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No antiviral treatment for coronavirus infection has been proven to be effective. Previous studies showed the combination of lopinavir and ritonavir may be beneficial for SARS-CoV and MERS-CoV infected patients [31, 32]. Treatment with intravenous remdesivir (a novel nucleotide analogue prodrug in development) showed significant improvement for the first case in US. A trial has been initiated quickly to assess the efficacy and safety of remdesivir in patients hospitalized with 2019-nCoV infection. Recently, a potent binding of 2019-nCoV spike protein by a SARS-CoV specific human monoclonal antibody were under investigation.
As the cytokine storm was observed in severe 2019-nCoV infection patients, low dose corticosteroids has been used to treat the patients for possible benefit by reducing inflammatory-induced lung injury. However, corticosteroids did not reduce the mortality for SARS-CoV and MERS-CoV infection by WHO interim guidance [34, 35].
Treatment regiments were classified into three categories depends on the severity of the disease: (1) For mild to moderate disease, the major treatment is supportive therapy; (2) for severe disease, oxygen inhalation through mask, high nasal oxygen flow inhalation, or non-invasive ventilation is needed. Careful and dynamic evaluation of patients oximeter and Chest imaging as well as laboratory examination is important; (3) for very severe disease, protective mechanical ventilation after tracheal intubation is required, and prone position ventilation followed if P/F ratio not improved, and eventually extracorporeal membrane oxygenation (ECMO) might be implemented if prone position plus mechanical ventilation did not work. Notably, the anxiety and depression of patients need to be consideration. We should not only pay attention to disease treatment, but also the mental issues of patients.
In addition, some traditional Chinese medicine (TCM), such as Snow Lotus (Saussuea involucrata), LianHuaQingWen, LiuShenWan might be beneficial for coronavirus infection treatment through immunity enhancement. Further evidence is needed to assess the effect of TCM treatment for patients infected with 2019-nCoV.
Bed rest, strengthen supportive treatment, ensure sufficient energy; pay attention to water-electrolytes balance and maintain the stability of the internal environment; closely monitor vital signs and finger oxygen saturation, and so on.Monitor the blood routine, urine routine, C-reactive protein (CRP) and health indications (liver enzyme, myocardial enzyme, renal function, etc.), coagulation function, arterial blood gas analysis if necessary, and recheck chest imaging.According to the change of oxygen saturation, give effective oxygen therapy in time, including oxygen given by nasal catheter or mask. If necessary, apply high flow oxygen therapy via the nose, noninvasive or invasive mechanical ventilation, and so on.Antiviral treatment: no effective antiviral drug at present. Treat with IFN-α aerosol inhalation (five million U per time for adults, two times per day), and/or Lopinavir/Ritonavir oral administration (two tablets per time, two times per day).Antibiotic treatment: avoid blind and improper use of antibiotics, especially the combination use of broad-spectrum antibiotics. Strengthen bacteriological monitoring. Antibiotics should be used in time in secondary bacterial infection.
Ideally, infected patients should be treated with a customized treatment plan. However, currently, no specific antiviral therapies are available for 2019-nCoV. The National Health Commission recommends the following treatment for infected individuals.8
Initially, interferons-α nebulization, broad-spectrum antibiotics, and anti-viral drugs were used to reduce the viral load,,, however, only remdesivir has shown promising impact against the virus. Remdesivir only and in combination with chloroquine or interferon beta significantly blocked the SARS-CoV-2 replication and patients were declared as clinically recovered,,. Various other anti-virals are currently being evaluated against infection. Nafamostat, Nitazoxanide, Ribavirin, Penciclovir, Favipiravir, Ritonavir, AAK1, Baricitinib, and Arbidol exhibited moderate results when tested against infection in patients and in-vitro clinical isolates,,,. Several other combinations, such as combining the antiviral or antibiotics with traditional Chinese medicines were also evaluated against SARS-CoV-2 induced infection in humans and mice. Recently in Shanghai, doctors isolated the blood plasma from clinically recovered patients of COVID-19 and injected it in the infected patients who showed positive results with rapid recovery. In a recent study, it was identified that monoclonal antibody (CR3022) binds with the spike RBD of SARS-CoV-2. This is likely due to the antibody’s epitope not overlapping with the divergent ACE2 receptor-binding motif. CR3022 has the potential to be developed as a therapeutic candidate, alone or in combination with other neutralizing antibodies for the prevention and treatment of COVID-19 infection.
Supportive care with appropriate infection control is the mainstay of current CDC treatment guidelines for 2019-nCoV. There are not yet any approved antiviral treatments for 2019-nCoV. Emergency Use Authorizations (EUA) for compassionate use cases may be forthcoming from the US federal government for normally unapproved treatments. Supportive treatment predominantly includes respiratory support, hydration, and antipyretics. General treatment for severe cases should focus on the preservation of vital organ function. In the future, antiviral medications may be available. If a secondary bacterial infection such as pneumonia develops, targeted antibiotics are indicated.
Based on the experience of fighting the epidemic SARS-CoV and MERS-CoV previously, we may learn some lessons for some treatment strategies against coronavirus. Antiviral drugs and systemic corticosteroid treatment commonly used in clinical practice previously, including neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, etc), ganciclovir, acyclovir, and ribavirin, as well as methylprednisolone [46, 75] for influenza virus, are invalid for COVID-19 and not recommended. Remdesivir (GS-5734) is a 1′-cyano-substituted adenosine nucleotide analog prodrug and shows broad-spectrum antiviral activity against several RNA viruses. Based on the data collected from in vitro cell line and mouse model, remdesivir could interfere with the NSP12 polymerase even in the setting of intact ExoN proofreading activity. Remdesivir has been reported to treat the first US case of COVID-19 successfully. Chloroquine is a repurposed drug with great potential to treat COVID-19. Chloroquine has been used to treat malaria for many years, with a mechanism that is not well understood against some viral infections. Several possible mechanisms are investigated: Chloroquine can inhibit pH-dependent steps of the replication of several viruses, with a potent effect on SARS-CoV infection and spread. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of TNF-α and IL-6. It also works as a novel class of autophagy inhibitor, which may interfere with viral infection and replication. Several studies have found that chloroquine interfered with the glycosylation of cellular receptors of SARS-CoV and functioned at both entry and at post-entry stages of the COVID-19 infection in Vero E6 cells. A combination of remdesivir and chloroquine was proven to effectively inhibit the recently emerged SARS-CoV-2 in vitro.
Scientists previously confirmed that the protease inhibitors lopinavir and ritonavir, used to treat infection with human immunodeficiency virus (HIV), could improve the outcome of MERS-CoV and SARS-CoV patients. It has reported that β-coronavirus viral loads of a COVID-19 patient in Korea significantly decreased after lopinavir/ritonavir (Kaletra®, AbbVie, North Chicago, IL, USA) treatment. Additionally, clinicians combined Chinese and Western medicine treatment including lopinavir/ritonavir (Kaletra®), arbidol, and Shufeng Jiedu Capsule (SFJDC, a traditional Chinese medicine) and gained significant improvement in pneumonia associated symptoms in Shanghai Public Health Clinical Center, China.The other antiviral drugs include nitazoxanide, favipiravir, nafamostat, and so on (See Table 1 for details).
Treatment principle: based on symptomatic treatment, actively prevent and treat complications, treat basic diseases, prevent secondary infection, and timely apply organ function support.Respiratory support: apply noninvasive mechanical ventilation for two hours, if the condition is not improved, or the patient is intolerable to noninvasive ventilation, accompanied with increased airway secretions, severe coughing, or unstable hemodynamics, the patient should be transferred to invasive mechanical ventilation in time. The “lung-protective ventilation strategy” with low tidal volume should be adopted in invasive mechanical ventilation to reduce ventilator-associated lung injury. If necessary, ventilation in the prone position, recruitment maneuver, or extracorporeal membrane oxygenation (ECMO) can be used.Circulation support: improve microcirculation based on full fluid resuscitation, use vasoactive drugs, and apply hemodynamic monitoring if necessary.Others: according to the degree of dyspnea and the progress of chest imaging, use glucocorticoids appropriately for a short time (3–5 days) with the recommended dose no more than what is equivalent to methylprednisolone 1–2 mg/kg·day.
As the case count and death toll of the epidemic continue to increase, it becomes imperative to identify therapeutic options for COVID-19. Once in vitro and in vivo systems have been established, these tests can proceed. Drug repurposing may prove to be the best strategy for quick development of novel therapeutic options. A novel therapeutic being tested is remdesivir (19, 20), which in combination with chloroquine has been found to inhibit SARS-CoV-2 growth in vitro (21). It was recently announced by the NIH that remdesivir would be entering phase 3 clinical trials in humans. Chloroquine has also been reported to be effective in patients in China (22). A combination of lopinavir and ritonavir is also under investigation in human cases of COVID-19 in China. Many more people will need to be treated with these drugs to determine true efficacy, but they are promising leads.
Given the lack of effective antiviral therapy against COVID-19, current treatments mainly focused on symptomatic and respiratory support according to the Diagnosis and Treatment of Pneumonia Caused by COVID-19 (updated to version 6) issued by National Health Commission of the People’s Republic of China. Nearly all patients accepted oxygen therapy, and WHO recommended extracorporeal membrane oxygenation (ECMO) to patients with refractory hypoxemia. Rescue treatment with convalescent plasma and immunoglobulin G are delivered to some critical cases according to their conditions.
There is no available vaccine against COVID-19, while previous vaccines or strategies used to develop a vaccine against SARS-CoV can be effective. Recombinant protein from the Urbani (AY278741) strain of SARS-CoV was administered to mice and hamsters, resulted in the production of neutralizing antibodies and protection against SARS-CoV,. The DNA fragment, inactivated whole virus or live-vectored strain of SARS-CoV (AY278741), significantly reduced the viral infection in various animal models,,,,,. Different other strains of SARS-CoV were also used to produce inactivated or live-vectored vaccines which efficiently reduced the viral load in animal models. These strains include, Tor2 (AY274119),, Utah (AY714217), FRA (AY310120), HKU-39849 (AY278491),, BJ01 (AY278488),, NS1 (AY508724), ZJ01 (AY297028), GD01 (AY278489) and GZ50 (AY304495). However, there are few vaccines in the pipeline against SARS-CoV-2. The mRNA based vaccine prepared by the US National Institute of Allergy and Infectious Diseases against SARS-CoV-2 is under phase 1 trial. INO-4800-DNA based vaccine will be soon available for human testing. Chinese Centre for Disease Control and Prevention (CDC) working on the development of an inactivated virus vaccine,. Soon mRNA based vaccine’s sample (prepared by Stermirna Therapeutics) will be available. GeoVax-BravoVax is working to develop a Modified Vaccina Ankara (MVA) based vaccine. While Clover Biopharmaceuticals is developing a recombinant 2019-nCoV S protein subunit-trimer based vaccine.
Although research teams all over the world are working to investigate the key features, pathogenesis and treatment options, it is deemed necessary to focus on competitive therapeutic options and cross-resistance of other vaccines. For instance, there is a possibility that vaccines for other diseases such as rubella or measles can create cross-resistance for SARS-CoV-2. This statement of cross-resistance is based on the observations that children in china were found less vulnerable to infection as compared to the elder population, while children are being largely vaccinated for measles in China.
After an initial push to look for therapeutic and vaccine options to help treat and prevent COVID-19, it will be important to better understand the host response to infection and the pathology of disease. A prerequisite step will of course be the development of appropriate animal models. Better understanding of how SARS-CoV-2 causes pathology and the way in which the host responds may help direct further therapeutic avenues. Understanding how comorbidities such as diabetes impact the host response to infection will also be important to better understand COVID-19.
So far, Chinese physicians have developed an empirical treatment and triage algorithm based on their experience with patients from Wuhan (Zhang, et al., 2020b). This triage scheme proposes a separation of patients into those receiving home treatment and those receiving treatments for regular community acquired pneumonia. Suspected viral pneumonia cases are tested for the novel coronavirus under isolated observation; in case of dyspnoea and hypoxia development, supplemental oxygen supply will be given. The viral pneumonia patients were treated with arbidol, approved in Russia and China for influenza treatment. When the diagnosis of the novel coronavirus has been confirmed, a patient has been transferred to a specially designated hospital. The efficacy of arbidol against coronavirus is not, however, well substantiated scientifically or clinically.
Emergency conditions call for a need for speed in drug development. A promising approach is the repurposing of drugs tried against coronaviruses from previous outbreaks with SARS or Middle East Respiratory Syndrome (MERS) coronavirus (Li and De Clercq, 2020). MERS, in contrast with SARS, is a coronavirus zoonosis of likely bat origin with camels as intermediate hosts that is still circulating. The four non‐structural proteins that were preclinically explored as antiviral targets against SARS and MERS coronaviruses are reasonably well conserved in the novel coronavirus, raising hopes for this approach. However, patient enrolment for a MERS treatment trial with lopinavir (an antiretroviral proteinase inhibitor)/ritonavir (cytochrome P450 inhibitor to prolong the half‐life of lopinavir) and interferon‐β1b (MIRACLE) is still ongoing. Numerous clinical trials have been registered in China to test different compounds or combinations of compounds against the new coronavirus infection. Test drugs range from antiviral nucleotide analogs over viral protease inhibitors to traditional Chinese herbal medicine (e.g. Forsythia derivative Lian qiao) (Maxmen, 2020). It is important to start the tests now to get the informative patients enrolled and tested before the current epidemic stops. WHO suggests a shared standard clinical protocol for these trials to make the outcomes comparable.
With virus neutralization tests now at hand, Chinese researchers have already done in vitro efficacity tests against the novel coronavirus (Wang et al., 2020a). The most promising effects were observed with the nucleotide analog remdesivir and the anti‐malaria compound chloroquine. Both showed inhibition of the novel coronavirus in the low micromolar concentration range. Remdesivir acts on viral RNA transcription at the postviral entry level, while chloroquine needs to be applied at the beginning of the infection; chloroquine’s action on lysosome membranes might interfere with the viral entry–fusion events. It is of note that the nucleotide analog remdesivir had a better activity against MERS coronavirus than the protease inhibitor lopinavir combined with ritonavir, and this both in cell culture and in mouse infections. In the mouse MERS infection model remdesivir improved pulmonary function, reduced lung viral loads and decreased severe lung pathology (Sheahan et al., 2020). In addition, remdesivir given prophylactically to MERS virus‐challenged rhesus monkeys significantly reduced viral titres in the lung and prevented lung pathology as assessed by histology or by X‐ray radiographs when compared to control animals (de Wit et al., 2020). Treatment with remdesivir 12 h after viral challenge had a more limited protective effect in rhesus monkeys. In early February, two randomized, placebo‐controlled clinical trials testing the therapeutic efficacy of remdesivir were started in China. One trial will enrol 308 patients with mild or moderate novel coronavirus disease (ClinicalTrials.gov: NCT04252664) and the other 453 patients with severe disease (ClinicalTrials.gov: NCT04257656). The enrolment is planned to be completed by end of April and May 2020 respectively. The importance of evidence‐based treatments proven in controlled clinical trials must be stressed since in the SARS epidemic untested drug treatment seems to have done more harm than no treatment (A. Danchin, personal communication). Therapeutics directed against immunopathological host responses might have a treatment value in view of the ‘cytokine storm’ seen in some patients with novel coronavirus infections.
COVID-19 related pediatric disease has an array of symptomatic presentations and outcomes. While the majority of those on the spectrum of the disease will recover well with symptomatic care, this article serves to highlight how myocardial disease, lung pathology, and the substantially higher risk of mortality in certain sub-populations should be kept in the mind. As such, based on our limited data, the authors favor an approach that relies on ensuring potential markers of poorer outcomes, such as evidence of organ dysfunction, evidence of superimposed bacterial infection, and other metrics highlighted in the article, are screened for at an earlier stage. For those children that are deemed sick enough to require admission, the potential need for further investigation for myocardial disease, coagulopathy, and organ damage should be kept in mind.
A recent study has demonstrated invitro efficacy of chloroquine and remdesivir in inhibiting replication of SARS-COV2. Moreover, emerging reports from China suggests that chloroquine has shown a superiority in reducing both the severity and the duration of clinical disease without significant adverse events in almost one hundred patients. In light of this results, an expert consensus group in China has recommended chloroquine for COVID-19 treatment.
Standard nosocomial preventive control measures are in urgent need to block further spreading of the disease. The in-hospital preventive control measures should vary among patients, close contacts, and health care workers in precision medicine approach.
The triage of patients by disease severity is the priority; patients should be triaged as soon as possible when they come to the clinic or hospital, depending on disease severity.
The infection is defined as severe when a patient meets any of the criteria established by the Diagnosis and Treatment Scheme issued by the National Health Commission4:
(i) A respiration rate greater than 30 breaths per minute, dyspnea;(ii) A blood oxygen saturation of <93% in resting state;(iii) A PaO2:FiO2 ratio (the ratio of arterial oxygen partial pressure to fractional inspired oxygen) of <300 mm Hg;(iv) Radiologic evidence of foci in multiple lobes or more than a 50% progression of lung inflammation.
The infection is defined as critical when any one of following is met:
(i) Respiratory failure and the need for mechanical ventilation;(ii) Shock;(iii) Multiple organ failure and admission to the intensive care unit.
According to the Diagnosis and Treatment Scheme, timely isolation of suspected cases is essential.4 Patients suspected of infection with 2019-nCoV should be examined only in an isolated area where health workers are protected by protective clothing with adequate protection level.
Once the virus is detected, patients should be admitted to a negative-pressure isolation ward or to private rooms. Several researchers have found that confinement to an isolation ward can prevent the airborne spread of pathogens.15 Patients with mild symptoms can be observed in separate isolation wards or during home quarantine if hospital beds are unavailable. However, all critically ill patients should be immediately admitted to isolation wards with environmental negative pressure equipment and medical protection.
Health care workers should be given appropriate equipment, including respirators (NIOSH-certified N95, EU FFP2, or higher-level protection), eye protection (goggles or a face shield), and clean, long-sleeved gown and gloves.12 Equipment should be thoroughly disinfected between patients, and health workers should wash their hands for at least 20 seconds after patient contact. Occupational exposures in workplace should be immediately reported to the infection control unit at the hospital, and the exposed doctor or nurse should be quarantined in the hospital.
People in close contact with patients or with those suspected of 2019-nCoV infection should be examined immediately if they experience respiratory symptoms, such as fever, or related symptoms. Even if their test result is negative, they should be temporarily isolated at home for 14 days after the last contact with confirmed patients—since 14 days is the disease maximum incubation period.16 The National Health Commission also recommends that members of the public should wash their hands with soap and water for at least 20 seconds and, when going outside, wear a medical face mask and cover their nose and mouth with a tissue, arm, or hand when coughing or sneezing.
The recommended dose for COVID-19 is the 400/100 mg bid (the standard dose used for HIV therapy). In case of swallowing difficulties or unconscious patient the oral solution of lopinavir/ritonavir should be administrated (tablets cannot be crushed).
Several attempts have been made to develop vaccines against human coronavirus infection in the past decades. But the degree of cross-protection provided by such vaccines is greatly limited due to the extensive diversity in antigenic variants even within the strains of a phylogenetic sub-cluster (Graham et al. 2013). As for MERS and SARS coronaviruses, there is no licensed specific antiviral treatment or vaccine available till now. However, few of the advances made in developing vaccines and therapeutics for SARS-CoV and MERS-CoV could be exploited for the countering 2019-nCoV. But since the efforts to design and develop any vaccine or antiviral agent to tackle the presently emerging coronavirus pathogen would take some time, therefore till then we need to rely extensively on enforcing highly effective prevention and control measures to minimize the risk of 2019-nCoV transmission and spread to the best feasible extent (Cheng et al. 2020). Majority of the vaccines that are being developed for coronaviruses targets the Spike glycoprotein or S protein (Graham et al. 2013). This is mainly because of the fact that S protein is the major inducer of neutralizing antibodies (Jiang et al. 2005). Several kinds of vaccines and antiviral drugs that are based on S protein have been previously evaluated. Among them, the S protein-based vaccines include full-length S protein vaccines, viral vector-based vaccine, DNA-based vaccine, recombinant S protein-based and recombinant RBD protein-based vaccines. Whereas S protein based antiviral therapies include RBD–ACE2 blockers, S cleavage inhibitors, fusion core blockers, neutralizing antibodies, protease inhibitors, S protein inhibitors, and small interfering RNAs (Du et al. 2009). Even though such therapeutic options have proven efficacy in the in vitro studies, however most of these haven’t undergone randomized animal or human trials and hence are of limited use in our present 2019-nCoV scenario. Remdesivir is a novel nucleotide analog prodrug that was intended to be used for the treatment of Ebola virus disease. It also has anti-coronavirus activity due to its inhibitory action on the SARS-CoV and MERS-CoV replication (Sheahan et al. 2017). At present, efforts are being made to identify and develop monoclonal antibodies that are specific and effective against 2019-nCoV. Combination therapy with 2019-nCoV specific monoclonal antibodies and remdesivir can be considered as the ideal therapeutic option for 2019-nCoV (Cohen 2020). Further evaluation is required before confirming the efficacy of such combination therapy. A variety of different therapeutic and vaccine designing approaches against coronaviruses are being explored and yet to be evaluated in terms of their potency, efficacy and safety, but hopefully the process of evaluation will be accelerated in the coming days (Cyranoski 2020; Lu 2020; Pillaiyar et al. 2020; Zaher et al. 2020).
As outlined above, admission criteria for 2019-nCoV are similar to that of other patients. If patients do not meet medical criteria for hospitalization, they may be discharged home with isolation precautions and continued observation. EPs must notify local public health authorities so appropriate monitoring and community protective measures can be instituted.
Transmission of 2019-nCoV probably occurs through spreading airborne and contact. Aerosol and fecal–oral transmission remain unclear. Public health measures, including quarantining in the community as well as timely diagnosis and strict adherence to universal precautions in health care settings, were critical in reducing the transmission of 2019-nCoV.
For healthcare personnel, to minimize the chance of exposures to 2019-nCoV needs to follow the standard of contact and airborne precautions, personal protection including gloves, gowns, respiratory protection, eye protection, and hand hygiene. Some procedures performed on 2019-nCoV infected patients could generate infectious aerosols, e.g., nasopharyngeal specimen collection, sputum induction, and open suctioning of airways should be performed cautiously. If performed, these procedures should take place in an airborne infection isolation room, and personnel should use respiratory and eye protection, and hand hygiene. In addition, management of environmental infection control including laundry, food service utensils, and medical waste should also be performed. Artificial Intelligence (AI), alternative selection to reducing infection for medical personnel, should be explored (Joint developed by Respiratory Research Institution of Zhongshan Hospital, Fudan University and RealMax Ltd Co), which will be benefit for remote guidance of practices.
At present, there are no drugs available that can target SARS-CoV-2. Therefore, treatment was focused on symptomatic and respiratory support. All the children inhaled interferon and one of the twins was prescribed ribavirin (10–15 mg/kg.d) in addition. Ten (71.4%) adults with pneumonia were treated Lopinaviritonavir (200/50 mg, 2 tablets, bid), interferon and Chinese medicine. The patients with higher infection index (such as CRP, PCT, ESR, SAA, IL-6) were prescript antibiotics for 5–7 days in addition. All the nine children and 14 adult patients recovered in 2–3 weeks and were discharged after two negative nucleic acid tests. Unfortunately, our follow up found that there were five discharged children were admitted again before we submit this article because their stool showed positive result in SARS-CoV-2 PCR. Meanwhile, all their families were negative in all the specimen.
Control number of visiting patients
Reducing outpatient visitors will be critical to decrease cross-infection. Patients are asked to make an appointment before going to the hospital.
b)Make good use of online platforms
Online platforms such as the hospital’s official website or WeChat should be well utilized. Online platforms can provide notice for decreasing outpatient visits and updates on COVID-19, help patients distinguish between urgent and non-urgent ocular diseases, recommend safe and self-executing treatments for common nonurgent ocular diseases, remind patients to prepare correct personal protection before coming to the hospital, advise patients with suspicious symptoms such as fever to first visit the screening center before coming to the ophthalmic clinic, and give targeted guidance for common chronic eye diseases during this period.
c)Online ordering and delivery of prescribed medication
Both hospital and patients can benefit from submitting prescriptions online and having patient medication sent to their doorsteps via non-contact delivery.
Prevention and control strategies and methods are reported at three levels: national level, case-related population level, and general population level. At the national level, the National Health Commission of the People’s Republic of China issued the “No.1 announcement” on 20 January 2020, which officially included the COVID-19 into the management of class B legal infectious diseases, and allowed for class A infectious disease preventive and control measures to be implemented. Under this policy, medical institutes can adopt isolation treatment and observation protocols to prevent and control the spread of the COVID-19. On 22 January 2020, the National Health Commission published national guidelines for the prevention and control of COVID-19 for medical institutes to prevent nosocomial infection. On 28 January 2020, the National Health Commission issued protocols for rapid prevention and control measures in order to effectively contain the spread of the epidemic through a “big isolation and big disinfection” policy during the Chinese Spring Festival. National-level strategies have also been issued with targeted measures for rural areas (issued on 28 January 2020) and the elderly population (issued on 31 January 2020) [48, 49]. Several public health measures that may prevent or slow down the transmission of the COVID-19 were introduced; these include case isolation, identification and follow-up of contacts, environmental disinfection, and use of personal protective equipment.
To date, no specific antiviral treatment has been confirmed to be effective against COVID-19. Regarding patients infected with COVID-19, it has been recommended to apply appropriate symptomatic treatment and supportive care [3, 16]. There are six clinical trials registered in both the International Clinical Trials Registry platform and the Chinese Clinical Trial Registry to evaluate the efficacy or safety of targeted medicine in the treatment or prognosis of COVID-19 (Additional file 2) [51, 52]. Regarding infected patients with COVID-19, it has been recommended to apply appropriate symptomatic treatment and supportive care [3, 16]. Studies have also explored the prevention of nosocomial infection and psychological health issues associated with COVID-19. A series of measures have been suggested to reduce nosocomial infection, including knowledge training for prevention and control, isolation, disinfection, classified protections at different degrees in infection areas, and protection of confirmed cases [18, 50, 53]. Concerning psychological health, some suggested psychological intervention for confirmed cases, suspected cases, and medical staff [18, 54].
For the general population, at this moment there is no vaccine preventing COVID-19. The best prevention is to avoid being exposed to the virus. Airborne precautions and other protective measures have been discussed and proposed for prevention. Infection preventive and control (IPC) measures that may reduce the risk of exposure include the following: use of face masks; covering coughs and sneezes with tissues that are then safely disposed of (or, if no tissues are available, use a flexed elbow to cover the cough or sneeze); regular hand washing with soap or disinfection with hand sanitizer containing at least 60% alcohol (if soap and water are not available); avoidance of contact with infected people and maintaining an appropriate distance as much as possible; and refraining from touching eyes, nose, and mouth with unwashed hands.
The WHO also issued detailed guidelines on the use of face masks in the community, during care at home, and in the health care settings of COVID-19. In this document, health care workers are recommended to use particulate respirators such as those certified N95 or FFP2 when performing aerosol-generating procedures and to use medical masks while providing any care to suspected or confirmed cases. According to this guideline, individuals with respiratory symptoms are advised to use medical masks both in health care and home care settings properly following the infection prevention guidelines. According to this guideline, an individual without respiratory symptoms is not required to wear a medical mask when in public. Proper use and disposal of masks is important to avoid any increase in risk of transmission.
In addition to articles published in research journals, the China CDC published a guideline to raise awareness of the prevention and control of COVID-19 among the general population. The key messages of the guideline include causes, how to choose and wear face masks, proper hand washing habits, preventive measures at different locations (e.g., at home, on public transportation, and in public space), disinfection methods, and medical observation at home. In addition to scientific knowledge on ways to handle the COVID-19 outbreak, the guideline also suggests ways to eliminate panic among the general population.
In December 2019, a novel pneumonia caused by a previously unknown pathogen emerged in Wuhan, a city of 11 million people in central China. The initial cases were linked to exposures in a seafood market in Wuhan.1 As of January 27, 2020, the Chinese authorities reported 2835 confirmed cases in mainland China, including 81 deaths. Additionally, 19 confirmed cases were identified in Hong Kong, Macao and Taiwan, and 39 imported cases were identified in Thailand, Japan, South Korea, United States, Vietnam, Singapore, Nepal, France, Australia and Canada. The pathogen was soon identified as a novel coronavirus (2019-nCoV), which is closely related to sever acute respiratory syndrome CoV (SARS-CoV).2 Currently, there is no specific treatment against the new virus. Therefore, identifying effective antiviral agents to combat the disease is urgently needed.
An efficient approach to drug discovery is to test whether the existing antiviral drugs are effective in treating related viral infections. The 2019-nCoV belongs to Betacoronavirus which also contains SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Several drugs, such as ribavirin, interferon, lopinavir-ritonavir, corticosteroids, have been used in patients with SARS or MERS, although the efficacy of some drugs remains controversial.3 In this study, we evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir (GS-5734) and favipiravir (T-705) against a clinical isolate of 2019-nCoV in vitro.
Standard assays were carried out to measure the effects of these compounds on the cytotoxicity, virus yield and infection rates of 2019-nCoVs. Firstly, the cytotoxicity of the candidate compounds in Vero E6 cells (ATCC-1586) was determined by the CCK8 assay. Then, Vero E6 cells were infected with nCoV-2019BetaCoV/Wuhan/WIV04/20192 at a multiplicity of infection (MOI) of 0.05 in the presence of varying concentrations of the test drugs. DMSO was used in the controls. Efficacies were evaluated by quantification of viral copy numbers in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR) and confirmed with visualization of virus nucleoprotein (NP) expression through immunofluorescence microscopy at 48 h post infection (p.i.) (cytopathic effect was not obvious at this time point of infection). Among the seven tested drugs, high concentrations of three nucleoside analogs including ribavirin (half-maximal effective concentration (EC50) = 109.50 μM, half-cytotoxic concentration (CC50) > 400 μM, selectivity index (SI) > 3.65), penciclovir (EC50 = 95.96 μM, CC50 > 400 μM, SI > 4.17) and favipiravir (EC50 = 61.88 μM, CC50 > 400 μM, SI > 6.46) were required to reduce the viral infection (Fig. 1a and Supplementary information, Fig. S1). However, favipiravir has been shown to be 100% effective in protecting mice against Ebola virus challenge, although its EC50 value in Vero E6 cells was as high as 67 μM,4 suggesting further in vivo studies are recommended to evaluate this antiviral nucleoside. Nafamostat, a potent inhibitor of MERS-CoV, which prevents membrane fusion, was inhibitive against the 2019-nCoV infection (EC50 = 22.50 μM, CC50 > 100 μM, SI > 4.44). Nitazoxanide, a commercial antiprotozoal agent with an antiviral potential against a broad range of viruses including human and animal coronaviruses, inhibited the 2019-nCoV at a low-micromolar concentration (EC50 = 2.12 μM; CC50 > 35.53 μM; SI > 16.76). Further in vivo evaluation of this drug against 2019-nCoV infection is recommended. Notably, two compounds remdesivir (EC50 = 0.77 μM; CC50 > 100 μM; SI > 129.87) and chloroquine (EC50 = 1.13 μM; CC50 > 100 μM, SI > 88.50) potently blocked virus infection at low-micromolar concentration and showed high SI (Fig. 1a, b).
Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV5) infection in cultured cells, mice and nonhuman primate (NHP) models. It is currently under clinical development for the treatment of Ebola virus infection.6 Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination.7 Our time-of-addition assay showed remdesivir functioned at a stage post virus entry (Fig. 1c, d), which is in agreement with its putative anti-viral mechanism as a nucleotide analogue. Warren et al. showed that in NHP model, intravenous administration of 10 mg/kg dose of remdesivir resulted in concomitant persistent levels of its active form in the blood (10 μM) and conferred 100% protection against Ebola virus infection.7 Our data showed that EC90 value of remdesivir against 2019-nCoV in Vero E6 cells was 1.76 μM, suggesting its working concentration is likely to be achieved in NHP. Our preliminary data (Supplementary information, Fig. S2) showed that remdesivir also inhibited virus infection efficiently in a human cell line (human liver cancer Huh-7 cells), which is sensitive to 2019-nCoV.2
Chloroquine, a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad-spectrum antiviral drug.8,9 Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV.10 Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells (Fig. 1c, d). Besides its antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo. Chloroquine is widely distributed in the whole body, including lung, after oral administration. The EC90 value of chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM, which can be clinically achievable as demonstrated in the plasma of rheumatoid arthritis patients who received 500 mg administration.11 Chloroquine is a cheap and a safe drug that has been used for more than 70 years and, therefore, it is potentially clinically applicable against the 2019-nCoV.
Our findings reveal that remdesivir and chloroquine are highly effective in the control of 2019-nCoV infection in vitro. Since these compounds have been used in human patients with a safety track record and shown to be effective against various ailments, we suggest that they should be assessed in human patients suffering from the novel coronavirus disease.
Practice social distancing in the registration and waiting areas
Patients should stay at least 1.5 m apart from one another when in registration and waiting area.
b)Limit the number of people in the room
Keeping 1 doctor and 1 patient in 1 room is required except for visually impaired patients, patients with communication/mobility difficulties or parents of small children. The room should be well-ventilated. After each patient’s consultation or treatment, the used instruments such as slit lamp must be disinfected immediately.
c)Reduce outpatient examinations
Operation of many ophthalmic equipment requires close proximity, reducing outpatient examinations helps protect both doctors and patients.
Micro-aerosols can be generated when non-contact tonometry is used. Air-puff ophthalmic equipment like non-contact tonometry should be avoided if unnecessary. It is advised to place the tonometer in a ventilated place, and that the measurement interval between patients should be extended. During the measurement, patients should wear a face mask.
Direct ophthalmoscope examination is not recommended, which can be replaced by slit light lens or fundus photography. Protective shields (better transparent) should be installed on slit lamps and any other equipment used which needs close doctor-patient contact. Both doctor and patient should refrain from bare face-to-face speaking during any examination.
Traditional Chinese herbal medicine involving extracts from herbs, single or mixture herbal formulas regardless of their compositions or forms. Traditional Chinese herbal medicine combined with one or more other pharmacological intervention will also be included. There will be no restrictions with respect to dosage, frequency, duration, or follow-up time of treatment.