The effect of control strategies to reduce social mixing on outcomes of the Covid-19 epidemic in Wuhan, China: a modelling study. Prem K, Liu Y, Russell TW, Kucharski AJ, et al. The Lancet Public Health March 25, 2020. Online First. https://doi.org/10.1016/S2468-2667(20)30073-6

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, emerged in Wuhan, China. Since then, the city of Wuhan has taken unprecedented measures in response to the outbreak, including extended school and workplace closures. The researchers aimed to estimate the effects of physical distancing measures on the progression of the Covid-19 epidemic, hoping to provide some insights for the rest of the world. 

They examined how changes in population mixing have affected outbreak progression in Wuhan. They used synthetic location-specific contact patterns in Wuhan and adapted these in the presence of school closures, extended workplace closures, and a reduction in mixing in the general community. Using these matrices and the latest estimates of the epidemiological parameters of the Wuhan outbreak, they simulated the ongoing trajectory of an outbreak in Wuhan using an age-structured susceptible-exposed-infected-removed (SEIR) model for several physical distancing measures. They then fitted the latest estimates of epidemic parameters from a transmission model to data on local and internationally exported cases from Wuhan in an age-structured epidemic framework and investigated the age distribution of cases. 

They also simulated lifting of the control measures by allowing people to return to work in a phased-in way and looked at the effects of returning to work at different stages of the underlying outbreak (at the beginning of March or April). The authors’ projections show that physical distancing measures were most effective if the staggered return to work was at the beginning of April; this reduced the median number of infections by more than 92% (IQR 66-97) and 24% (13-90) in mid-2020 and end-2020, respectively. There are benefits to sustaining these measures until April in terms of delaying and reducing the height of the peak, median epidemic size at end-2020, and affording healthcare systems more time to expand and respond. However, the modelled effects of physical distancing measures vary by the duration of infectiousness and the role school children have in the epidemic. Restrictions on activities in Wuhan, if maintained until April, would probably help to delay the epidemic peak. These projections suggest that premature and sudden lifting of interventions could lead to an earlier secondary peak, which could be flattened by relaxing the interventions gradually. However, there are limitations to the analysis, including large uncertainties around estimates of R₀ (basic infection reproduction number) and the duration of infectiousness.

Potential impact of seasonal forcing on a SARS-CoV-2 pandemic. Neher RA, Dyrdak R, Druelle V, et al. Swiss Med Wkly. 2020 Mar 16;150:w20224. doi: 10.4414/smw.2020.20224. eCollection 2020 Mar 9

A novel coronavirus (SARS-CoV-2) first detected in Wuhan, China, has spread rapidly since December 2019. The outbreak has been declared a pandemic by the WHO. This study explores how seasonal variation in transmissibility could modulate a SARS-CoV-2 pandemic. Data from routine diagnostics show a strong and consistent seasonal variation of the four endemic coronaviruses (229E, HKU1, NL63, OC43) and the researchers parameterise their model for SARS-CoV-2 using these data. The model allows for many subpopulations of different size with variable parameters. 

Simulations of different scenarios show that plausible parameters result in a small peak in early 2020 in temperate regions of the northern hemisphere and a larger peak in winter 2020/2021. Variation in transmission and migration rates can result in substantial variation in prevalence between regions. While the uncertainty in parameters is large, the scenarios explored show that transient reductions in the incidence rate might be due to a combination of seasonal variation and infection control efforts but do not necessarily mean the epidemic is contained. Seasonal forcing on SARS-CoV-2 should thus be taken into account in the further monitoring of the global transmission. The likely aggregated effect of seasonal variation, infection control measures, and transmission rate variation is a prolonged pandemic wave with lower prevalence at any given time, thereby providing a window of opportunity for better preparation of healthcare systems.

Patients of Covid-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of Covid-19 progression. Liu F, Xu A, Zhang Y, et al. Int J Infect Dis. 2020 Mar 12. pii: S1201-9712(20)30132-6. doi: 10.1016/j.ijid.2020.03.013. [Epub ahead of print]

This study explored the epidemiological information, clinical characteristics, therapeutic outcomes and temporal progression of laboratory findings in 2019-coronavirus disease (Covid-19) patients exposed to lopinavir.

Data was collected from 10 Covid-19 patients admitted between January 22, 2020 and February 11, 2020 at Xixi hospital in Hangzhou, China.

Of 10 patients, secondary, tertiary and quartus patients emerged; the incubation period was three to seven days. The main initial symptoms were cough and low fever (37.3-38.0ºC). An asymptomatic case presented with normal radiography; the others showed ground glass opacities. All cases (three transferred, seven discharged) were exposed to lopinavir on initial hospitalisation. Three patients stopped using lopinavir because of adverse effects, two of them deteriorated, one was hospitalised longer than others who had sustained lopinavir use. Levels of potassium, albumin, lymphocyte were low, but increased persistently after treatment. Eosinophil values were low on initial hospitalisation, then all returned to normal before discharge. Viral load of SARS-CoV-2, radiography and eosinophil improved continuously in 3-14, 6-8 and 7-9 days, respectively.

The researchers said increasing eosinophils may be an indicator of Covid-19 improvement. The Covid-19 patients may benefit from sustained lopinavir treatment. More research on a larger scale are needed to verify these points, they said.

A systematic review on the efficacy and safety of chloroquine for the treatment of Covid-19. Cortegiani A, Ingoglia G, et al. J Crit Care. 2020 Mar 10. pii: S0883-9441(20)30390-7. doi: 10.1016/j.jcrc.2020.03.005. [Epub ahead of print]

Covid-19 (coronavirus disease 2019) is a public health emergency of international concern. As of this time, there is no known effective pharmaceutical treatment, although it is much needed for patients contracting the severe form of the disease. The aim of this systematic review was to summarise the evidence regarding chloroquine for the treatment of Covid-19. PubMed, EMBASE, and three trial registries were searched for studies on the use of chloroquine in patients with Covid-19.

The conclusions were that there is rational, pre-clinical evidence of the effectiveness and evidence of safety from long-time clinical use for other indications to justify clinical research on chloroquine in patients with Covid-19. However, clinical use should either adhere to the Monitored Emergency Use of Unregistered Interventions (MEURI) framework or be ethically approved as a trial as stated by the WHO. Safety data and data from high-quality clinical trials are urgently needed.

Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Covid-19: anti-inflammatory strategies. Conti P, Ronconi G, Caraffa A, et al. J Biol Regul Homeost Agents. 2020 Mar 14;34(2). pii: 1. doi: 10.23812/CONTI-E.. [Epub ahead of print]

Covid-19 (coronavirus disease-19) involves humans as well as animals and may cause serious damage to the respiratory tract including the lung. This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease. When Covid-19 infects the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1b and IL-6. 

The binding of Covid-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1b which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1b which is a mediator of lung inflammation, fever and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Ra receptor. IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP) kinase. This cytokine inhibits class II histocompatibility complex (MHC) molecules and inflammation in inflammatory diseases by suppressing MyD88 and subsequently IL-1β, IL-6, TNF and CCL2. The suppression of IL-1b by IL-37 in inflammatory state induced by Covid-19 can have a new therapeutic effect previously unknown. Another inhibitory cytokine is IL-38, the newest cytokine of the IL-1 family members, produced by several immune cells including beta cells and macrophages. IL-38 is also a suppressor cytokine which inhibits IL-1b and other pro-inflammatory IL-family members. IL-38 is a potential therapeutic cytokine which inhibits inflammation in viral infections including that caused by Covid-19.

Possible therapeutic role of a highly standardized mixture of active compounds derived from cultured Lentinula edodes mycelia (AHCC) in patients infected with 2019 novel coronavirus. Di Pierro F, Bertuccioli A, Cavecchia I. Minerva Gastroenterol Dietol. 2020 Mar 12. doi: 10.23736/S1121-421X.20.02697-5. [Epub ahead of print]

The outbreak of SARS-CoV-2 disease (Covid-19) is currently, in March 2020, affecting more than 100,000 people worldwide and, according to the WHO, a pandemic is shortly expected (the pandemic had been declared by the time of going to print). The virus infects the lower respiratory tract and causes severe pneumonia and mortality in approximately 10% and 3-5% respectively, of cases, mainly among the elderly and/or people affected by other diseases. 

AHCC is an α-glucan-based standardised mushroom extract that has been extensively investigated as an immunostimulant both in animals and/or in humans affected by West Nile virus, influenza virus, avian influenza virus, hepatitis C virus, papillomavirus, herpes virus, hepatitis B virus and HIV by promoting a regulated and protective immune response. Although the efficacy of AHCC has not yet been specifically evaluated with respect to SARS-CoV-2 disease, its action in promoting a protective response to a wide range of viral infections, and the current absence of effective vaccines, could support its use in the prevention of diseases provoked by human pathogenic coronavirus, including Covid-19.

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Gurwitz D. Drug Dev Res. 2020 Mar 4. doi: 10.1002/ddr.21656. [Epub ahead of print]

Therapeutics that may assist to contain Covid-19’s rapid spread and reduce high mortality rates are urgently needed. Developing vaccines against the SARS-CoV-2 virus may take many months. Moreover, vaccines based on viral-encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new influenza virus strains emerge every year, requiring new immunisations. 

A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS-CoV-2 virus infections. This idea is based on observations that the angiotensin-converting enzyme 2 (ACE2) very likely serves as the binding site for SARS-CoV-2, the strain implicated in the current Covid-19 epidemic, similarly to strain SARS-CoV implicated in the 2002-2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS-CoV-2 infections, and proposes a research direction based on data-mining of clinical patient records for assessing its feasibility.