COVID-19 RESEARCH STUDIES FACT SHEET

ASM is a statutory body of eminent Malaysian scientists elected for their contributions to science. At this period of unprecedented uncertainty due to the Covid-19 pandemic, ASM has established a Special Interest Group (SIG) on COVID-19 comprising Fellows of the Academy, Young Scientists Network (YSN-ASM) and Top Research Scientists Malaysia (TRSM) who are the expert network of ASM to review key research findings around the world and issue fact sheets to help the public understand the implications (and limitations) of the research studies.

What is the current medication for COVID-19?

Currently, there is no antiviral medication approved to treat COVID-19. Treatment focuses on managing and relieving the symptoms. New medicines and vaccines are currently under clinical trials[1].

How are COVID-19 patients treated?

Not all COVID-19 positive patients require medical care. Patients with mild disease (uncomplicated upper respiratory tract infection with non-specific symptom) do not require hospital care while given antipyretics for fever. Yet, isolation is necessary to contain the virus transmission to others. Patients with severe disease (fever or suspected respiratory infection with either respiratory rate > 30 breaths/min or severe respiratory distress or normal blood oxygen saturation levels (SpO2 ) ≤ 93% on room air) will be hospitalised and medical care will be provided including supplemental oxygen therapy[2].

When can a patient with positive COVID-19 be discharged from the hospital?

A patient can be discharged from the hospital when clinically recovered upon two negative tests, at least 24 hours apart, at least eight days after onset of symptoms. It can also depend on the case-by-case basis upon consultation from the medical authorities[2].

There is a possibility of positive detection again after hospital discharge while remaining asymptomatic [3]. This could be due to prolonged viral shedding (median duration of 20 days)[4] which is highly associated with male gender, delayed admission, concomitant hypertension medication and invasive mechanical ventilation [5]. Hence, it is highly recommended to continue self-isolation at home or a safe place for an additional 14 days.

“What is viral shedding? It is a process of excreting viral progeny from the host.”

Are there any drugs available to treat COVID-19?

Several drugs showed promising in vitro outcome but had limited clinical findings. These drugs (except remdesivir) are registered with the National Pharmaceutical Regulatory Agency (NPRA) for the treatment of other illnesses and are under clinical trials for the treatment of COVID-19. These drugs are also currently under trials to investigate if they can reduce the viral shedding duration and reduce the transmission. Brief pharmacological aspects of these drugs as follows.

“What is NPRA? NPRA is an agency under the Ministry of Health, Malaysia that ensures the quality and safety of pharmaceutical and cosmetic products before marketing in Malaysia.”

1

CHLOROQUINE

Chloroquine is an antimalarial and amebicide drug which is approved for the prevention and treatment of malaria and amebiasis [1, 6]. Mechanism of action: The target of the drug has not been clearly elucidated. The drug believed to alter pH levels at the surface of cell membrane. This inhibits the fusion of the virus to the cell membrane which prevents the entry and transport of the virus [1, 7].
2

HYDROXYCHLOROQUINE

Hydroxychloroquine is a less toxic derivate of chloroquine. It is prescribed to treat autoimmune diseases, i.e. systemic lupus erythematosus and rheumatoid arthritis. Hydroxychloroquine has been reported to be more potent than chloroquine at inhibiting the SARS -CoV-2 virus [8]. Mechanism of action: It is not well elucidated but suggested to be similar to the parent compound, chloroquine [9, 10].
3

LOPINAVIR / RITONAVIR

Lopinavir/ritonavir is a fixeddose combination medication (lopinavir with a low dose of ritonavir) for the treatment and prevention of HIV. Mechanism of action: Lopinavir acts on a protease enzyme involved in the coronavirus replication. Protease enzyme is crucial in the formation of new viral proteins and enzymes. Ritonavir inhibits the lopinavir-metabolising enzymes to enhance lopinavir exposure [11].
4

RIBAVIRIN

Ribavirin in combination with other antiviral medications used for the treatment of hepatitis C virus and respiratory syncytial virus. Mechanism of action: The drug inhibits the replication of viruses via interfering with polymerase and dehydrogenase enzymes [12].
5

TOCILIZUMAB

Tocilizumab is a biopharmaceutical drug, monoclonal antibody interleukin-6 (IL-6) receptor antagonist. It is used to treat rheumatoid arthritis. Mechanism of action: Tocilizumab binds to IL-6 receptors to inhibit chronic inflammation in the human cells [13].
6

REMDESIVIR

Remdesivir is still at the investigational stage for the treatment of Ebola virus disease and Marburg virus infections which gained attention for the treatment of COVID-19 virus. NPRA has not approved this drug. Mechanism of action: Remdesivir acts on viral RNA polymerase enzymes to inhibit viral replication [14].

Is there any traditional medicine available?

Up to date, no traditional medicine, including traditional Chinese medicine (TCM) or Ayurvedic medication, has been approved for the treatment of COVID-19. Though one TCM study reported an effective cure rate of over 90 % against COVID-19 cases [15], the findings are anecdotal and require large clinical trials to prove its efficacy and safety.

Take home message

Up to date, there is no well-established or proven medication for the treatment of COVID-19. Clinical trials are ongoing for the discovery of a definitive treatment option.

Self-medication is strongly prohibited. It is not only illegal, but it is also highly dangerous. Public MUST consult the physicians before undertaking any treatments.

Prevention is better than cure. Social distancing, regular handwashing with soap, wearing a face mask at public places and disinfecting high-touch surfaces are the most effective ways to prevent the infection.

“What is self-medication? A process of medicating oneself without consulting a health care professional.”

Authors:

Dr Thaigarajan Parumasivam
School of Pharmaceutical Sciences, Universiti Sains Malaysia
YSN-ASM Affiliate

 

References

  1. Dong, L., S. Hu, and J. Gao, Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discoveries & Therapeutics, 2020. 14(1): p. 58-60.
  2. WHO. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected, Interim guide. 2020 [cited 03/04/2020].
  3. Lan, L., et al., Positive RT-PCR test results in patients recovered from COVID-19. JAMA, 2020. 323(15): p. 1502-1503.
  4. Zhou, F., et al., Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet, 2020. 395(10229): p. 1054-1062.
  5. Xu, K., et al., Factors associated with prolonged viral RNA shedding in patients with COVID-19. Clinical Infectious Diseases, 2020. ciaa351.
  6. Liu, J., et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery, 2020. 6(1): p. 16.
  7. Singh, A.K., et al., Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes & metabolic syndrome, 2020. 14(3): p. 241-246.
  8. Yao, X., et al., In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases : an official publication of the Infectious Diseases Society of America, 2020: p. ciaa237.
  9. Fox, R.I., Mechanism of action of hydroxychloroquine as an antirheumatic drug. Seminars in Arthritis and Rheumatism, 1993. 23(2, Supplement 1): p. 82-91.
  10. Savarino, A., et al., New insights into the antiviral effects of chloroquine. The Lancet Infectious Diseases, 2006. 6(2): p. 67-69.
  11. Cao, B., et al., A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. New England Journal of Medicine, 2020.
  12. Khalili, J.S., et al., Novel coronavirus treatment with ribavirin: Groundwork for evaluation concerning COVID-19. Journal of Medical Virology, 2020. 10.1002/jmv.25798(n/a).
  13. Sanders, J.M., et al., Pharmacologic treatments for Coronavirus Disease 2019 (COVID-19): A review. JAMA, 2020. 10.1001/jama.2020.6019.
  14. Gordon, C.J., et al., The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. Journal of Biological Chemistry, 2020. NEJMoa2001282.
  15. Ren, J.-l., A.-H. Zhang, and X.-J. Wang, Traditional Chinese medicine for COVID-19 treatment. Pharmacological Research, 2020. 155: p. 104743.

COVID-19 Epidemic and Pandemic

Epidemic and pandemic both refer to the sudden occurrence of a disease that affects a large number of people at the same time. The difference between the two terms lies on how widespread the disease is.

EPIDEMIC

If the disease occurs in a large region (such as a city or even a country), it is referred to as an epidemic.

PANDEMIC

If the disease has spread over many countries and continents, it is called a pandemic.

In fact, the World Health Organization (WHO) defines a pandemic as “the worldwide spread of a new disease”[1].

COVID-19 was first reported in Wuhan, China in late December 2019. At the beginning of the COVID-19 outbreak, the disease was called an epidemic because it occurred almost exclusively in Wuhan, China, and a few other countries such as South Korea, Japan, and Italy[2]. However, on 11 March 2020, the WHO declared COVID-19 a pandemic when the infection has spread to over 100 countries across all continents with no sign of slowing down[3].

COVID-19 Epidemic in Malaysia

Confirmed cases of COVID-19 in Malaysia were first reported on 25 January 2020. There were 22 cases during the first wave (January 25 until February 15), involving majority imported cases and non-Malaysians. February 27 marked the second wave of infection which involved majority local transmission among Malaysians. By March 16, confirmed cases were reported from all states and the federal territories in Malaysia. In response to the nationwide spread of infection, a movement control order (MCO) was issued by the government from March 18 to March 31. During the first phase of MCO, the number of total cases continue to increase exponentially as seen in Figure 1, which leads to an extension of longer MCO period[4].

Figure 1: Epidemic Curve for COVID-19 in Malaysia, as of 4 May 2020

Controlling the Outbreak

In response to the COVID-19 outbreak in Wuhan, China banned travel to and from Wuhan city on 23 January and implemented a national emergency response. In addition to the Wuhan lockdown, suspending intra-city public transport, closing entertainment venues and banning public gatherings appears to have reduced new cases and limited the size of COVID-19 epidemic in China, resulting in significant reduction in the number of new cases by 19 February (day 50 of the epidemic)[5].

Community mitigation, which refers to a set of actions that persons and communities can take to help slow the spread of virus infections, is especially important before a vaccine is available[6]. According to a commentary article published in The Lancet[7], the effect of COVID-19 response in China has shown that quarantine, social distancing, and isolation of infected populations can contain the epidemic. Singapore and Hong Kong have also been managing COVID-19 well by early government action to identify cases, isolate infected individuals, contact tracing, and through social distancing measures taken by individuals.

Restriction of mass gatherings and events such as religious gatherings, cultural celebrations, and conferences also helps to reduce the spread of infection.

Figure 2: The Illustration of “Flattening the Curve”.
Image source: Lam, 2020 [9].
Figure 2: The Illustration of “Flattening the Curve”. Image source: Lam, 2020 [9].

Monitoring the Progress of Outbreak

When there is a new infectious outbreak in the human population which have no vaccine and effective medications, an exponential rise in the cases that will exceed the healthcare capacity can be observed in a short period of time. Eventually, the epidemic curve will decline when the outbreak has subsided in the population or when measures implemented to control the outbreak. However, in a situation where the outbreak exceeded the healthcare capacity, this will place huge strains on the healthcare resources (shortages of medical equipment, supplies, and staff) and result in unnecessary deaths. To avoid this situation, it is important to slow the spread of infection with control measures such as physical distancing[8].

The term, “flattening the curve” is an idea to prevent a sharp peak of cases (Figure 2) and slowing the spread of infection over a longer period of time to avoid overloading the healthcare system[9].

Over time, when the number of new infections in the population reduces, the exponential rise of new cases as seen in Figure 1 will peak and decline. In addition, when the number of daily new cases is significantly lower than the number of patients being discharged from hospital and recovered from the infection, this will indicate that the outbreak is under control[8].

On the other hand, if the MCO is lifted too early before the outbreak is under control, there is a possibility of another surge of infection in the community as forecasted by statistical modelling[10].

After 76-days of lockdown, China lifted the lockdown in Wuhan city in early April when the outbreak is finally under control with significantly low number of new daily cases and higher number of patients leaving the hospital than admission of new cases[11]. The successful control of COVID-19 outbreak in Wuhan was associated with a series of public health interventions as shown in Figure 3[12]. However, after the travel restriction in China was lifted, a resurgence of new cases were reported comprising mostly imported cases involving individuals entering China from other countries[13].

Figure 3: Epidemic Curve for COVID-19 Outbreak in Wuhan, China with Key Events and Public Health Interventions. Image Source: Pan et al., 2020 [12].

Deciding to Lift a Lockdown

The following are six criteria listed by the WHO for countries to consider when deciding to lift lockdown restrictions[14]:

  1. Transmission is controlled
  2. Health system capacities are in place to detect, test, isolate and treat every case and trace every contact
  3. Outbreak risks are minimised in special settings like health facilities and nursing homes
  4. Preventive measures are in place in workplaces, schools and other places where it is essential for people to go
  5. Importation risks can be managed
  6. Communities are fully educated, engaged, and empowered to adjust to the ‘new norm’

Important Takeaway Messages

  • Following the MCO strictly is important to break the chain of virus transmission in the community and to flatten the curve.
  • Our actions will determine the course of COVID-19 outbreak in Malaysia.
  • The outbreak will be under control when a significantly low number of new daily cases is observed in the epidemic curve.
  • Lifting the MCO too early could lead to a third wave of community infection.

Authors:

Dr Ernest Mangantig
Advanced Medical and Dental Institute, Universiti Sains Malaysia
YSN-ASM Affiliate

Dr Bong Yii Bonn
UM Industry and Community Engagement (UM ICE), Universiti Malaya
YSN-ASM Affiliate

Dr Tan Shing Cheng
UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia
YSN-ASM Affiliate

ChM. Dr Mohd Sukor Su’ait
Solar Energy Research Institute, Universiti Kebangsaan Malaysia
YSN-ASM Member

 

References

  1. WHO. What is a Pandemic? Available at: https://www.who.int/csr/disease/swineflu/frequently_asked_questions/pandemic/en. Date accessed: 9 April 2020

  2. Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Mil Med Res. 2020;7(1):11. doi:10.1186/s40779-020-00240-0

  3. WHO. WHO Director-General’s opening remarks at the media briefing on COVID-19-11 March 2020. Available at: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020. Date accessed: 9 April 2020

  4. Malaysian Ministry of Health. COVID-19 (Pusat Media) Kenyataan Akhbar. Available at: http://www.moh.gov.my/index.php/pages/view/2019-ncov-wuhan-kenyataan-akhba. Date accessed: 9 April 2020

  5. Tian H, Liu Y, Li Y, et al. An investigation of transmission control measures during the first 50 days of the COVID-19 epidemic in China. Science. 2020. DOI: 10.1126/science.abb6105

  6. CDC. Implementation of mitigation strategies for communities with local COVID-19 transmission. Available at: https://www.cdc.gov/coronavirus/2019-ncov/downloads/community-mitigation-strategy.pdf. Date accessed: 9 April 2020

  7. Anderson RM, Heesterbeek H, Klinkenberg D, Hollingsworth TD. How will country-based mitigation measures influence the course of the COVID-19 epidemic?. The Lancet. 2020; 1;395(10228):931-4.

  8. Nelson KE, Williams CM. Infectious Disease Epidemiology: Theory and Practice. Third Edition. Jones and Bartlett Publishers, 2014.

  9. Lam SK. Covid-19: What does ‘flattening the curve’ mean? https://www.thestar.com.my/lifestyle/health/2020/03/22/covid-19-what-does-039flattening-the-curve039-mean. Date accessed: 9 April 2020

  10. Salim N, Weng HC, Shuhaimi M, et al. COVID-19 Epidemic in Malaysia: Impact of Lock-down on Infection Dynamics. medRxiv. 2020. doi: https://doi.org/10.1101/2020.04.08.20057463. Available at: https://www.medrxiv.org/content/10.1101/2020.04.08.20057463v1.full.pdf+html

  11. Gan N. China lifts 76-day lockdown on Wuhan as city reemerges from coronavirus crisis. Available at: https://edition.cnn.com/2020/04/07/asia/coronavirus-wuhan-lockdown-lifted-intl-hnk/index.html. Date accessed: 9 April 2020

  12. Pan A, Liu L, Wang C, et al. Association of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China. JAMA. Published online April 10, 2020. doi:10.1001/jama.2020.6130

  13. Lee SY, Zhang, L. China’s new coronavirus cases rise to near six-week high. Available at: https://www.reuters.com/article/us-health-coronavirus-china-toll/chinas-new-coronavirus-cases-rise-to-near-six-week-high-idUSKCN21V01A. Date accessed: 5 May 2020

  14. WHO. WHO Director-General’s opening remarks at the media briefing on COVID-19-13 April 2020. Available at: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19–13-april-2020. Date accessed:5 May 2020

COVID-19 is an ongoing pandemic affecting the world. The disease was first reported in Wuhan, the capital of Hubei, China and caused serious respiratory illness such as pneumonia and lung failure. The etiological agent of COVID-19 is a novel coronavirus, known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has triggered enormous human casualties and serious economic loss posing global threat. The number of cases has soared dramatically ever since the outbreak in China. As of 24 April 2020, the disease has affected more than 2.6 million individuals and resulted in more than 180,000 deaths worldwide.

Understanding the characteristics of COVID-19 patients is important for informing public health decision-making. For example, when public health experts learned that fever is one of the most common symptoms of COVID-19, they could recommend the implementation of temperature screening measures in high risk areas such as the airport. For this reason, a number of scientific reports have described the characteristics of COVID-19 patients in many countries. Some discrepancies were observed in the data presented in these scientific reports, presumably due to the small number of patients included in each of the reports. Recently, one of the authors of this factsheet has carried out a systematic review of the scientific literature and performed a pooled analysis to combine data from all these reports with the aim to get a more complete picture of the characteristics of COVID-19 patients. The complete report of this systematic review and pooled analysis has been deposited in a medical research preprint database, medRxiv, and can be accessed by the public and experts alike (please see Reference 1 of this factsheet). Based on the data presented in this pooled analysis and a few other reliable sources, the following are some of the characteristics known so far.

1

Age

COVID-19 is known to affect people of all ages. The youngest patient reported was a 30-hour old newborn, while the oldest was a 104-year old centenarian. A large-scale analysis by the Chinese Center of Disease Control and Prevention revealed that all age groups are susceptible to COVID-19 infection, as shown in the table below:

Age group (years) Prevalence (%)
0-9 0.9
10-19 1.2
20-29 8.1
30-39 17.0
40-49 19.2
50-59 22.4
60-69 19.2
70-79 8.8
> 80 3.2

It should be noted, however, that the prevalence of each age group may vary among different countries. Moreover, since COVID-19 is an ongoing outbreak, the data may change over time.

From the table above, although it appears that COVID-19 was relatively less common among children, this observation can be attributed to the fewer outdoor activities among children. In addition, although the prevalence of COVID-19 was not particularly high among the elderlies, some studies have suggested that older age, along with several other risk factors (such as male gender and comorbidities described below), are slightly more likely to result in severe form of the disease and poorer clinical outcomes. Data from Malaysia suggest that the median age of patients who died of COVID-19 was 65 years old (range: 23-92 years) as of 25 April 2020.

What does this mean?

  • COVID-19 affects people of all ages equally, although older patients are slightly more likely to suffer from the severe form of the disease
  • Limiting outdoor activities can reduce the possibility of contracting the virus

2

Sex

Since the beginning of the outbreak, many have suggested that men could be more susceptible to SARS-CoV-2 infection than women. However, the pooled analysis mentioned above found that out of 44,760 COVID-19 patients, 23,032 (51.46%) were males while 21,728 (48.54%) were females. The ratio of males to females was therefore very close to 1:1, suggesting that they are equally prone to the infection. Nonetheless, data from the Global Health 5050 shows that in most countries, the majority of people dying from COVID-19 are men. Data from Malaysia also indicate that as of 25 April 2020, around 77% of patients who died of COVID-19 were males. These observations suggest that male gender is more likely to result in COVID-19-related mortality.

What does this mean?

  • Males and females are equally susceptible to COVID-19 infection, although men are more likely to suffer from deaths caused by the diseas

3

Pre-existing conditions (comorbidities)

Similar to male gender, it has been suggested that people with pre-existing conditions (comorbidities) are more susceptible to COVID-19. However, the same pooled analysis above revealed that 74.07% of the patients did not have any comorbidity. Among the patients who had, hypertension and diabetes were the most common disorders. It has also been demonstrated that patients with any comorbidity yielded poorer clinical outcomes than those without. In fact, data from Malaysia also showed that the majority of the death cases have comorbidities such as hypertension, diabetes, and heart disease.

What does this mean?

  • The presence of comorbidity does not make an individual more susceptible to COVID-19, but patients with comorbidity may have worse clinical outcomes

4

Race/ethnicity/nationality/religion

COVID-19 has been reported in more than 200 regions (countries, territories and areas) in the world. The patients in these countries comprised Asians, Caucasians, Africans, and virtually every race and ethnicity, including isolated indigenous tribes. The disease has also been observed in people of different religions.

What does this mean?

  • COVID-19 does not discriminate on the basis of race, ethnicity, nationality, or religion.

5

Signs and symptoms

A wide range of signs and symptoms have been observed in COVID-19 patients. More recent evidence also suggests that a significant proportion of COVID-19 cases are asymptomatic. In some studies, it has been estimated that the proportion of asymptomatic patients could be as high as 78%. Nevertheless, among patients who developed symptoms, fever is the most common symptom observed (occurring in 88.7% of the patients), followed by cough (57.6%). Other less common symptoms observed include muscle ache or fatigue, sputum production, shortness of breath, headache, sore throat, chill, nausea and vomiting, diarrhea, chest tightness, nasal congestion or runny nose, loss of appetite, and many other mild symptoms.

What does this mean?

  • COVID-19 symptoms are non-specific and can be very mild (or even asymptomatic)
  • If surveillance of the disease relies solely on temperature screening, a significant number of infected patients would be missed

Authors:

Dr Tan Shing Cheng
Universiti Kebangsaan Malaysia
YSN-ASM Affiliate

Dr Bong Yii Bonn
Universiti Malaya
YSN-ASM Affiliate

Dr Ernest Mangantig
Universiti Sains Malaysia
YSN-ASM Affiliate

ChM. Dr Mohd Sukor Su’ait
Universiti Kebangsaan Malaysia
YSN-ASM Member

 

References

  1. Tan SC. Clinical and epidemiological characteristics of Coronavirus Disease 2019 (COVID-19) patients. medRxiv. 2020:2020.04.02.20050989. DOI: 10.1101/2020.04.02.20050989 Available from: https://www.medrxiv.org/content/10.1101/2020.04.02.20050989v1.full.pdf+html
  2. World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report – 95. Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200424-sitrep-95-covid-19.pdf?sfvrsn=e8065831_4
  3. Chinese Center of Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Chinese Journal of Epidemiology. 2020;41(2):145-151. DOI: 10.3760/cma.j.issn.0254-6450.2020.02.003.
  4. Lee PI, Hu YL, Chen PY, Huang YC, Hsueh PR. Are children less susceptible to COVID-19? J Microbiol Immunol Infect. 2020. DOI:10.1016/j.jmii.2020.02.011.
  5. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, Liu XQ, Chen RC, Tang CL, Wang T, Ou CQ. Comorbidity and its impacton 1590 patients with Covid-19 in China: A Nationwide Analysis. European Respiratory Journal. 2020. DOI:10.1183/13993003.00547-2020.
  6. Ministry of Health Malaysia. Daily media briefing on the latest development of COVID-19 in Malaysia. Available from: https://www.facebook.com/kementeriankesihatanmalaysia/
  7. https://www.reuters.com/article/us-china-health-infant/mothers-may-pass-coronavirus-to-unborn-children-say-chinese-doctors-state-tv-idUSKBN1ZZ1C3
  8. https://www.straitstimes.com/world/united-states/104-year-old-american-is-worlds-oldest-coronavirus-survivor
  9. https://www.theguardian.com/global-development/2020/apr/02/brazil-confirms-first-indigenous-case-of-coronavirus-in-amazon
  10. https://globalhealth5050.org/covid19/
  11. https://www.aarp.org/health/conditions-treatments/info-2020/coronavirus-severe-seniors.html
  12. Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ. 2020;369:m1375. DOI: 10.1136/bmj.m1375.
  13. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020:101623. DOI: 10.1016/j.tmaid.2020.101623.

Therapeutic options for COVID-19 patients

There are no proven treatments for COVID-19. Current clinical management is directed at relieving symptoms and supportive care, i.e. maintaining fluid status and nutrition, and supporting physiological functions.

Efforts are levitated to develop COVID-19 therapeutics. Currently, COVID-19 patients are receiving either chloroquine, hydroxychloroquine, lopinavir-ritonavir, favipiravir, remdesivir, azithromycin, ribavirin, interferon, convalescent plasma, steroids, or anti–IL-6 as treatment agents. The therapeutics are based on their in vitro antiviral and/or anti-inflammatory properties. The prescribing should be done on a case-by-case basis by trained clinicians to avoid undesirable side effects and contraindications.

Therapeutic Rationale for Drug Repurposing in COVID-19

All the drugs mentioned above are repurposed, off-label, and are of compassionate use natures.

How can repurposing drugs help? The conventional anti-SARS-CoV-2 drug discovery from scratch is time-consuming. A licensed drug or one that is already under investigation and development would have passed phase 1 trials and is expected to reach patients more quickly.

However, there is one obvious disadvantage of this drug repurposing route: there is no efficacy and safety evidence of the drugs (in fact, any drugs) targeting SARS-CoV-2 in humans. Therefore, there is a global effort to accelerate clinical trials of various therapeutic agents to evaluate their safety and efficacy in COVID-19 patients.

What is drug repurposing? Drug repurposing, also known as drug reprofiling or drug repositioning, is the process of “redeploying a drug that is already approved to treat one disease to see if it works for a different disease”.

What is off-label use? Off-label use (of a drug) is the use of a licensed drug for indications that have not been approved by a regulatory authority. For example, the antimalarial drug, chloroquine or the related hydroxychloroquine is used for inflammatory disorders, but it is now used to treat COVID-19.

What is compassionate use? It is the use of a new drug to treat a certain disease when no other treatment options are available. Remdesivir is an example of a compassionate use drug for COVID-19 as it is yet to be approved by any legal authority.

Clinical trial for COVID-19

Several promising agents for COVID-19 treatment that are currently in clinical trial pipelines, to name a few:

  • Remdesivir (still an investigational agent)
  • Lopinavir/ Ritonavir (approved for HIV use) with or without interferon
  • Hydroxychloroquine and chloroquine (oral prescription drugs for treatment of malaria and certain inflammatory conditions)
  • Other drugs (investigational antivirals, immunotherapeutic, and host-directed therapies)
  • Favipiravir (antiviral for influenza use)
  • Tocilizumab (immunosuppressive monoclonal antibody for rheumatoid arthritis, IL-6 inhibitor)
  • Convalescent plasma therapy (adaptive immunotherapy used in the treatment of SARS, MERS, and 2009 H1N1 pandemic)

A number of trials of different scales are underway to study different treatments, some of which are funded by different pharmaceutical companies and initiated by different medical institutions (Table 1). Universiti Malaya Medical Centre is initiating a clinical trial using tocilizumab starting middle of April 2020.

Malaysia is also one of the countries in the global Solidarity trial launched by the World Health Organization (WHO) mainly looking at the safety and effectiveness of remdesivir, lopinavir/ritonavir, lopinavir/ritonavir with Interferon beta-1a, and chloroquine or hydroxychloroquine. The rationale of this global Solidarity trial is to recruit as many patients as possible over 90 countries by providing them with standardized trial design. Through this initiative, faster results will be generated, hence providing collectively strong evidence to determine the relative effectiveness of potential treatments.

Table 1: A few clinical trials of SARS-CoV-2 infection and treatment of patients with mild, moderate, and severe COVID-19

Therapy Study Participating countries Phase
Remdesivir A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults US, Denmark, Germany, Japan, Korea, Mexico, Singapore, UK 3
Lopinavir/ Ritonavir COVID-19 Ring-based Prevention Trial With Lopinavir/Ritonavir Canada 3
Lopinavir/ Ritonavir, Hydroxychloroquine Randomized Controlled Clinical Trials of Lopinavir/Ritonavir or Hydroxychloroquine in Patients with Mild Coronavirus Disease (COVID-19) Korea 2
Tocilizumab Multicenter Study on the Efficacy and Tolerability of Tocilizumab in the Treatment of Patients With COVID-19 Pneumonia Italy 2
Convalescent plasma Convalescent Plasma to Stem Coronavirus: A Randomized, Blinded Phase 2 Study Comparing the Efficacy and Safety Human Coronavirus Immune Plasma (HCIP) vs. Control (SARS-CoV-2 Non-immune Plasma) Among Adults Exposed to COVID-19 US 2

Source: clinicaltrials.gov

What is an adaptive study? A study that allows modifications to the study design based on accumulating data obtained from the trial.

What is a multicentre study? A study that is carried out at more than one medical institution.

What is a randomized study? A study design that randomly assigns participants into an experimental group or a control group.

What is a controlled study? A study whereby one of the interventions is the standard of comparison or control.

What is an open-label study? A study whereby both the researchers and participants know which drug (or intervention) is being given to participants.

What is a blinded study? A study whereby the participants do not know (is blinded as to) what treatment they are receiving.

What is a Phase 2 study? A stage in clinical trials that collect preliminary data on whether a drug works for a certain condition/disease (testing the drug’s effectiveness).

What is a Phase 3 study? A stage in clinical trials to collect information about a drug’s safety and effectiveness by studying different dosages or drug combination. This phase typically involves more participants.

Ethics of Clinical Trial for COVID-19

Preserving clinical trial integrity while ensuring participant health and safety during the coronavirus pandemic is very important. One concern is whether it is ethical to give patients a placebo (a substance that has no therapeutic effect) during this pandemic. It is argued that a placebo group (receiving the established standard of care) would be safer than the experimental group (receiving new drugs). As compared to randomised trials, single group cohorts or studies without controls may be less safe and might lead to the delay in discovering a new therapy. Optimally, an adaptive design approach should be prioritised to allow modification of certain experimental design. Ethics approval and trial protocol also need to be promptly initiated and approved without overlooking the scientific validity, and participants’ rights and safety in studies conducted during any infectious disease outbreaks.

TAKE HOME MESSAGE

With the current COVID-19 pandemic, more clinical trials are needed to discover and validate new therapies, otherwise, there will be no proven treatments for future coronavirus pandemics.

Author:

Dr Phan Chia Wei
Head of Clinical Investigation Centre (CIC), Universiti Malaya Medical Centre
Senior Lecturer, Faculty of Pharmacy, Universiti Malaya
Member, YSN-ASM

 

References

FDA. Coronavirus Treatment Acceleration Program (CTAP).
www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap

FDA. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic Guidance for Industry, Investigators, and Institutional Review Boards. www.fda.gov/media/136238/download

FDA. “Solidarity” clinical trial for COVID-19 treatments. www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments

Kalil AC. Treating COVID-19—Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics. JAMA. Published online March 24, 2020. doi:10.1001/jama.2020.4742

McDermott MM, Newman AB. Preserving Clinical Trial Integrity During the Coronavirus Pandemic. JAMA. Published online March 25, 2020. doi:10.1001/jama.2020.4689

Clinical Characteristics of COVID-19: The China Experience

[https://www.nejm.org/doi/full/10.1056/NEJMoa2002032]

The symptoms, risk factors and death rates of those infected by SARS-CoV-2 were described in this study, based on the Wuhan experience. It is notable that COVID-19 spreads rapidly with varying severity and often without fever.

What does this research mean?

  1. Fever and cough are the most common symptoms; but a significant number of infected persons can be asymptomatic.

  2. Almost two-thirds of infected persons reported history of contact with another exposed person; another one-third reported history of travel to the epidemic area.

  3. Most would not develop severe disease or cause death, but some might end up with breathing difficulties that require intensive care and a ventilator (machine to support breathing).

  4. In the presence of risk factors or severe illness including breathing difficulties, the death rate is high.

What should we do now?

  1. If you have symptoms or is at risks for infection, seek immediate medical attention to get tested.
  2. It is advisable to wear a mask and keep your hands clean (with soap or hand sanitizer) to reduce the risk of exposure.
  3. Through measures such as Movement Control Order (MCO), the Government hopes to reduce the number of people at any one time (i.e. flattening the curve). If there is a low number of patients infected at any one time, most healthcare systems will have enough ventilators to cope.
  4. Individuals who are older or with pre-existing medical conditions (such as heart disease, respiratory problems, diabetes, and cancer) need to take extra precaution to reduce their risk of infection.

Clinical course and risk factors for death among hospitalised adults with COVID-19

[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext]

In this paper by Lancet, risk factors for death among hospitalised adults were described. In addition, investigators identified prolonged viral shedding even in those patients who recovered.

What does this research mean?

  1. The risk factors associated with death being older age as well as development of sepsis (organ involvement and failure from overwhelming infection).
  2. Among the survivors, the virus continued to shed for an average of 20 days. Meanwhile, the virus continued to shed among those who died.

What should we do now?

  1. Elderly and those with chronic diseases need to take greater precautions to reduce their risk of infection. Once hospitalised, their risks for intensive care admission and death may increase significantly.
  2. Since individuals could continue to be infectious, quarantine needs to continue for those who have recovered.

Early transmission dynamics of those with COVID-19 associated chest infection

[https://www.nejm.org/doi/full/10.1056/NEJMoa2001316]

In this paper, investigators have confirmed human-to-human transmission with SARS-CoV-2 virus. The dynamic of transmission was also described.

What does this research mean?

  1. This study confirms human-to-human transmission with a reproductive number of R0 of 2.2. This means that each infected person may infect an average of more than two other people. In comparison, R0 for SARS is 3.0 and for MERS-COV is below 1.
  2. In the early stage of the epidemic, the number of infected persons doubled every 7.4 days.
  3. On average, the incubation (from contact to symptom) period is 5.2 days and hospitalisation occurs in about 12 days, supporting a quarantine period of 14 days for the exposed persons.

What should we do now?

  1. As long as R0 is more than 1, the epidemic will keep increasing. Therefore, it is important to have movement control measures in place in order to reduce the R0 to less than 1.
  2. It is important to perform contact tracing and rapid testing to confirm infection; if not the number of infected people may increase rapidly.
  3. Exposed person should be quarantined for at least 14 days. Development of symptoms should be monitored during the quarantine period.

Author:

Professor Dr Lee Yeong Yeh, MD, PhD, FACP, FRCP, FAMM, FACG, AGAF
Consultant Physician & Gastroenterologist
Honorary Member, YSN-ASM

By Professor Dr Shamala Devi Sekaran FASc & Professor Datuk Dr Asma Ismail FASc, Fellow Academy of Sciences Malaysia

BACKGROUND INFORMATION

Virus isolation, viral detection, and amplification of nucleic acid (PCR) are methods that provide the highest degree of confidence in viral diagnostics result. A COVID-19 Nucleic Acid Real-Time Reverse Transcription Polymerase Chain Reaction (RT-PCR) Test is used for qualitative detection of nucleic acid from SARS-CoV-2. Specimens used in this test are taken from the nasopharynx (behind your nose and above the back of your throat) and oropharynx (the part of the throat at the back of the mouth behind the oral cavity). However, this test requires specialised technical skills and equipment, is time-consuming and costly, and may produce false negatives.

RESULT ANALYSIS AND RECOMMENDATION

  • RT-PCR’s limitations means it is not the best for field work; new commercial kits are available, but these are costly and are not completely validated.
  • The table shows that different levels of COVID-19 was detected from different specimen types; this shows that specimen type is important.
  • Bronchioalveolar lavage fluid provided the highest concentration (93%) but it requires trained personnel to extract and hence not recommended.
  • Because the virus is transmitted via respiratory droplets, the best alternative specimens are sputum and nasal swabs (72% and 63% positivity, respectively)
  • However, there is a lower positivity rate that also depends on time of collection. Therefore, a minimum of two tests are needed to confirm negativity and the tests should be carried out 5-7 days apart.
  • Any negative must be verified as a true negative.
  • Asymptomatic patients or those with mild symptoms can still spread the virus.

COMPLEMENTING VIRUS DIAGNOSTICS WITH SEROLOGY

  • COVID-19 IgM and IgG testing are used to detect IgM and IgG antibodies. This is based on the host response following a SARS-CoV-2 infection (as shown in Figure 1).
  • IgM provides the first specific defence, an indicator of a current infection; IgM appears within four to 10 days of exposure and can remain for up to two weeks or more.
  • IgM will later be replaced by IgG; IgG provides lasting immunity, an added advantage that indicates a lasting or cross-immunity.
  • A serology test supplements the diagnosis of COVID-19; it does not replace the RT-PCR Test.
  • Even though serology testing does not confirm infection, it provides an evidence of recent infection. This is an important immunological evidence for physicians that is also useful for monitoring during treatment.

IMPROVING DIAGNOSTICS: THE WAY FORWARD

  • There is an urgent need for a test to quickly identify infected patients to prevent virus transmission and assure timely treatment of patients.
  • Researchers and pharmaceutical companies are developing PCR kits, antigen and serological tests. Professor Jackie Ying from NanoBio Lab, Singapore showed that the use of nanoparticles and dyes can speed up testing.
  • Even though her test is not commercially available yet, a collaboration with Malaysian labs could provide the data on accuracy that is necessary to speed up its recommendation to be used in COVID-19 diagnosis.
  • Another test kit developed by a South Korean company detects the antigen in 10 minutes using monoclonal antibodies.
  • User places swabs of nasal discharge into the lateral flow cassette; results can be obtained within 10 minutes with an accuracy of 85%.
  • The Korean test kit needs further evaluation; it is useable but should be used as a quick test to complement a PCR Test.

IMPORTANT TAKEAWAY MESSAGES 

  • Performing only a single test to diagnose COVID-19 could lead to a false-negative result or misdiagnosis.
  • Therefore, to ensure that those who are negative are true negatives, DUAL SAMPLING must be done; a second sample taken seven days apart will confirm this.
  • Implementing a diagnostic workflow that follows the disease’s time frame will provide a comprehensive diagnosis.

References

  1. Jin YH et al: A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 7(1):4, 2020
  2. www.thelancet.com Published online February 12, 2020 https://doi.org/10.1016/S0140-6736(20)30374-3
  3. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med 2020; 382:970.17.
  4. Li Z, Yi Y, Luo X, et al. Development and Clinical Application of A Rapid IgM-IgG Combined Antibody Test for SARS-CoV-2 Infection Diagnosis. J Med Virol 2020.
  5. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25727 Development and Clinical Application of A Rapid IgM-IgG Combined Antibody Test for SARS-CoV-2 Infection Diagnosis
  6. WHO: Coronavirus Disease (COVID-19) Technical Guidance: Early Investigations Protocols. Accessed March 23, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/early-investigations
  7. WHO.Disease outbreak news: acute respiratory syndrome in China.Feb 11, 2003. https://www.who.int/csr/don/2003_02_11/en/ (accessed Feb 11, 2020).
  8. WHO.Global surveillance for human infection with novel coronavirus (2019-nCoV). 2020. https://www.who.int/publications-detail/globalsurveillance-for-human-infection-with-novel-coronavirus-(2019-ncov) (accessed Feb 11, 2020).
  9. https://www.asiatechdaily.com/korea-firm-covid19-testing kit. Korean firm develops simple tester to detect COVID 19 in 10 minutes.
  10. https://www.straitstimes.com/singapore/health/singapore-scientists-on-front-lines-of fight -against -covid-19. Coronavirus: Singapore scientists on the front lines of fight against Covid-19. Published March 25,2020
  11. Welig Wand et al. Detection of SARS –CoV-2 in different types of clinical specimens. JAMA Published on line March 11,2020 doi:10.1001/jama.2020.3786

Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

[https://www.nejm.org/doi/pdf/10.1056/NEJMc2004973]

In this study, investigators at the National Institutes of Health (USA) used a nebuliser to spray either the SARS-CoV-2 or SARS-CoV-1 into a tank, and they measured whether each virus is still alive after different periods of time. SARS-CoV-1 is the virus associated with the SARS epidemic and SARS-CoV-2 is the virus associated with the Covid-19 pandemic.

What does this research mean?

  1. This research confirms what doctors already knew, that people can be infected by the coughing and sneezing of an infected person. This implies that all infected individuals should wear a mask when they come close to another individual, and staying 3-6 feet away can help reduce the risk of spreading infection.
  2. This research suggests that plastic and steel surfaces are more likely than copper and paper surfaces to have viable virus. This suggests that we should take care to clean plastic and steel surfaces because these are more likely to have a viable virus for a longer period. The risk of infection is much higher from close contact with an infected person than from touching a contaminated plastic or steel surface. Plastic and steel surfaces should be cleaned properly and tissue paper that an infected person sneezes into should be disposed of carefully. Everyone should continue to keep clean hands and to wash their hands regularly and avoid touching their eyes, nose and mouth.
  3. This research shows that SARS-CoV-2 and SARS-CoV-1 are very similar in terms of infection rate. It is therefore necessary to find another reason to explain why SARS was limited to a few countries in Asia, whereas Covid-19 has become a pandemic. The researchers suggest that one possible reason is that SARS patients develop symptoms quickly and are therefore isolated quickly, whereas Covid-19 patients develop symptoms slowly (or don’t develop symptoms at all) and therefore they go around infecting more people.

What should we do now?

  1. Public should continue to practice social distancing: stay at home as much as possible and if you go out, wear a mask and stay 3-6 feet away from other people.
  2. Public should continue to practice good hygiene practices including avoiding touching the mouth, eyes and nose, washing hands with soap on a regular basis, and disposing used tissues immediately.
  3. Healthcare facilities or homecare facilities providing quarantine facilities for individuals with Covid-19 or individuals with symptoms (fever and dry cough) should clean all surfaces that the individuals come into contact with on a regular basis, particularly plastic and steel surfaces.

Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2)

[https://science.sciencemag.org/content/early/2020/03/13/science.abb3221]

In this study, investigators at Imperial College London, Columbia, and Tsinghua University, built a computer model to explain why Covid-19 spread so quickly. They found that the virus was undetected for weeks and as a result, many people were infected but did not have any symptoms. Therefore, there is a delay in preventing further infections which resulted in more people being infected.

What does this research mean?

  1. This research confirms what doctors already knew, that unlike SARS where people developed symptoms quickly, Covid-19 does not always cause symptoms immediately.

What should we do now?

  1. Public should continue to practice social distancing: stay at home as much as possible and if you go out, wear a mask and stay 3-6 feet away from other people.
  2. Anyone who has come into close contact with a Covid-19 patient should self-isolate as soon as possible, inform their close contacts and inform the Ministry of Health.

Download PDF version

FACT SHEET 7: COVID-19 Therapeutics

FACT SHEET 6: COVID-19 Epidemiology: Know When The Outbreak is Under Control

FACT SHEET 5: Characteristics of COVID-19 Patients

FACT SHEET 4: Clinical Trial for COVID-19

FACT SHEET 3: Clinical Characteristics of COVID-19

FACT SHEET 2: COVID-19 DIAGNOSTICS: Know How to Interpret

FACT SHEET 1: Understanding the Stability of Coronavirus Disease 2019 ( COVID-19)

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