TYPE Original Research PUBLISHED 22 February 2023 DOI 10.3389/fcimb.2023.1097809 Plitidepsin in adult patients with OPEN ACCESS COVID-19 requiring hospital EDITED BY Josep Quer, Vall d’Hebron Research Institute (VHIR), admission: A long-term Spain REVIEWED BY follow-up analysis Benjamin Florian Koch, Goethe University Frankfurt, Germany Francisco López Medrano, Jose F. Varona 1,2*, Pedro Landete 3,4, Roger Paredes 5,6, Research Institute Hospital 12 de Octubre, Spain Roberto Vates 7, Miguel Torralba 8,9, Pablo Guisado-Vasco 10,11, *CORRESPONDENCE Lourdes Porras 12, Patricia Muñoz 13, Paloma Gijon 13, Jose F. Varona Julio Ancochea 3,4, Elena Saiz 14, Fernanda Meira 14, jfvarona@hmhospitales.com Jose M. Jimeno 14, Jose A. Lopez-Martin 14 SPECIALTY SECTION This article was submitted to and Vicente Estrada 15,16 Clinical Microbiology, 1 Departamento de Medicina Interna, Hospital Universitario HM Monteprincipe, HM Hospitales, a section of the journal Madrid, Spain, 2 Facultad de Medicina, Universidad San Pablo-Centro de Estudios Universitarios (CEU), Frontiers in Cellular and Madrid, Spain, 3 Departamento de Neumología, Hospital Universitario La Princesa, Madrid, Spain, Infection Microbiology 4 Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain, 5 Infectious Diseases RECEIVED 14 November 2022 Department, IrsiCaixa Acquired Immunodeficiency Syndrome (AIDS) Research Institute, ACCEPTED 27 January 2023 Barcelona, Spain, 6 Servicio de Enfermedades Infecciosas Hospital Germans Trias I Pujol, PUBLISHED 22 February 2023 Barcelona, Spain, 7 Internal Medicine Department, Hospital Universitario de Getafe, Madrid, Spain, 8 Medicine Department, Health Sciences Faculty, University of Alcalá, Madrid, Spain, 9 Internal Medicine CITATION Department, Guadalajara University Hospital, Guadalajara, Spain, 10 Internal Medicine Department, Varona JF, Landete P, Paredes R, Vates R, Hospital Universitario Quironsalud Madrid, Madrid, Spain, 11 Departamento de Medicina, Facultad de Torralba M, Guisado-Vasco P, Porras L, Ciencias Biomédicas y de la Salud, Universidad Europea, Madrid, Spain, 12 Internal Medicine, Hospital Muñoz P, Gijon P, Ancochea J, Saiz E, General de Ciudad Real, Ciudad Real, Spain, 13 Clinical Microbiology and Infectious Diseases Meira F, Jimeno JM, Lopez-Martin JA and Department, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Hospital General Estrada V (2023) Plitidepsin in adult Universitario Gregorio Marañón, Madrid, Spain, 14 Virology Unit, PharmaMar, SA, Madrid, Spain, patients with COVID-19 requiring hospital 15 Departamento de Medicina Interna Hospital Clı´nico San Carlos, Madrid, Spain, 16 Facultad de Medicina, admission: A long-term follow-up analysis. Universidad Complutense de Madrid, Madrid, Spain Front. Cell. Infect. Microbiol. 13:1097809. doi: 10.3389/fcimb.2023.1097809 COPYRIGHT © 2023 Varona, Landete, Paredes, Vates, Torralba, Guisado-Vasco, Porras, Muñoz, Gijon, Ancochea, Saiz, Meira, Jimeno, Lopez- Introduction: The APLICOV-PC study assessed the safety and preliminary efficacy Martin and Estrada. This is an open-access article distributed under the terms of the of plitidepsin in hospitalized adult patients with COVID-19. In this follow-up study Creative Commons Attribution License (E-APLICOV), the incidence of post-COVID-19 morbidity was evaluated and any (CC BY). The use, distribution or reproduction in other forums is permitted, long-term complications were characterized. provided the original author(s) and the copyright owner(s) are credited and that Methods: Between January 18 and March 16, 2022, 34 of the 45 adult patients who the original publication in this journal is cited, in accordance with accepted received therapy with plitidepsin in the APLICOV-PC study were enrolled in E- academic practice. No use, distribution or APLICOV (median time from plitidepsin first dose to E-APLICOV enrollment, 16.8 reproduction is permitted which does not months [range, 15.2–19.5 months]). All patients were functionally autonomous comply with these terms. with regard to daily living (Barthel index: 100) and had normal physical examinations. Results: From the APLICOV-PC date of discharge to the date of the extension visit, neither Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5) grade 3-4 complications nor QT prolongation or significant electrocardiogram (EKG) abnormalities were reported. Five (14.7%) patients had another COVID-19 episode after initial discharge from APLICOV-PC, and in 2 patients (5.9%), previously unreported chest X-ray findings were documented. Spirometry and lung-diffusion tests were normal in 29 (85.3%) and 27 (79.4%) patients, respectively, Frontiers in Cellular and Infection Microbiology 01 frontiersin.org Varona et al. 10.3389/fcimb.2023.1097809 and 3 patients needed additional oxygen supplementation after initial hospital discharge. None of these patients required subsequent hospital readmission for disease-related complications. Discussion: In conclusion, plitidepsin has demonstrated a favorable long-term safety profile in adult patients hospitalized for COVID-19. With the constraints of a low sample size and a lack of control, the rate of post-COVID-19 complications after treatment with plitidepsin is in the low range of published reports. (ClinicalTrials.gov Identifier: NCT05121740; https://clinicaltrials.gov/ct2/show/ NCT05121740). KEYWORDS plitidepsin, COVID-19, SARS-CoV-2, long COVID, post-COVID-19 complications Introduction acute COVID-19 infection may be protective from long COVID responses (Koc et al., 2022). Treatments that facilitate rapid As of 2 October 2022, the severe acute respiratory syndrome resolution of the acute infection could therefore be protective coronavirus 2 (SARS-CoV-2) pandemic has resulted in more than 615 against the effects of long COVID. million infections and 6.5 million deaths, at significant costs to The APLICOV-PC proof-of-concept study (NCT04382066) healthcare systems and societies worldwide (World Health assessed the safety and preliminary efficacy of 3 dose levels of Organization, 2022). Though initial public health responses focused plitidepsin (1.5 mg, 2.0 mg and 2.5 mg) administered for three on reducing the acute burden of coronavirus disease 2019 (COVID- consecutive days in hospitalized adult patients with COVID-19 19), it has become increasingly apparent that SARS-CoV-2 infection (Varona et al., 2022). The trial met the primary endpoint of safety can also provoke longer-term mental and physical health and feasibility of the 3 plitidepsin doses administered. In addition, consequences, thus heightening the concern of the healthcare results from APLICOV-PC suggested that plitidepsin was associated systems (Greenhalgh et al., 2020; National Institute for Health and with reductions of viral load (mean 3.25-log10 reduction in baseline Care Research, 2020; National Institute for Health and Care viral load by Day 15), inducing recovery (87% of the patients had Excellence, 2020). The persistence of symptoms –such as fatigue, moderate to severe illness when they entered the study; by Day 15, dyspnea, chest pain, cognitive disturbances, or arthralgia – 3 months 82% of the patients had been discharged), and providing relevant after SARS-CoV-2 infection is referred to as post-COVID-19 disease impact on lymphocyte reconstitution and other inflammatory or “long COVID” (National Institute for Health and Care Excellence, parameters (Varona et al., 2022). 2020). Between 10 and 25% of patients will experience long COVID, The E-APLICOV study (NCT05121740) described herein was resulting in a significant limitation of daily activities, an increase in designed to evaluate whether plitidepsin treatment in patients long-term sick leave from work, and the appearance of sequelae that hospitalized for COVID-19 could have a relevant impact on the may continue for more than one year (Carfì et al., 2020; Augustin emergence of long-term sequelae resulting from SARS-CoV- et al., 2021). 2 infection. Post-COVID-19 sequelae in patients who required hospitalization due to a severe SARS-CoV-2 infection are generally a consequence of structural damage to different organs by the infection itself and/or Methods associated complications. Various studies point to sequelae not only restricting the respiratory apparatus but also affecting the Study design and participants cardiovascular system, the kidneys and the central and peripheral nervous system (Carfì et al., 2020; Salehi et al., 2020; Vindegaard and APLICOV-PC was conducted in 10 hospital centers in Spain Benros, 2020; Ojha et al., 2020; Sudre et al., 2021; Huang et al., 2021). between May 12, 2020 and November 26, 2020 (second COVID-19 Psychiatric and psychological sequelae have also been documented pandemic wave). Details and results of the study have been previously (Vindegaard and Benros, 2020). published (Varona et al., 2022). This multi-site extension of the Risk factors for post-COVID-19 sequelae include the severity of APLICOV-PC clinical study (ran from January 18, 2022 to March acute COVID-19 infection, age, biological sex and sex hormones, and 16, 2022) invited patients who received previous therapy with the presence of pre-existing conditions (Koc et al., 2022). plitidepsin for COVID-19. Patients were enrolled after signing Furthermore, it has been reported that viral load during acute informed consent to participate in this extension study. The COVID-19 may correlate with the severity of long COVID patients included in the extension study received no treatment manifestation, and a rapid drop in the viral load of patients with whatsoever in relation to the study. Frontiers in Cellular and Infection Microbiology 02 frontiersin.org Varona et al. 10.3389/fcimb.2023.1097809 Procedures APLICOV-PC study through the end of the extension study: 1) readmissions to hospitals and their causes; 2) the need for oxygen The sites participating in the study were supervised by monitors therapy and duration of the same; and 3) the incidence of appointed by the sponsor. Monitors performed periodic visits to the site complications (See Supplementary Table 1). before, during and at the end of the trial, or failing that, by telephone contact or written communication. Remote verification of source data were performed in agreement with the participating centers. Statistical analysis Data were collected through electronic case report forms (eCRFs) from each center participating in the study, and were provided by the All data has been analyzed with the SAS statistical analysis system, Clinical Research Organization (CRO). The data was collected and version 9.4. All analyses have been carried out mainly by descriptive processed with the appropriate precautions to guarantee statistical methods. Continuous endpoints have been described using confidentiality and compliance with the current legislation maximum, minimum, Q1 and Q3, mean, median and standard regarding data privacy (EU Regulation 2016/679 of the European deviation. Categorical endpoints have been described with Parliament and of the Council of 27 April 2016 on the protection of frequencies and percentages as well as the exact 95% confidence natural persons with regard to the processing of personal data and on interval of the relevant study variables. All demographic and patient the free movement of such data and with Organic Law 03/2018 on characteristics are reported using the initiation of the E-APLICOV protection of personal data and guarantee of digital rights). study as baseline unless otherwise noted. Study objective Results The main objective of this study was to evaluate the incidence of Of the 45 adult patients who received therapy with plitidepsin in post-COVID-19 morbidity and characterize the profile of the APLICOV-PC study, 34 were enrolled into this extension complications in patients who participated in the APLICOV-PC (Figure 1). Of those included in E-APLICOV, 5 (14.7%), 19 (55.9%) study, assessing the incidence of post-COVID-19 complications and 10 (29.4%) patients had mild, moderate, and severe COVID-19 after exposure to therapeutic intervention with plitidepsin at flat (FDA criteria), respectively, at the time of treatment with plitidepsin doses of 1.5, 2.0, and 2.5 mg/day, for 3 consecutive days as a 90-min (Table 1). A median of 16.8 months (range 15.2 – 19.5 months) had IV infusion (Varona et al., 2022). elapsed from the time patients received their first dose of plitidepsin To complete this objective, the following information was to the start of this extension (Table 1). Most patients were male (23 gathered for the time spanning from the patient’s last visit in the patients, 67.6%) and Caucasian (23 patients, 67.6%) (Table 1). Their FIGURE 1 Flowchart of exclusions. Frontiers in Cellular and Infection Microbiology 03 frontiersin.org Varona et al. 10.3389/fcimb.2023.1097809 TABLE 1 Demographic and baseline characteristics for the 34 patients included in the E-APLICOV study. 1.5 mg 2.0 mg 2.5 mg Total N=9 N=14 N=11 N=34 Age, median (range) years 53 52,5 54 53 (33-70) (36-72) (43-68) (33-72) Gender, n (%) male 7 (77.8) 10 (71.4) 6 (54.5) 23 (67.6) Ethnicity, n (%) Caucasian 7 (77.8) 9 (64.3) 7 (63.6) 23 (67.6) Latin 2 (22.2) 3 (21.4) 4 (36.4) 9 (26.5) North African – 1 (7.1) – 1 (2.9) Asian – 1 (7.1) – 1 (2.9) 2 Body mass index, median (range) kg/m 27.7 30.3 29.8 29.7 (18.4-34.2) (22.0-46.2) (21.9-41.5) (18.4-46.2) Median (range) time from plitidepsin first dose to E-APLICOV inclusion, months 17.6 (15.3-19.5) 17.2 (15.7-18.6) 16.2 (15.2-17.8) 16.8 (15.2-19.5) Number of comorbidities, n (%) None 3 (33.3) 2 (14.3) 0 (0) 5 (14.7) One 1 (11.1) 6 (42.9) 6 (54.5) 13 (38.2) Two or more 5 (55.6) 6 (42.9) 5 (45.5) 16 (47.1) A Disease status at randomization, n (%) Mild COVID-19 1 (11.1) 3 (21.4) 1 (9.1) 5 (14.7) Moderate COVID-19 5 (55.6) 7 (50) 7 (63.6) 19 (55.9) Severe COVID-19 3 (33.3) 4 (28.6) 3 (27.3) 10 (29.4) Vaccination status (COVID-19) Non-vaccinated patients, n (%) 1 (11.1) – – 1 (2.9) Vaccinated patients, n (%) 8 (88.9) 14 (100) 11 (100) 33 (97.1) 1 dose 1 (11.1) 4 (28.6) 1 (9.1) 6 (17.6) 2 doses 4 (44.4) 7 (50.0) 10 (90.9) 21 (61.8) 3 doses 3 (33.3) 3 (21.4) – 6 (17.6) Serostatus against SARS-CoV-2, n (%) Negative 1 (11.1) 1 (7.1) 1 (9.1) 3 (8.8) Positive 8 (88.9) 13 (92.9) 10 (90.9) 31 (91.2) A Estimated using baseline assessments recorded in Electronic Data Capture using severity definitions in FDA Guidance for Industry “COVID-19: Developing Drugs and Biological Products for Treatment or Prevention”: mild (no shortness of breath or dyspnea, SpO2 ≥ 95%, respiratory rate < 20 breaths/min, heart rate < 90 bpm), moderate (shortness of breath with exertion, SpO2 > 93% but < 95%, respiratory rate ≥ 20 breaths/min or heart rate ≥ 90 bpm), and severe (shortness of breath at rest or respiratory distress, SpO2 ≤ 93%, respiratory rate ≥ 30 breaths/min, heart rate ≥ 125 bpm). bpm, beats per minute; FDA, Food and Drug Administration; Kg, kilogram; m2, square meter; mg, milligram; min, minutes; N, n, number; SpO2, oxygen saturation. –, No patients. median age was 53 years (range: 33-72 years) and their median body- (17.6%), 21 (61.8%), and 6 (17.6%) patients, respectively, had received mass index (BMI) was 29.7 kg/m2 (range: 18.4-46.2 kg/m2) (Table 1). 1, 2, and 3 doses of a COVID-19 vaccine since the conclusion of the Obesity (BMI > 30 kg/m2) was observed in 16 (47%) patients. Sixteen initial study (Table 1). A total of 3 patients were seronegative (8.8%) at (47.1%) patients had two or more co-morbidities at randomization entry into the extension study (Table 1). The median values of (Table 1). Eighty-five percent of patients had received some form of analytical parameters relevant to COVID-19 at study entry are pharmacological treatment at E-APLICOV study entry. Thirty-eight shown in Supplementary Table 3. Patients in this analysis had a percent of all patients were treated with lipid modifying agents and median total lymphocyte count of 1.98 x109 cells/L (interquartile 35.3% with drugs used in diabetes. Analgesics (23.5% of patients) and range [IQR], 1.56–2.56), C-reactive protein [CRP] of 1.36 mg/dL anti-inflammatory and antirheumatic products (23.5% of patients) (IQR, 0.9–2.9) and D-dimer of 240.5 ng/mL (IQR, 201–343). were also among the most frequently used medications for patients At study entry, none of the patients showed functional limitations included in the study (See Supplementary Table 2). There was only 1 for their daily living activities (Barthel index: 100) and there were no (2.9%) unvaccinated patient at the start of E-APLICOV, whereas 6 reports of physical and neurological abnormalities. There were no Frontiers in Cellular and Infection Microbiology 04 frontiersin.org Varona et al. 10.3389/fcimb.2023.1097809 CTCAE v5 grade 3–4 complications from the date of APLICOV-PC decompensation, hyperglycemia, and interstitial lung disease. Grade 2 discharge to the date of the extension visit. Nearly 15% of patients (n=5) asthenia was described in 2 patients (5.9%) (Table 2). There were no were diagnosed with COVID-19 after the completion of the APLICOV- reports on clinically relevant abnormalities in hematological PC study (approximately 13-15 months after the last patient inclusion parameters. None of the patients experienced a thromboembolic event. in the APLICOV-PC study). Among the post-COVID-19 Two patients (5.9%) presented chest X-ray findings (hilar complications occurring in the patients analyzed in the study (See adenopathies and bilateral micronodules, impingement of the left Supplementary Tables 4, 5), the investigators found the following lateral costophrenic sinus and calcified atheromatosis of the aortic events, reported as grade 2 disease-related complications, in one arch) not reported previously. Electrocardiogram (EKG) patient each (2.9%): alopecia, cough, diabetic metabolic abnormalities (e.g., atrial fibrilation, left axis deviation or sinus TABLE 2 Summary of post-COVID-19 complications, related to study disease, overall. Worst grade per patient. Grade Total Post-COVID-19 complications Missing G1 G2 N % N % N % N % Alanine aminotransferase increased . . 1 2.9 . . 1 2.9 Alopecia . . . . 1 2.9 1 2.9 Anxiety . . 2 5.9 . . 2 5.9 Aspartate aminotransferase increased . . 1 2.9 . . 1 2.9 Asthenia . . 11 32.4 2 5.9 13 38.2 Attention deficit . . 5 14.7 . . 5 14.7 Back pain . . 1 2.9 . . 1 2.9 Blood cholesterol increased . . 1 2.9 . . 1 2.9 Blood triglycerides increased . . 1 2.9 . . 1 2.9 COVID-19 pneumonia . . 1 2.9 . . 1 2.9 Chest pressure . . 1 2.9 . . 1 2.9 Cough . . 4 11.8 1 2.9 5 14.7 Diabetic metabolic decompensation . . . . 1 2.9 1 2.9 Diarrhea . . 1 2.9 . . 1 2.9 Dizziness 1 2.9 3 8.8 . . 4 11.8 Dyspnea . . 1 2.9 . . 1 2.9 Febricula . . 1 2.9 . . 1 2.9 Fibrin D-dimer increased . . 1 2.9 . . 1 2.9 Gamma-glutamyltransferase increased . . 2 5.9 . . 2 5.9 General malaise . . 5 14.7 . . 5 14.7 Headaches . . 3 8.8 . . 3 8.8 Hyperglycemia . . . . 1 2.9 1 2.9 Interstitial lung disease . . . . 1 2.9 1 2.9 Joint pains . . 2 5.9 . . 2 5.9 Low mood . . 3 8.8 . . 3 8.8 Memory lapses . . 4 11.8 . . 4 11.8 Muscle aches and pains . . 3 8.8 . . 3 8.8 Palpitations . . 2 5.9 . . 2 5.9 Serum ferritin increased . . 2 5.9 . . 2 5.9 Tingling in extremity . . 5 14.7 . . 5 14.7 G, grade; N, number. –, No patients. Frontiers in Cellular and Infection Microbiology 05 frontiersin.org Varona et al. 10.3389/fcimb.2023.1097809 TABLE 3 Pulmonary function assessment. 1.5 mg 2 mg 2.5 mg Total Pulmonary function assessment N % N % N % N % Spirometry FVC result Normal 7 77.8 14 100.0 11 100.0 32 94.1 Reduced 2 22.2 . . . . 2 5.9 FEV1 result Normal 7 77.8 13 92.9 9 81.8 29 85.3 Reduced 2 22.2 1 7.1 2 18.2 5 14.7 FEV1/FVC result Normal 9 100.0 12 85.7 8 72.7 29 85.3 Reduced . . 2 14.3 3 27.3 5 14.7 Dyspnea assessment mMRC 0 5 55.6 7 50.0 9 81.8 21 61.8 1 2 22.2 6 42.9 2 18.2 10 29.4 2 . . 1 7.1 . . 1 2.9 3 2 22.2 . . . . 2 5.9 Lung-diffusion testing DLCO result Normal 9 100.0 10 71.4 8 72.7 27 79.4 High . . 3 21.4 2 18.2 5 14.7 Low . . 1 7.1 1 9.1 2 5.9 0 (Symptoms: Little; Description: Dyspnea only with strenuous exercise); 1 (Symptoms: Mild; Description: Dyspnea when hurrying or walking up a slight hill); 2 (Symptoms: Moderate; Description: Walks slower than people of the same age because of dyspnea or has to stop for breath when walking at own pace); 3 (Symptoms: Many; Description: Stops for breath after walking just under 100 m (100 yards) or after a few minutes); 4 (Symptoms: Very much; Description: Too dyspneic to leave house or breathless when dressing) DLCO, diffusing capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; mg, milligram; mMRC, modified Medical Research Council; N, number. ., No patients. tachycardia) were found in 5 patients (14.7%) but were not judged as reduce the risk of post-COVID-19 complications is increasingly clinically significant. No QT prolongation was described in any of the gaining strength (Rajan et al., 2021). 34 patients. The previous APLICOV-PC proof-of-concept study confirmed Spirometry and lung-diffusion tests were normal in 29 (85.3%) plitidepsin safety in adult COVID-19 patients requiring hospital and 27 (79.4%) patients, respectively, at study entry (Table 3). The admission. Data gathered suggested that treatment of hospitalized pre-test 6-minute walk test scored 0–2 (no or slight dyspnea) in all patients with plitidepsin could sharply reduce SARS-CoV-2 viral load, patients (Borg scale). After the test, 24 (70.6%) patients had scores of promote recovery, and positively impact on the absolute lymphocyte 0–2, 6 (17.6%) patients of 2.5–4 (moderate dyspnea), and 4 (11.8%) counts and other inflammatory parameters (Varona et al., 2022). This patients had severe dyspnea (Supplementary Table 6). Only 2 trend toward increasing the total number of lymphocytes is of utmost patients, 1 with moderate COVID-19 and 1 in the severe group, importance given that the depth of lymphopenia may be associated stopped or paused during the test and none of the patients with poor prognosis, including higher COVID-19 mortality (Lee experienced symptoms at the end of the exercise. et al., 2021). To the best of our knowledge, an increase in Subsequent hospital readmission for disease-related complications lymphocyte counts has not been reported with other antiviral was not required for any of the patients. Three patients (8.82%, 2 with therapies (Barratt-Due et al., 2021). severe and 1 with moderate COVID-19 disease) required additional Due to plitidepsin’s putative effect on rapidly reducing the SARS- oxygen supplementation, via nasal cannula or Venturi mask, after initial CoV-2 viral load and normalizing certain immune system parameters, hospital discharge. we sought to characterize the incidence of post-COVID-19 morbidity and long-term complications in patients who participated in APLICOV-PC. As the last patient in the APLICOV-PC study was Discussion enrolled in November 2020, there was already an extensive margin of follow-up time of almost 12 months to evaluate these parameters in this Treatments to manage or prevent the development of sequelae study. Despite the relatively high severity of COVID-19 (85% were arising from acute SARS-CoV-2 infection are urgently needed. graded as moderate to severe in the original study) and prevalence of Growing evidence suggests that the pathophysiologic model comorbidity (85% of patients had ≥1 comorbidity), we observed few underlying post-COVID-19 sequelae stems from a dysregulated long-term complications in this group of patients previously treated immune system that, after acute infection, continues releasing with plitidepsin. None of the patients included in the E-APLICOV aberrantly high levels of proinflammatory cytokines that lead to study had experienced functional restrictions in performing physical chronic low-grade inflammation and multiorgan symptomatology actions needed in everyday life. Reports of neurological Grade 1 post- (Buonsenso et al., 2022). Further, the hypothesis that a rapid COVID-19 complications, deemed to be related to study disease, reduction in SARS-CoV-2 viral load during acute infection may included attention deficit (n=5; 14.7%), memory lapses (n=4; 11.8%), Frontiers in Cellular and Infection Microbiology 06 frontiersin.org Varona et al. 10.3389/fcimb.2023.1097809 low mood (n=3; 8.8%), headaches (n=3; 8.8%), and anxiety (n=2; 5.9%). In summary, considering the absence of CTCAE v5 grade 3-4 These low rates are in contrast with reports from an electronic follow- complications and of clinically significant EKG abnormalities, as well up record of 236,379 patients during the first six months following as the low rate of disease-related complications, chest X-ray findings COVID-19 diagnosis, in which neuropsychiatric complications and requirement of oxygen supplementation in patients included in emerged in 34% of cases, not including headache. The most this study, plitidepsin has demonstrated long-term safety in adult commonly reported complications include mood and anxiety patients hospitalized for COVID-19. Despite the limitations of a low disorders and psychoses (24%), neuropathies (2.1%), and dementia sample size and a lack of control group in APLICOV-PC, the rate of (0.67%) (Taquet et al., 2021). On the other hand, the most frequent post-COVID-19 complications after treatment with plitidepsin neurological symptoms are headache and cognitive changes, described appears to be in the lower limit of the 95% confidence interval of in up to 68% and 81% of patients, respectively, with some sort of the prevalence of post-COVID-19 complications reported in a recent neurological symptoms after week 12 following acute infection meta-analysis [80% (95% CI 65–92)] (Lopez-Leon et al., 2021). (Graham et al., 2021). In patients who present with severe COVID-19, the main sequelae is the development of pulmonary fibrosis. According to a recent meta- Data availability statement analysis, approximately 30% of patients hospitalized with pneumonia due to SARS-CoV-2 have shown fibrotic changes that persist for the The original contributions presented in the study are included in first 12 months after discharge from the hospital (Fabbri et al., 2022). the article/Supplementary Material. Further inquiries can be directed In this study, grade 1 COVID-19 pneumonia was reported in only 1 to the corresponding author. patient (2.9%) and only 2 patients (5.9%) presented chest X-ray findings, which were not suggestive of pulmonary fibrosis. None of the patients experienced a pulmonary embolism. Ethics statement Finally, it should be highlighted that the dose range proposed in the APLICOV-PC study, which was based on pharmacokinetic/ The studies involving human participants were reviewed and pharmacodynamic modeling, anticipated that antiviral concentrations approved by CEIm HM Hospitales. The patients/participants of plitidepsin would be reached in distal anatomical compartments. In- provided their written informed consent to participate in this study. vivo biodistribution of plitidepsin confirms that key organs in SARS- CoV-2 are exposed to therapeutic concentrations. Considering that SARS-CoV-2 infection is a systemic process that goes beyond affecting Author contributions the respiratory tract, the biodistribution of plitidepsin might result in a widespread reduction of organ dysfunction, potentially protecting SARS- The specific additional participation of each author is as follows: CoV-2-affected organs (Machhi et al., 2020; Rajan et al., 2021). Indeed, JV: conceptualization, investigation, writing and reviewing of the data from the COVERSCAN study conducted in the United Kingdom, original draft. PL: investigation. RP: conceptualization and which carried out serial Magnetic Resonance Imaging (MRI) scanning in investigation. RV, MT, PG-V, LP, PM, PG, and JA: Investigation. a sample of 201 generally-healthy, middle-aged individuals, with ES and FM: data supervision. JJ: conceptualization, formal analysis, COVID-19, showed evidence of mild organ impairment of the heart supervision, validation, investigation, methodology, and writing & (32%), lungs (33%), kidneys (12%), liver (10%), pancreas (17%), and critical review of the article. JL-M: conceptualization, data curation, spleen (6%) (Rajan et al., 2021). Significant heart injuries, including software, formal analysis, supervision, validation, investigation, myocarditis with reduced systolic function and arrhythmias, have been visualization, methodology, writing & critical review of the article. documented in patients with severe forms of COVID-19. Myocardial VE: conceptualization and investigation. All authors contributed to injury has been reported, which may be due to direct damage to the the article and approved the submitted version. cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, and hypoxia (Babapoor-Farrokhran et al., 2020). Due to significant myocardial injuries in patients with severe COVID-19 symptoms, the Funding morbidity and lethality of the illness could be high (Aggarwal et al., 2020; Clerkin et al., 2020; Bansal, 2020). Moreover, it has been shown that right This study has been funded by Pharma.Mar, S.A. (Madrid, Spain). ventricular abnormalities can occur after SARS-CoV-2 infection and likely reflect the consequences of COVID-19-associated severe pneumonia (Singh et al., 2022). It should be noted, however, that no Acknowledgments clinically significant functional heart abnormalities were found in patients of the E-APLICOV study. At the E-APLICOV study entry, spirometry We are indebted to the women and men that gave their consent to and lung-diffusion tests were abnormal in only 14.7% and 20.6% of the participate in this study, and to their relatives, for understanding their patients, respectively, percentages below the COVID-19-derived lung decision in these exceptional circumstances. We would like to thank dysfunction rates previously described in the literature (Rajan Alvaro Belgrano for data curation and Timothy Silverstein and et al., 2021). Raquel Lloris for providing editorial support. Frontiers in Cellular and Infection Microbiology 07 frontiersin.org Varona et al. 10.3389/fcimb.2023.1097809 Conflict of interest The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be VE has received personal fees from Janssen, Gilead, and ViiV and construed as a potential conflict of interest. grants from MSD. RP has participated in Advisory Boards from Gilead, MSD, ViiV Healthcare, and Theratechnologies. MT has received consulting fees as a member of Advisory Committee and honoraria Publisher’s note and speaking fees from Gilead, Janssen, MSD, and ViiV Companies. PG- V received speaker fees from FLS Science, Pharma Mar SA Madrid, Spain All claims expressed in this article are solely those of the authors and GlaxoSmithKline Spain; consulting fees from Angelini Pharma and and do not necessarily represent those of their affiliated organizations, Pharma Mar SA; served as an advisory board member for Berlin Cures or those of the publisher, the editors and the reviewers. Any product GmbH and Pharma Mar SA; and meeting grants from GlaxoSmithKline that may be evaluated in this article, or claim that may be made by its and Pharma Mar SA. JJ holds stocks of Pangaea Oncology, has a non- manufacturer, is not guaranteed or endorsed by the publisher. remunerated role in the Scientific Advisory Board and holds stocks of Promontory Therapeutics, and is a full-time employee of Pharmamar, SA Madrid, Spain and owns stocks. JL-M is a full-time employee and shareholder of Pharmamar, SA Madrid, Spain. ES and FM are full- Supplementary material time employees of Pharmamar, SA Madrid, Spain. JL-M is a co-inventor of a patent for plitidepsin WO2008135793A1. JJ is a co-inventor on a The Supplementary Material for this article can be found online patent for didemnin WO99/42125 and on patents for aplidine WO03/ at: https://www.frontiersin.org/articles/10.3389/fcimb.2023.1097809/ 033013 and WO 2004/080421. full#supplementary-material References Aggarwal, G., Cheruiyot, I., Aggarwal, S., Wong, J., Lippi, G., Lavie, C. J., et al. (2020). Lopez-Leon, S., Wegman-Ostrosky, T., Perelman, C., Sepulveda, R., Rebolledo, P. 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