Effectiveness of aprepitant in post-acute COVID19 syndrome

Clin Case Rep. 2021;00:e04646. | 1 of 4 https://doi.org/10.1002/ccr3.4646 wileyonlinelibrary.com/journal/ccr3 1 | INTRODUCTION The postacute COVID- 19 syndrome (PACS) includes a plethora of nonspecific symptoms with no approved therapy. We present a clinical case of a patient with PACS who reported considerable improvement with aprepitant, a neurokinin 1 receptor (NK- 1R) inhibitor. A 39- yearold woman, a nurse by profession, current smoker, diagnosed with asthma, and a depressive syndrome, was diagnosed with COVID- 19 in May 2020, after a serological test carried out by ELISA assay. In mid- July 2020, she developed a severe PACS with significant physical limitation. She decided to selfmedicate with aprepitant at her own risk for 3 consecutive days at doses of 125mg on day 1, and 80mg on days 2 and 3, reporting improvement, with disappearance of most symptoms. This is the first case of a patient taking aprepitant for a PACS, which may encourage researchers to look for the evidence for the efficacy and safety of NK- 1R antagonists in PACS. Despite the considerable impact on incidence and mortality of the current SARS- CoV- 2 pandemic, many patients survive acute infection thanks to the therapeutic measures available. In recent months, some patients have been described whose symptoms persist despite having overcome the acute infection, which has given rise to the term postacute COVID- 19syndrome (PACS).1 The syndrome known as PACS includes the presence of persistent symptoms that could be related to three main spheres of the disease, namely the phenomena of persistent inflammation in the convalescent phase of the infection, damage to specific organs and the impact on preexisting health conditions and in many cases prolonged mechanical ventilation after admission to intensive care.2- 4 Unfortunately, due to the nonspecificity of the symptoms and the multiple systems involved, to date there is no consensual and systematized diagnostic approach, nor any approved therapeutic option. The following is a clinical case of Received: 14 May 2021 | Revised: 21 June 2021 | Accepted: 4 July 2021 DOI: 10.1002/ccr3.4646 CASE REPORT Effectiveness of aprepitant in postacute COVID19 syndrome RocíoReinoso- Arija1 | CeciliaLópez- Ramírez1 | José AntonioJimenez- Ruiz3 | JoséLuisLópez- Campos1,2 This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 1Unidad Médico- Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/ Universidad de Sevilla, Sevilla, Spain 2Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain 3Research Group on Electronic Technology and Industrial Computing (TIC- 150), University of Sevilla, Sevilla, Spain Correspondence Rocío Reinoso- Arija. Hospital Universitario Virgen del Rocío. Avda. Manuel Siurot, s/n. 41013 Sevilla, Spain. Email: [email protected] Abstract This is the first case of a patient taking aprepitant for a postacute COVID- 19syndrome. This case may encourage researchers to look for the evidence for the efficacy and safety of a neurokinin 1 receptor antagonist in this frequent syndrome. KEYWORDS aprepitant, postacute, COVID19, SARS- CoV- 2 2 of 4 | REINOSOARIJA Et Al. a patient with PACS who reported considerable improvement with aprepitant, a neurokinin 1 receptor (NK- 1R) inhibitor which is indicated for the treatment of nausea and vomiting associated with chemotherapy, and which is currently being explored for use in acute COVID19. 2 | CASE RECORD The patient is a 39- yearold woman, a nurse by profession, current smoker. The medical history of interest included chronic bronchial asthma with treatment with formoterol/budesonide 4.5/160 two inhalations every 12hours with an adequate control, and a depressive syndrome treated with venlafaxine retard 150mg daily. During an occupational health checkup at her workplace in May 2020, a serological test for SARS- CoV- 2 was carried out by ELISA assay, which produced a negative result for IgM and positive for IgG. With this information, the patient was diagnosed with an asymptomatic COVID19 infection and, accordingly, no treatment for this infection was prescribed. In mid- July 2020, she developed pain and edema in the lower limbs, together with asthenia. Over the following days, the symptoms increased progressively, including headaches, dizziness, blurred vision and photophobia, slight hearing loss, and sonophobia. This clinical deterioration progressed over the following months, with increased asthenia and muscle weakness, arthromyalgia and psychomotor slowness and significant physical limitation, and assistance in walking was required. In addition, from a neuropsychiatric point of view, increased lack of concentration, memory loss, and emotional lability were noted. After several months with these symptoms, as a healthcare worker, she carried out a search in PubMed and decided to selfmedicate with aprepitant at her own risk. At the beginning of March 2021, she took aprepitant for 3 consecutive days at doses of 125mg on day 1, and 80mg on days 2 and 3. On day 4, the patient reported improvement, with disappearance of pain, asthenia, and psychomotor slowness, although with some variability over the 18days, as she monitored her own symptoms using a diary of symptoms that she made herself. Today, two months later, the patient reports being in reasonably good health. 3 | DISCUSSION The present article describes the subjective positive response to aprepitant of a patient with PACS. Although aprepitant and similar compounds are under exploration for acute COVID- 19 (Clinicaltrials.gov NCT04326426 and NCT04468646) with a positive preprint publication on the effect of aprepitant combined with dexamethasone in severe to critical COVID- 19 patients,5 this is the first report of a clinical experience in a PACS case. PCAS is now considered part of the clinical expression of COVID- 19. Case series have been reported with the incidence of persistent symptoms ranging from 40 to 90% of patients, identifying PACS as a very frequent clinical outcome.1 However, the interpretation of the results is hampered by unsystematic and shortterm evaluations, with a considerable number of confounding variables in relation to age, severity of infection, followup, and characteristics of the clinical evaluation. Accordingly, at the present time there are no universally accepted diagnostic criteria for this new clinical condition and the publications that describe this new syndrome are based on clinical descriptions referred by patients as in the case we present.6,7 Interestingly, neither these symptoms were not present before the acute infection nor the patient did suffer from any clinical condition that conditioned these symptoms before COVID. Today, we know the infection caused by SARS- CoV- 2 is a multisystemic disease that goes beyond the wellknown respiratory symptoms. Among the systemic implications described is its ability to generate a state of neuroinflammation by entering the central nervous system either by retrograde neuronal dissemination through the olfactory nerves, through the autonomous nervous system, or via infected leukocytes that cross the bloodbrain barrier allowing the virus to enter the brain and disrupt cells.8- 10 Considering all the potential systemic symptoms associated with this, therapeutic options are currently needed. Aprepitant is an antagonist of NK- 1R and is a selective antagonist of the NK1 receptors of neurokinins, whose main natural ligand is substance P, which is capable by itself of inducing intense emesis. Its current indication is the prevention of nausea and vomiting associated with moderate and highly emetogenic cancer chemotherapy in adults and adolescents from 12years of age. Substance P belongs to the tachykinin family,11is widely distributed, and is expressed in sensory nerve fibers that innervate the airways and lymphoid organs, in glial cells and cells of the immune system. It is involved in a large number of both physiological and pathological processes where there is inflammation, which makes it a possible target for certain inflammatory processes. When substance P interacts with its highaffinity receptor, NK- 1R stimulates and modulates the release of cytokines. The main mechanisms by which substance P promotes inflammation, vasodilation and increased vascular permeability, facilitate the migration of leukocytes from the blood to the damaged tissue, and direct cell stimulation.12,13 It is currently known that aprepitant can cross the bloodbrain barrier after oral administration.14 In this way, aprepitant would | 3 of 4 REINOSOARIJA Et Al. block the storm of cytokines that maintain the state of neuroinflammation activated by substance P. The current case reports the subjective improvement of PACS after aprepitant intake. Although there was no objective physiological measurement of this improvement of the symptoms, the scientific rationale and the clinical impact of the role of NK- 1R inhibitors both in PACS and in the acute phase would be worth exploring. Currently, aprepitant and similar compounds like Tradipitant are being studied in prospective clinical trials for acute COVID19, with patients now being recruited. Similarly, a preprint publication has recently reported the beneficial effects of a combination of aprepitant plus dexamethasone in the treatment of acute COVID19.5 Therefore, its role as part of the therapeutic approach should be evaluated in prospective clinical trials. One intriguing question remained related to the persistence of this effect on PACS over time. Our patient took only one cycle of three doses of aprepitant, and she monitored her symptoms during an 18- day period, and so the question of the persistence of the beneficial effect remains unclear. Apparently, the women continued to feel well and the biological rationale for a more prolonged impact of aprepitant after one single cycle should also be studied, if this therapeutic effect is maintained. In summary, this is the first case of a patient taking aprepitant for a PACS. Considering the rationale, this clinical case may encourage researchers to look for the evidence for the efficacy and safety of NK- 1R antagonist in PACS. If these findings are confirmed, we could be facing the first effective treatment against this frequent syndrome consequence of the current SARS- CoV- 2 pandemic. ACKNOWLEDGMENTS The authors would like to thank Simon Armour from the British Academy for reviewing and helping to improve the English of this manuscript. Published with written consent of the patient. CONFLICT OF INTEREST JLLC has received honoraria for lecturing, scientific advice, participation in clinical studies or writing for publications for (alphabetical order): AstraZeneca, Bayer, Boehringer Ingelheim, Cantabria Pharma, Chiesi, CSL Behring, Esteve, Faes, Ferrer, Gebro, GlaxoSmithKline, Grifols, Menarini, MSD, Novartis, Pfizer, Rovi, Teva and Takeda. The other authors declare no conflicts of interest. AUTHOR CONTRIBUTIONS RRA, and JLLC summarized the clinical data over the time and wrote the drafts. JLLC and CLR provided her expertise on the studied syndrome and supervised the content. JAJR participated in the conception of the importance of the case and supervised and approved the content. ETHICAL STATEMENT Informed consent was obtained from the patient included in the case report. DATA AVAILABILITY STATEMENT The authors confirm that the data supporting the findings of this case are available within the article. 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