The lessons of COVID-19

World Health Organisation (WHO) chief Tedros Adhanom Ghebreyesus announced that the disease caused by the new coronavirus (SARS-CoV-2) was being named as COVID-19. The ‘co’ stands for ‘corona’, ‘vi’ for ‘virus’ and ‘d’ for ‘disease; and ‘19’ marks the year when the outbreak was first identified (31 December, 2019). WHO declared the novel coronavirus outbreak (2019-nCov) a Public Health Emergency of International Concern (PHEIC) on 30 January, 2020 when there were 7,818 confirmed cases worldwide with a majority in China and 82 in 18 other countries. WHO declared COVID-19 as a Global Pandemic on 11 March after it spread rapidly to 114 countries at the time.

As a 77-year-old physician, I have witnessed the last epidemic of smallpox in India, including the one in Ladakh in 1972, and the first cholera epidemic in Ladakh in 1991. I was part of the team that treated and contained these two epidemics. I have also followed global epidemics like SARS in 2003 and Ebola in 2014. I was not surprised with the emergence of COVID-19 in Wuhan, China. In fact, I had written an article in the March 2015 issue (Vol. 2, Issue 3) of stawa on ‘Ebola response and preparedness’ where I warned public health authorities to prepare for such an epidemic. I am surprised by the lack of institutional memory and callousness of the Chinese government, especially in the context of the SARS epidemic that also originated in China. The SARS epidemic had many lessons for the world community, which were conveniently forgotten. This reminds me of 19th century Danish Philosopher Soren Kierkegaard’s words, “Life must be lived forwards but it can only be understood backwards.”

There are obvious parallels between the SARS epidemic and COVID-19. Both began in winter and originated in China’s unregulated wet markets. The genetic data of SARS-CoV-2 is similar to the one responsible for SARS (SARS-CoV) as they both have spike protein with adaptation to bind with a specific protein in human cells called Angiotensin-converting enzyme (ACE2).

There are uncanny parallels in the roles of Dr Carlo Urbani during the SARS epidemic and Dr Li Wenliang during the COVID-19 epidemic. Dr Carlo Urbani was an infectious disease specialist at WHO’s Hanoi office. He volunteered to work at the Hanoi French Hospital where he identified SARS as a new viral disease. This led to the introduction of infection control and a global alert that helped contain the epidemic. By dealing with the outbreak openly and decisively, Vietnam and Hong Kong risked damage to their economy. This was a story where things went right when public health was prioritised over politics. Dr Urbani died of SARS on 29 March, 2003 in Bangkok. Dr Li Wenliang, a 33-year-old doctor in Wuhan, had warned colleagues and authorities in December 2019 of a possible outbreak of a SARS-like disease. He was reprimanded by the local police for “spreading rumours”. Li died of COVID-19 on 7 February, 2020. His voice was silenced in a system that prioritised politics over public health. The result is there for all of us to see.

Healthcare workers have a duty to care for their patient and often work in less-than-ideal circumstances and with depleted resources. The important lessons to be learnt from SARS and Ebola is the role of astute clinicians who can alert the world about impending epidemics.

Chronology of Covid-19

The first case of COVID-19 appeared in early December 2019 in Wuhan, Hubei Province, China. It is assumed to have emerged from an unregulated wet market that sold wildlife. In December 2019, hospitals in Wuhan started witnessing a growing number of atypical viral pneumonia cases. This is when Dr Li Wenliang warned colleagues and authorities about the possibility of an outbreak resembling SARS. His warning was ignored and he was reprimanded. On 31 December, 2019, China informed WHO about cases of ‘pneumonia of an unknown sort’ detected in Wuhan linked to human exposure to a wholesale wet market. On 5 January, 2020, Chinese scientists sequenced the genome of the virus and made it publically available on 7 January, 2020. On 14 January, Maria Ven Kerkhoe, acting head of WHO’s Emerging Disease Unit gave a mixed assessment of the situation, which included, “…no sustained human-to-human transmission.” However, on 19 January, Chinese authorities confirmed human-to-human transmission. On 22 January, three days before the Chinese New Year, the authorities suspended all rail and air-links from Wuhan and imposed a complete lockdown in the city of 11 million people and other urban centres in the province. By then, the new virus had already reached other countries. The first case of the novel corona virus outside China was reported in Thailand on 13 January: A 61-year-old Chinese lady with travel history to Wuhan who had never visited the wet market. This provides evidence of human-to-human transfer. India reported its first case in Kerala on 30 January from a batch of 72 medical and nursing students who had returned from Wuhan for the Lunar New Year holiday. By this time, the virus had already spread to 18 countries including South Korea, Iran, Italy, Spain, France and United States.

On 7 March, two people in Ladakh tested positive after they returned from Iran. The chain of human-to-human transmission progressed in similar manner across the world. India started screening international passengers on 6 March. The first confirmed death in India from COVID-19 was reported on 12 March. As of 18 June, 2020, WHO reported 8,242,999 cases worldwide with 445,535 deaths with other sources estimating around 4,100,000 recoveries in this period. For India; WHO reports 366,946 with 12,237 deaths for this period and other sources estimate that around 204,000 people have recovered so far.

Perhaps the most important lesson from COVID-19 is the Chinese failure to disclose the emergence of the virus in December and the failure to suspend air and rail links in early December 2019 that has resulted in the current global pandemic. The Prime Minister of India announced a Janata Curfew on 22 March and then enforced a 21-day nationwide lockdown from 24 March that was later extended to 31 May. While migrant labourers faced many problems in this period, the lockdown seems to have helped curb the pandemic by increasing the doubling time, rate of recovery, rate of testing facilitates and availability of PPE, ventilators, isolation beds and administrative quarantine facilities.

Virology: Corona viruses are enveloped single-stranded RNA viruses that are zoonotic (transmitted from animals to humans) in nature and cause symptoms ranging from those similar to a common cold to severe respiratory symptoms and rarely symptoms related to intestine, colon, liver, blood vessels and nervous system. There are six other coronaviruses, in addition to the present one, which infect humans. Coronaviruses have already caused three pandemics in the last two decades: SARS, MERS, and now, COVID-19.

Chinese researchers collected 585 environmental samples from Huanan Seafood Market in Wuhan between 1 and 12 January 2020. Of these, 33 samples contained SARS-CoV-2, which indicates that it originated from wild animals sold at the market. The researchers also collected lung fluids, blood and throat swab samples from 15 patients, which revealed that virus-specific nucleic acid sequences in the samples were different from known human coronaviruses but was similar to beta corona virus genera found in bats. They then conducted next-generation sequencing from Bronchoalveolar lavage fluids and cultured isolates from nine patients in Wuhan with viral pneumonia who tested negative for common respiratory pathogens. They found that the match for SARS-CoV-2 was 79% for SARS-CoV and 50% for MERS-CoV while it had a 87.9% and 87.2% sequence match with two bat-derived coronaviruses. Studies also reported that COVID- 19 S-protein supported strong interaction with human ACE2 molecules despite its dissimilarity with SARS-CoV. A study titled ‘The proximal origin of SARS-CoV-2’ in the journal Nature Medicine published in March 2020, used bio-informatics tools to compare publically-available genomic data for several coronaviruses. They focussed on the parts of the coronavirus genomes that encode the spike protein that gives this virus family a distinctive crown-like appearance. (‘corona’ is Latin for crown). All coronaviruses rely on spike proteins to infect other cells and each virus fashions this protein slightly differently overtime. The genomic data of SARS-CoV-2 show that its spike protein contains some unique adaptations. One adaptation it provides enables it to bind to a specific protein in human cells called ACE2. The coronavirus that causes SARS in humans also seeks out ACE2. Computer models had predicted that SARS-CoV-2 would not bind to ACE2 as well as SARS-CoV but the inverse has turned out to be true. This is probably due to genetic adaptations that enabled SARS-CoV-2 to take advantage of a previously unidentified alternate binding site. This is being cited asevidence that SARS-CoV-2 was not developed in a laboratory as no bioengineer could have chosen the particular configuration for the spike protein. Furthermore, SARS-CoV-2 genome closely resembles a bat coronavirus though the part that binds ACE2 resembles a virus found in pangolins (scaly anteaters). The origins of the virus remain unclear as of now. One probable explanation is that SARS-CoV-2 evolved in its natural host, possibly bats or pangolins, where the spike proteins mutated to bind to molecules similar to human cells. Another explanation is that SARS-CoV-2 developed this capacity after it crossed from animals to humans.

Based on virus genome sample data collected between 24 December, 2019 and 4 March, 2020, researchers in the UK and Germany have identified three distinct ‘variants’ of SARS-CoV-2. The original human virus genome (type A) seen in Wuhan includes variants that were later seen in Chinese and Americans who lived in Wuhan and in patients in the USA and Australia. Type B was the major type found in Wuhan and patients in East Asia. Type C is the variant found in Europe, especially early patients from France, Italy, Sweden, and England. It was not found in samples taken in mainland China but was seen in Singapore, Hong Kong, and South Korea. This study did not look at samples from India.

Researchers Parta Majumdar and Nirdhan Biswas at the National Institute of Biomedical Genomics, West Bengal studied more than 3,600 samples of the SARS-CoV-2 genome collected from around 55 countries and found 11 strains of SARS-CoV-2. They found that the strain A2a was dominant in 1,848 global and Indian samples. Thus, vaccine development must focus on this strain. Indian researchers are now increasing the sample size and trying to understand how the A2a strain became more efficient at infecting human as compared to other strains. It is important to study such mutations as a virus can acquire new functions to become more infectious or virulent. This will help identify and target processes important for the survival of the virus and assist in the development of a vaccine and cure.

Transmission patterns: Many domestic and wild animals like bats, camel, cats, and pangolins serve as hosts for coronaviruses. Generally, animal coronaviruses do not spread to humans though there are exceptions such as SARS and MERS. In the case of COVID-19, initial patients are believed to have some links with Huanan Seafood Market in Wuhan suggesting that these infections were due to animal-to-person transmission. Later cases were reported among medical staff and others with no links to the market or Wuhan, which indicates human-to-human transmission. Three main transmission channels for COVID-19 are through droplets, contact and aerosol.

Droplet transmission occurs when respiratory droplets produced when an infected person coughs or sneezes are ingested or inhaled by someone standing in close proximity. This is why it is important to cover one’s mouth and nose with a tissue or handkerchief while coughing or sneezing and discarding the tissue in covered containers. Similarly, wearing face masks will probably become a normal practice now.

Contact transmission occurs when a person touches a surface contaminated with the virus and then touches his/her mouth, nose and eyes. Studies have shown that SARS-CoV-2 stays viable for over 72 hours on surfaces like plastic and steel, for four to six hours on surfaces such as garments and for shorter periods in air. This is why health advisories recommend frequent hand washing with soap and water for about 20 seconds and warn against touching the mouth, nose and eyes without washing one’s hands. Alcohol-based sanitisers are an alternative when water is not readily available.

Aerosol transmission occurs when respiratory droplets mixed with air form aerosols and cause infection when inhaled in high doses in a relatively closed environment. While SARS-CoV infects the lower respiratory tract, SARS-CoV-2 also infects the upper respiratory passage. Studies report that SARS-CoV-2 remains viable in aerosol for a considerable period, which is why social distancing is a crucial strategy to contain COVID-19. Corona and influenza viruses are going to stay with us for a long time and such preventive measures will help us contain them. A fourth mode of transmission, though less important, is through the gastrointestinal tract i.e. faecal transmission. Such transmission has been reported by Chinese researchers and was also reported during the 2003 SARS epidemic.

Symptoms: COVID-19 causes a respiratory infection with a highly variable course depending on the host’s health. Mild cases observed in 81% of patients in the initial Wuhan report were manifest as self-limited respiratory symptoms typical of viral pneumonia including fever, dry cough, breathlessness, fatigue, muscle pain, headache and sore throat and interestingly, loss of smell and taste. One study found that 39.6% of 140 COVID-19 patients had gastrointestinal symptoms. The incubation period for COVID-19 ranges from two to 14 days in human-to-human transmission. The spectrum of the disease severity includes asymptomatic, symptomatic with mild or severe symptoms, requiring hospitalisation, and fatal. The fatality rate for SARS and MERS were higher though COVID-19 is more contagious.

Chest Tomography (CT) images of COVID-19 patients include ground glass opacity, bi-hilar patchy shadows and segmental areas of consolidation, sometimes with a rounded morphology and a peripheral lung distribution. Lung abnormalities were most severe about 10 days after the onset of symptoms. However, CT manifestation of COVID-19 has been diverse and changing fast. A normal chest CT image cannot rule out COVID-19. RT-PCR is a diagnostic test that uses nasal swab, tracheal aspirate, or brochoalveolar lavage specimens. The preferred method for diagnosis is to collect upper respiratory samples via nasopharyngeal and oro-pharyngeal swabs. The specificity of RT-PCR seems to be very high and it is able to detect RNA viruses like SARS-CoV-2. However, the patent-holders have included royalties in the cost of the enzyme, which has caused resentment amongst scientists especially during a global pandemic.

Pulmonary fibrosis and consolidation in lung biopsy specimens were less severe in COVID-19 than SARS and MERS but exudation was more obvious. However, we need more research to understand the pathogenesis of COVID-19 and develop therapeutic strategies. An Italian pathologist at a hospital in Bergamo performed 50 autopsies on patients who died of COVID-19 and found Disseminated Intravascular Coagulation (DIC) rather than pneumonia. This implies that the virus not only kills pneumocytes (a kind of cells in the lung) but also uses an inflammatory storm to create an endothelial vascular thrombosis (clots in blood vessels). As in DIC, the lung is the most affected as it is inflamed but it can also cause heart attacks and strokes. However, more research is needed in this matter. If these finding are true, then the strategy to fight COVID-19 will change dramatically to treat patients with antibiotics, anti-virals, anti-inflamatosis and anti-coagulants. We currently do not have a holistic understanding of SARS-CoV-2. Data from different parts of the world will continue trickling in and it will take scientists time to understand the virus. Till then, we must practice social distancing, use a face mask, wash hands frequently, and protect elderly citizens, children, pregnant women and those with other health conditions and on immunosuppressant drugs. A balanced approach between a lockdown and freedom to carry out everyday activities with proper precaution is the way ahead.

WHO has reported that a number of treatments for COVID-19 are under clinical trials but none have been approved so far. It has launched the Solidarity Trial to carry out clinical trials for specific drugs for COVID-19. More than 2,500 patients have enrolled in this multi-site clinical trial. The Indian Council of Medical Research (ICMR) has approved nine hospitals in India under WHO’s Solidarity Trial.

Plasma therapy: When a person is infected by a virus or bacteria, the body responds by creating antibodies. When a virus or bacteria attacks us for the first time, we do not have antibodies for it. However, once created, the antibodies protect us from subsequent infections. Vaccines employ this mechanism by introducing an attenuated virus or bacteria that is not strong enough to cause the disease and yet trigger the production of antibodies. It is assumed that people who have recovered from COVID-19 have antibodies against the virus. Plasma therapy entails taking specific components of blood from such patients and giving it to patients suffering from COVID-19 in the hope that the antibodies will protect them. This sounds good in theory but trials are underway to test its efficiency.

Hydroxycholroquine: ICMRrecommended chemoprophylaxis with hydroxychloroquine for asymptomatic health workers treating COVID-19 patients, and for asymptomatic contact individuals. This endorsement along with that of US President, Donald Trump may lead to widespread self-medication. In the current chaos, it is difficult to screen people for potential risks to prevent adverse side-effects or to prevent shortage of hydroxichloroquine for patients of malaria, rheumatoid arthritis etc. So far, clinical trials have not found any significant impact of this course of treatment.

Remdesivir: This is aninvestigational broad-spectrum antiviral treatment developed by Gilead Science and administered by daily infusion for 10 days. Initial results from clinical trials suggest that Remdesivir does have some impact in treating COVID-19 though more detailed studies are required. Remdesivir is a nucleotide analogue, in the same drug class as HIV and Hepatitis B medication. If it works, we must ensure sufficient supply of the drug and correct pricing to ensure that it is affordable by everyone.

COVID-19 in UT Ladakh: As on 18 June, 2020, UT Administration has reported 687 COVID-19 cases for Ladakh and one death. So far, 95 patients have made an uneventful and timely recovery despite coming from an area where environmental silicosis is prevalent and impairs lung defence mechanisms. Researchers investigated the epidemiology of COVID-19 in high altitude regions in Tibet, Bolivia and Ecuador. In all cases, the number of COVID-19 cases has been low (134 in Tibet, 54 and 722 cases in high altitude regions of Bolivia and Ecuador). In Tibet, about 10% developed severe medical condition, some of whom had co-morbid conditions like chronic respiratory and cardiovascular problems. According to the paper published in the journal Respiratory Physiology & Neurobiology, all the patients recovered fully with medical treatment. It appears that the pathogenesis of COVID-19 differs in populations that live in high altitude regions and are three to four-fold less than areas below altitudes of 2,500m above mean seal level.

These findings probably reflect physiological and environmental factors. High altitude areas are characterised by a dry climate, drastic changes in temperature between day and night, and high level of ultraviolet (UV) radiation that is capable of altering DNA and RNA—UV radiations probably act as ‘sanitisers’ in high altitude areas. All these factors may dramatically reduce the ‘survival’ of SARS-CoV-2 in such regions and reduce its virulence. Furthermore, lower air density and greater distance between molecules at high altitudes probably reduces the size of airborne virus inoculum than at sea level. In addition, hypoxia-mediated respiratory regulation leads to a decreased expression of ACE2 in pulmonary epithelia among high altitude inhabitants. This may provide some protections against severe, and often lethal, pulmonary oedema as ACE2 is the main binding site for SARS-Cov and SARS-CoV-2. These findings vindicate my belief that studies of high altitude natives, their environment and adaptation can give us insights to understand and treat many diseases afflicting people the world over. This is probably the most opportune time for Ladakh to establish a state-of-the-art molecular biology laboratory with support from ICMR and links with national institutes. Ladakh has at least two senior genetic scientists working at renowned university laboratories in the USA. They can be approached to guide the UT administration to establish this laboratory.

Overall,the UT administration in Ladakh has done a commendable job by proactively preparing for COVID-19. This includes screening of incoming travellers, establishing isolation beds for COVID-19 patients, quarantine facilities, outsourcing sample testing to accredited laboratories, sourcing adequate quantities of PPEs and ventilators, providing essential services in containment zones, establishing an efficient surveillance system, contact-tracing and testing, proactive engagement with the media to provide COVID-19 updates and propagate health advisories.

In my opinion, such viruses are going to become a normal part of our lives. It is thus important for us to adopt practices such as frequent hand-washing, use of face mask in public places, and maintaining social distancing. We also need to strengthen our healthcare system with adequate funding for a separate infectious disease hospital for each district and increase ICU capacity. Our community health centres, and primary health centres need to be upgraded and integrate district surveillance programmes that must include Behaviour Risk Factor Surveillance Systems.

I hope that the UT administration in Ladakh will learn from this experience of dealing with a pandemic and implement a progressive healthcare strategy that includes a medical college, a state-of-the-art tertiary-level care facility and a critical academic environment; a dedicated cancer institute, a separate infectious disease hospital in each district, a public health institute and a molecular biology laboratory. It also needs to upgrade healthcare facilities at every level with an integrated disease surveillance programme. Investing in these centres will be very rewarding as they will attract qualified healthcare providers and improve the system by reducing the burden on tertiary-level hospitals that can focus on providing quality care to serious patients.

By Dr. Tsering Norboo

Dr. Tsering Norboo is founding member and honorary secretary of Ladakh Institute of Prevention

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