Covid-19: All facts, no myth

On December 31, 2019, the China Health Authority alerted WHO about 27 cases of pneumonia of unknown etiology in Wuhan City. It was subsequently named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and the disease as Coronavirus Disease 2019 (COVID-19). The disease has now become pandemic. Current review was done to summarize information on COVID-19 published in various scientific works. Electronic databases containing medical articles viz., MEDLINE/PubMed, Google Scholar etc were searched using the Medical Subject Headings 'COVID-19', '2019-nCoV', 'coronavirus' and 'SARS-CoV-2' during antecedent one year. All study designs were incorporated to harvest clinical, laboratory, imaging, and hospital course data. The intermediate host of the virus is still unknown. Respiratory droplets produced by the patient is main source of transmission. SARS-CoV-2 invades the airway epithelium by binding to angiotensin-converting enzyme-2 (ACE2) receptor with Coronavirus spike (S) protein. Most common symptoms are fever (98%), dry cough (77%), and dyspnea (63.5%). Later, complications like acute respiratory distress syndrome, septic shock etc may occur. Advanced age and co-morbidities like Diabetes have higher mortality otherwise Case Fatality Rate is 2-3%. RT-PCR is the diagnosis of choice. Since no universally accepted registered drug or FDA approved vaccine has come by now, prevention is the key. Hands should be regularly cleaned with soap or alcohol based sanitizer and in public, Nose and Mouth should be covered with face-mask and social distance of one meter should be maintained. While Vaccines are expected by early 2021, we should not forget to take comprehensive measures to prevent future outbreaks of zoonotic origin. Copyright © 2020, Kathmandu University. All rights reserved.

A European pharmacotherapeutic agent roflumilast exploring integrated preclinical and clinical evidence for SARS CoV-2 mediated inflammation to organ damage.

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma) seem more susceptible to severe illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Under preclinical studies, roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline and right heart thickening. The current study reviewed existing data that the PDE-4 inhibitor, a roflumilast, protects renal tissues and other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related to a decrease in oxidative and inflammatory burden, caspase-3 suppression and increased protein kinase A (PKA)/cyclic A.M.P. (cAMP) levels in renal and other organ tissue.

Scope of adjuvant therapy using roflumilast, a PDE-4 inhibitor against COVID-19.

The recent pandemic of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an extraordinary challenge to identify effective drugs for prevention and treatment. The pathogenesis implicate acute respiratory disorder (ARD) which is attributed to significantly triggered "cytokine storm" and compromised immune system. This article summarizes the likely benefits of roflumilast, a Phosphodiesterase-4 (PDE-4) inhibitor as a comprehensive support COVID-19 pathogenesis. Roflumilast, a well-known anti-inflammatory and immunomodulatory drug, is protective against respiratory models of chemical and smoke induced lung damage. There is significant data which demonstrate the protective effect of PDE-4 inhibitor in respiratory viral models and is likely to be beneficial in combating COVID-19 pathogenesis. Roflumilast is effective in patients with severe COPD by reducing the rate of exacerbations with the improvement of the lung function, which might further be beneficial for better clinical outcomes in COVID-19 patients. However, further clinical trials are warranted to examine this conjecture.

New putative insights into neprilysin (NEP)-dependent pharmacotherapeutic role of roflumilast in treating COVID-19.

Nowadays, coronavirus disease 2019 (COVID-19) represents the most serious inflammatory respiratory disease worldwide. Despite many proposed therapies, no effective medication has yet been approved. Neutrophils appear to be the key mediator for COVID-19-associated inflammatory immunopathologic, thromboembolic and fibrotic complications. Thus, for any therapeutic agent to be effective, it should greatly block the neutrophilic component of COVID-19. One of the effective therapeutic approaches investigated to reduce neutrophil-associated inflammatory lung diseases with few adverse effects was roflumilast. Being a highly selective phosphodiesterase-4 inhibitors (PDE4i), roflumilast acts by enhancing the level of cyclic adenosine monophosphate (cAMP), that probably potentiates its anti-inflammatory action via increasing neprilysin (NEP) activity. Because activating NEP was previously reported to mitigate several airway inflammatory ailments; this review thoroughly discusses the proposed NEP-based therapeutic properties of roflumilast, which may be of great importance in curing COVID-19. However, further clinical studies are required to confirm this strategy and to evaluate its in vivo preventive and therapeutic efficacy against COVID-19.

Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19.

The most severe presentation of COVID-19 is characterized by a hyperinflammatory state attributed to the massive pro-inflammatory cytokine release, called "cytokine storm". Several specific anti-inflammatory/immunosuppressive agents are being evaluated by ongoing clinical trials; however, there is currently insufficient evidence for their efficacy and safety in COVID-19 treatment. Given the role of phosphodiesterase 4 (PDE) 4 and cyclic adenosine monophosphate in the inflammatory response, we hypothesize that selective PDE4 inhibition may attenuate the cytokine storm in COVID-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-α, and the regulation of the pro-inflammatory/anti-inflammatory balance. Conversely, other anti-cytokine agents lead to the downstream inhibition of specific targets, such as IL-1, IL-6 or TNF-α, and may not be efficient in blocking the cytokine storm, once it has been triggered. Due to their mechanism of action targeting an early stage of the inflammatory response and ameliorating lung inflammation, we believe that selective PDE4 inhibitors may represent a promising treatment option for the early phase of COVID-19 pneumonia before the cytokine storm and severe multiorgan dysfunction take place. Furthermore, PDE4 inhibitors present several advantages including an excellent safety profile; the oral route of administration; the convenient dosing; and beneficial metabolic properties. Interestingly, obesity and diabetes mellitus type 2 have been reported to be risk factors for the severity of COVID-19. Therefore, randomized clinical trials of PDE4 inhibitors are necessary to explore their potential therapeutic effect as an adjunct to supportive measures and other therapeutic regiments.