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 Table of Contents  
EDITORIAL
Year : 2020  |  Volume : 5  |  Issue : 1  |  Page : 1-6

The story of the emerging coronavirus: SARS-CoV-2/COVID19: Challenges posed and lessons Learnt


Department of Transfusion Medicine, Manipal Hospital, Bengaluru, Karnataka, India

Date of Submission01-Apr-2020
Date of Decision02-Apr-2020
Date of Acceptance02-Apr-2020
Date of Web Publication17-Apr-2020

Correspondence Address:
Shivaram Chandrashekar
Department of Transfusion Medicine, Manipal Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GJTM.GJTM_28_20

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How to cite this article:
Chandrashekar S. The story of the emerging coronavirus: SARS-CoV-2/COVID19: Challenges posed and lessons Learnt. Glob J Transfus Med 2020;5:1-6

How to cite this URL:
Chandrashekar S. The story of the emerging coronavirus: SARS-CoV-2/COVID19: Challenges posed and lessons Learnt. Glob J Transfus Med [serial online] 2020 [cited 2020 Aug 6];5:1-6. Available from: http://www.gjtmonline.com/text.asp?2020/5/1/1/282735



Who would have imagined a few months ago that the common public would be so scared of a viral respiratory illness that they would stay away from doctors and hospitals to protect themselves! In the absence of adequate testing kits, adequate beds, and absence of approved medicines or vaccines, prevention has been the only solution to a novel coronavirus (CoV) raging through the world. “Stay Home, Stay safe” has been the campaign to control this infection in all countries developed or otherwise. The panic unleashed by this virus has brought humankind to its knees; shut down supermarkets, entertainment centers, and domestic and international travel; and crashed stock markets worldwide. The world for once does not care about the economic fallout. Governments have locked down entire countries hoping to control the spread. Hand washing and social distancing have been the only modes of interrupting the transmission chain, as this spreads by contact with an infected surface or through droplets. New unconfirmed reports suggest that micro-droplets generated during sneezing, coughing, or close conversation could remain suspended in air.


  What Is Severe Acute Respiratory Syndrome-Coronavirus-2/coronavirus Disease 2019? Top


A pneumonia of unknown cause detected in Wuhan, China, was first reported to the WHO Country Office in China on December 31, 2019.[1] A novel CoV distinct from the previously known CoVs was recognized as the causative agent, which quickly spread to more than 187 countries, sufficient enough to be called a pandemic. The WHO labeled the outbreak as a Public Health Emergency of International Concern on January 30, 2020.

This new virus has now been officially called severe acute respiratory syndrome-CoV 2 (SARS-CoV-2), because of its similarity to SARS-CoV of 2003, and the disease caused by it has been termed CoV disease or COVID-19. SARS-CoV-2 and COVID-19 are much like the terms HIV and AIDS. Viruses are named based on their genetic structure to facilitate the development of diagnostic tests, vaccines, and medicines by virologists, and so viruses are named by the International Committee on Taxonomy of Viruses. Diseases are named by the WHO which announced “COVID-19” as the name of this new disease on February 11, 2020.[2]

Although the related CoVs, SARS-CoV and Middle East respiratory syndrome (MERS)-CoV, are both closely related to SARS-CoV-2 and have bat reservoirs, the biological differences between these viruses are striking. SARS-CoV-2 is markedly more infectious, resulting in very different epidemiological dynamics to those of SARS-CoV and MERS. SARS-CoV-2 was found to have 79% similarity to SARS-CoV at the nucleotide level.[3] SARS-CoV-2, the CoV causing the CoV disease, COVID-19, is the seventh CoV in the human population along with SARS-CoV, MERS-CoV, HCoV-NL63, HCoV-229E, HCo-OC43, and HKU1. While SARS-CoV and MERS-CoV can cause severe respiratory syndrome, the other four only cause mild respiratory illness.[4]


  Evidence for Zoonotic Transmission of Severe Acute Respiratory Syndrome-Coronavirus-2 Top


Studies from China[5],[6] have documented an association between COVID-19 and the seafood and wildlife market in Wuhan city. Although bats have been implicated as a likely reservoir for SARS-CoV-2, it is believed that an intermediate host, Malayan pangolins (Manisjavanica), has been reported to harbor a virus which exhibits a strong similarity to SARS-CoV-2 in the receptor-binding domain. It has been hypothesized that pangolins should be considered as possible hosts in the emergence of novel CoVs and should be removed from wet markets to prevent zoonotic transmission. It is believed that this zoonotic virus acquired some of its key mutations during a period of “cryptic” spread in humans prior to its first detection in December 2019.


  Effects of Lockdown and Information Explosion Top


Thanks to the lockdown imposed in many countries and the idle time that comes with it, people have fallen prey to news in the print media, electronic media, and social media. This addiction and overdose of half-baked information has made COVID-19 and CoV a household name and created panic and stress on an unprecedented scale. In the current COVID-19 pandemic, not only the layman but health workers as well are facing great challenges in coping with the crisis affecting them both physically and mentally.[7] Fear psychosis created by the pandemic and the nonavailability of personal protective equipment (PPE) all add to this anxiety and stress.


  Risk Factors and Pathogenesis of Severe Acute Respiratory Infections and Coronavirus Disease 2019 Top


Severe acute respiratory infections such as SARS, MERS, and H1N1 can rapidly progress to acute respiratory failure with high lethality. SARS-CoV-2 is one such pathogen that can cause infections in humans ranging from mild upper respiratory tract infection, to severe acute respiratory distress syndrome (ARDS) and sepsis. ARDS can occur in 15%–30% of patients with COVID-19.[8]

Current research shows that the poor prognosis of patients with COVID-19 is related to male sex; advanced age (higher than 60 years); presence of comorbidities such as hypertension, diabetes, and cardiovascular disease, secondary ARDS; and other relevant factors.

Angiotensin-converting enzyme is hypothesized to have a protective effect against acute lung injury and ARDS. SARS-CoV-2 like SARS-CoV uses the angiotensin-converting enzyme 2 (ACE2) receptor to invade human alveolar epithelial cells and produce ARDS associated with a high-mortality rate.[9] This suppression of ACE2 expression during SARS-CoV infection has been proposed to play a role in the pathologic changes in the lung and contribute to severe pneumonia and acute lung failure.[10]

Although unproven, this organ's protective effect of ACE could be the reason for expert opinion on avoiding ACE inhibitor drugs being used as anti-hypertensives in some patients.


  What Makes Severe Acute Respiratory Syndrome-Coronavirus 2 So Scary? How Is it Different from Flu or Its Predecessor – Severe Acute Respiratory Syndrome-Coronavirus? Top


Unlike seasonal flu, there is no herd immunity toward SARS-CoV-2. This means that the virus is completely new to our immune system. From data on hand, it is evident that the mortality rate due to COVID-19 is substantially higher than that of seasonal flu (influenza). It is also evident that this new virus, SARS-CoV-2, is more infectious than its predecessors – SARS-CoV of 2003 and MERS-CoV of 2015, and individuals can transmit the virus when asymptomatic or presymptomatic, by means of droplet spread. Absence of drugs or vaccines compounds the problem.


  Challenges in Laboratory Diagnosis of Severe Acute Respiratory Syndrome-Coronavirus-2 Top


Real time-polymerase chain reaction (PCR) has been the only sure way of identifying a novel pathogen with certainty as serological assays can show cross-reactivity. Samples for testing are collected by throat swabs or nasopharyngeal swabs. When a new virus is discovered for the first time, licensed kits are hard to come by. Following the discovery of a new pathogen, its genome is sequenced and its unique sequences for designing primers are put up in public domain. In this case of SARS-CoV-2, as a first step, the Centers for Disease Control and Prevention (CDC) in China isolated and cultured a virus that was confirmed to be a CoV by electron microscopy followed by genome sequencing. Several groups then worked to design primers. Once primers/probes and controls are available, the designing of a PCR is then pretty straightforward requiring only a real-time-PCR setup. The only challenge when testing for a new pathogen like SARS-CoV-2 is that there can be cross reaction with other CoVs, notably SARS-CoV. Hence, every assay needs to be run with positive and negative controls and validated for sensitivity and specificity using a panel of samples prior to use or licensing. Hence, validation is the key to the successful development of an assay.

All PCRs involve the basic steps of extraction, amplification, and detection of viral genome. The viral genome (RNA/DNA) is extracted using the available extraction kits, followed by the addition of primers/probes which are virus specific. Primers are short fragments of DNA that are complementary to specific parts of the transcribed viral DNA. These fragments attach themselves to target sections of the viral DNA if the virus is present in a sample. Pathogen-specific primers and probes guarantee exact and reliable direct detection of infectious pathogens based on their gene sequence (DNA/RNA).

CoVs, being an RNA virus, are detected by reverse transcription (RT) which means the RNA is first converted to DNA using RT and then amplified in a thermal cycler by PCR. Hence, the technique is called RT-PCR.[11] Detection of the amplified product can be by using gel doc systems or by real-time-PCR that uses probes tagged with fluorescent dyes.

Progress of the disease in affected patients can be assessed by quantitative monitoring of viral load in lower respiratory tract samples using real-time-PCR. This helps to evaluate disease progression, especially in cases of low viral load.[12]

Many companies around the world including 16 Indian companies came forward to sell testing kits as soon as it was opened up to the private by the government.[13] A company, Mylabs, has come out with a complete solution for testing using self-designed diagnostic kits using primers/probes available in the public domain.


  Can Serological Tests Be an Effective Alternative to Reverse Transcription-Polymerase Chain Reaction? Top


Serological tests detect antibodies to SARS-CoV-2 infection, but absence of antibodies does not preclude infection, especially in those who have been in contact with the virus. Follow-up testing with confirmatory test by molecular methods is necessary, to rule out infection in these individuals. Results from antibody testing should not be used as the sole basis to diagnose or exclude SARS-CoV-2 infection. Further, positive results may be due to past or present infection with non-SARS-CoV-2 CoV strains, such as CoV HKU1, NL63, OC43, or 229E.[14]


  Who Should Be Tested? Top


The CDC provides guidance for who should be tested, but decisions about testing are at the discretion of state and local health departments and/or individual clinicians.[15] the screening/testing protocols vary from country to country. In the initial phases of COVID-19, countries restricted screening to those with a history of foreign travel, those who have come into contact with those affected by COVID-19, and health-care workers engaged in treatment. Treatment may also be offered to patients with pneumonia and ARDS where there is a strong suspicion of COVID-19. As the disease spreads first locally and then later when community spread occurs, greater testing may become necessary.


  Could an Effective Vaccine for Severe Acute Respiratory Syndrome-Coronavirus-2 Be on the Horizon? Top


The challenges in the development of an effective vaccine against CoV are manifold. Efforts to develop a broad-spectrum vaccine against the cluster of CoV are not new. Scientists have been at it since the emergence of SARS-CoV in 2003. Similarity in structure and cellular entry receptor suggests that some drugs and preclinical vaccines against SARS-CoV could theoretically be used to treat SARS-CoV-2.[16] However SARS-CoV-2 can mutate into a strain that the vaccine would not be able to protect.

SARS-CoV-1 vaccine candidates exhibited adverse side effects and even exacerbated symptoms upon viral challenge. SARS-CoV-1 vaccines utilizing either live SARS-CoV-1 or DNA-based S-protein were able to induce antibody formation and protection against SARS-CoV-1; however, the challenged mice developed pulmonary immunopathology (hypersensitivity) on challenge with the SARS virus.[17] SARS-CoV-2 virus to date has exhibited high-frequency mutations resulting in at least five different strains predicted to enhance viral entry into host cells, virulence, and viral transmission. CoVs have been shown to exhibit high-frequency recombination events, which could again pose challenges in vaccine development.[18] Thus, enough time, adequate patient samples, and lineage tracing of SARS-CoV-2 to identify unchanging viral proteins as suitable targets for prophylactic development is essential. Even when developed, trials for vaccines followed by regulatory clearance are justifiably a long-drawn process in the interest of safety and efficacy.


  Variable Impact of Coronavirus Disease 2019 Top


Although COVID-19 has spread to hundreds of countries, its impact is different in different countries. Varied reasons ranging from atmospheric temperature and humidity, to sanitation and hygiene levels and the variations in the virus which is constantly mutating, have been cited as reasons for this. Difference in cultural norms, mitigation efforts, and health infrastructure could also account for the difference in morbidity and mortality. Differences in testing strategies, for example, insufficient testing to account for the small number of cases, have been reported in some countries. Take the case of India. A country with a population of 130 billion has just under 1500 cases by March end 2020 and <40 deaths. If insufficient testing was the cause of such low numbers, then India and its neighboring countries should have experienced significant morbidity and mortality which is not being seen. Time will tell what the true magnitude is.

Bacillus Calmette–Guerin (BCG) vaccination has been shown to have a protective effect against other DNA and RNA viruses, and it is possible that universal immunization with BCG could be having a protective effect.[19] The evidence for this cited by some researchers is that COVID-19 is more active in countries such as Italy, the Netherlands, and the USA where the same is lacking.[20] The role of malaria, tuberculosis, and BCG vaccine is unclear at this time, and more research is needed to understand why some countries are less affected.


  Role of Convalescent Plasma in the Management of Coronavirus Disease 2019 Top


The mainstay of treatment of COVID-19 is currently supportive care, such as oxygen supply in mild cases and extracorporeal membrane oxygenation for the critically ill patients. Several drugs of the chloroquine group and antiviral drugs used to treat HIV and SARS-CoV are being tried. In the absence of drugs for treatment and vaccines for prevention, alternative time-tested methods are being used in critically ill patients. Use of convalescent plasma (CP) collected from patients, 28 days after full recovery, who harbor antibodies to the virus, is one such modality. Studies[21] have shown that there is evidence that CP from patients who have recovered from viral infections could be used without serious adverse effects. Therefore, it might be worthwhile to test the safety and efficacy of CP transfusion in SARS-CoV-2-infected patients. CP or immunoglobulins have been used in critically ill patients to improve the survival rate of patients with SARS. CP has been the subject of increasing attention, especially in the wake of large-scale epidemics.[22],[23]

Aphaeresis plasma is the preferred option for it permits collection of larger quantities of plasma in a single sitting (500 ml), without significant impact on the donor's hemoglobin. An easier and cheaper alternative would be to collect 450-ml whole blood and prepare 200-ml plasma from it. However, this would lead to wastage of red cells and platelets as no blood center would take the risk of transfusing them to non-COVID-19 healthy persons, which would further raise ethical concerns.

Studies have also showed a shorter hospital stay and lower mortality in patients treated with CP than those, not treated with CP. CP has been used to good effect in the past in the case of Ebola outbreaks, SARS, MERS, and HIN1 influenza pandemics. In the absence of effective drugs, CP from patients who have recovered from COVID-19 has been permitted to be used by the US Food and Drug Administration (FDA) on a case-by-case basis. CP continues to be an investigational new drug application, and doctors must obtain FDA approval on phone or by Fax for the use of CP in patients with serious or life-threatening COVID-19 infections. The plasma may be collected from recovered patients who qualify for blood donation, who have had no symptoms for 14 days and have recovered from COVID-19.

Severe disease is defined as dyspnea, respiratory rate ≥30 breaths/min, blood oxygen saturation ≤93%, ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50% within 24–48 h.

Life-threatening disease is defined as respiratory failure, septic shock, or multiorgan dysfunction or failure.

Other countries should take the lead and facilitate CP therapy for similar patients. CP by virtue of the antibodies present is likely to afford passive immunity to seriously ill patients. More studies are needed to know the dose of CP and frequency of administration.


  Management of Blood Transfusion Services in Times of Coronavirus Disease 2019 Top


The American Association of Blood Banks, FDA, and the CDC are not recommending any action by blood collection establishments because the risk for transfusion transmission of SARS-CoV-2 is only theoretical.[24] However, people directed to stay at home for their safety, deprive blood banks of blood donors. During most disasters, blood centers need to deal with a problem of plenty. One press release and people donate in response to it. However, COVID-19 cuts off not only donors, but also staff from the blood centers. Blood center staffs have to protect themselves by working in weekly shifts so that all of them do not fall sick together. Donors need help to reach the donation centers during times of lockdown by the government.

However, donor centers have modified donor questionnaire to address the history of travel, to regions endemic to SARS-CoV2, a history of contact with patients affected by COVID-19, and a history of respiratory illnesses manifesting as fever, cough, or shortness of breath. It is important to assure donors that the blood bank is a safe place visited by healthy people and facilitate their movement for blood donation with the help of police personnel. The WHO recommends[25] that blood centers must put in a system in place for donors to report post donation illness consistent with COVID-19 or contact with a case that is confirmed post donation. Testing of the blood supply for SARS-CoV-2 is premature in the absence of evidence of transfusion transmission or demonstrable infectivity of the COVID-19 virus in blood. Introduction of pathogen reduction technology to prevent COVID-19 is not cost-effective and hence not recommended. As an enveloped virus, SARS-CoV-2 is susceptible to the therapeutic agents used during plasma fractionation and hence, there is no risk of transmission through plasma products. In the event of severe blood shortages, at times of such pandemics, reduction in whole-blood donation intervals may be considered for donors with robust hemoglobin levels. COVID-19 virus-infected donors can re-enter blood donation, 28 days after full recovery. This may be particularly useful in collecting CP.

For countries in Asia with a fragmented blood transfusion service, holding out door camps at times of such crisis is going to be difficult. Blood banks need to liaise with their clinical colleagues in hospitals and impress upon them the need for postponing nonemergent surgeries/treatment needing blood. Interblood bank co-operation to overcome shortages will certainly help. Reduced number of blood issues will help to flatten the blood issue curve and help tide over the shortage of blood. Whether one is able to flatten the COVID-19 curve from spiraling or not is altogether a different question.


  Lessons Learned from Coronavirus Disease 2019 Crisis Top


No amount of disaster management planning can be helpful if nature wills otherwise. First, Asian countries need an emergency blood stock lasting for at least 2 weeks. Next, we need an emergency donor pool who will not mind taking some risk to go to a blood center and donate blood during such crisis. We need to upscale the number of staff at blood centers. Blood centers being nonprofit centers work with minimum staff, and this can further hamper operations during such crisis. Blood centers and hospitals should have sufficient staff to keep two–thirds of them home and provide emergency service with just one-third of staff. Mechanisms must be in place not only to issue emergency passes to donors but also to provide transportation to them to reach the nearest blood center.

As far testing for emerging pathogens, every country must have a research and development (R and D) center to begin manufacturing their own primers and controls unique to the new pathogen the moment the primer sequences are announced on the CDC website. Standardization of PCR must be completed in a week's time, and the standard operating procedure for testing along with primers and controls and extraction kits should be made available widely. Labs should not depend on industries to provide them with ready-made kits which can take months to be made, approved, and shipped. A quick local response with the help of private players followed by validation in a government-approved lab is essential and possible.

Measures for quarantine, be it home quarantine or hospital isolation, must be strengthened. Effectiveness of home quarantine must be studied and if not, mass quarantine centers can be identified. Unnecessary movement of quarantined people must be tracked using nonremovable wristbands with a global positioning system tracker. Minimum quantity of such wristbands and other PPE must be available at all times to safeguard the health of the community and the medical personnel engaged in treatment.

Hospitals for such infections must be identified and ready for use in the very first week of the illness. Fever clinics for such patients should be designed with a separate entrance, from the main hospital, and should be ready to use at short notice.

Finally, we need effective vaccines for not only influenza viruses, but group of CoVs, as these viruses are here to stay and mutate. Vaccine development and drug development are long-drawn processes, and we therefore need drug development on a war footing. Artificial intelligence and bio-informatics must be used for computational analysis of a drug's safety and efficacy and when the drug safety has been established previously for other conditions, such drugs should be quickly cleared for use.

Systems must be put in place by the WHO to advise states on when to ban international travel, and countries should have laid down policies on how, when, and for how long a region or country should be locked down. This will require a multidimensional analysis including not just health, but also social, economic, and psychological indicators. Finally, we need to understand that with so much of global co-operation if containment is such a herculean task, what will be our response in case of a genuine biological warfare? Are we prepared to handle the fallout of such an operation?



 
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