days, while group II patients improved clinically at 25 days and received hospital discharge at 33 days. This indicated faster clinical improvement with isotretinoin treatment.
Compared to controls, group I had higher TNF-α and reduced IL-6 and angiotensin II levels. In both groups, the levels of IgA, cholesterol, and lymphocytes increased, while the levels of thrombin, ferritin, CRP, DHT, and soluble ACE2 decreased. However, the changes were only significant in group I. Of these parameters, D-dimer, DHT, ferritin, and CRP values correlated most significantly with COVID-19 mortality.
To summarize, isotretinoin showed promising effects in improving COVID-19-associated morbidity and mortality. In particular, the severity of COVID-19 was higher in obese and diabetic patients and was associated with changes in D-dimer, DHT, ferritin and CRP levels. Thus, these parameters can be considered as important markers of COVID-19 severity.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered as crucial, guide clinical practice / health-related behavior or be treated as established information.