Pentoxifylline: A Drug with Antiviral and Anti-Inflammatory Effects to Be Considered in the Treatment of Coronavirus Disease 2019

In December 2019, a new coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged from China, causing pneumonia outbreaks first in the Wuhan region and has now spread worldwide. There are no specific drugs for the disease caused by this virus, coronavirus disease 2019 (COVID-19). Considering that new synthesized drugs cannot be applied immediately to patients, conventional drug in new use is a feasible solution. Chloroquine, remdesivir, favipiravir, lopinavir, ribavirin, and ritonavir have shown efficacy to inhibit coronavirus in vitro. Pentoxifylline, a drug with anti-inflammatory, immunomodulatory, and bronchodilatory effects, has previously been shown to inhibit several viral infections. Immunological studies have shown that most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines. Pentoxifylline is a phosphodiesterase inhibitor that increases the levels of cyclic adenosine monophosphate, which in turn activates protein kinase, leading to a reduction in the synthesis of pro-inflammatory cytokines and immune cell migration. Here, we propose pentoxifylline, a drug with low cost and toxicity, as a possible treatment for COVID-19 based on its interesting properties.     

Evaluation of minocycline combined with favipiravir therapy in coronavirus disease 2019 patients: A case-series study

The aim of this study was to investigate the efficacy and safety of minocycline (MIN) and favipiravir combination therapy in patients with coronavirus disease 2019 (COVID-19) admitted to our hospital in Fukui Prefecture, Japan, in March and April of 2020. In this retrospective study, a favipiravir monotherapy group (Control group, n = 9) was compared with a combined favipiravir plus MIN therapy group (MIN group, n = 12). No severe cases were present. The primary comparative endpoints evaluated were duration of fever, duration of hospitalization, duration from treatment initiation to severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (PCR)-negative results, and changes in cytokine and chemokine production. Median duration from start of treatment to negative PCR test was significantly shorter in the MIN group than in the Control group. Mean rates of cytokine and chemokine reduction were significantly greater for interleukin-6 and interleukin-8 in the MIN group. No difference in adverse event rates were seen between groups, and only minor adverse events were encountered. MIN has been reported to have not only broad antibacterial activity, but also antiviral and anti-inflammatory activity. The present results support the efficacy and safety of MIN plus favipiravir therapy for the treatment of COVID-19.     

Outcome of COVID-19 in interstitial lung disease patients treated with anti-inflammatory drugs and antiviral drugs

A recent study reported that patients with interstitial lung disease (ILD) are at increased risk of death from coronavirus disease 2019 (COVID-19). However, there are no studies on the outcome of COVID-19 patients with preexisting ILD treated with corticosteroids or antiviral drugs. We extracted 26 patients with preexisting ILD by medical records and HRCT pattern. Of 503 patients with COVID-19, we selected 52 patients as control matched for age and sex. Twenty out of the 26 ILD patients (76.9%) received corticosteroid therapy, and 23 patients (88.5%) also received antiviral treatment with remdesivir or favipiravir. Although no statistical difference was found, the proportion of severe patients in ILD group tended to be higher than in non-ILD group (23.1% vs. 42.3%; p = 0.114). Also, mortality rate in ILD group tended to be higher than in non-ILD patients (11.5% vs. 3.8%; p = 0.326). In univariate analysis to evaluate risk factors for severe condition, diagnosis of idiopathic pulmonary fibrosis, usual interstitial pneumonia pattern, and honeycomb lung were not risk factors of severe disease. Treatment with corticosteroids, antiviral drugs, and immunosuppressive agents may affect the outcome of COVID-19 patients with ILD.     

A case of COVID-19 pneumonia successfully treated with favipiravir (Avigan) in which serum SARS-CoV-2 RNA detected by LAMP method was clinically useful

A 49-year-old Japanese male was managed by mechanical ventilation due to coronavirus disease 2019 (COVID-19) pneumonia. Favipiravir as an antiviral therapy, and anti-inflammatory treatment were administered. SARS-CoV-2 RNA was detected in serum by the loop-mediated isothermal amplification (LAMP) method on Day 9; favipiravir treatment was continued. On Day 13, negative serum RNA was confirmed, followed by mechanical ventilation was removed. On Day 23, LAMP negative was confirmed in nasopharynx, after that the patient discharged on Day 27. We could treat successfully for severe COVID-19 pneumonia based on the LAMP method. We consider this method will be useful in COVID-19 treatment.     

Hypertransaminasemia in the course of infection with SARS-CoV-2: Incidence and pathogenetic hypothesis

In patients infected with severe acute respiratory syndrome coronavirus 2, the respiratory symptoms, such as fever, cough and dyspnea, are the most frequent clinical manifestations. These patients may also present with less well-defined symptoms like diarrhea, nausea, vomiting and/or abdominal discomfort both at the time of diagnosis and during the clinical course. In a few cases, these symptoms may also present before the appearance of respiratory symptoms. To penetrate the body, Severe acute respiratory syndrome coronavirus 2 uses ACE2 receptors, which are present not only in respiratory epithelium but also in gastrointestinal mucosa and liver cholangiocytes. In several cases, viral RNA is detectable in the stool of patients with coronavirus disease 2019 (COVID-19). The liver damage seems to show a multifactorial origin. About 2%-11% of patients with COVID-19 have known underlying hepatic pathologies. In 14%-53% of COVID-19 cases, there is an alteration of the indices of liver cytolysis and is more frequently observed in severe forms of COVID-19, especially during hospitalization.     

一起家庭聚集性新型冠状病毒肺炎救治而引发的关于病毒脱落期的思考

新型冠状病毒肺炎疫情席卷了一百多个国家和地区，世界卫生组织已正式将其定性为全球大流行。自该病发生以来，已陆续有很多文章对COVID-19患者的流行病学和临床特征进行了分析报道，但有关死亡患者的危险因素分析和该病的临床病程，特别是病毒脱落持续情况等的相关报道较少。本文对一起家庭聚集性疫情进行报道，发现COVID-19患者病毒脱落持续时间与疾病严重程度并非完全一致，由此引发对此问题的思考。目前针对该疾病仍缺乏特异性治疗药物，对于该疾病的研究一直未停止。     

Interhospital transportation of a COVID-19 patient undergoing veno-venous extracorporeal membrane oxygenation by helicopter

Some coronavirus disease 2019 (COVID-19) patients develop rapidly progressive acute respiratory distress syndrome and require veno-venous extracorporeal membrane oxygenation (V-V ECMO). A previous study recommended the transfer of ECMO patients to ECMO centers. However, because of the pandemic, a limited number of ECMO centers are available for patient transfer. The safe long-distance interhospital transport of these patients is a concern. To minimize transportation time, helicopter use is a suitable choice. We report the first case of a COVID-19 patient on V-V ECMO, transferred to our ECMO center by helicopter.A 45-year-old man with rheumatoid arthritis history, treated with immunosuppressants, presented with fever and sore throat. He was diagnosed with COVID-19 following a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test result and was subsequently prescribed favipiravir. However, his respiratory failure progressively worsened. On day 10 of hospitalization at the previous hospital, he was intubated, and we received a request for ECMO transport on the next day. The ECMO team, who wore personal protective equipment (N95 respirators, gloves, gowns, and face shields), initiated V-V ECMO in the referring hospital and safely transported the patient by helicopter. The flight time was 7 min. He was admitted to the intensive care unit of our hospital and received tocilizumab. He was discharged on hospital day 31 with no significant sequelae.In this case report, we discuss important factors for the safe and appropriate interhospital transportation of COVID-19 patients on ECMO as well as staff and patient safety during helicopter transportation.     

Role of the extracellular matrix in COVID-19

An outbreak of coronavirus disease 2019 (COVID-19) has spread globally, with over 500 million cases and 6 million deaths to date. COVID-19 is associated with a systemic inflammatory response and abnormalities of the extracellular matrix (ECM), which is also involved in inflammatory storms. Upon viral infection, ECM proteins are involved in the recruitment of inflammatory cells and interference with target organ metabolism, including in the lungs. Additionally, serum biomarkers of ECM turnover are associated with the severity of COVID-19 and may serve as potential targets. Consequently, understanding the expression and function of ECM, particularly of the lung, during severe acute respiratory syndrome of the coronavirus 2 infection would provide valuable insights into the mechanisms of COVID-19 progression. In this review, we summarize the current findings on ECM, such as hyaluronic acid, matrix metalloproteinases, and collagen, which are linked to the severity and inflammation of COVID-19. Some drugs targeting the extracellular surface have been effective. In the future, these ECM findings could provide novel perspectives on the pathogenesis and treatment of COVID-19.     

Stem cell therapy: A promising treatment for COVID-19

Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. SARS-CoV-2 is an RNA virus and has a glycosylated spike (S) protein used for genome encoding. COVID-19 can lead to a cytokine storm and patients usually have early respiratory signs and further secondary infections, which can be fatal. COVID-19 has entered an emergency phase, but there are still no specific effective drugs for this disease. Mesenchymal stem cells (MSCs) are multipotent stromal cells, which cause antiapoptosis and can repair damaged epithelial cells. Many clinical trials have proved that MSC therapy could be a potential feasible therapy for COVID-19 patients, especially those with acute respiratory distress syndrome, without serious adverse events or toxicities. However, more studies are needed in the future, in order to confirm the effect of this therapy.     

心血管系统常用药物对新型冠状病毒肺炎感染风险及不良预后的影响

心血管疾病是新型冠状病毒肺炎(新冠肺炎)最为常见的合并症,在新冠肺炎大流行期间降压、降脂、抗血小板、抗凝、降糖及抗心律失常等心血管系统常用药物的安全性和有效性尚未形成统一明确的认识,相关指南也有待进一步完善。随着全球新冠肺炎病例数量的增加和第二波感染的发生,更好地了解这些药物对新冠肺炎患者的影响是当务之急。本文旨在总结心血管系统常用药物对新冠肺炎感染风险以及不良预后的关联,并对合并心血管疾病的新冠肺炎患者用药提出建议。     

Prolonged presence of SARS-CoV-2 in a COVID-19 case with rheumatoid arthritis taking iguratimod treated with ciclesonide

We report a coronavirus disease 2019 (COVID-19) case with rheumatoid arthritis taking iguratimod. The patient who continued iguratimod therapy without dose reduction was treated with ciclesonide had an uneventful clinical course, but prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was observed after resolution of symptoms. The effects of disease-modifying antirheumatic drugs (DMARDs) and ciclesonide on clinical course and viral shedding remain unknown and warrant further investigation.     

COVID-19: Considerations about immune suppression and biologicals at the time of SARS-CoV-2 pandemic

The extent of the profound immunological and nonimmunological responses linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is currently being investigated worldwide due to the large burden associated with death due to SARS-CoV-2 and the short-term consequences of coronavirus disease 2019 (COVID-19). It has been hypothesized that patients on immunosuppressive treatments, including biologics, may have an augmented risk of being infected by SARS-CoV-2; however, there are currently no definitive data about biological drugs and COVID-19 in immune-mediated inflammatory diseases. Current epidemiological models developed to understand how long the COVID-19 epidemic may last are not conclusive and range from sustained epidemics to complete elimination. Nevertheless, even in the best-case scenario of apparent elimination, there is concordance about a possible contagion resurgence as late as 2024. Therefore, knowledge of the impact of SARS-CoV-2 on immune-mediated diseases and among patients treated with biologicals, together with the results of novel and promising COVID-19 treatment strategies targeting the virus and the host immune response (or both), will help us to best manage our patients during this pandemic over the next few years.     

Role of monoclonal antibody drugs in the treatment of COVID-19

Currently clinicians all around the world are experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical presentation of this pathology includes fever, dry cough, fatigue and acute respiratory distress syndrome that can lead to death infected patients. Current studies on coronavirus disease 2019 (COVID-19) continue to highlight the urgent need for an effective therapy. Numerous therapeutic strategies have been used until now but, to date, there is no specific effective treatment for SARS-CoV-2 infection. Elevated inflammatory cytokines have been reported in patients with COVID-19. Evidence suggests that elevated cytokine levels, reflecting a hyperinflammatory response secondary to SARS-CoV-2 infection, are responsible for multi-organ damage in patients with COVID-19. For these reason, numerous randomized clinical trials are currently underway to explore the effectiveness of biopharmaceutical drugs, such as, interleukin-1 blockers, interleukin-6 inhibitors, Janus kinase inhibitors, in COVID-19. The aim of the present paper is to briefly summarize the pathogenetic rationale and the state of the art of therapeutic strategy blocking hyperinflammation.     

Neuroleptic malignant syndrome in patients with COVID-19

We report the first two cases of Coronavirus Disease 2019 (COVID-19) who were receiving intensive care including favipiravir, and were clinically diagnosed with neuroleptic malignant syndrome (NMS) to focus attention on NMS in COVID-19 management. Case 1: A 46-year-old-man with acute respiratory distress syndrome (ARDS) caused by COVID-19 infection was being administered favipiravir. Fentanyl, propofol, and rocuronium were also given. On day 3, midazolam administration was initiated for deep sedation. On day 5, his high body temperature increased to 41.2 °C, creatine kinase level elevated, and he developed tachycardia, tachypnea, altered consciousness, and diaphoresis. NMS was suspected, and supportive therapy was initiated. High-grade fever persisted for 4 days and subsided on day 9. Case 2: A 44-year-old-man with ARDS caused by COVID-19 infection was being treated with favipiravir. On day 5, risperidone was started for delirium. On day 7, his body temperature suddenly increased to 40.8 °C, his CK level elevated, and he developed tachycardia, tachypnea, altered consciousness, and diaphoresis. NMS diagnosis was confirmed, and both, favipiravir and risperidone were discontinued on day 8. On the same day, his CK levels decreased, and his body temperature normalized on day 9.Patients with COVID-19 infection frequently require deep sedation and develop delirium; therefore, more attention should be paid to the development of NMS in patients who are being administered such causative agents. The mechanism underlying the occurrence of NMS in COVID-19 patients treated with favipiravir remains unknown. Therefore, careful consideration of NMS development is necessary in the management of COVID-19 patients.